Ian G McKeith, Bradley F Boeve, Dennis W Dickson, Glenda Halliday, John-Paul Taylor, Daniel Weintraub, Dag Aarsland, James Galvin, Johannes Attems, Clive G Ballard, Ashley Bayston, Thomas G Beach, Frédéric Blanc, Nicolaas Bohnen, Laura Bonanni, Jose Bras, Patrik Brundin, David Burn, Alice Chen-Plotkin, John E Duda, Omar El-Agnaf, Howard Feldman, Tanis J Ferman, Dominic Ffytche, Hiroshige Fujishiro, Douglas Galasko, Jennifer G Goldman, Stephen N Gomperts, Neill R Graff-Radford, Lawrence S Honig, Alex Iranzo, Kejal Kantarci, Daniel Kaufer, Walter Kukull, Virginia M Y Lee, James B Leverenz, Simon Lewis, Carol Lippa, Angela Lunde, Mario Masellis, Eliezer Masliah, Pamela McLean, Brit Mollenhauer, Thomas J Montine, Emilio Moreno, Etsuro Mori, Melissa Murray, John T O'Brien, Sotoshi Orimo, Ronald B Postuma, Shankar Ramaswamy, Owen A Ross, David P Salmon, Andrew Singleton, Angela Taylor, Alan Thomas, Pietro Tiraboschi, Jon B Toledo, John Q Trojanowski, Debby Tsuang, Zuzana Walker, Masahito Yamada, Kenji Kosaka
Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium.
Neurology. 2017 Jul 4;89(1):88-100. doi: 10.1212/WNL.0000000000004058. Epub 2017 Jun 7.
Abstract/Text
The Dementia with Lewy Bodies (DLB) Consortium has refined its recommendations about the clinical and pathologic diagnosis of DLB, updating the previous report, which has been in widespread use for the last decade. The revised DLB consensus criteria now distinguish clearly between clinical features and diagnostic biomarkers, and give guidance about optimal methods to establish and interpret these. Substantial new information has been incorporated about previously reported aspects of DLB, with increased diagnostic weighting given to REM sleep behavior disorder and123iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. The diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations is also described. Minor modifications to pathologic methods and criteria are recommended to take account of Alzheimer disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss. Recommendations about clinical management are largely based upon expert opinion since randomized controlled trials in DLB are few. Substantial progress has been made since the previous report in the detection and recognition of DLB as a common and important clinical disorder. During that period it has been incorporated into DSM-5, as major neurocognitive disorder with Lewy bodies. There remains a pressing need to understand the underlying neurobiology and pathophysiology of DLB, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support.
Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
Seok Ming Lim, Andrew Katsifis, Victor L Villemagne, Rene Best, Gareth Jones, Michael Saling, Jennifer Bradshaw, John Merory, Michael Woodward, Malcolm Hopwood, Christopher C Rowe
The 18F-FDG PET cingulate island sign and comparison to 123I-beta-CIT SPECT for diagnosis of dementia with Lewy bodies.
J Nucl Med. 2009 Oct;50(10):1638-45. doi: 10.2967/jnumed.109.065870. Epub 2009 Sep 16.
Abstract/Text
UNLABELLED: Neuroimaging is increasingly used to supplement the clinical diagnosis of dementia with Lewy bodies (DLB) by showing reduced occipital metabolism and perfusion and reduced striatal dopaminergic innervation. We aimed to optimize the interpretation of (18)F-FDG PET images for differentiating DLB from Alzheimer disease (AD) and to compare the results with dopamine transporter imaging using (123)I-beta-carbomethoxy-3ss-(4-iodophenyl)tropane ((123)I-beta-CIT) SPECT.
METHODS: Fourteen subjects with a clinical diagnosis of DLB and 10 with AD underwent both (18)F-FDG PET and (123)I-beta-CIT SPECT. Four DLB and 1 AD diagnoses were subsequently confirmed at autopsy. Diagnostic accuracy was calculated for visual interpretation by 3 readers of standard 3-plane and stereotactic surface projection (18)F-FDG PET images, receiver-operating-characteristic analysis of regional (18)F-FDG uptake, and a cutoff value for the striatal-to-occipital binding ratio of beta-CIT defined by receiver-operating-characteristic analysis.
RESULTS: Visual interpretation of 3-plane (18)F-FDG PET images had a sensitivity of 83% and specificity of 93% for DLB, slightly higher than the results with the stereotactic surface projection images. Regionally, hypometabolism in the lateral occipital cortex had the highest sensitivity (88%), but relative preservation of the mid or posterior cingulate gyrus (cingulate island sign) had the highest specificity (100%). Region-of-interest analysis revealed that occipital hypometabolism and relative preservation of the posterior cingulate both had a sensitivity of 77% and specificity of 80%. beta-CIT achieved 100% accuracy and greater effect size than did (18)F-FDG PET (Cohen d = 4.1 vs. 1.9).
CONCLUSION: Both (18)F-FDG PET and (123)I-beta-CIT SPECT appear useful for the diagnosis of DLB, although the latter provides more robust results. The cingulate island sign may enhance the specificity of (18)F-FDG PET.
Ian McKeith, John O'Brien, Zuzana Walker, Klaus Tatsch, Jan Booij, Jacques Darcourt, Alessandro Padovani, Raffaele Giubbini, Ubaldo Bonuccelli, Duccio Volterrani, Clive Holmes, Paul Kemp, Naji Tabet, Ines Meyer, Cornelia Reininger, DLB Study Group
Sensitivity and specificity of dopamine transporter imaging with 123I-FP-CIT SPECT in dementia with Lewy bodies: a phase III, multicentre study.
Lancet Neurol. 2007 Apr;6(4):305-13. doi: 10.1016/S1474-4422(07)70057-1.
Abstract/Text
BACKGROUND: Dementia with Lewy bodies (DLB) needs to be distinguished from other types of dementia because of important differences in patient management and outcome. Current clinically based diagnostic criteria for DLB have limited accuracy. Severe nigrostriatal dopaminergic degeneration occurs in DLB, but not in Alzheimer's disease or most other dementia subtypes, offering a potential system for a biological diagnostic marker. The primary aim of this study was to investigate the sensitivity and specificity, in the ante-mortem differentiation of probable DLB from other causes of dementia, of single photon emission computed tomography (SPECT) brain imaging with the ligand (123)I-2beta-carbometoxy-3beta-(4-iodophenyl)-N-(3-fluoropropyl) nortropane ((123)I-FP-CIT), which binds to the dopamine transporter (DAT) reuptake site. Diagnostic accuracy, positive and negative predictive values, and inter-reader agreement were the secondary endpoints and a subgroup of possible DLB patients was also included.
METHODS: We did a phase III study in which we used a (123)I-FP-CIT SPECT scan to assess 326 patients with clinical diagnoses of probable (n=94) or possible (n=57) DLB or non-DLB dementia (n=147) established by a consensus panel (in 28 patients no diagnosis could be made). Three readers, unaware of the clinical diagnosis, classified the images as normal or abnormal by visual inspection. The study had 90% power to detect the differences between our anticipated sensitivity (0.80) and specificity (0.85) targets and prespecified lower thresholds (sensitivity 0.65, specificity 0.73) using one-sided binomial tests with a significance level of alpha=0.025.
FINDINGS: Abnormal scans had a mean sensitivity of 77.7% for detecting clinical probable DLB, with specificity of 90.4% for excluding non-DLB dementia, which was predominantly due to Alzheimer's disease. A mean value of 85.7% was achieved for overall diagnostic accuracy, 82.4% for positive predictive value, and 87.5% for negative predictive value. Inter-reader agreement for rating scans as normal or abnormal was high (Cohen's kappa=0.87). The procedure was well tolerated with few adverse events.
INTERPRETATION: A revision of the International Consensus Criteria for DLB has recommended that low DAT uptake in the basal ganglia, as shown by SPECT or PET imaging, be a suggestive feature for diagnosis. Our findings confirm the high correlation between abnormal (low binding) DAT activity measured with (123)I-FP-CIT SPECT and a clinical diagnosis of probable DLB. The diagnostic accuracy is sufficiently high for this technique to be clinically useful in distinguishing DLB from Alzheimer's disease.
Marine Soret, Pierre Malick Koulibaly, Jacques Darcourt, Irène Buvat
Partial volume effect correction in SPECT for striatal uptake measurements in patients with neurodegenerative diseases: impact upon patient classification.
Eur J Nucl Med Mol Imaging. 2006 Sep;33(9):1062-72. doi: 10.1007/s00259-005-0003-4. Epub 2006 Apr 26.
Abstract/Text
PURPOSE: In single-photon emission computed tomography (SPECT) of the dopaminergic system, measurements of striatal uptake are useful for diagnosis and patient follow-up but are strongly biased by the partial volume effect (PVE). We studied whether PVE correction might improve patient classification based on binding potential (BP) measurements.
METHODS: Patients with a probable diagnosis of dementia with Lewy bodies (DLB, 10 patients) or Alzheimer's disease (AD, 13 patients) were studied by( 123)I-FP-CIT SPECT. SPECT images were reconstructed with and without PVE correction. Each patient SPECT scan was also simulated to obtain SPECT data whose characteristics were fully known. In addition, 17 SPECT scans were simulated with striatal uptake values mimicking pre-symptomatic cases of DLB.
RESULTS: Without PVE correction, mean putamen BP values were 2.9+/-0.4 and 0.9+/-0.2 for AD and DLB patients respectively, while with PVE correction, they were 8.6+/-1.5 and 1.9+/-0.5 respectively. All patients were properly identified as having AD or DLB when considering mean putamen BP measured on their real or simulated SPECT scan, with and without PVE correction. All 30 simulations mimicking pre-symptomatic DLB and AD patients were accurately classified with PVE correction, but without PVE correction 15 mean putamen BP values were in a range where AD and DLB could not be distinguished.
CONCLUSION: We conclude that putamen BP values measured without PVE correction can be used to differentiate probable DLB and AD due to the already severe reduction in dopamine transporter levels. PVE correction appeared useful for accurate differential diagnosis between AD and pre-symptomatic DLB.
J Eerola, P J Tienari, S Kaakkola, P Nikkinen, J Launes
How useful is [123I]beta-CIT SPECT in clinical practice?
J Neurol Neurosurg Psychiatry. 2005 Sep;76(9):1211-6. doi: 10.1136/jnnp.2004.045237.
Abstract/Text
OBJECTIVE: To assess the accuracy and clinical usefulness of [(123)I]beta-CIT (2beta-carbomethoxy-3beta-(4-iodophenyl)tropane) SPECT in the differential diagnosis of Parkinson's disease.
SUBJECTS: 185 consecutive patients with symptoms of movement disorder were studied. The diagnoses were Parkinson's disease (92), essential tremor (16), vascular parkinsonism (15), various Parkinson plus syndromes (P+) (12), dementia with Lewy bodies (DLB) (5), dystonia (5), drug induced movement disorder (12), and other diagnoses (8). A reference group (psychogenic parkinsonism) comprised 20 subjects with complaints suggesting extrapyramidal disease but with no unequivocal signs on clinical examination and no abnormalities on brain imaging.
RESULTS: beta-CIT uptake was significantly lower in the whole striatum as well as separately in the putamen and in the caudate nucleus in Parkinson's disease than in the reference group or in drug induced movement disorder, essential tremor, or dystonia. The uptake of beta-CIT in the vascular parkinsonism group was heterogeneous and mean beta-CIT uptake fell between the reference group and the Parkinson's disease group. In the P+ and DLB groups the striatal uptake ratios overlapped those of the Parkinson's disease group.
CONCLUSIONS: [(123)I]beta-CIT SPECT may not be as useful a tool in the clinical differential diagnosis of Parkinson's disease as was previously believed, but it was 100% sensitive and specific for the diagnosis in younger patients (age <55 years). In older patients (age >55 years) specificity was substantially lower (68.5%). This differential specificity reflected the different distribution of differential diagnostic disorders (P+, DLB, vascular parkinsonism) in the older and younger age groups.
Sean J Colloby, E David Williams, David J Burn, Jim J Lloyd, Ian G McKeith, John T O'Brien
Progression of dopaminergic degeneration in dementia with Lewy bodies and Parkinson's disease with and without dementia assessed using 123I-FP-CIT SPECT.
Eur J Nucl Med Mol Imaging. 2005 Oct;32(10):1176-85. doi: 10.1007/s00259-005-1830-z. Epub 2005 Jun 2.
Abstract/Text
PURPOSE: The objective of this study was to investigate the rate of progression of nigrostriatal dopaminergic loss in subjects with dementia with Lewy bodies (DLB), Parkinson's disease (PD) and PD with dementia (PDD) using serial 123I-FP-CIT SPECT imaging. We hypothesised that striatal rates of decline in patients would be greater than in controls, and that DLB and PDD would show similar rates, reflecting the similarity in neurobiological mechanisms of dopaminergic loss between the two disorders.
METHODS: We studied 20 patients with DLB, 20 with PD, 15 with PDD and 22 healthy age-matched controls. Semi-automated region of interest (ROI) analysis was performed on both baseline and repeat scans for each subject and mean striatal uptake ratios (caudate, anterior and posterior putamen) were calculated.
RESULTS: Rates of decline in striatal binding between groups were assessed using ANCOVA. Significant differences between patients and controls were observed in caudate (DLB, PD, PDD, p< or =0.01), anterior putamen (DLB, PDD, p< or =0.05; PD, p=0.07) and posterior putamen (DLB, PD, PDD, p<0.006). Rates of decline were similar between DLB, PD and PDD.
CONCLUSION: In conclusion, this is the first study to show that significant progressive dopaminergic loss occurs in DLB and PDD using serial 123I-FP-CIT SPECT. Dementia severity and motor impairment were correlated with decline, suggesting that dopaminergic loss may play an important role in cognitive as well as motor features.
Sean J Colloby, John T O'Brien, John D Fenwick, Michael J Firbank, David J Burn, Ian G McKeith, E David Williams
The application of statistical parametric mapping to 123I-FP-CIT SPECT in dementia with Lewy bodies, Alzheimer's disease and Parkinson's disease.
Neuroimage. 2004 Nov;23(3):956-66. doi: 10.1016/j.neuroimage.2004.06.045.
Abstract/Text
Dopaminergic loss can be visualised using (123)I-FP-CIT single photon emission computed tomography (SPECT) in several disorders including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Most previous SPECT studies have adopted region of interest (ROI) methods for analysis, which are subjective and operator-dependent. The purpose of this study was to investigate differences in striatal binding of (123)I-FP-CIT SPECT using the automated technique of statistical parametric mapping (SPM99) in subjects with DLB, Alzheimer's disease (AD), PD and healthy age-matched controls. This involved spatial normalisation of each subject's image to a customised template, followed by smoothing and intensity normalisation of each image to its corresponding mean occipital count per voxel. Group differences were assessed using a two-sample t test. Applying a height threshold of P
Paul M Kemp, Sandra A Hoffmann, Livia Tossici-Bolt, John S Fleming, Clive Holmes
Limitations of the HMPAO SPECT appearances of occipital lobe perfusion in the differential diagnosis of dementia with Lewy bodies.
Nucl Med Commun. 2007 Jun;28(6):451-6. doi: 10.1097/MNM.0b013e328155d143.
Abstract/Text
OBJECTIVE: To assess the utility of the appearances of occipital lobe perfusion on HMPAO SPECT in the diagnosis of dementia with Lewy bodies (DLB) using the 123I-FP-CIT findings as the diagnostic 'gold standard'.
METHODS: Eighty-four consecutive patients underwent both HMPAO SPECT and 123I-FP-CIT as part of their routine investigations for suspected DLB.
RESULTS: Thirty-nine of the 84 FP-CIT scans were abnormal indicating a prevalence of 44% of patients with DLB in this series. In those patients classified as DLB, 28% of HMPAO SPECT scans demonstrated occipital hypoperfusion. In those patients with a dementia other than DLB 31% of patients demonstrated occipital hypoperfusion (P=0.8).
CONCLUSION: Occipital lobe hypoperfusion as demonstrated by HMPAO SPECT in patients with suspected Lewy body dementia does not appear to be able to either rule in, or rule out, the diagnosis of DLB.
M J Firbank, S J Colloby, D J Burn, I G McKeith, J T O'Brien
Regional cerebral blood flow in Parkinson's disease with and without dementia.
Neuroimage. 2003 Oct;20(2):1309-19. doi: 10.1016/S1053-8119(03)00364-1.
Abstract/Text
Tc99 HMPAO SPECT and T1 weighted 3D MRI scans were acquired in cognitively intact subjects with Parkinson's disease (PD) (n = 31), and in PD subjects with dementia (PDD) (n = 34), healthy controls (n = 37), those with Alzheimer's disease (AD) (n = 32), and those with dementia with Lewy bodies (DLB) (n = 15). We used SPM99 to look for regions which showed a reduction in perfusion on SPECT not related to associated structural brain changes assessed by a MRI scan. The precuneus and inferior lateral parietal regions showed a perfusion deficit in Parkinson's disease with dementia, similar to the pattern observed in DLB. In comparison, AD showed a perfusion deficit in the midline parietal region, in a more anterior and inferior location than in PDD, involving the posterior cingulate as well as the precuneus. The perfusion deficits in PDD are similar those in DLB, and in a location associated with visual processing, and may be associated with the visuospatial perception deficits which are present in persons with DLB and PDD.
Sean J Colloby, John D Fenwick, E David Williams, Sean M Paling, Kyriakos Lobotesis, Clive Ballard, Ian McKeith, John T O'Brien
A comparison of (99m)Tc-HMPAO SPET changes in dementia with Lewy bodies and Alzheimer's disease using statistical parametric mapping.
Eur J Nucl Med Mol Imaging. 2002 May;29(5):615-22. doi: 10.1007/s00259-002-0778-5. Epub 2002 Mar 5.
Abstract/Text
Differences in regional cerebral blood flow (rCBF) between subjects with Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and healthy volunteers were investigated using statistical parametric mapping (SPM99). Forty-eight AD, 23 DLB and 20 age-matched control subjects participated. Technetium-99m hexamethylpropylene amine oxime (HMPAO) brain single-photon emission tomography (SPET) scans were acquired for each subject using a single-headed rotating gamma camera (IGE CamStar XR/T). The SPET images were spatially normalised and group comparison was performed by SPM99. In addition, covariate analysis was undertaken on the standardised images taking the Mini Mental State Examination (MMSE) scores as a variable. Applying a height threshold of P < or = 0.001 uncorrected, significant perfusion deficits in the parietal and frontal regions of the brain were observed in both AD and DLB groups compared with the control subjects. In addition, significant temporoparietal perfusion deficits were identified in the AD subjects, whereas the DLB patients had deficits in the occipital region. Comparison of dementia groups (height threshold of P < or = 0.01 uncorrected) yielded hypoperfusion in both the parietal [Brodmann area (BA) 7] and occipital (BA 17, 18) regions of the brain in DLB compared with AD. Abnormalities in these areas, which included visual cortex and several areas involved in higher visual processing and visuospatial function, may be important in understanding the visual hallucinations and visuospatial deficits which are characteristic of DLB. Covariate analysis indicated group differences between AD and DLB in terms of a positive correlation between cognitive test score and temporoparietal blood flow. In conclusion, we found evidence of frontal and parietal hypoperfusion in both AD and DLB, while temporal perfusion deficits were observed exclusively in AD and parieto-occipital deficits in DLB.
E K Doubleday, J S Snowden, A R Varma, D Neary
Qualitative performance characteristics differentiate dementia with Lewy bodies and Alzheimer's disease.
J Neurol Neurosurg Psychiatry. 2002 May;72(5):602-7.
Abstract/Text
OBJECTIVES: To determine whether dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) can be differentiated on the basis of qualitative performance characteristics during neuropsychological evaluation.
METHODS: Forty one patients with clinically defined DLB were matched with 26 patients with AD for age, illness duration, nature and severity of cognitive deficits, and regional blood flow distribution on SPECT. The presence or absence of a set of qualitative performance characteristics, observed and recorded during the patients' initial cognitive evaluation, was identified by retrospective analysis of patients' records and the groups compared.
RESULTS: Inattention, visual distractibility, impairments in establishing and shifting mental set, incoherence, confabulatory responses, perseveration, and intrusions were significantly more common in DLB than AD. Intrusions were particularly common in DLB, occurring in 78% of the group. They included externally cued intrusions arising from the visual environment, a feature never seen in AD. In a stepwise logistic regression analysis impaired mental set shifting, perseveration, and the presence of intrusions correctly classified 79% of patients.
CONCLUSION: It is possible to differentiate DLB and AD on the basis of qualitative features of performance. As many features are amenable to detection at clinical interview, they ought to contribute to clinicians' diagnostic armoury, leading to improved clinical recognition of DLB.
Kazunari Ishii, Tomonori Kanda, Takafumi Uemura, Naokazu Miyamoto, Toshiki Yoshikawa, Kenichi Shimada, Shingo Ohkawa, Satoshi Minoshima
Computer-assisted diagnostic system for neurodegenerative dementia using brain SPECT and 3D-SSP.
Eur J Nucl Med Mol Imaging. 2009 May;36(5):831-40. doi: 10.1007/s00259-008-1051-3. Epub 2009 Jan 16.
Abstract/Text
PURPOSE: To develop a computer-assisted automated diagnostic system to distinguish among Alzheimer disease (AD), dementia with Lewy bodies (DLB), and other degenerative disorders in patients with mild dementia.
METHODS: Single photon emission computed tomography (SPECT) images with injection of N-Isopropyl-p-[(123)I]iodoamphetamine (IMP) were obtained from patients with mild degenerative dementia. First, datasets from 20 patients mild AD, 15 patients with dementia with DLB, and 17 healthy controls were used to develop an automated diagnosing system based on three-dimensional stereotactic surface projections (3D-SSP). AD- and DLB-specific regional templates were created using 3D-SSP, and critical Z scores in the templates were established. Datasets from 50 AD patients, 8 DLB patients, and 10 patients with non-AD/DLB type degenerative dementia (5 with frontotemporal dementia and 5 with progressive supranuclear palsy) were then used to test the diagnostic accuracy of the optimized automated system in comparison to the diagnostic interpretation of conventional IMP-SPECT images. These comparisons were performed to differentiate AD and DLB from non-AD/DLB and to distinguish AD from DLB. A receiver operating characteristic (ROC) analysis was performed.
RESULTS: The area under the ROC curve (Az) and the accuracy of the automated diagnosis system were 0.89 and 82%, respectively, for AD/DLB vs. non-AD/DLB patients, and 0.70 and 65%, respectively, for AD vs. DLB patients. The mean Az and the accuracy of the visual inspection were 0.84 and 77%, respectively, for AD/DLB vs. non-AD/DLB patients, and 0.70 and 65%, respectively, for AD vs. DLB patients. The mean Az and the accuracy of the combination of visual inspection and this system were 0.96 and 91%, respectively, for AD/DLB vs. non-AD/DLB patients, and 0.70 and 66%, respectively, for AD vs. DLB patients.
CONCLUSION: The system developed in the present study achieved as good discrimination of AD, DLB, and other degenerative disorders in patients with mild dementia as the commonly performed visual inspection of conventional SPECT images. A combination of visual inspection and this system is helpful in the differential diagnosis of patients with mild dementia.
Shuhei Kasama, Hisao Tachibana, Keita Kawabata, Hiroo Yoshikawa
Cerebral blood flow in Parkinson's disease, dementia with Lewy bodies, and Alzheimer's disease according to three-dimensional stereotactic surface projection imaging.
Dement Geriatr Cogn Disord. 2005;19(5-6):266-75. doi: 10.1159/000084551. Epub 2005 Mar 18.
Abstract/Text
Regional brain perfusion was analyzed using single-photon emission computed tomography with three-dimensional stereotactic surface projections (3D-SSP) in 69 patients with Parkinson's disease (PD), 16 patients with dementia with Lewy bodies (DLB) and 15 patients with Alzheimer's disease (AD), and compared with that in 24 age-equivalent normal subjects. Nondemented PD patients revealed less parietal and frontal flow than controls. With mental impairment, flow reduction extended to other areas including occipital regions. PD with dementia and DLB showed similar reduction patterns, although frontal flow showed a greater reduction in DLB. AD showed little occipital reduction, but a severe parieto-temporal reduction. Thus, 3D-SSP appears to be useful in the detection of cortical lesions and the differential diagnosis of patients with cognitive impairment.
T Miyamoto, M Miyamoto, Y Inoue, Y Usui, K Suzuki, K Hirata
Reduced cardiac 123I-MIBG scintigraphy in idiopathic REM sleep behavior disorder.
Neurology. 2006 Dec 26;67(12):2236-8. doi: 10.1212/01.wnl.0000249313.25627.2e.
Abstract/Text
Idiopathic REM sleep behavior disorder (RBD) may represent prodromal synucleinopathies. We report markedly reduced cardiac (123)I-metaiodobenzylguanidine uptake, consistent with the loss of sympathetic terminals, in idiopathic RBD. We also demonstrate that this reduction is of the same magnitude as that found in patients with Parkinson disease. The results are consistent with the hypothesis that idiopathic RBD in older patients is a forme fruste of Lewy body disease.
M Yoshita, J Taki, K Yokoyama, M Noguchi-Shinohara, Y Matsumoto, K Nakajima, M Yamada
Value of 123I-MIBG radioactivity in the differential diagnosis of DLB from AD.
Neurology. 2006 Jun 27;66(12):1850-4. doi: 10.1212/01.wnl.0000219640.59984.a7.
Abstract/Text
OBJECTIVE: To evaluate the diagnostic reliability of cardiac iodine-123 metaiodobenzylguanidine ((123)I-MIBG) radioactivity in discriminating dementia with Lewy bodies (DLB) from Alzheimer disease (AD) regardless of parkinsonism.
BACKGROUND: The diagnosis of DLB may be confounded by the absence of parkinsonism. This highlights the need to improve the accuracy of antemortem diagnosis of DLB without parkinsonism.
METHODS: Cardiac sympathetic denervation was examined using myocardial (123)I-MIBG scintigraphy in 37 patients with DLB, 42 patients with AD, and 10 normal elderly controls. The DLB patients consisted of seven patients without parkinsonism (DLB/P-) and 30 patients with parkinsonism (DLB/P+) at the time of the study.
RESULTS: The heart-to-mediastinum uptake ratio (H/M ratio) of myocardial MIBG uptake was decreased in both the DLB groups vs the AD group (p < 0.0001) and control group (p < 0.0001). The washout rate (WR) was higher in the DLB group than in the control group (p < 0.0001) and AD group (p < 0.0001). No differences were found between the AD and control groups or between the DLB/P+ and DLB/P- groups in either the early or delayed H/M ratio or WR. In discriminating between DLB and AD, regardless of parkinsonism, the delayed H/M ratio had a sensitivity of 100%, a specificity of 100%, and a positive predictive value of 100% at a cutoff value of 1.68.
CONCLUSIONS: Our results indicate that dementia with Lewy bodies results in cardiac sympathetic denervation and that iodine-123 metaiodobenzylguanidine myocardial scintigraphy is a sensitive tool for discriminating dementia with Lewy bodies from Alzheimer disease even in patients without parkinsonism.
Panitha Jindahra, Athasit Vejjajiva, Rawiphan Witoonpanich, Rojana Sirisriro, Chanika Sritara, Teeratorn Pulkes
Differentiation of dementia with Lewy bodies, Alzheimer's disease and vascular dementia by cardiac 131I-meta-iodobenzylguanidine (MIBG) uptake (preliminary report).
J Med Assoc Thai. 2004 Oct;87(10):1176-81.
Abstract/Text
OBJECTIVE: Differentiation of dementia with Lewy bodies (DLB), vascular dementia (VAD), and Alzheimer's disease (AD) is difficult in clinical practice. Several new techniques have been used for differentiation of various types of dementia. Among these techniques 123I-meta-iodobenzylguanidine (MIBG) uptake was reported to have benefit in distinguishing DLB from AD. The authors study the role of MIBG as a tool for differentiation of DLB, AD and VAD.
METHOD: Patients with dementia were recruited to the study by DSMIIIR criteria. Diagnosis of each dementia type was made by standard clinical criteria. Brain imagings and 131I-MIBG uptake were performed in all the studied patients.
RESULTS: Five DLB, 3 AD and 3 VAD patients were clinically diagnosed. The heart/mediastinum (H/M) ratio in 4 out of 5 in DLB was significantly lower than H/M ratio in patients with AD and VAD. AD patients had the highest uptake of MIBG MIBG uptake of VAD patients was in the range between AD and DLB but the values were close to the AD group.
CONCLUSIONS: 131I-MIBG is helpful in differentiating DLB from AD.
Giorgio Treglia, Ernesto Cason, Antonella Stefanelli, Fabrizio Cocciolillo, Daniela Di Giuda, Giorgio Fagioli, Alessandro Giordano
MIBG scintigraphy in differential diagnosis of Parkinsonism: a meta-analysis.
Clin Auton Res. 2012 Feb;22(1):43-55. doi: 10.1007/s10286-011-0135-5. Epub 2011 Jul 27.
Abstract/Text
OBJECTIVE: Differential diagnosis between Parkinson's disease (PD) and other Parkinsonism using clinical criteria or imaging methods is often difficult. The purpose of this study is to systematically review and meta-analyze published data about the diagnostic performance of myocardial innervation imaging using (123)I-metaiodobenzylguanidine (MIBG) scintigraphy in differential diagnosis between PD and other Parkinsonism.
METHODS: A comprehensive computer literature search of studies published through March 2011 regarding MIBG scintigraphy in patients with PD and other Parkinsonism was performed in PubMed/MEDLINE and Embase databases. Only studies in which MIBG scintigraphy was performed for differential diagnosis between PD and other Parkinsonism were selected. Pooled sensitivity, pooled specificity and area under the ROC curve were calculated to measure the accuracy of MIBG scintigraphy in differential diagnosis between PD and other Parkinsonism.
RESULTS: Nineteen studies comprising 1,972 patients (1,076 patients with PD, 117 patients with other Lewy body diseases and 779 patients with other diseases) were included in this meta-analysis. The pooled sensitivity of MIBG scintigraphy in detecting PD was 88% (95% CI 86-90%); the pooled specificity of MIBG scintigraphy in discriminating between PD and other Parkinsonism was 85% (95% CI 81-88%). The area under the ROC curve was 0.93.
CONCLUSIONS: In patients with clinically suspected PD, myocardial innervation imaging demonstrated high sensitivity and specificity. MIBG scintigraphy is an accurate test in this setting. Nevertheless, possible causes of false-negative and false-positive results should be kept in mind when interpreting the scintigraphic results.
Alisha E King, Jim Mintz, Donald R Royall
Meta-analysis of 123I-MIBG cardiac scintigraphy for the diagnosis of Lewy body-related disorders.
Mov Disord. 2011 Jun;26(7):1218-24. doi: 10.1002/mds.23659. Epub 2011 Apr 7.
Abstract/Text
Patients with parkinsonism pose a diagnostic challenge. Parkinson's disease may be difficult to distinguish from multiple system atrophy and progressive supranuclear palsy, whereas Parkinson's disease and dementia with Lewy bodies can be difficult to distinguish from Alzheimer's disease and other dementias. A number of studies have found diminished cardiac (123) I-metaiodobenzylguanidine uptake in Lewy body-related conditions (Parkinson's disease and Lewy body dementia). In 2005, the Dementia With Lewy Bodies Consortium considered (123) I-metaiodobenzylguanidine cardiac scintigraphy a "supportive" diagnostic feature, based on limited evidence. We report a meta-analysis of the literature and an assessment of the utility of (123) I-metaiodobenzylguanidine for the diagnosis of dementia with Lewy bodies and Parkinson's disease. A search was conducted of articles published between 1950 and June 2010. Forty-six studies involving neuropsychiatric and movement disorders, comprising 2680 subjects, were included in the analysis. A mixed-effects regression model was used to analyze the delayed mean heart-to-mediastinum ratio of (123) I-metaiodobenzylguanidine uptake. (123) I-metaiodobenzylguanidine cardiac scintigraphy sensitively detected and specifically distinguished 2 diagnostic clusters: (1) Parkinson's disease, dementia with Lewy bodies, and rapid eye movement sleep behavior disorder; and (2) normal controls and patients with Alzheimer's disease, multiple system atrophy, progressive supranuclear palsy, vascular dementia, and frontotemporal dementia. The area under the receiver operating characteristic curve was 0.987 at a cluster discriminatory heart-to-mediastinum ratio threshold of 1.77. This threshold yielded 94% sensitivity and 91% specificity for the discrimination of these diagnostic clusters. (123) I-metaiodobenzylguanidine cardiac scintigraphy can accurately distinguish between 2 movement disorders, Parkinson's disease and multiple system atrophy, and between 2 common causes of dementia, Alzheimer's disease and dementia with Lewy bodies. © 2011 Movement Disorder Society.
Copyright © 2011 Movement Disorder Society.
Giorgio Treglia, Ernesto Cason
Diagnostic performance of myocardial innervation imaging using MIBG scintigraphy in differential diagnosis between dementia with lewy bodies and other dementias: a systematic review and a meta-analysis.
J Neuroimaging. 2012 Apr;22(2):111-7. doi: 10.1111/j.1552-6569.2010.00532.x. Epub 2010 Nov 17.
Abstract/Text
BACKGROUND AND PURPOSE: This study was designed to review the diagnostic performance of myocardial innervation imaging using iodine-123-metaiodobenzylguanidine (MIBG) scintigraphy in differential diagnosis between dementia with Lewy bodies (DLB) and other dementias.
METHODS: A comprehensive computer literature search of studies published through May 2010 regarding MIBG scintigraphy in patients with DLB was performed in PubMed/MEDLINE and Embase databases. Only studies in which MIBG scintigraphy was performed for differential diagnosis between DLB and other dementias were selected. Pooled sensitivity and specificity of MIBG scintigraphy were presented with a 95% confidence interval (CI). The area under the ROC curve was calculated to measure the accuracy of MIBG scintigraphy in differential diagnosis between Lewy body diseases and other dementias.
RESULTS: Ultimately, we identified 8 studies comprising a total of 346 patients with dementia (152 patients with DLB and 194 patients with other dementias). The pooled sensitivity of MIBG scintigraphy in detection of DLB was 98% (95% CI, 94-100%); the pooled specificity of MIBG scintigraphy in differential diagnosis between DLB and other dementias was 94% (95% CI, 90-97%). The area under the ROC curve was .99.
CONCLUSIONS: Myocardial innervation imaging with MIBG scintigraphy demonstrated high pooled sensitivity and specificity in patients with suspected DLB. MIBG scintigraphy is an accurate test for differential diagnosis between DLB and other dementias.
Copyright © 2010 by the American Society of Neuroimaging.
Yoshikuni Mizuno
[Progress in Parkinson's disease].
Nihon Rinsho. 2004 Sep;62(9):1597-600.
Abstract/Text
There has been lots of progress in Parkinson's disease. First of all, in Japan, a guideline for the treatment of Parkinson's disease was published. This guideline contains both EBM based systematic review of every drugs being used in the treatment of Parkinson's disease including those drugs for the management of side effects and other problems arising during the course of the treatment and an algorithm of the practical treatment of Parkinson's disease patients. This is an official publication of Japanese Neurological Society. In the diagnosis of Parkinson's disease, many specialists in Parkinson's disease have recognized the usefulness of MIBG SPECT of the cardiac sympathetic endings. MIBG uptake shows remarkable decrease in Lewy body positive Parkinson's disease patients from the early stage except for some of the stage I patients. In the basic aspect, studies on familial forms of Parkinson's disease have contributed a lot to the understanding of the pathogenesis of sporadic Parkinson's disease. Mutations of alpha-synuclein cause autosomal dominant Parkinson's disease. Recently, triplication of one of the alpha-synuclein genes was found as the third mutation of PARK1. Thus just overproduction of normal alpha-synuclein is toxic to nigral neurons. In this form and sporadic Parkinson's disease, oxidative damage plays an important role in nigral neurodegeneration. PARK2 is caused by mutations of the parkin gene. Parkin protein is an ubiquitin-protein ligase. In this form also, oxidative damage appears to be operating in neurodegeneration. Thus a common mechanism appears to be present in different forms of Parkinson's disease. Future investigation to find neuroprotective drugs should take this concept of common mechanism into their research strategies.
Rosie Watson, Andrew M Blamire, John T O'Brien
Magnetic resonance imaging in lewy body dementias.
Dement Geriatr Cogn Disord. 2009;28(6):493-506. doi: 10.1159/000264614. Epub 2009 Dec 8.
Abstract/Text
Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) share common clinical, neuropsychological and pathological features. In clinical diagnosis, distinguishing between these conditions and other dementia subtypes such as Alzheimer's disease (AD) can be difficult. Despite the development of consensus diagnostic criteria, sensitivity for diagnosis remains low, especially outside specialist centres. Neuroimaging techniques using magnetic resonance (MR) can assess changes in structure, microstructure through diffusion tensor imaging and metabolism using spectroscopy and cerebral perfusion. Identification of such changes may contribute to our understanding of the disease process, assist in refining ante-mortem diagnosis and allow disease progression to be measured. This may be both clinically useful and a tool for assessing outcome in therapeutic trials. DLB and PDD share a similar pattern of MRI changes including global brain volume loss, a predominantly subcortical pattern of cerebral atrophy and structural preservation of the medial temporal lobe compared to AD. This review summarises the application and findings from MR studies in DLB and PDD to provide further insight into the similarities between the conditions, highlight the potential for the clinical application of MR techniques and outline promising areas for further research.
Murat Emre
Dementia associated with Parkinson's disease.
Lancet Neurol. 2003 Apr;2(4):229-37.
Abstract/Text
Dementia affects about 40% of patients with Parkinson's disease; the incidence of dementia in these patients is up to six times that in healthy people. Clinically, the prototype of dementia in PD is a dysexecutive syndrome. Loss of cholinergic, dopaminergic, and noradrenergic innervation has been suggested to be the underlying neurochemical deficits. Nigral pathology alone is probably not sufficient for the development of dementia. Although there is some controversy with regard to the site and type of pathology involved, dementia is likely to be associated with the spread of pathology to other subcortical nuclei, the limbic system, and the cerebral cortex. On the basis of more recent studies, the main pathology seems to be Lewy-body-type degeneration with associated cellular and synaptic loss in cortical and limbic structures. Alzheimer's disease-type pathology is commonly associated with dementia but less predictive. Recent evidence from small studies suggests that cholinesterase inhibitors may be effective in the treatment of dementia associated with PD.
W G Reid, M A Hely, J G Morris, G A Broe, M Adena, D J Sullivan, P M Williamson
A longitudinal of Parkinson's disease: clinical and neuropsychological correlates of dementia.
J Clin Neurosci. 1996 Oct;3(4):327-33.
Abstract/Text
Neuropsychological assessments were performed in ninety-one de novo patients participating in the Sydney Multicentre Study of Parkinson's disease. Assessments were made at baseline and after 3 and 5 years. Performance at baseline and after 5 years was compared with controls. At baseline 37% of patients whose symptoms of Parkinson's disease had begun after the age of 70 years were demented. This compared with a prevalence of dementia of 8.8% in patients whose symptoms had begun before the age of 70 years. By 5 years the prevalence of dementia in the two groups had risen to 62.3% and 17.3% respectively. The death rate was higher over the 5 year period in the demented patients. Demented patients had more symmetrical signs, higher disability and bradykinesia scores and more impairment of gait and balance at baseline than non-demented patients. The presence of dementia at baseline predicted a poor response to treatment. The dementia at baseline had features of a subcortical dementia. Subsequently, aphasia, apraxia and agnosia emerged, making the dementia indistinguishable from that of Alzheimer's disease. Patients with well preserved cognitive function at baseline had a good response to levodopa and were more likely to develop levodopa induced dyskinesia. These results show that the clinical features of Parkinson's disease and response to treatment are influenced by the age of onset of symptoms and by the presence of dementia.
R H Mindham, S W Ahmed, C G Clough
A controlled study of dementia in Parkinson's disease.
J Neurol Neurosurg Psychiatry. 1982 Nov;45(11):969-74.
Abstract/Text
Tests of cognitive functions were carried out in a group of patients with Parkinson's disease and repeated after a three-year interval. Comparison was made with a control group drawn from a population of psychiatric patients, matched for age and sex. No differences in cognitive functions were found between the groups, either initially, or between those surviving for three years. Deaths among the index group included a high proportion of patients with cognitive impairment and there was an increasing prevalence and severity of dementia in the index group which exceeded that observed in the control group. Requirements for a methodologically sound study of dementia in Parkinson's disease are discussed.
F Boller, T Mizutani, U Roessmann, P Gambetti
Parkinson disease, dementia, and Alzheimer disease: clinicopathological correlations.
Ann Neurol. 1980 Apr;7(4):329-35. doi: 10.1002/ana.410070408.
Abstract/Text
Clinical records and neuropathological specimens from 36 patients with autopsy-demonstrated idiopathic Parkinson disease (PD) were reviewed independently and the results compared. Nine (31%) of the 29 patients with adequate clinical data had severe dementia and 7 (24%) had mild dementia. The cerebral cortex showed senile plaques and fibrillary tangles in 15 of the 36 patients (42%). These changes were found in all 9 patients with severe dementia, in 3 of the 7 with mild dementia, and in 3 of the 13 patients with normal mental status. The prevalence of pathologically established Alzheimer changes and dementia among the patients with PD (33%) was over six times that found in an age-matched population (5.1%). Survival after the onset of PD with Alzheimer disease was shorter than in PD without Alzheimer disease.
K Marder, D Leung, M Tang, K Bell, G Dooneief, L Cote, Y Stern, R Mayeux
Are demented patients with Parkinson's disease accurately reflected in prevalence surveys? A survival analysis.
Neurology. 1991 Aug;41(8):1240-3.
Abstract/Text
We re-reviewed 257 patient records previously reviewed for an incidence study of dementia in Parkinson's disease (PD) to determine the frequency, date of death, and cause of death. We posited that if disease duration is shortened when dementia occurs, then dementia may be far more common than reflected in prevalence studies. There were 17 deaths among 65 demented patients and 28 deaths among 168 nondemented patients. When we matched a subset of the nondemented patients to the demented patients by age and disease duration distributions, the demented subjects had significantly more deaths (p less than 0.02), and survival among demented subjects was decreased (p less than 0.05). Dementia was a significant predictor of death in this sample. We conclude that dementia reduces survival in patients with PD. Incidence is a much better measure of dementia in PD than prevalence because shortened duration makes it less likely to detect dementia in prevalence surveys.
Connie Marras, Paula Rochon, Anthony E Lang
Predicting motor decline and disability in Parkinson disease: a systematic review.
Arch Neurol. 2002 Nov;59(11):1724-8.
Abstract/Text
CONTEXT: The clinical course of Parkinson disease (PD) varies from patient to patient. A number of studies investigating predictors of prognosis in patients with PD have been performed.
OBJECTIVE: To summarize evidence on predicting the rate of motor decline and increasing disability in early PD.
DATA SOURCES: English-language and French-language literature cited in the MEDLINE database (1966-2002).
STUDY SELECTION: Cohort and case-control studies investigating associations between clinical features and subsequent motor impairment or disability were selected.
DATA EXTRACTION: Study methods and results were abstracted by a single reviewer.
DATA SYNTHESIS: The results of 13 studies were summarized qualitatively. Study methods were highly variable, particularly regarding the choice of outcome measure. Baseline motor impairment and cognitive impairment are probable predictors of more rapid motor decline and disability. A lack of tremor at onset and older age both appear to be predictive of increasing disability, but conflicting results exist for their association with the rate of change of motor impairment. Family history of PD does not appear to be prognostically important. The prognostic value of many other factors studied is uncertain owing to conflicting or unconfirmed results.
CONCLUSIONS: Uncertainty remains about the prognostic importance of many baseline clinical features in PD. Greater baseline impairment, early cognitive disturbance, older age, and lack of tremor at onset appear to be adverse prognostic factors.
Lonneke M L de Lau, C Maarten A Schipper, Albert Hofman, Peter J Koudstaal, Monique M B Breteler
Prognosis of Parkinson disease: risk of dementia and mortality: the Rotterdam Study.
Arch Neurol. 2005 Aug;62(8):1265-9. doi: 10.1001/archneur.62.8.1265.
Abstract/Text
BACKGROUND: Most prognostic studies on Parkinson disease have been hospital based or have applied register-based case-finding methods. Potential under-representation of mild cases may have given biased results.
OBJECTIVE: To evaluate whether Parkinson disease is associated with an increased risk of dementia and death.
DESIGN: Population-based cohort study. Parkinson disease and dementia were assessed through in-person examination at baseline (1990-1993) and 2 follow-up visits (1993-1994 and 1997-1999). Computerized linkage to medical and municipality records provided additional information on disease outcomes and mortality.
SETTING: General population.
PARTICIPANTS: A total of 6969 participants, including 99 prevalent and 67 incident cases of Parkinson disease.
MAIN OUTCOME MEASURES: Incident dementia and death. Adjusted hazard ratios were calculated through Cox proportional hazards regression analysis.
RESULTS: Patients with Parkinson disease had an increased risk of dementia (hazard ratio, 2.8; 95% confidence interval, 1.8-4.4), which was especially pronounced in participants carrying at least 1 apolipoprotein E gene (APOE) epsilon2 allele (13.5; 4.5-40.6). Parkinson disease was associated with an increased mortality risk (1.8; 1.5-2.3). The association consistently diminished when analyses were sequentially restricted to patients with shorter disease duration and after adjustment for the occurrence of dementia.
CONCLUSIONS: Especially patients with Parkinson disease who carry an APOE epsilon2 allele have an increased risk of developing dementia. Increased mortality risk in Parkinson disease is dependent on disease duration and is only modest in the absence of dementia.
Claudio Lucetti, Gianna Gambaccini, Paolo Del Dotto, Roberto Ceravolo, Chiara Logi, Giuseppe Rossi, Luigi Murri, Ubaldo Bonuccelli
Long-term clinical evaluation in patients with Parkinson's disease and early autonomic involvement.
Parkinsonism Relat Disord. 2006 Jun;12(5):279-83. doi: 10.1016/j.parkreldis.2005.12.005. Epub 2006 Mar 23.
Abstract/Text
OBJECTIVE: To evaluate in a prospective longitudinal study the evolution of functional disability and the response to dopaminergic therapy in PD patients with and without autonomic involvement.
METHODS: Sixty untreated consecutive patients with PD underwent autonomic cardiovascular function evaluation using the five autonomic tests of Ewing. An integrated index (Autonomic Score=AS), taking in account the results of all subtests, was calculated. Patients were treated with pergolide and bromocriptine during a 5-year follow-up until the level of functional disability was sufficient to warrant the initiation of levodopa therapy.
RESULTS: Results of autonomic testing were compared with those of a group of age-matched healthy subjects. A value of AS>2 was considered as indicative of autonomic failure. Eighteen patients with PD (35%) showed AS>2 (autonomically impaired group=AI), the remaining 33 (65%) had AS<2 (nonautonomically impaired group=non-AI). During the follow-up levodopa was added to the treatment regimen of 10/18 (55%) patients in AI group, and 6/33 (18%) patients in non-AI group (p<.01).
CONCLUSIONS: The increased occurrence of levodopa adjunct in autonomically impaired PD suggests that there is a more rapid deterioration of functional performance in parkinsonian patients with early autonomic involvement.
K H Karlsen, J P Larsen, E Tandberg, J G Maeland
Influence of clinical and demographic variables on quality of life in patients with Parkinson's disease.
J Neurol Neurosurg Psychiatry. 1999 Apr;66(4):431-5.
Abstract/Text
OBJECTIVES: To identify the clinical and demographic factors that are associated with a poor quality of life in patients with Parkinson's disease.
METHODS: 233 of a total of 245 patients identified in a community based study in a Norwegian county participated in the study. Quality of life was measured by the Nottingham Health Profile (NHP). The results were compared with those in 100 healthy elderly people. Clinical and demographic variables were determined during a semistructured interview and by clinical examination by a neurologist. Multiple regression analyses were used to determine which variables were associated with higher distress scores.
RESULTS: Patients with Parkinson's disease had higher distress scores than the healthy elderly people for all the NHP dimensions. The variables that most strongly predicted a high total NHP score were depressive symptoms, self reported insomnia, and a low degree of independence, measured by the Schwab and England scale. Severity of parkinsonism contributed, but to a lesser extent. Nearly half the patients with Parkinson's disease reported lack of energy, compared with a fifth of the control group. Severity of depressive symptoms and a higher score on the UPDRS motor subscale only partly accounted for this finding. Only 30% of the variation in NHP energy score was explained by the predictive variables identified in this study.
CONCLUSIONS: Parkinson's disease has a substantial impact on health related quality of life. Depressive symptoms and sleep disorders correlated strongly with high distress scores. Patients with Parkinson's disease should be examined for both conditions, which require treatment. Low energy was commonly reported and may be a separate entity of Parkinson's disease.
A Schrag, M Jahanshahi, N Quinn
What contributes to quality of life in patients with Parkinson's disease?
J Neurol Neurosurg Psychiatry. 2000 Sep;69(3):308-12.
Abstract/Text
OBJECTIVE: To identify the factors that determine quality of life (QoL) in patients with idiopathic Parkinson's disease in a population based sample. Quality of life (QoL) is increasingly recognised as a critical measure in health care as it incorporates the patients' own perspective of their health.
METHODS: All patients with Parkinson's disease seen in a population based study on the prevalence of parkinsonism were asked to complete a disease-specific QoL questionnaire (PDQ-39) and the Beck depression inventory. A structured questionnaire interview and a complete neurological examination, including the Hoehn and Yahr scale, the Schwab and England disability scale, the motor part of the unified Parkinson's disease rating scale (UPDRS part III), and the mini mental state examination were performed by a neurologist on the same day.
RESULTS: The response rate was 78%. The factor most closely associated with QoL was the presence of depression, but disability, as measured by the Schwab and England scale, postural instability, and cognitive impairment additionally contributed to poor QoL. Although the UPDRS part III correlated significantly with QoL scores, it did not contribute substantially to predicting their variance once depression, disability, and postural instability had been taken into account. In addition, patients with akinetic rigid Parkinson's disease had worse QoL scores than those with tremor dominant disease, mainly due to impairment of axial features.
CONCLUSION: Depression, disability, postural instability, and cognitive impairment have the greatest influence on QoL in Parkinson's disease. The improvement of these features should therefore become an important target in the treatment of the disease.
Global Parkinson's Disease Survey Steering Committee
Factors impacting on quality of life in Parkinson's disease: results from an international survey.
Mov Disord. 2002 Jan;17(1):60-7.
Abstract/Text
Current management guidelines for the treatment of patients with Parkinson's disease (PD) are limited due to the lack of knowledge of factors that influence health-related quality of life (HRQL). To assess the HRQL of people with PD, and to systematically identify and evaluate those factors (other than disease severity and medication, which could have an impact), we undertook a cross-sectional, randomized selection, multicenter international survey of patients with PD, caregivers, and clinicians. Face-to-face interviews were conducted with subjects in six countries. Disease severity, medication, and other factors hypothesized to influence HRQL were assessed using a combination of specially developed questionnaires and validated instruments including the Parkinson's Disease Questionnaire-39 (HRQL), Hoehn and Yahr Stage (disease severity), and Beck's Depression Inventory (BDI; depression). Multiple linear regression models were used to demonstrate whether the factors investigated contribute significantly to HRQL. The results obtained indicated that Hoehn and Yahr stage and medication explained only 17.3% of the variability in HRQL of patients with PD, although both were significant (R(2) = 0.173, P < 0.05). Other factors increased the explanatory power to adjusted R(2) = 0.597, with BDI being the most significant predictor of variability in HRQL (adjusted R(2) = 0.582; P < 0.001), followed by "Satisfaction with the explanation of the condition at diagnosis" and "Current feelings of optimism" (both P < 0.05). These factors, in addition to disease severity and medication, explain 59.7% of the variability in HRQL across the population. In conclusion, depression (as measured by the BDI) in PD, "satisfaction with the explanation of the condition at diagnosis" and "current feelings of optimism" have a significant impact on HRQL. The completion of this initial analysis is the first step towards developing management guidelines that truly influence the HRQL of patients with PD.
Copyright 2001 Movement Disorder Society.
D Grosset, L Taurah, D J Burn, D MacMahon, A Forbes, K Turner, A Bowron, R Walker, L Findley, O Foster, K Patel, C Clough, B Castleton, S Smith, G Carey, T Murphy, J Hill, U Brechany, P McGee, S Reading, G Brand, L Kelly, K Breen, S Ford, M Baker, A Williams, J Hearne, N Qizilbash, K Ray Chaudhuri
A multicentre longitudinal observational study of changes in self reported health status in people with Parkinson's disease left untreated at diagnosis.
J Neurol Neurosurg Psychiatry. 2007 May;78(5):465-9. doi: 10.1136/jnnp.2006.098327. Epub 2006 Nov 10.
Abstract/Text
BACKGROUND: The issue of when to start treatment in Parkinson's disease (PD) remains controversial. Some favour treatment at diagnosis while others opt for a "wait and watch" policy. The effect of the latter policy on the self reported health status of people with PD is unknown.
AIMS: To record self reported health status through longitudinal use of a validated PD specific questionnaire (PDQ-39) in untreated PD patients in multiple centres in the UK. To compare patients who were left untreated with those who were offered treatment during follow-up.
METHODS: A multicentre, prospective, "real life" observational audit based study addressing patient reported outcomes in relation to self reported health status and other sociodemographic details.
RESULTS: 198 untreated PD were assessed over a mean period of 18 months. During two follow-up assessments, the self reported health status scores in all eight domains of the PDQ-39 and the overall PDQ-39 summary index worsened significantly (p<0.01) in patients left untreated. In a comparative group in whom treatment was initiated at or soon after diagnosis, there was a trend towards improvement in self reported health status scores after treatment was started.
CONCLUSIONS: This study addresses for the first time self reported health status, an indicator of health related quality of life, in untreated PD. The findings may strengthen the call for re-evaluation of the policy to delay treatment in newly diagnosed patients with PD.
日本神経学会監：「パーキンソン病診療ガイドライン」作成委員会編：パーキンソン病診療ガイドライン2018．医学書院．2018．.
Mariese A Hely, Wayne G J Reid, Michael A Adena, Glenda M Halliday, John G L Morris
The Sydney multicenter study of Parkinson's disease: the inevitability of dementia at 20 years.
Mov Disord. 2008 Apr 30;23(6):837-44. doi: 10.1002/mds.21956.
Abstract/Text
After 20 years follow-up of newly diagnosed patients with Parkinson's disease (PD), 100 of 136 (74%) have died. The mortality rate fell in the first 3 years of treatment, then rose compared to the general population, the standardized mortality ratio from 15 to 20 years reaching 3.1. Drug induced dyskinesia and end of dose failure were experienced by most patients, but the main current problems relate to the non-levodopa responsive features of the disease. Dementia is present in 83% of 20-year survivors. Dementia correlates with increasing age and probably reflects an interplay of multiple pathologies. Seventeen people with dementia had postmortems. Eight had diffuse Lewy bodies as the only cause of dementia, while others had mixed neuropathology. Only one person lives independently and 48% are in nursing homes. Excessive daytime sleepiness is noted in 70%, falls have occurred in 87%, freezing in 81%, fractures in 35%, symptomatic postural hypotension in 48%, urinary incontinence in 71%, moderate dysarthria in 81%, choking in 48%, and hallucinations in 74%. The challenge is to understand the cellular mechanisms underlying the diverse features of advanced PD that go far beyond a lack of dopamine.
(c) 2008 Movement Disorder Society.
T C Buter, A van den Hout, F E Matthews, J P Larsen, C Brayne, D Aarsland
Dementia and survival in Parkinson disease: a 12-year population study.
Neurology. 2008 Mar 25;70(13):1017-22. doi: 10.1212/01.wnl.0000306632.43729.24.
Abstract/Text
BACKGROUND: The risk for dementia in Parkinson disease (PD) is high, with important clinical consequences for patients with PD. However, the absolute risk of dementia and how it affects survival in PD are not known. Such questions are important for patients, their families, and service providers but require long-term studies.
METHODS: This study is a prospective longitudinal cohort study with patients from a prevalence study of PD in Norway. Patients were reassessed 4, 8, 9, 10, 11, and 12 years after prevalence day. A dementia diagnosis according to Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised, criteria was based on a semistructured caregiver interview, cognitive rating scales, and neuropsychological tests. Progression from PD to PD with dementia and death was modeled using a continuous-time three-state irreversible Markov model.
RESULTS: A total of 233 PD patients were included, and 140 patients (60%, 95% CI 54% to 66%) had developed dementia by the end of the study period. The cumulative incidence of dementia steadily increases with age and duration of PD and, conditional on survival, increases to 80% to 90% by age 90 years. Women live with PD longer than men and spend more years with dementia. At age 70 years, a man with PD but no dementia has a life expectancy of 8 years, of which 5 years would be expected to be dementia free and 3 years would be expected to be with dementia.
CONCLUSION: Dementia is a key part of survival in Parkinson disease and must be planned for in services for this condition.
B Ravina, M Putt, A Siderowf, J T Farrar, M Gillespie, A Crawley, H H Fernandez, M M Trieschmann, S Reichwein, T Simuni
Donepezil for dementia in Parkinson's disease: a randomised, double blind, placebo controlled, crossover study.
J Neurol Neurosurg Psychiatry. 2005 Jul;76(7):934-9. doi: 10.1136/jnnp.2004.050682.
Abstract/Text
OBJECTIVE: To study the safety and efficacy of a cholinesterase inhibitor, donepezil hydrochloride, for the treatment of dementia in Parkinson's disease (PD).
METHODS: This was a randomised double blind, placebo controlled, crossover study in 22 subjects with PD and dementia. Participants were randomised to receive either donepezil followed by identical placebo, or placebo followed by donepezil. Donepezil was administered at 5-10 mg/day. Treatment periods were 10 weeks with a washout period of 6 weeks between the two periods. The primary outcome measure was the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAScog).
RESULTS: Donepezil was well tolerated and most adverse events were mild. There was no worsening of PD symptoms as measured by the total or motor sections of the Unified Parkinson's Disease Rating Scale.There was a 1.9 point trend toward better scores on the ADAScog on treatment compared with placebo that was not statistically significant. The secondary cognitive measures showed a statistically significant 2 point benefit on the Mini Mental Status Examination and no change on the Mattis Dementia Rating Scale (MDRS). The Clinical Global Impression of Change (CGI) showed a significant 0.37 point improvement on donepezil. No improvement was observed on the MDRS or the Brief Psychiatric Rating Scale. Carryover between treatment periods was observed but was not statistically significant.
CONCLUSIONS: Donepezil was well tolerated and did not worsen PD. There may be a modest benefit on aspects of cognitive function. The possible clinical benefit measured by CGI was reflected in only one of the cognitive scales used in this study.
Iracema Leroi, Jason Brandt, Stephen G Reich, Constantine G Lyketsos, Stephen Grill, Richard Thompson, Laura Marsh
Randomized placebo-controlled trial of donepezil in cognitive impairment in Parkinson's disease.
Int J Geriatr Psychiatry. 2004 Jan;19(1):1-8. doi: 10.1002/gps.993.
Abstract/Text
OBJECTIVE: To evaluate the efficacy and safety of donepezil, an acetylcholinesterase inhibitor, as a treatment for cognitive impairment and dementia in patients with Parkinson' s disease (PD).
METHODS: Using a randomized, double-blind, placebo-controlled design, nine patients received placebo and seven patients received donepezil (2.5-10 mg/day) for a mean (SD) duration of 15.2 (3.4) weeks. The primary efficacy outcomes were derived from a neuropsychological battery that assessed global cognitive status as well as memory, attention, psychomotor speed, and visuospatial and executive functions. Secondary efficacy outcomes were psychiatric symptom and activities of daily living ratings. Primary safety measures were motor signs and assessments of adverse effects.
RESULTS: Patients on donepezil showed selective and significant (p<0.05) improvement on the memory subscale of the Dementia Rating Scale. There was also a trend toward improvement on a measure of psychomotor speed and attention. There were no group differences in psychiatric status, motor function, or activities of daily living as measured at baseline or end-point. Adverse effects resulted in premature withdrawal of four patients on donepezil, two for peripheral cholinergic effects and one for increased parkinsonism. Side effects were associated with dosage increases.
CONCLUSION: Donepezil has a beneficial effect on memory and may improve other cognitive deficits in patients with PD and cognitive impairment. However, variable tolerability in our sample underscores the need for careful monitoring when prescribing donepezil to patients with PD, especially with dosage increases.
Copyright 2004 John Wiley & Sons, Ltd.
D Aarsland, K Laake, J P Larsen, C Janvin
Donepezil for cognitive impairment in Parkinson's disease: a randomised controlled study.
J Neurol Neurosurg Psychiatry. 2002 Jun;72(6):708-12.
Abstract/Text
OBJECTIVE: To study the safety and efficacy of the cholinesterase inhibitor donepezil in patients with Parkinson's disease (PD) and cognitive impairment.
METHODS: This was a double blind, randomised and placebo controlled, crossover study in which 14 patients with PD and cognitive impairment received donepezil (5 or 10 mg per day) or matching placebo during two sequential periods lasting 10 weeks each. The primary outcome measures were the mini mental state examination (MMSE) score, the clinician's interview based impression of change plus caregiver input (CIBIC+) score, and the motor subscale of the unified Parkinson's disease rating scale (UPDRS).
RESULTS: Two patients on donepezil (14%) dropped out after one and four weeks of the first treatment period because of peripheral cholinergic side effects, otherwise the adverse effects were few and not severe. Carryover or residual effects were not observed. Parkinsonism did not increase during donepezil treatment. After 10 weeks of treatment, the mean MMSE score was increased by 2.1(SD 2.7) points on donepezil and 0.3 (SD 3.2) points on placebo, and the CIBIC+ score was 3.3 (SD 0.9) on donepezil and 4.1 (SD 0.8) on placebo. Statistical analysis of the repeated measurements and crossover study design showed significant effects of donepezil compared with placebo for MMSE (p=0.013) and CIBIC+ (p=0.034). Five (42%) patients on donepezil and two (17%) on placebo were rated as improved on the basis of the CIBIC+ score.
CONCLUSIONS: Donepezil improves cognition, and seems to be well tolerated and not to worsen parkinsonism in patients with cognitive impairment.
Manabu Ikeda, Etsuro Mori, Kenji Kosaka, Eizo Iseki, Mamoru Hashimoto, Noriyuki Matsukawa, Kazutaka Matsuo, Masaki Nakagawa, Donepezil-DLB Study Investigators
Long-term safety and efficacy of donepezil in patients with dementia with Lewy bodies: results from a 52-week, open-label, multicenter extension study.
Dement Geriatr Cogn Disord. 2013;36(3-4):229-41. doi: 10.1159/000351672. Epub 2013 Aug 15.
Abstract/Text
BACKGROUND/AIMS: To investigate the safety and efficacy of long-term administration (52 weeks) of donepezil in patients with dementia with Lewy bodies (DLB).
METHODS: This was a 52-week, multicenter, open-label extension study. Up to 8 weeks after the completion of the preceding randomized, placebo-controlled trial (RCT), patients started treatment with 3 mg of donepezil daily for 2 weeks, followed by 5 mg daily for the remaining 50 weeks. Cognitive function, behavioral and psychiatric symptoms, cognitive fluctuations, and caregiver burden were assessed using the Mini-Mental State Examination, Neuropsychiatric Inventory, Cognitive Fluctuation Inventory, and the Zarit Caregiver Burden Interview, respectively. Safety parameters were monitored throughout.
RESULTS: In total, 108 patients were enrolled in the study. Cognitive function and dementia-related behavioral symptoms, including cognitive fluctuations, were improved after the start of donepezil treatment, and improvement was maintained for 52 weeks. Reduction in caregiver burden observed in the preceding RCT returned to the baseline level at 52 weeks. There was no significant imbalance in the incidence of adverse events (AEs) by onset time, and delayed AE onset induced by the long-term administration of donepezil was unlikely to appear.
CONCLUSION: The long-term administration of donepezil at 5 mg/day was well tolerated in patients with DLB and is expected to exhibit lasting effects, improving impaired cognitive function and psychiatric symptoms up to 52 weeks.
© 2013 S. Karger AG, Basel.
Murat Emre, Dag Aarsland, Alberto Albanese, E Jane Byrne, Günther Deuschl, Peter P De Deyn, Franck Durif, Jaime Kulisevsky, Teus van Laar, Andrew Lees, Werner Poewe, Alain Robillard, Mario M Rosa, Erik Wolters, Peter Quarg, Sibel Tekin, Roger Lane
Rivastigmine for dementia associated with Parkinson's disease.
N Engl J Med. 2004 Dec 9;351(24):2509-18. doi: 10.1056/NEJMoa041470.
Abstract/Text
BACKGROUND: Cholinergic deficits are prominent in patients who have dementia associated with Parkinson's disease. We investigated the effects of the dual cholinesterase inhibitor rivastigmine in such patients.
METHODS: Patients in whom mild-to-moderate dementia developed at least 2 years after they received a clinical diagnosis of Parkinson's disease were randomly assigned to receive placebo or 3 to 12 mg of rivastigmine per day for 24 weeks. Primary efficacy variables were the scores for the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) and Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change (ADCS-CGIC). Secondary clinical outcomes were the scores for the Alzheimer's Disease Cooperative Study-Activities of Daily Living, the 10-item Neuropsychiatric Inventory, the Mini-Mental State Examination, Cognitive Drug Research power of attention tests, the Verbal Fluency test, and the Ten Point Clock-Drawing test.
RESULTS: A total of 541 patients were enrolled, and 410 completed the study. The outcomes were better among patients treated with rivastigmine than among those who received placebo; however, the differences between these two groups were moderate and similar to those reported in trials of rivastigmine for Alzheimer's disease. Rivastigmine-treated patients had a mean improvement of 2.1 points in the score for the 70-point ADAS-cog, from a baseline score of 23.8, as compared with a 0.7-point worsening in the placebo group, from a baseline score of 24.3 (P<0.001). Clinically meaningful improvements in the scores for the ADCS-CGIC were observed in 19.8 percent of patients in the rivastigmine group and 14.5 percent of those in the placebo group, and clinically meaningful worsening was observed in 13.0 percent and 23.1 percent, respectively (mean score at 24 weeks, 3.8 and 4.3, respectively; P=0.007). Significantly better outcomes were seen with rivastigmine with respect to all secondary efficacy variables. The most frequent adverse events were nausea (affecting 29.0 percent of patients in the rivastigmine group and 11.2 percent of those in the placebo group, P<0.001), vomiting (16.6 and 1.7 percent, P<0.001), and tremor (10.2 and 3.9 percent, P=0.01).
CONCLUSIONS: In this placebo-controlled study, rivastigmine was associated with moderate improvements in dementia associated with Parkinson's disease but also with higher rates of nausea, vomiting, and tremor.
Copyright 2004 Massachusetts Medical Society.
I Maidment, C Fox, M Boustani
Cholinesterase inhibitors for Parkinson's disease dementia.
Cochrane Database Syst Rev. 2006 Jan 25;(1):CD004747. doi: 10.1002/14651858.CD004747.pub2. Epub 2006 Jan 25.
Abstract/Text
BACKGROUND: The loss of cholinergic, dopaminergic and noradrenergic innervations seen in Parkinson's Disease Dementia (PDD) suggest a potential role for cholinesterase inhibitors. Concerns have been expressed about a theoretical worsening of Parkinson's disease related symptoms particularly movement symptoms.
OBJECTIVES: To assess the efficacy, safety, tolerability and health economic data relating to the use of cholinesterase inhibitors in PDD.
SEARCH STRATEGY: The trials were identified from the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 19 April 2005 using the search term parkinson*This register contains records from major health care databases and many ongoing trial databases and is updated regularly.Comprehensive searches of abstracts from major scientific meetings were performed. Pharmaceutical companies were approached for information regarding additional and ongoing studies.
SELECTION CRITERIA: Randomized, double-blind, placebo-controlled studies assessing the effectiveness of cholinesterase inhibitors in PDD. Inclusion and exclusion criteria were stated to limit bias.
DATA COLLECTION AND ANALYSIS: Two reviewers (IM, CF) independently reviewed the quality of the studies utilising criteria from the Cochrane Collaboration Handbook. Medications were examined separately and as a group. The outcome measures assessed were in the following domains: neuropsychiatric features, cognition, global impression, daily living activities, quality of life, burden on caregiver, Parkinsonian related symptoms, treatment acceptability as determined by withdrawal from trials, safety as determined by the frequency of adverse events, institutionalisation, death and health economic factors.
MAIN RESULTS: A detailed and systematic search of relevant databases identified one published randomized, double-blind, placebo-controlled study (Emre 2004) involving 541 patients that compared rivastigmine with placebo. Rivastigmine produced statistically significant improvements in several outcome measures. On the primary cognitive measure, the ADAS-Cog, rivastigmine was associated with a 2.80 point ADAS-Cog improvement [WMD -2.80, 95% Cl -4.26 to -1.34, P = 0.0002] and a 2.50 point ADCS-ADL improvement [95% Cl 0.43 to 4.57, P = 0.02] relative to placebo. Clinically meaningful (moderate or marked) improvement occurred in 5.3% more patients on rivastigmine, and meaningful worsening occurred in 10.1% more patients on placebo. Tolerability appeared to be a significant issue. Significantly more patients on rivastigmine dropped out of the study due to adverse events [62/362 versus 14/179, OR 2.44, 95% Cl 1.32 to 4.48, P = 0.004]. Nausea [20/179 versus 105/362, OR 3.25, 95% Cl 1.94 to 5.45, P < 0.00001], tremor [7/179 versus 37/362, OR 2.80, 95% Cl 1.22 to 6.41, P = 0.01] and in particular vomiting [3/179 versus 60/362, OR 11.66, 95% Cl 3.60 to 37.72, P < 0.0001] were significantly more common with rivastigmine. However, significantly fewer patients died on rivastigmine than placebo [4/362 versus 7/179, OR 0.27, 95% CI 0.08 to 0.95, P = 0.04]
AUTHORS' CONCLUSIONS: Rivastigmine appears to improve cognition and activities of daily living in patients with PDD. This results in clinically meaningful benefit in about 15% of cases. There is a need for more studies utilising pragmatic measures such as time to residential care facility and both patient and carer quality of life assessments. Future trials should involve other cholinesterase inhibitors, utilise tools to analyse the data that limit any bias and measure health economic factors. It is unlikely that relying solely on the last observation carried forward (LOCF) is sufficient. Publication of the observed case data in the largest trial would assist (Emre 2004). Adverse events were associated with the cholinergic activity of rivastigmine, but may limit patient acceptability as evidenced by the high drop out rate in the active arm.
David Burn, Murat Emre, Ian McKeith, Peter Paul De Deyn, Dag Aarsland, Chuanchieh Hsu, Roger Lane
Effects of rivastigmine in patients with and without visual hallucinations in dementia associated with Parkinson's disease.
Mov Disord. 2006 Nov;21(11):1899-907. doi: 10.1002/mds.21077.
Abstract/Text
We aimed to determine prospectively whether rivastigmine, an inhibitor of acetylcholinesterase and butyrylcholinesterase, provided benefits in patients with and without visual hallucinations in a population with dementia associated with Parkinson's disease (PDD). This was a 24-week double-blind placebo-controlled study. Primary efficacy measures were the Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog) and Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change (ADCS-CGIC). Secondary efficacy measures included activities of daily living, behavioral symptoms, and executive and attentional functions. Patients were stratified according to the presence of visual hallucinations at baseline. The study included 188 visual hallucinators (118 on rivastigmine, 70 on placebo) and 348 nonvisual hallucinators (239 on rivastigmine, 109 on placebo). Rivastigmine provided benefits in both visual hallucinators and nonvisual hallucinators. Absolute responses to rivastigmine on the ADAS-cog were comparable over 6 months, although rivastigmine-placebo differences tended to be larger in visual hallucinators (4.27; P = 0.002) than in nonhallucinators (2.09; P = 0.015). On the ADCS-CGIC, differences between rivastigmine and placebo were 0.5 in visual hallucinators (P = 0.030) and 0.3 in nonhallucinators (P = 0.111). Rivastigmine provided benefits on all secondary efficacy measures, and placebo declines and treatment differences were more marked in visual hallucinators. Adverse events were reported more frequently by rivastigmine-treated patients, although this difference was less marked in visual hallucinators. Visual hallucinations appear to predict more rapid decline and possibly greater therapeutic benefit from rivastigmine treatment in PDD.
D Aarsland, M Hutchinson, J P Larsen
Cognitive, psychiatric and motor response to galantamine in Parkinson's disease with dementia.
Int J Geriatr Psychiatry. 2003 Oct;18(10):937-41. doi: 10.1002/gps.949.
Abstract/Text
BACKGROUND: Cholinesterase inhibitors with additional nicotinic activity, such as galantamine, may be useful in PD patients with dementia (PDD) since stimulation of nicotinic receptors may prevent the down-regulation that is likely to accompany cholinesterase inhibition and facilitate dopamine release in the striatum.
METHODS: Sixteen PDD patients (six female) with onset of cognitive impairment after at least one year with parkinsonism participated in this open-label trial of galantamine. Cognitive, psychiatric, and motor symptoms were assessed before and after 8 weeks of treatment with galantamine using unstructured clinical assessment as well as rating scales including the Mini-Mental State Examination (MMSE), clock drawing test, verbal fluency and selected items from the Neuropsychiatric Inventory (NPI).
RESULTS: Age (mean, SD) was 75.6 (5.2) years, duration of PD 13.4 (5.9), duration of dementia 2.1 (1.7) years, Hoehn and Yahr score was 3.8 (0.8) and baseline MMSE score was 17.7 (6.7). Side-effects caused discontinuation in three patients, but were rare and mild in the remaining 13. Improvement of global mental symptoms was noted in eight patients, whereas worsening was reported in four. Hallucinations improved in seven of the nine patients with hallucinations before treatment. Parkinsonism improved in six patients, but a mild worsening of tremor was noted in three. Clock-drawing improved (p=0.016), and trends towards improvement on MMSE (p=0.09) and verbal fluency (p=0.16) were found.
CONCLUSIONS: Although controlled trials are needed, the findings suggest that galantamine is useful in patients with PDD.
Copyright 2003 John Wiley & Sons, Ltd.
Victoria Larsson, Dag Aarsland, Clive Ballard, Lennart Minthon, Elisabet Londos
The effect of memantine on sleep behaviour in dementia with Lewy bodies and Parkinson's disease dementia.
Int J Geriatr Psychiatry. 2010 Oct;25(10):1030-8. doi: 10.1002/gps.2506.
Abstract/Text
OBJECTIVE: Two common and characteristic sleep disturbances have been described in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD); excessive daytime sleepiness and REM sleep behaviour disorder (RBD). This study is an analysis of a secondary outcome measure of a larger study already reported, aimed to determine whether memantine has an effect on the sleep disturbances in DLB and PDD patients.
METHODS: Patients with DLB or PDD were included in a placebo-controlled, randomised controlled study of memantine (20 mg per day) for 24 weeks. The Stavanger Sleep Questionnaire and the Epworth Sleepiness Scale were used to evaluate the effect on sleep disturbances.
RESULTS: Forty two patients started treatment; 20 with memantine and 22 with placebo. The primary analysis was the comparison of change between the two groups during a 24-week period, using the modified ITT population (last observation carried forward). At 24 weeks, patients treated with memantine were less physically active during sleep while patients in the placebo group worsened. Mean difference between the groups (0.5 [0.05-0.90]) was significant (p = 0.006). No significant change was observed in severity of excessive daytime sleepiness.
CONCLUSIONS: Memantine decreases probable REM sleep behaviour disorder in patients with DLB and PDD. Both diagnostic groups contributed equally to the outcome.
Copyright © 2010 John Wiley & Sons, Ltd.
Murat Emre, Magda Tsolaki, Ubaldo Bonuccelli, Alain Destée, Eduardo Tolosa, Alexandra Kutzelnigg, Andrés Ceballos-Baumann, Slobodan Zdravkovic, Anna Bladström, Roy Jones, 11018 Study Investigators
Memantine for patients with Parkinson's disease dementia or dementia with Lewy bodies: a randomised, double-blind, placebo-controlled trial.
Lancet Neurol. 2010 Oct;9(10):969-77. doi: 10.1016/S1474-4422(10)70194-0. Epub 2010 Aug 20.
Abstract/Text
BACKGROUND: Previous studies have suggested that patients with Lewy-body-related dementias might benefit from treatment with the N-methyl D-aspartate receptor antagonist memantine, but further data are needed. Therefore, the efficacy and safety of memantine were investigated in patients with mild to moderate Parkinson's disease dementia (PDD) or dementia with Lewy bodies (DLB).
METHODS: Patients (≥50 years of age) with mild to moderate PDD or DLB were recruited from 30 specialist centres in Austria, France, Germany, the UK, Greece, Italy, Spain, and Turkey. They were randomly assigned to placebo or memantine (20 mg per day) according to a computer-generated list. Patients and all physicians who had contact with them were masked to treatment assignment. No primary endpoint was defined. Safety analyses were done for all patients who took at least one dose of memantine or placebo, and efficacy analyses were done for all patients who had at least one valid postbaseline assessment. This trial is registered with ClinicalTrials.gov, number NCT00855686.
FINDINGS: Of the 199 patients randomly assigned to treatment, 34 with DLB and 62 with PDD were given memantine, and 41 with DLB and 58 with PDD were given placebo. 159 (80%) patients completed the study: 80 in the memantine group and 79 in the placebo group. 93 patients treated with memantine and 97 patients treated with placebo were included in the efficacy analysis. At week 24, patients with DLB who received memantine showed greater improvement according to Alzheimer's disease cooperative study (ADCS)-clinical global impression of change scores than did those who received placebo (mean change from baseline 3·3 vs 3·9, respectively, difference -0·6 [95% CI -1·2 to -0·1]; p=0·023). No significant differences were noted between the two treatments in patients with PDD (3·6 with memantine vs 3·8 with placebo, -0·1 [-0·6 to 0·3]; p=0·576) or in the total population (3·5 with memantine vs 3·8 with placebo, -0·3 [-0·7 to 0·1]; p=0·120). Neuropsychiatric-inventory scores showed significantly greater improvement in the memantine group than in the placebo group (-4·3 vs 1·7, respectively, -5·9 [-11·6 to -0·2]; p=0·041) in patients with DLB, but not in those with PDD (-1·6 vs -0·1, respectively, -1·4 [-5·9 to 3·0]; p=0·522) or in the total patient population (-2·6 vs 0·4, respectively, -2·9 [-6·3 to 0·5]; p=0·092). In most of the cognitive test scores, ADCS-activities of daily living, and Zarit caregiver burden scores, there were no significant differences between the two treatment groups in any of the study populations. The incidence of adverse events and number of discontinuations due to adverse events were similar in the two groups. The most common serious adverse events were stroke (n=3 in memantine group), falls (n=2 in memantine group; n=1 in placebo group), and worsening of dementia (n=2 in memantine group).
INTERPRETATION: Memantine seems to improve global clinical status and behavioural symptoms of patients with mild to moderate DLB, and might be an option for treatment of these patients.
FUNDING: Lundbeck.
Copyright © 2010 Elsevier Ltd. All rights reserved.
C Johansson, C Ballard, O Hansson, S Palmqvist, L Minthon, D Aarsland, E Londos
Efficacy of memantine in PDD and DLB: an extension study including washout and open-label treatment.
Int J Geriatr Psychiatry. 2011 Feb;26(2):206-13. doi: 10.1002/gps.2516.
Abstract/Text
OBJECTIVE: This 30-week extension trial was a continuation of the first double-blind randomized controlled trial (RCT) to study memantine in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). The objective was to evaluate the presence of recurrence of symptoms upon drug withdrawal. Furthermore, the aim was to explore washout dynamics in order to inform clinical practice.
METHODS: Patients were enrolled from psychiatric, memory and neurological outpatient clinics in Norway, Sweden and the UK. The trial comprised a 4-week washout period and a 26-week open-label treatment period. Outcome measures were presence of recurrence of symptom upon drug withdrawal, Clinical Global Impression of Change (CGIC) and modified motor Unified Parkinson's Disease Rating Scale (UPDRS).
RESULTS: recurrence of symptoms occurred more frequently (p=0.04) in patients receiving memantine (58%) than in patients receiving placebo (25%). There was a significant global deterioration (p=0.0003) during washout within the memantine group as measured by CGIC. The patients seemed to recover during the open-label treatment, however these findings were non-significant.
CONCLUSIONS: The findings inform clinical practice that any possible memantine-associated benefits might be rapidly lost after drug withdrawal. The magnitude of deterioration suggests a symptomatic rather than a disease-modifying effect of the drug. Open-label results should merely be considered inspiration for future trials.
Copyright © 2010 John Wiley & Sons, Ltd.
Dag Aarsland, Clive Ballard, Zuzana Walker, Fredrik Bostrom, Guido Alves, Katja Kossakowski, Iracema Leroi, Francisco Pozo-Rodriguez, Lennart Minthon, Elisabet Londos
Memantine in patients with Parkinson's disease dementia or dementia with Lewy bodies: a double-blind, placebo-controlled, multicentre trial.
Lancet Neurol. 2009 Jul;8(7):613-8. doi: 10.1016/S1474-4422(09)70146-2. Epub 2009 Jun 10.
Abstract/Text
BACKGROUND: Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are common forms of dementia that substantially affect quality of life. Currently, the only treatment licensed for PDD is rivastigmine, and there are no licensed treatments for DLB. We aimed to test the safety and efficacy of the N-methyl D-aspartate (NMDA) receptor antagonist memantine in patients with PDD or DLB.
METHODS: We did a parallel-group, 24-week, randomised controlled study of memantine (20 mg per day) versus placebo at four psychiatric and neurological outpatient clinics in Norway, Sweden, and the UK during 2005-08. Patients were included if they fulfilled the UK Parkinson's Disease Society Brain Bank clinical diagnostic criteria for Parkinson's disease (PD) and developed dementia according to the Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM IV) criteria at least 1 year after the onset of motor symptoms (PDD) or met the revised consensus operationalised criteria for DLB. Patients were assigned to a computer-generated randomisation list. All physicians who had contact with patients were masked to treatment allocation. The primary outcome measure was clinical global impression of change (CGIC), which ranged from 1 to 7 points, and a low score means a better outcome. Analysis was by intention to treat based on the last observation carried forward. This trial is registered, number ISRCTN89624516.
FINDINGS: 72 patients with PDD or DLB were randomly assigned and started treatment: 34 with memantine and 38 with placebo. 56 (78%) completed the study. All withdrawals were owing to adverse events, but the proportion of withdrawals was similar in both groups. At week 24 the patients in the memantine group had better CGIC scores than those taking placebo (mean difference 0.7, 95% CI 0.04-1.39; p=0.03). With the exception of improved speed on attentional tasks in the memantine group (a quick test of cognition [AQT] form: difference 12.4, 95% CI 6.0-30.9; p=0.004), there were no significant differences between the groups in secondary outcome measures.
INTERPRETATION: Patients with DLB or PDD might benefit from treatment with memantine, which was well tolerated. Large-scale studies are now required to confirm our preliminary findings.
FUNDING: The Western Norway Regional Health Authority; H Lundbeck A/S.
Iracema Leroi, Ross Overshott, E Jane Byrne, Emily Daniel, Alistair Burns
Randomized controlled trial of memantine in dementia associated with Parkinson's disease.
Mov Disord. 2009 Jun 15;24(8):1217-21. doi: 10.1002/mds.22495.
Abstract/Text
The objective of this study is to investigate the safety and tolerability of memantine, a glutamatergic modulator, in patients suffering from dementia associated with Parkinson's disease (PDD), an increasingly common complication of PD. This was a 22-week trial of 25 participants with a DSM-IV diagnosis of PDD who were randomized to either placebo or 20 mg/day of memantine. Memantine was well tolerated by participants at 20 mg/day dosing. No participant was withdrawn due to memantine-related adverse events. Six weeks after drug withdrawal, a significantly greater proportion (P = 0.04) of memantine-treated participants deteriorated globally compared with those treated with placebo. These findings suggest that continued treatment with memantine may be needed to maintain global level of functioning over time. Based on the findings of this pilot study, memantine is safe and very well-tolerated in PDD.
(c) 2009 Movement Disorder Society.
R L Allen, Z Walker, P J D'Ath, C L Katona
Risperidone for psychotic and behavioural symptoms in Lewy body dementia.
Lancet. 1995 Jul 15;346(8968):185.
Abstract/Text
I G McKeith, C G Ballard, R W Harrison
Neuroleptic sensitivity to risperidone in Lewy body dementia.
Lancet. 1995 Sep 9;346(8976):699.
Abstract/Text
P Pollak, F Tison, O Rascol, A Destée, J J Péré, J M Senard, F Durif, I Bourdeix
Clozapine in drug induced psychosis in Parkinson's disease: a randomised, placebo controlled study with open follow up.
J Neurol Neurosurg Psychiatry. 2004 May;75(5):689-95.
Abstract/Text
OBJECTIVE: To compare the efficacy and safety of clozapine in drug induced psychosis in Parkinson's disease (PD).
METHODS: A four week, randomised, double blind, parallel comparison of clozapine and placebo, followed by a 12 week clozapine open period, plus a one month period after drug discontinuation, in 60 patients with PD. The primary efficacy outcome was the "clinical global impression scale" (CGI); the positive subscore of the "positive and negative syndrome scale" (PANSS) was used as the secondary efficacy parameter and the "unified Parkinson's disease rating scale" (UPDRS) and the "mini mental test examination" (MMSE) as safety outcomes.
RESULTS: The mean (SD) dosage of clozapine was 35.8 (12.5-50) mg at the end of the double blind period. The mean (SD) scores on the CGI improved by 1.8 (1.5) for the clozapine group compared with 0.6 (1.1) for the placebo group (p = 0.001). The mean (SD) positive subscore of PANSS improved by 5.6 (3.9) for the clozapine group (0.8 (2.8) for the placebo group; p < 0.0001). At the end of the open period, 25 patients had completely recovered from delusions and hallucinations, and 19 experienced a relapse within one month after the clozapine washout period. The UPDRS motor and MMSE mean scores did not change significantly in either group. Somnolence was more frequent with clozapine than with placebo.
CONCLUSIONS: Clozapine at a mean dose lower than 50 mg/day improves drug induced psychosis in PD without significant worsening of motor function, and the effect wears off once the treatment stops.
William G Ondo, Ron Tintner, Kevin Dat Voung, Dejian Lai, George Ringholz
Double-blind, placebo-controlled, unforced titration parallel trial of quetiapine for dopaminergic-induced hallucinations in Parkinson's disease.
Mov Disord. 2005 Aug;20(8):958-63. doi: 10.1002/mds.20474.
Abstract/Text
We completed a single site, double-blind, placebo-controlled, parallel design study of quetiapine for hallucinations in PD. Thirty-one subjects with PD and prominent visual hallucinations and Mini-Mental State Examination score >21 were randomly assigned in a 2:1 drug to placebo ratio, up to 200 mg daily of quetiapine or matching placebo given in two doses. They were seen at 3 weeks (100 mg/day) and 12 weeks (200 mg/day, with optional dose reduction). Evaluation included the Unified Parkinson's Disease Rating Scale (UPDRS), the Baylor PD Hallucination Questionnaire, and a battery of neuropsychological tests. The demographics between subjects randomized to drug (n = 21) vs. placebo (n = 10) were similar. The final dose of active drug was 200 (n = 11), 150 (n = 2), 100 (n = 3), and 75 (n = 1) mg per day. All placebo subjects were on the equivalent of 200 mg per day. The UPDRS Activities of Daily Living and Motor scores did not significantly change compared to placebo. Compared to placebo, there were no significant changes in our hallucination questionnaire, the Brief Psychiatric Rating Scale (BPRS), or question 12 (hallucination item) of the BPRS. There were no significant changes on any of the neuropsychological measures. Adverse events on drug included sedation (n = 9), but no drug-related adverse events precipitated discontinuation and none were rated as serious. Quetiapine, up to 200 mg daily, was well tolerated and did not worsen UPDRS scores; however, there was no significant improvement in psychosis rating scales compared to placebo. Larger doses of drug and greater sample sizes might be considered in future studies.
Copyright 2005 Movement Disorder Society
Jose M Rabey, Tatiana Prokhorov, Ala Miniovitz, Eugenia Dobronevsky, Colin Klein
Effect of quetiapine in psychotic Parkinson's disease patients: a double-blind labeled study of 3 months' duration.
Mov Disord. 2007 Feb 15;22(3):313-8. doi: 10.1002/mds.21116.
Abstract/Text
This double-blind randomized study examined the effect of quetiapine (QTP) on drug-induced psychosis (DIP) in Parkinson's disease (PD). Conventional antipsychotic drugs are associated with adverse extrapyramidal effects. QTP is a new atypical antipsychotic drug used in the treatment of psychosis in PD. A total of 58 consecutive psychotic PD patients (mean age, 75 +/- 8.3 years; mean disease duration, 10.5 +/- 6.4 years; 29 with dementia) were randomly assigned to 2 groups: 30 were treated with QTP (mean dose, 119.2 +/- 56.4 mg) and 28 received placebo for 3 months. The motor part of the Unified Parkinson's Disease Rating Scale, the Brief Psychiatric Rating Scale, the Mini-Mental State Examination, the Hamilton Rating Scale for Depression, the Epworth Sleepiness Score, and the Clinical Global Impression Scale were administered before and during the study. No significant difference was found between the groups in all parameters. There were 32 PD patients (55%) completed the 3-month study (15 [26%] QTP and 17 [29%] placebo). Treatment was interrupted in 15 patients in the QTP and 11 in the placebo groups. This double-blind study did not show a beneficial effect of QTP for the treatment of DIP in PD. The high rate of withdrawal probably influenced the results. Larger double-blind studies are required.
Roger Kurlan, Jeffrey Cummings, Rema Raman, Leon Thal, Alzheimer's Disease Cooperative Study Group
Quetiapine for agitation or psychosis in patients with dementia and parkinsonism.
Neurology. 2007 Apr 24;68(17):1356-63. doi: 10.1212/01.wnl.0000260060.60870.89.
Abstract/Text
OBJECTIVE: To assess the efficacy and tolerability of quetiapine for agitation or psychosis in patients with dementia and parkinsonism.
METHODS: Multicenter randomized, double-blind, placebo-controlled parallel groups clinical trial involving 40 patients with dementia with Lewy bodies (n = 23), Parkinson disease (PD) with dementia (n = 9), or Alzheimer disease with parkinsonian features (n = 8). The main outcome measure for efficacy was change in the Brief Psychiatric Rating Scale (BPRS) from baseline to 10 weeks of therapy. For tolerability it was change in the Unified PD Rating Scale (UPDRS) motor section over the same time period. The trial was confounded by the need for a design change and incomplete recruitment.
RESULTS: No significant differences in the primary or secondary outcome measures of efficacy were observed. An unexpectedly large placebo effect, inadequate dosage (mean 120 mg/day), and inadequate power may have contributed to lack of demonstrable benefit. Quetiapine was generally well-tolerated and did not worsen parkinsonism, but was associated with a trend toward a decline on a measure of daily functioning.
CONCLUSIONS: Quetiapine was well-tolerated and did not worsen parkinsonism. Although conclusions about efficacy may be limited, the drug in the dosages used did not show demonstrable benefit for treating agitation or psychosis in patients with dementia and parkinsonism. These findings are in keeping with prior studies reporting limited efficacy of various medications for reducing behavioral problems in demented patients.
Doron Merims, Meirav Balas, Chava Peretz, Herzel Shabtai, Nir Giladi
Rater-blinded, prospective comparison: quetiapine versus clozapine for Parkinson's disease psychosis.
Clin Neuropharmacol. 2006 Nov-Dec;29(6):331-7. doi: 10.1097/01.WNF.0000236769.31279.19.
Abstract/Text
OBJECTIVE: To compare the safety and efficacy of quetiapine versus clozapine for the treatment of psychosis in patients with Parkinson's disease (PD).
METHODS: Twenty-seven patients with PD and recent-onset psychosis were randomly allocated to 2 arms of 22 weeks' treatment with quetiapine or clozapine after 2 weeks of adjustment of antiparkinsonian medications. Assessment was done by a blinded neuropsychologist using the Clinical Global Impression of Change (CGIC) questionnaire and the Neuropsychiatric Inventory (NPI). Mixed-effect models were used to compare CGIC and Neuropsychological Inventory scores over time between the 2 groups.
RESULTS: Both drugs were equally effective based on the CGIC. Clozapine had a trend over quetiapine in controlling the frequency of hallucinations (P = 0.097) and a significant advantage in reducing delusions (P = 0.011). However, one patient in the clozapine arm developed leukopenia. None of the drugs worsened parkinsonism.
CONCLUSIONS: Clozapine and quetiapine are effective atypical neuroleptics for the treatment of psychotic symptoms in PD. Clozapine had greater efficacy in reducing hallucinations and delusions frequency, but its use is associated with an increased risk of leukopenia.
Colin Klein, Tatiana Prokhorov, Alla Miniovich, Eugenia Dobronevsky, Jose M Rabey
Long-term follow-up (24 months) of quetiapine treatment in drug-induced Parkinson disease psychosis.
Clin Neuropharmacol. 2006 Jul-Aug;29(4):215-9. doi: 10.1097/01.WNF.0000228176.98582.93.
Abstract/Text
OBJECTIVES: To evaluate the long-term outcome of quetiapine (QTP) use for drug-induced psychosis in Parkinson disease as assessed by the primary caregiver using the Clinical Global Impression Scale.
METHODS: Thirty-five patients (mean age+/-SD, 76.1+/-5.9 years; mean disease duration+/-SD, 10.3+/-5.3 years; 19 with dementia) were followed up over a 24-month period.
RESULTS: At 6 months, 20 (57%) responded to QTP, of whom 11 (31%) maintained their improvement in the long term (for 24 months). Altogether, 15 patients (43%) responded to QTP in the long term (11 were still on treatment at 24 months, 3 stopped because of improvement and medication was no longer required, and 3 stopped because of financial reasons [one was responding positively by the time of stopping medication]). The medications of nonresponding patients (n=15) were switched to clozapine, with a positive response in 12 patients (80%).
CONCLUSIONS: In long-term follow-up, 31% of parkinsonian patients with psychosis treated with QTP were still on QTP therapy at 24 months. For those failing to respond to QTP, clozapine was an effective alternative therapy.
Alan Breier, Virginia K Sutton, Peter D Feldman, Deborah L Kadam, Iris Ferchland, Padraig Wright, Joseph H Friedman
Olanzapine in the treatment of dopamimetic-induced psychosis in patients with Parkinson's disease.
Biol Psychiatry. 2002 Sep 1;52(5):438-45.
Abstract/Text
BACKGROUND: Studies in elderly patients demonstrate antipsychotic efficacy and favorable safety profiles for olanzapine. We report results from two placebo-controlled, double-blind studies of olanzapine for treatment of dopamimetic drug-induced psychosis in patients with Parkinson's disease (PD).
METHODS: Patients were treated with olanzapine or placebo for 4 weeks while dopamimetic therapy was held constant. Olanzapine was initiated at 2.5 mg/day, with 2.5-mg/day increases allowed every 3 to 4 days up to the maximum dose of 15 mg/day.
RESULTS: Olanzapine patients showed significant improvements from baseline on positive symptoms and most efficacy measures, but no significant treatment-group differences were observed. Olanzapine performed significantly worse than placebo in both studies on the Unified Parkinson's Disease Rating Scale (UPDRS) total, Motor, and Activities of Daily Living scales, but not the UPDRS Tremor item or Complications scores. Corrected QT interval, vital signs, and body weight were not significantly different from placebo.
CONCLUSIONS: These findings did not demonstrate superior efficacy of olanzapine for treatment of dopamimetic-induced psychosis in PD. The initial dose-titration schedule and mild baseline levels of psychosis may account for these findings. Future studies involving gradual dose titration are needed to explore further olanzapine's optimum use for patients with PD with treatment-related psychosis.
William G Ondo, Joel K Levy, Kevin Dat Vuong, Christine Hunter, Joseph Jankovic
Olanzapine treatment for dopaminergic-induced hallucinations.
Mov Disord. 2002 Sep;17(5):1031-5. doi: 10.1002/mds.10217.
Abstract/Text
Atypical antipsychotic medications with lower affinities for D2 receptors are considered useful alternatives to treat drug-induced hallucinations in Parkinson's disease (PD). We conducted a double-blind, placebo-controlled, unforced titration, parallel design study (2:1 drug to placebo randomization ratio) using olanzapine (2.5-10 mg/day to effect) in 30 PD patients with drug-induced hallucinations. We performed an extensive battery of neuropsychological tests, the Unified Parkinson's Disease Rating Scale (UPDRS), assessments of on and off time at baseline and at 9 weeks after starting the medication. Sixteen patients on olanzapine (mean dose, 4.6 mg/night) and 11 on placebo completed the study. Compared with placebo, performance on the UPDRS item 2 (thought disorder), and a structured interview for hallucinations, both tended to improve on drug but neither reached statistical significance. A neuropsychological test battery did not show any significant differences. Total on UPDRS motor scores (P < 0.05) and timed tapping (P < 0.01) worsened while on drug compared to placebo. Bradykinesia (P < 0.01) and gait (P < 0.001) items on the UPDRS largely accounted for this deterioration. After completion of the study, 8 of 16 patients randomly assigned to drug continued olanzapine at a mean dose of 2.4 mg/day. However, at the last recorded visit only 5 of 24 (20.8%) of all patients exposed to drug (including those originally randomly assigned to placebo) remained on olanzapine. In patients with PD, low-dose olanzapine did not significantly improve hallucinations but did worsen motor function.
Copyright 2002 Movement Disorder Society
T Ellis, M E Cudkowicz, P M Sexton, J H Growdon
Clozapine and risperidone treatment of psychosis in Parkinson's disease.
J Neuropsychiatry Clin Neurosci. 2000 Summer;12(3):364-9.
Abstract/Text
The authors compared efficacy and safety of risperidone and clozapine for the treatment of psychosis in a double-blind trial with 10 subjects with Parkinson's disease (PD) and psychosis. Mean improvement in the Brief Psychiatric Rating Scale psychosis score was similar in the clozapine and the risperidone groups (P=0.23). Although the mean motor Unified Parkinson's Disease Rating Scale score worsened in the risperidone group and improved in the clozapine group, this difference did not reach statistical significance. One subject on clozapine developed neutropenia. In subjects with PD, risperidone may be considered as an alternative to clozapine because it is as effective for the treatment of psychoses without the hematologic, antimuscarinic, and seizure side effects. However, risperidone may worsen extrapyramidal symptoms more than clozapine and therefore must be used with caution.
Joseph H Friedman, Robert M Berman, Christopher G Goetz, Stewart A Factor, William G Ondo, Joanne Wojcieszek, William H Carson, Ronald N Marcus
Open-label flexible-dose pilot study to evaluate the safety and tolerability of aripiprazole in patients with psychosis associated with Parkinson's disease.
Mov Disord. 2006 Dec;21(12):2078-81. doi: 10.1002/mds.21091.
Abstract/Text
Psychosis affects at least 5% to 8% of medication-treated patients with idiopathic Parkinson's disease (PD). Treatment options include reducing medications used for the treatment of PD-related motor symptoms or introducing an atypical antipsychotic drug. Only clozapine has been demonstrated to be efficacious and tolerated in double-blind controlled trials. This study evaluated the effect of aripiprazole, an atypical antipsychotic, on psychosis in PD in an open-label pilot study. Fourteen patients meeting entry criteria were started on aripiprazole 1 mg/day and titrated up to a maximum dose of 5 mg as needed. Subjects were evaluated on the Unified Parkinson's Disease Rating Scale (UPDRS) part III for motor function, the Neuropsychiatric Inventory (NPI), and the Brief Psychiatric Rating Scale (BPRS) for psychiatric response. Statistically significant improvement in mean BPRS and positive BPRS subscales occurred with open-label aripiprazole, but eight subjects discontinued the study due to worsened Parkinsonism (three), worsened psychosis (two), worsening of both (two), and lack of efficacy (one). While some patients had a favorable response, aripiprazole was associated with an exacerbation of motor symptoms. In this small study on psychosis in PD, aripiprazole did not appear promising.
Copyright 2006 Movement Disorder Society.
Juan Carlos Gómez-Esteban, Juan J Zarranz, Fernando Velasco, Elena Lezcano, M C Lachen, Idoia Rouco, Joseba Barcena, Sabas Boyero, Roberto Ciordia, Isidro Allue
Use of ziprasidone in parkinsonian patients with psychosis.
Clin Neuropharmacol. 2005 May-Jun;28(3):111-4.
Abstract/Text
Twelve patients with Parkinson disease and psychosis were included in an open-label 12-week trial of ziprasidone. Two patients withdrew from the treatment because of adverse effects. The remaining 10 patients reported a significant improvement in psychiatric symptoms. Altogether, there was no deterioration of motor symptoms (UPDRS III score: basal 40.4 +/- 11.1, first month 41.1 +/- 10.8; final visit, 37.7 +/- 13.3). Two patients (20%) suffered a slight deterioration in motor symptoms and another patient suffered deterioration of gait. No analytic alterations or serious adverse effects that could limit the use of ziprasidone were observed. Although controlled trials are needed, the findings suggest that ziprasidone may be effective in parkinsonian patients with psychosis.
Hideto Shinno, Etsuko Utani, Shihoh Okazaki, Tetsuya Kawamukai, Hideaki Yasuda, Takuji Inagaki, Yasushi Inami, Jun Horiguchi
Successful treatment with Yi-Gan San for psychosis and sleep disturbance in a patient with dementia with Lewy bodies.
Prog Neuropsychopharmacol Biol Psychiatry. 2007 Oct 1;31(7):1543-5. doi: 10.1016/j.pnpbp.2007.07.002. Epub 2007 Aug 3.
Abstract/Text
Koh Iwasaki, Masahiro Maruyama, Naoki Tomita, Katsutoshi Furukawa, Miyako Nemoto, Hironori Fujiwara, Takashi Seki, Masahiko Fujii, Manabu Kodama, Hiroyuki Arai
Effects of the traditional Chinese herbal medicine Yi-Gan San for cholinesterase inhibitor-resistant visual hallucinations and neuropsychiatric symptoms in patients with dementia with Lewy bodies.
J Clin Psychiatry. 2005 Dec;66(12):1612-3.
Abstract/Text
Lon S Schneider, Karen S Dagerman, Philip Insel
Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials.
JAMA. 2005 Oct 19;294(15):1934-43. doi: 10.1001/jama.294.15.1934.
Abstract/Text
CONTEXT: Atypical antipsychotic medications are widely used to treat delusions, aggression, and agitation in people with Alzheimer disease and other dementia; however, concerns have arisen about the increased risk for cerebrovascular adverse events, rapid cognitive decline, and mortality with their use.
OBJECTIVE: To assess the evidence for increased mortality from atypical antipsychotic drug treatment for people with dementia.
DATA SOURCES: MEDLINE (1966 to April 2005), the Cochrane Controlled Trials Register (2005, Issue 1), meetings presentations (1997-2004), and information from the sponsors were searched using the terms for atypical antipsychotic drugs (aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone), dementia, Alzheimer disease, and clinical trial.
STUDY SELECTION: Published and unpublished randomized placebo-controlled, parallel-group clinical trials of atypical antipsychotic drugs marketed in the United States to treat patients with Alzheimer disease or dementia were selected by consensus of the authors.
DATA EXTRACTION: Trials, baseline characteristics, outcomes, all-cause dropouts, and deaths were extracted by one reviewer; treatment exposure was obtained or estimated. Data were checked by a second reviewer.
DATA SYNTHESIS: Fifteen trials (9 unpublished), generally 10 to 12 weeks in duration, including 16 contrasts of atypical antipsychotic drugs with placebo met criteria (aripiprazole [n = 3], olanzapine [n = 5], quetiapine [n = 3], risperidone [n = 5]). A total of 3353 patients were randomized to study drug and 1757 were randomized to placebo. Outcomes were assessed using standard methods (with random- or fixed-effects models) to calculate odds ratios (ORs) and risk differences based on patients randomized and relative risks based on total exposure to treatment. There were no differences in dropouts. Death occurred more often among patients randomized to drugs (118 [3.5%] vs 40 [2.3%]. The OR by meta-analysis was 1.54; 95% confidence interval [CI], 1.06-2.23; P = .02; and risk difference was 0.01; 95% CI, 0.004-0.02; P = .01). Sensitivity analyses did not show evidence for differential risks for individual drugs, severity, sample selection, or diagnosis.
CONCLUSIONS: Atypical antipsychotic drugs may be associated with a small increased risk for death compared with placebo. This risk should be considered within the context of medical need for the drugs, efficacy evidence, medical comorbidity, and the efficacy and safety of alternatives. Individual patient analyses modeling survival and causes of death are needed.
Koh Iwasaki, Kenji Kosaka, Hideo Mori, Reina Okitsu, Katsutoshi Furukawa, Yuta Manabe, Mitsuhiro Yoshita, Aya Kanamori, Nobuo Ito, Kenji Wada, Michio Kitayama, Jun Horiguchi, Shuhei Yamaguchi, Shin Takayama, Ryuji Fukuhara, Shinji Ouma, Seigo Nakano, Mamoru Hashimoto, Toru Kinoshita
Improvement in delusions and hallucinations in patients with dementia with Lewy bodies upon administration of yokukansan, a traditional Japanese medicine.
Psychogeriatrics. 2012 Dec;12(4):235-41. doi: 10.1111/j.1479-8301.2012.00413.x.
Abstract/Text
BACKGROUND: This multicentre open-label trial examined the efficacy and safety of the traditional Japanese medicine, or Kampo medicine, yokukansan (YKS), for behavioural and psychological symptoms of dementia (BPSD) in patients with dementia with Lewy bodies.
METHODS: Sixty-three dementia with Lewy bodies patients with probable BPSD (M:W, 30:33; mean age, 78.2±5.8 years) were enrolled and treated with YKS for 4 weeks.
RESULTS: Significant improvements in Neuropsychiatric Inventory scores (mean decrease, 12.5 points; P<0.001) and Zarit Burden Interview-Japanese edition tests (mean decrease, 3.6 points; P=0.024) were observed. In patients who consented to an assessment after 2 weeks of treatment, a time-dependent significant improvement was observed in the Neuropsychiatric Inventory score (n=23; mean decrease, 14.4; P<0.001), each subscale, including delusions and hallucinations, the Zarit Burden Interview-Japanese edition (n=22; mean decrease, 8.2; P<0.01) and the behavioural pathology in Alzheimer's disease insomnia subscale. The Mini-Mental State Examination and the Disability Assessment for Dementia (DAD) showed no significant change. Adverse events were observed in 11 (18%) patients. Three patients (5%) discontinued YKS due to adverse reactions, namely, spasticity and exacerbation of BPSD, edema, and nausea. Hypokalaemia (<3.5 mEq/L) was present in four patients (6%) at the study endpoint. Worsening of extrapyramidal symptoms was not observed.
CONCLUSION: YKS improved BPSD in dementia with Lewy bodies patients and caregiver burden scores without deterioration in cognitive function. YKS is useful for the treatment of delusions and hallucinations in BPSD.
© 2012 The Authors. Psychogeriatrics © 2012 Japanese Psychogeriatric Society.
A M Hakim, G Mathieson
Dementia in Parkinson disease: a neuropathologic study.
Neurology. 1979 Sep;29(9 Pt 1):1209-14.
Abstract/Text
Thirty-four autopsy cases conforming to the standard neuropathologic criteria of Parkinson disease were sex- and age-matched with controls who had died of infarct or trauma. All brains were reviewed for changes compatible with Alzheimer disease, and available clinical data were retrospectively reviewed. Nineteen (56 percent) of the Parkinson cases had shown some degree of dementia. The average parkinsonian brain weight was 1281 gm; it was 1365 gm for the controls (p less than 0.02). Plaques, neurofibrillary tangles, granulovacuolar degeneration, and cortical cell loss were present in all but one of the parkinsonian brains; these pathologic changes were present in fewer controls and to a lesser degree. The higher incidence of dementia in patients with Parkinson disease may be explained by the simultaneous presence of Alzheimer disease.
Lewy FH (1923) Die Lehre vom Tonus und der Bewegung. Zugleich systematische Untersuchungen zur Klinik, Physiologie, Pathologie und Pathogenese der Paralysis agitans. Springer, Berlin.
Robert Thornhill Monroe. Diseases in Old Age: A Clinical and Pathological Study of 7941 Individuals Over 61 Years of Age. 1951. Harvard Univ Monogr Med Public Heal Harvard Univ Press.
Bernd Holdorff
Friedrich Heinrich Lewy (1885-1950) and his work.
J Hist Neurosci. 2002 Mar;11(1):19-28. doi: 10.1076/jhin.11.1.19.9106.
Abstract/Text
In 1912, Friedrich Heinrich Lewy first described the inclusion bodies named after him and seen in paralysis agitans (p.a.). Tretiakoff had found (1919) that the nucleus niger is most likely to be affected but in a subsequent large-scale series of post-mortem examinations (1923). Lewy was able to confirm this for a minority of cases only, with the exception of those that displayed postencephalitic Parkinsonism (and an unknown number of atypical Parkinson syndrome cases not identified until the 1960s). In a speculative paper (1932), he saw similarities between inclusion bodies in p.a. and viral diseases like lyssa and postulated a viral genesis of p.a. In a historical review of basal ganglia diseases (1942), he did not mention the putative significance of the inclusion bodies for the post-mortem diagnosis. It seems that their importance was seen only after Lewy's death, long after Tretiakoff's initial naming of the 'corps de Lewy'. Lewy, however, had already described their diffuse and cortical distribution (1923). An identification of diffuse Lewy body disease or dementia followed much later. Lewy's career in many diverse branches of neurology and internal medicine was strongly affected by World War I and the difficult situation faced by Jews in Germany. Shortly after the Neurological Institute was founded in Berlin in 1932 (as a clinic and research institute), he was forced, in 1933, to emigrate. His exile in England and the United States mirrors the fate of many German Jews and academics in the first half of the 20th century.
Bernd Holdorff
Fritz Heinrich Lewy (1885-1950).
J Neurol. 2006 May;253(5):677-8. doi: 10.1007/s00415-006-0130-2.
Abstract/Text
Dag Aarsland, Julia Zaccai, Carol Brayne
A systematic review of prevalence studies of dementia in Parkinson's disease.
Mov Disord. 2005 Oct;20(10):1255-63. doi: 10.1002/mds.20527.
Abstract/Text
Substantial variation in the prevalence of dementia in Parkinson's disease (PDD) has been reported. The aim of this study was to review systematically and critically previous studies of the prevalence of PDD using PubMed to search the literature. Studies focusing on PD and PDD, as well as those examining on the epidemiology of dementia subtypes, were included. Predefined inclusion and exclusion criteria were used and the quality of the studies included was rated. Articles were included if: (1) the proportion of PDD among patients with either PD or dementia was reported in an original study; (2) patients had been subjected to prospective clinical examination; and (3) strategies to include all subjects with either PD or dementia within the community or hospital clinics within a geographical area were employed. Twelve studies of the prevalence of PD or PDD (1,767 patients included) and 24 prevalence studies of dementia subtypes (4,711 patients included) met the inclusion criteria. In the PD/PDD studies, the proportion (mean and 95% confidence interval) with PDD in PD was 24.5% (17.4-31.5). There were significant methodological variations between studies and in the four studies that matched the quality criteria most closely, the rate of PDD was 31.1% (20.1-42.1). The prevalence of PDD was estimated as 0.5% in subjects 65 years or older. The percentage of PDD among those with dementia was 3.6% (3.1-4.1), with an estimated prevalence of PDD of 0.2% in subjects aged 65 years or older. Despite methodological variation, this systematic review suggests that 24 to 31% of PD patients have dementia, and that 3 to 4% of the dementia in the population would be due to PDD. The estimated prevalence of PDD in the general population aged 65 years and over is 0.2 to 0.5%.
Copyright (c) 2005 Movement Disorder Society.
F Tison, J F Dartigues, S Auriacombe, L Letenneur, F Boller, A Alpérovitch
Dementia in Parkinson's disease: a population-based study in ambulatory and institutionalized individuals.
Neurology. 1995 Apr;45(4):705-8.
Abstract/Text
We examined the frequency of dementia and depressive symptomatology in 60 Parkinson's disease (PD) patients, identified in a large representative sample of the population, aged 65 years and older, living at home or in institutions in Gironde, France. Dementia, diagnosed according to DSM-III-R criteria, was present in 17.6%, and depressive symptomatology, assessed by the Center for Epidemiologic Studies-Depression Scale, was present in 32.7%. The frequency of dementia in PD increased strongly with age and was higher in institutionalized PD patients than in those living at home. PD was significantly associated with dementia for individuals living at home (odds ratio = 8.2, adjusted for age and symptoms of depression.
Dag Aarsland, Kjeld Andersen, Jan P Larsen, Anette Lolk, Per Kragh-Sørensen
Prevalence and characteristics of dementia in Parkinson disease: an 8-year prospective study.
Arch Neurol. 2003 Mar;60(3):387-92.
Abstract/Text
BACKGROUND: Few longitudinal studies of dementia in Parkinson disease (PD) have been reported, and the proportion of patients with PD who eventually develop dementia is unknown.
OBJECTIVE: To examine the 8-year prevalence, characteristics, and risk factors of dementia in patients with PD.
METHODS: Patients were recruited from an epidemiological study of PD in the county of Rogaland, Norway, using explicit criteria for PD. Subjects with cognitive impairment at disease onset were excluded. A semistructured caregiver-based interview, cognitive rating scales, and neuropsychological tests were used to diagnose dementia according to criteria from the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition at baseline and 4 and 8 years later. A population-based sample of 3295 subjects in the municipality of Odense, Denmark, was used as a comparison group and examined at baseline and after 2 and 5 years.
RESULTS: We included 224 patients with PD (116 women). At baseline, 51 patients (26%) had dementia. Fifty-five patients died, and 10 refused follow-up without their dementia status known. Forty-three and 28 new cases of dementia were identified at the 4- and 8-year evaluations, respectively. The 4-year prevalence of dementia in PD was nearly 3 times higher than in the non-PD group. The 8-year prevalence in PD was 78.2% (95% confidence interval [CI], 71.1-84.0). Risk factors for dementia were hallucinations before baseline (odds ratio [OR] = 3.1; 95% CI, 1.6-6.2) and akinetic-dominant or mixed tremor/akinetic PD (OR = 3.3; 95% CI, 1.2-8.5).
CONCLUSIONS: More than three quarters of this representative PD cohort developed dementia during the 8-year study period. Early hallucinations and akinetic-dominant PD were associated with an increased risk of dementia.
David J Burn, Elise N Rowan, Thais Minett, Jonathon Sanders, Pat Myint, Jonathon Richardson, Alan Thomas, Jane Newby, Jenny Reid, John T O'Brien, Ian G McKeith
Extrapyramidal features in Parkinson's disease with and without dementia and dementia with Lewy bodies: A cross-sectional comparative study.
Mov Disord. 2003 Aug;18(8):884-9. doi: 10.1002/mds.10455.
Abstract/Text
Risk factors predicting an increased risk of dementia in Parkinson's disease (PD) are not fully established. The dementia associated with PD (PDD) closely resembles dementia with Lewy bodies (DLB). Based upon a high frequency of non-dopaminergic mediated clinical features in DLB, we predicted that a motor subtype comprising postural instability and balance problems would be more common in PDD. We examined extrapyramidal, cognitive, and affective features in 38 PD, 43 PDD, and 26 DLB patients in a cross-sectional study design. Motor subtype was subdivided into postural-instability gait difficulty (PIGD) or tremor (TD) dominant. The PIGD-subtype was more common in PDD (88% of cases) and DLB (69% of cases) groups compared with the PD group (38% of cases), in which TD and PIGD sub-types were more equally represented (P < 0.001). Although the mean depression scores overall were modest, PDD patients scored significantly higher than PD, but not DLB patients (Cornell; P = 0.006, and Geriatric Depression scale, GDS-15; P = 0.001), while within the PD group, those patients with a PIGD subtype had greater depression scores than the TD subtype (GDS-15; P < 0.05). We conclude that non-dopaminergic motor features are frequent in PDD. Neurodegeneration within the cholinergic system is likely to mediate many of these motor problems, as well as playing a significant role in determining the neuropsychiatric symptomatology of both PDD and DLB.
Copyright 2003 Movement Disorder Society
Dag Aarsland, Robert Perry, Jan P Larsen, Ian G McKeith, John T O'Brien, Elaine K Perry, David Burn, Clive G Ballard
Neuroleptic sensitivity in Parkinson's disease and parkinsonian dementias.
J Clin Psychiatry. 2005 May;66(5):633-7.
Abstract/Text
BACKGROUND: Severe sensitivity to neuroleptic agents is a major clinical problem in dementia with Lewy bodies (DLB), but has not been determined in Parkinson's disease (PD) and PD with dementia (PDD).
METHOD: Severe neuroleptic sensitivity reactions (NSRs) were evaluated according to an operationalized definition blind to clinical and neuropathologic diagnoses in prospectively studied patients exposed to neuroleptics from 2 centers. The study was conducted from June 1995 to May 2003.
RESULTS: Ninety-four patients were included (15 with DLB, 36 with PDD, 26 with PD, 17 with Alzheimer's disease, all diagnosed with various operational criteria). Severe NSR only occurred in patients with Lewy body disease: DLB (8 [53%]), PDD (14 [39%]), and PD (7 [27%]), but did not occur in Alzheimer's disease (p = .006). Severe NSR was not associated with other clinical or demographic features. In DLB, severe NSR was not associated with neuropathologic indices (Consortium to Establish a Registry for Alzheimer's Disease staging, Braak staging, or cortical distribution of Lewy bodies).
CONCLUSIONS: An operationalized evaluation of severe NSR blind to diagnosis confirmed the high prevalence in DLB and identified high frequencies in Parkinson's disease and PDD with important implications for clinical practice.
C Ballard, J O'Brien, A Swann, D Neill, P Lantos, C Holmes, D Burn, P Ince, R Perry, I McKeith
One year follow-up of parkinsonism in dementia with Lewy bodies.
Dement Geriatr Cogn Disord. 2000 Jul-Aug;11(4):219-22. doi: 17240.
Abstract/Text
The progression of parkinsonism over 1 year was evaluated in a prospective cohort of patients (n = 338), suffering from dementia with Lewy bodies (DLB), Alzheimer's disease (AD) or vascular dementia (VaD). Parkinsonism was assessed using the modified Unified Parkinson's Disease Rating Scale. Significant parkinsonism was significantly commoner in DLB sufferers (71%) than amongst patients with AD (7%) or VaD (10%). DLB patients with established parkinsonism had an annual increase in severity of 9%, but progression was more rapid (49% in 1 year) in patients with early parkinsonism. Parkinsonism was frequent at all severities in DLB patients, but usually only present in other dementias when MMSE <10.
Copyright 2000 S. Karger AG, Basel.
S Molloy, I G McKeith, J T O'Brien, D J Burn
The role of levodopa in the management of dementia with Lewy bodies.
J Neurol Neurosurg Psychiatry. 2005 Sep;76(9):1200-3. doi: 10.1136/jnnp.2004.052332.
Abstract/Text
BACKGROUND: One of the core clinical features of dementia with Lewy bodies (DLB) is extrapyramidal syndrome (EPS). Levodopa is currently the gold standard oral therapy for Parkinson's disease (PD), but its use in DLB has been tempered by concerns of exacerbating neuropsychiatric symptoms.
AIM: To assess the efficacy and tolerability of L-dopa in managing EPS in DLB and to compare the motor response with that seen in PD and PD with dementia (PDD).
METHOD: EPS assessment consisted of the Unified Parkinson's Disease Rating Scale, motor subsection (UPDRS III), and finger tapping and walking tests. Patients with DLB were commenced on L-dopa. After 6 months, patients were examined in the "off" state, given L-dopa and assessed for motor responses. Identical assessments were performed in patients with PD and PDD also receiving L-dopa.
RESULTS: Acute L-dopa challenge in 14 DLB patients yielded a mean 13.8% (p = 0.02) improvement in UPDRS III score, compared with 20.5% in PD (n = 28, p < 0.0001) and 23% in PDD (n = 30, p<0.0001) respectively. Finger tapping scores increased (12.3% v 20% and 23%), while walking test scores decreased (32% v 41% and 67%). Of the DLB patients, 36% were classified as "responders" on L-dopa challenge, compared with 70% of the PDD and 57% of the PD patients. Nineteen DLB patients were treated for 6 months with L-dopa (mean daily dose 323 mg). Two withdrew prematurely with gastrointestinal symptoms and two with worsening confusion.
CONCLUSION: L-dopa was generally well tolerated in DLB but produced a significant motor response in only about one third of patients. Younger DLB cases were more likely to respond to dopaminergic treatment.
S B Bonelli, G Ransmayr, M Steffelbauer, T Lukas, C Lampl, M Deibl
L-dopa responsiveness in dementia with Lewy bodies, Parkinson disease with and without dementia.
Neurology. 2004 Jul 27;63(2):376-8.
Abstract/Text
The authors analyzed whether nondemented (PD) and demented Parkinson patients (PDD) and patients with dementia with Lewy bodies (DLB) respond similarly in the levodopa test (LDT). Percentage of motor improvement was similar in the three groups; the proportion of patients with 10% and more improvement was greater in PD than in PDD and DLB. Positive LDT was predictive for favorable response in chronic levodopa treatment, but also some nonresponsive demented patients profited from chronic levodopa therapy.
John E Duda, Benoit I Giasson, Meghann E Mabon, Virginia M-Y Lee, John Q Trojanowski
Novel antibodies to synuclein show abundant striatal pathology in Lewy body diseases.
Ann Neurol. 2002 Aug;52(2):205-10. doi: 10.1002/ana.10279.
Abstract/Text
Intracytoplasmic inclusions composed of alpha-synuclein (alpha-syn) are characteristic of neurodegenerative Lewy body disorders. Using novel monoclonal antibodies raised against altered alpha-syn, we uncovered an unprecedented and extensive burden of alpha-syn pathology in the striatum of Lewy body disorders. The highest density of striatal pathology was observed in patients with a combination of Alzheimer's disease and dementia with Lewy bodies or pure dementia with Lewy bodies, and these alpha-syn aggregates may contribute to the parkinsonism seen in these disorders.
Jose A Obeso, Maria C Rodriguez-Oroz, Christopher G Goetz, Concepcion Marin, Jeffrey H Kordower, Manuel Rodriguez, Etienne C Hirsch, Matthew Farrer, Anthony H V Schapira, Glenda Halliday
Missing pieces in the Parkinson's disease puzzle.
Nat Med. 2010 Jun;16(6):653-61. doi: 10.1038/nm.2165. Epub 2010 May 23.
Abstract/Text
Parkinson's disease is a neurodegenerative process characterized by numerous motor and nonmotor clinical manifestations for which effective, mechanism-based treatments remain elusive. Here we discuss a series of critical issues that we think researchers need to address to stand a better chance of solving the different challenges posed by this pathology.
Dag Aarsland, Mona K Beyer, Martin W Kurz
Dementia in Parkinson's disease.
Curr Opin Neurol. 2008 Dec;21(6):676-82. doi: 10.1097/WCO.0b013e3283168df0.
Abstract/Text
PURPOSE OF REVIEW: Cognitive impairment and dementia are among the most common nonmotor changes in Parkinson's disease. The purpose of this review is to present recent findings of clinical and neurobiological aspects of dementia in Parkinson's disease.
RECENT FINDINGS: New consensus criteria for a clinical diagnosis of dementia in Parkinson's disease have been proposed. A very high cumulative prevalence of dementia in Parkinson's disease has been shown in two independent long-term cohorts. Mild cognitive impairment occurs even in early Parkinson's disease and is associated with a shorter time to dementia. Emerging evidence from pathology, as well as in-vivo studies using novel techniques within genetics, imaging, and cerebrospinal fluid research, indicates that alpha-synuclein aggregation and disturbances of other candidate proteins are associated with dementia in Parkinson's disease. Clinical, pathological, and electrophysiological studies support the hypothesis of different subtypes of dementia in Parkinson's disease, potentially related to different underlying brain changes.
SUMMARY: Increased understanding of underlying mechanisms of cognitive decline and dementia in Parkinson's disease has been achieved. This will hopefully lead to novel treatment with the potential of preventing or delaying the onset of dementia by influencing these mechanisms.
G Levy, M-X Tang, E D Louis, L J Côté, B Alfaro, H Mejia, Y Stern, K Marder
The association of incident dementia with mortality in PD.
Neurology. 2002 Dec 10;59(11):1708-13.
Abstract/Text
OBJECTIVE: To evaluate the association of incident dementia with mortality in a cohort of patients with idiopathic PD who were nondemented at baseline evaluation, controlling for extrapyramidal sign (EPS) severity at each study visit.
BACKGROUND: The development of dementia has been associated with reduced survival in PD. Because EPS severity is associated with both dementia and mortality in PD, the association of dementia with mortality may be confounded by disease severity.
METHODS: A cohort of patients with PD was followed annually with neurologic and neuropsychological evaluations. The association of incident dementia and the total Unified PD Rating Scale (UPDRS) motor score with mortality in PD was examined using Cox proportional hazards models with time-dependent covariates. All analyses were adjusted for age at baseline, sex, years of education, ethnicity, and duration of PD.
RESULTS: Of 180 PD patients, 41 (22.8%) died during a mean follow-up period of 3.9 +/- 2.2 years. Among those who died during the study period, 48.8% (20 of 41) became demented during follow-up, as compared to 23.0% (32 of 139) of those who remained alive. Both incident dementia (RR: 2.2, 95% CI: 1.1 to 4.5, p = 0.04) and the total UPDRS motor score at each study visit (RR: 1.04, 95% CI: 1.02 to 1.07, p = 0.001) were associated with mortality in PD when included in the same Cox model.
CONCLUSIONS: Incident dementia has an independent effect on mortality when controlling for EPS severity. The development of dementia is associated with a twofold increased mortality risk in PD.
G Webster Ross, Helen Petrovitch, Robert D Abbott, Caroline M Tanner, Jordan Popper, Kamal Masaki, Lenore Launer, Lon R White
Association of olfactory dysfunction with risk for future Parkinson's disease.
Ann Neurol. 2008 Feb;63(2):167-73. doi: 10.1002/ana.21291.
Abstract/Text
OBJECTIVE: Although olfactory dysfunction is commonly associated with Parkinson's disease (PD), it is not known whether such dysfunction can predate the onset of clinical PD in a community-based population. This study examines the association of olfactory dysfunction with future development of PD in Honolulu-Asia Aging Study cohort members
METHODS: Olfaction was assessed from 1991 to 1996 in 2,267 men in the Honolulu-Asia Aging Study aged 71 to 95 years who were free of clinical PD and dementia at the time of olfaction testing. Participants were followed for up to 8 years for incident PD RESULTS: In the course of follow-up, 35 men were diagnosed with PD (24.6/10,000 person-years). The average age at the time of diagnosis was 82.9 +/- 3.8 (range, 76-93) years, and the average time to a diagnosis was 4.0 +/- 1.9 (range, 1-8) years. During the first 4 years of follow-up, age-adjusted incidence of PD declined from 54.5/10,000 person-years in the lowest quartile of odor identification to 26.6, 8.2, and 8.4/10,000 person-years in the second, third, and fourth quartiles, respectively (p < 0.001 for trend). After adjustment for age and other potential confounders, the odds ratios for PD in the lowest quartile was 5.2 (95% confidence interval, 1.5-25.6) compared with the top two quartiles. This relation was not evident beyond 4 years of follow-up.
INTERPRETATION: Impaired olfaction can predate clinical PD in men by at least 4 years and may be a useful screening tool to detect those at high risk for development of PD in later life.
Mirthe M Ponsen, Diederick Stoffers, Jan Booij, Berthe L F van Eck-Smit, Erik Ch Wolters, Henk W Berendse
Idiopathic hyposmia as a preclinical sign of Parkinson's disease.
Ann Neurol. 2004 Aug;56(2):173-81. doi: 10.1002/ana.20160.
Abstract/Text
Olfactory dysfunction is an early and common symptom in Parkinson's disease (PD). In an effort to determine whether otherwise unexplained (idiopathic) olfactory dysfunction is associated with an increased risk of developing PD, we designed a prospective study in a cohort of 361 asymptomatic relatives (parents, siblings, or children) of PD patients. A combination of olfactory detection, identification, and discrimination tasks was used to select groups of hyposmic (n = 40) and normosmic (n = 38) individuals for a 2-year clinical follow-up evaluation and sequential single-photon emission computed tomography (SPECT), using [123I]beta-CIT as a dopamine transporter ligand, to assess nigrostriatal dopaminergic function at baseline and 2 years from baseline. A validated questionnaire, sensitive to the presence of parkinsonism, was used in the follow-up of the remaining 283 relatives. Two years from baseline, 10% of the individuals with idiopathic hyposmia, who also had strongly reduced [123I]beta-CIT binding at baseline, had developed clinical PD as opposed to none of the other relatives in the cohort. In the remaining nonparkinsonian hyposmic relatives, the average rate of decline in dopamine transporter binding was significantly higher than in the normosmic relatives. These results indicate that idiopathic olfactory dysfunction is associated with an increased risk of developing PD of at least 10%.
Copyright 2004 American Neurological Association
Mirthe M Ponsen, Diederick Stoffers, Erik Ch Wolters, Jan Booij, Henk W Berendse
Olfactory testing combined with dopamine transporter imaging as a method to detect prodromal Parkinson's disease.
J Neurol Neurosurg Psychiatry. 2010 Apr;81(4):396-9. doi: 10.1136/jnnp.2009.183715. Epub 2009 Dec 3.
Abstract/Text
Objective Olfactory dysfunction is an early and common symptom in Parkinson disease (PD). Previously, the authors demonstrated that idiopathic olfactory dysfunction in first-degree relatives of PD patients is associated with an increased risk of developing PD within 2 years. The aim of the present study was to determine the value of combined olfactory testing and SPECT scanning in predicting future PD in the same population of relatives over a 5-year period. Methods In a cohort of 361 non-parkinsonian, non-demented first-degree relatives of PD patients, a combination of olfactory processing tasks was used to select groups of hyposmic (n=40) and normosmic (n=38) individuals for a 5-year clinical follow-up evaluation and sequential SPECT scanning, using a dopamine transporter ligand to assess nigrostriatal dopaminergic function at baseline and 5 years from baseline. A validated questionnaire, sensitive to the presence of parkinsonism, was used in the follow-up of the remaining 283 relatives. Results Five years from baseline, five out of the 40 hyposmic relatives fulfilled clinical diagnostic criteria for PD. None of the other 349 relatives available for follow-up developed PD. All hyposmic individuals developing PD had an abnormal baseline SPECT scan. Discussion In conclusion, idiopathic hyposmia in first-degree relatives of PD patients is associated with an increased risk of developing clinical PD of 12.5% over a 5-year period. The present data suggest that a two-step approach using olfactory testing followed by SPECT scanning in hyposmic individuals has a very high sensitivity and specificity in detecting PD. The usefulness of this two-step approach needs to be confirmed in larger populations.
Toru Baba, Akio Kikuchi, Kazumi Hirayama, Yoshiyuki Nishio, Yoshiyuki Hosokai, Shigenori Kanno, Takafumi Hasegawa, Naoto Sugeno, Masatoshi Konno, Kyoko Suzuki, Shoki Takahashi, Hiroshi Fukuda, Masashi Aoki, Yasuto Itoyama, Etsuro Mori, Atsushi Takeda
Severe olfactory dysfunction is a prodromal symptom of dementia associated with Parkinson's disease: a 3 year longitudinal study.
Brain. 2012 Jan;135(Pt 1):161-9. doi: 10.1093/brain/awr321.
Abstract/Text
Dementia is one of the most debilitating symptoms of Parkinson's disease. A recent longitudinal study suggests that up to 80% of patients with Parkinson's disease will eventually develop dementia. Despite its clinical importance, the development of dementia is still difficult to predict at early stages. We previously identified olfactory dysfunction as one of the most important indicators of cortical hypometabolism in Parkinson's disease. In this study, we investigated the possible associations between olfactory dysfunction and the risk of developing dementia within a 3-year observation period. Forty-four patients with Parkinson's disease without dementia underwent the odour stick identification test for Japanese, memory and visuoperceptual assessments, (18)F-fluorodeoxyglucose positron emission tomography scans and magnetic resonance imaging scans at baseline and 3 years later. A subgroup of patients with Parkinson's disease who exhibited severe hyposmia at baseline showed more pronounced cognitive decline at the follow-up survey. By the end of the study, 10 of 44 patients with Parkinson's disease had developed dementia, all of whom had severe hyposmia at baseline. The multivariate logistic analysis identified severe hyposmia and visuoperceptual impairment as independent risk factors for subsequent dementia within 3 years. The patients with severe hyposmia had an 18.7-fold increase in their risk of dementia for each 1 SD (2.8) decrease in the score of odour stick identification test for Japanese. We also found an association between severe hyposmia and a characteristic distribution of cerebral metabolic decline, which was identical to that of dementia associated with Parkinson's disease. Furthermore, volumetric magnetic resonance imaging analyses demonstrated close relationships between olfactory dysfunction and the atrophy of focal brain structures, including the amygdala and other limbic structures. Together, our findings suggest that brain regions related to olfactory function are closely associated with cognitive decline and that severe hyposmia is a prominent clinical feature that predicts the subsequent development of Parkinson's disease dementia.
武田 篤：重度嗅覚障害はパーキンソン病認知症の前駆徴候である．臨床神経 2013；53:91-97.
H OKAZAKI, L E LIPKIN, S M ARONSON
Diffuse intracytoplasmic ganglionic inclusions (Lewy type) associated with progressive dementia and quadriparesis in flexion.
J Neuropathol Exp Neurol. 1961 Apr;20:237-44.
Abstract/Text
K Kosaka, S Oyanagi, M Matsushita, A Hori
Presenile dementia with Alzheimer-, Pick- and Lewy-body changes.
Acta Neuropathol. 1976 Nov 15;36(3):221-33.
Abstract/Text
An autopsy case of unclassifiable presenil dementia is reported. The outstanding pathological findings were as follows; 1. presence of senile plaques, neurofibrillary changes, Pick bodies, Hirano bodies, granulovacuolar degeneration of neurons, etc. 2. numerous Lewy bodies in the brain stem and diencephalon, 3. peculiar swollen neurons with intracytoplasmic, eosinophilic and argentophilic inclusions ("Lewy-like-bodies") in the cerebral cortices. Detailed study of the last mentioned inclusions indicates that they are almost identical to Lewy bodies, though there are some minor differences, in histochemical and electronmicroscopic findings. Nosologically, this case may represent either a combination of Alzheimer's disease, Pick's disease and idiopathic Parkinsonism with "Lewy-like-bodies" in the cerebral cortices, or a single disease. As far as we know, no similar case been reported.
K Kosaka
Lewy bodies in cerebral cortex, report of three cases.
Acta Neuropathol. 1978 May 24;42(2):127-34.
Abstract/Text
The histochemical and structural properties and the topographical distribution pattern of Lewy bodies in the cerebral cortex as well as in the brain stem and diencephalon were studied in three cases. The Lewy bodies in the cerebral cortex were found in the small or medium-sized neurons of the fifth and sixth layers, particularly in the anterior frontal, temporal, insular, and cingulate cortex, and showed minor differences in their histochemical and structural properties from typical Lewy bodies in the brain stem and diencephalon. By light microscopy they were more irregular in shape, less eosinophilic, less sharply demarcated, and did not have clear halos and central cores. From the ultrastructural aspect, the filaments in them did not radiate, but were arranged at random, and circular profiles were not associated in the central zone. This type of Lewy body was also distributed in the basal ganglia. A close relationship between Lewy bodies and monoamines in the cerebral cortex of our cases was not recognized. These three cases showed also concomitant senile changes, i.e., senile plaques and neurofibrillary tangles.
小阪憲司, 松下正明, 小柳新策, Mehraein P. “Lewy小体病”の臨床神経病理学的研究. 精神神経学雑誌. 1980 82(5):292-311.
M Yoshimura
Cortical changes in the parkinsonian brain: a contribution to the delineation of "diffuse Lewy body disease".
J Neurol. 1983;229(1):17-32.
Abstract/Text
K Kosaka, M Yoshimura, K Ikeda, H Budka
Diffuse type of Lewy body disease: progressive dementia with abundant cortical Lewy bodies and senile changes of varying degree--a new disease?
Clin Neuropathol. 1984 Sep-Oct;3(5):185-92.
Abstract/Text
The term Lewy body disease (LBD) was proposed earlier to describe a disease classified into three types (A, B, and C) according to the distributional pattern of Lewy bodies in the CNS. Group A (diffuse type of LBD) shows clinical symptoms of "dementia-parkinsonism syndrome". The most remarkable pathologic feature is the widespread appearance of numerous Lewy bodies not only in the brain stem and diencephalon (as in group C), but also in the cerebral cortex and basal ganglia, which is complicated by senile changes of various degrees. Group B is the transitional type between groups A and C. Group C (brain stem type of LBD) is identical with idiopathic Parkinson's disease. In this paper, 12 of our cases with diffuse type LBD were studied clinicopathologically and compared with eight similar cases in the literature. The neuropathologic substrate of progressive dementia in this disease is also discussed. LBD is a clinicopathologic entity; the diffuse type of LBD, a special form of this disease, presents mainly a presenile dementia.
K Kosaka
Diffuse Lewy body disease in Japan.
J Neurol. 1990 Jun;237(3):197-204.
Abstract/Text
Thirty-seven Japanese autopsy cases with diffuse Lewy body disease (DLBD) were reviewed from a clinicopathological viewpoint. Based on the neuropathological finding of whether or not many concomitant senile plaques (SPs) and/or neurofibrillary tangles (NFTs) are present. DLBD is divided into two forms: a common form and a pure form. In the common form not only numerous Lewy bodies but also many SPs and/or NFTs are found in the cerebral cortex, whereas in the pure form there are no or few senile changes. Of the 37 cases, 28 cases had the common form, and 9 had the pure form of DLBD. In the common form all cases had shown progressive cortical dementia in the presenile or senile period. About 60% of the cases began with memory disturbance, while 25% showed Parkinson's or Shy-Drager syndrome initially. Parkinson's syndrome, consisting mainly of muscular rigidity and akinesia, was usually marked in the later stage, although there were also 8 cases (28.6%) in which no parkinsonian symptoms were detected even in the terminal stage. On the other hand, almost all cases with the pure form of DLBD showed juvenile Parkinson's syndrome, followed by progressive cortical dementia, although there was one presenile case with mild dementia and Parkinson's syndrome. These Japanese cases are compared with cases reported in Western countries.
R H Perry, D Irving, G Blessed, A Fairbairn, E K Perry
Senile dementia of Lewy body type. A clinically and neuropathologically distinct form of Lewy body dementia in the elderly.
J Neurol Sci. 1990 Feb;95(2):119-39.
Abstract/Text
A dementing syndrome has been identified in a group of psychiatric cases aged 71-90 years, presenting initially with a subacute/acute confusional state, often fluctuating and associated with visual hallucinations and behavioural disturbances. Clinically, these cases did not meet criteria for a diagnosis of Alzheimer's disease, and many were assigned to the multiinfarct dementia group, although no significant ischaemic lesions were evident at autopsy. Mild extrapyramidal features were apparent in a number of cases but the characteristic clinical triad of Parkinson's disease, i.e., tremor, rigidity, and akinesia, was absent. Detailed neuropathological examination revealed Lewy body formation and selective neuronal loss in brain stem and other subcortical nuclei, accompanied by Lewy body formation in neo- and limbic cortex, at densities well below those previously reported in diffuse Lewy body disease. A variable degree of senile degenerative change was present; numerous senile plaques and minimal neurofibrillary tangles in most cases. Neither the clinical nor the neuropathological features of this group are typical of Parkinson's or Alzheimer's disease, but suggest a distinct neurodegenerative disorder, part of the Lewy body disease spectrum, in which mental symptoms predominate over motor disabilities and lead to eventual psychogeriatric hospital admission. In a sequential series of autopsies conducted on clinically assessed demented patients, neuropathological analysis has indicated that such cases may comprise up to 20% of a hospitalized population of demented old people over the age of 70 years, an observation clearly relevant to the diagnosis and management of dementia in the elderly.
L Hansen, D Salmon, D Galasko, E Masliah, R Katzman, R DeTeresa, L Thal, M M Pay, R Hofstetter, M Klauber
The Lewy body variant of Alzheimer's disease: a clinical and pathologic entity.
Neurology. 1990 Jan;40(1):1-8.
Abstract/Text
Thirty-six clinically diagnosed and pathologically confirmed Alzheimer's disease (AD) patients included 13 with cortical and subcortical Lewy bodies (LBs). The patients with LBs appeared to constitute a distinct neuropathologic and clinical subset of AD, the Lewy body variant (LBV). The LBV group showed gross pallor of the substantia nigra, greater neuron loss in the locus ceruleus, substantia nigra, and substantia innominata, lower neocortical ChAT levels, and fewer midfrontal tangles than did the pure AD group, along with a high incidence of medial temporal lobe spongiform vacuolization. Analysis of neuropsychological tests from 9 LBV subjects and 9 AD patients matched for age and degree of dementia revealed greater deficits in attention, fluency, and visuospatial processing in the LBV group. Similar comparisons of neurologic examinations showed a significant increase in masked facies; in addition there was an increase in essential tremor, bradykinesia, mild neck rigidity, and slowing of rapid alternating movements in the LBV group. Extremity rigidity, flexed posture, resting tremor, or other classic parkinsonian features were not characteristic of the LBV patient. In some cases, it may be possible to diagnose LBV premortem on the basis of the clinical and neuropsychological features.
S Kuzuhara, H Mori, N Izumiyama, M Yoshimura, Y Ihara
Lewy bodies are ubiquitinated. A light and electron microscopic immunocytochemical study.
Acta Neuropathol. 1988;75(4):345-53. doi: 10.1007/BF00687787.
Abstract/Text
The nature of Lewy bodies (LBs) in the brain stem and cerebral cortex in five cases of diffuse Lewy body disease and one case of Parkinson's disease with dementia were investigated immunocytochemically with various antibodies to cytoskeletal proteins, paired helical filaments (PHF) and ubiquitin. Antibodies to 200-kDa component of neurofilament, tau and PHF showed no significant reactions with most of LBs. Antibodies to high-molecular weight microtubule-associated proteins (HMWMAPs) moderately stained the periphery of a few of LBs. A monoclonal antibody to PHF (DF2) which recognizes ubiquitin, and polyclonal antibodies to ubiquitin immunostained virtually all of the typical and cortical LBs as intensely as Alzheimer's neurofibrillary tangles and senile plaque neurites: the periphery of LBs was darkly stained, whereas the central core of typical LBs and central zone of cortical LBs were less intensely stained or remained unstained. Immunoelectron microscopy of the LBs with DF2 revealed that immune reaction products were located on the filaments exclusively in the periphery of LBs, but not on those in the center. These findings suggest that both types of LBs are immunocytochemically indistinguishable despite some structural differences, and that peripherally located filaments in LBs are tagged with ubiquitin, an element required for the ATP-dependent proteolysis system in the cell. Antibodies to ubiquitin are the most useful marker of LBs ever known.
I G McKeith, D Galasko, K Kosaka, E K Perry, D W Dickson, L A Hansen, D P Salmon, J Lowe, S S Mirra, E J Byrne, G Lennox, N P Quinn, J A Edwardson, P G Ince, C Bergeron, A Burns, B L Miller, S Lovestone, D Collerton, E N Jansen, C Ballard, R A de Vos, G K Wilcock, K A Jellinger, R H Perry
Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop.
Neurology. 1996 Nov;47(5):1113-24.
Abstract/Text
Recent neuropathologic autopsy studies found that 15 to 25% of elderly demented patients have Lewy bodies (LB) in their brainstem and cortex, and in hospital series this may constitute the most common pathologic subgroup after pure Alzheimer's disease (AD). The Consortium on Dementia with Lewy bodies met to establish consensus guidelines for the clinical diagnosis of dementia with Lewy bodies (DLB) and to establish a common framework for the assessment and characterization of pathologic lesions at autopsy. The importance of accurate antemortem diagnosis of DLB includes a characteristic and often rapidly progressive clinical syndrome, a need for particular caution with neuroleptic medication, and the possibility that DLB patients may be particularly responsive to cholinesterase inhibitors. We identified progressive disabling mental impairment progressing to dementia as the central feature of DLB. Attentional impairments and disproportionate problem solving and visuospatial difficulties are often early and prominent. Fluctuation in cognitive function, persistent well-formed visual hallucinations, and spontaneous motor features of parkinsonism are core features with diagnostic significance in discriminating DLB from AD and other dementias. Appropriate clinical methods for eliciting these key symptoms are described. Brainstem or cortical LB are the only features considered essential for a pathologic diagnosis of DLB, although Lewy-related neurites, Alzheimer pathology, and spongiform change may also be seen. We identified optimal staining methods for each of these and devised a protocol for the evaluation of cortical LB frequency based on a brain sampling procedure consistent with CERAD. This allows cases to be classified into brainstem predominant, limbic (transitional), and neocortical subtypes, using a simple scoring system based on the relative distribution of semiquantitative LB counts. Alzheimer pathology is also frequently present in DLB, usually as diffuse or neuritic plaques, neocortical neurofibrillary tangles being much less common. The precise nosological relationship between DLB and AD remains uncertain, as does that between DLB and patients with Parkinson's disease who subsequently develop neuropsychiatric features. Finally, we recommend procedures for the selective sampling and storage of frozen tissue for a variety of neurochemical assays, which together with developments in molecular genetics, should assist future refinements of diagnosis and classification.
I G McKeith, D W Dickson, J Lowe, M Emre, J T O'Brien, H Feldman, J Cummings, J E Duda, C Lippa, E K Perry, D Aarsland, H Arai, C G Ballard, B Boeve, D J Burn, D Costa, T Del Ser, B Dubois, D Galasko, S Gauthier, C G Goetz, E Gomez-Tortosa, G Halliday, L A Hansen, J Hardy, T Iwatsubo, R N Kalaria, D Kaufer, R A Kenny, A Korczyn, K Kosaka, V M Y Lee, A Lees, I Litvan, E Londos, O L Lopez, S Minoshima, Y Mizuno, J A Molina, E B Mukaetova-Ladinska, F Pasquier, R H Perry, J B Schulz, J Q Trojanowski, M Yamada, Consortium on DLB
Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium.
Neurology. 2005 Dec 27;65(12):1863-72. doi: 10.1212/01.wnl.0000187889.17253.b1. Epub 2005 Oct 19.
Abstract/Text
The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.
C F Lippa, J E Duda, M Grossman, H I Hurtig, D Aarsland, B F Boeve, D J Brooks, D W Dickson, B Dubois, M Emre, S Fahn, J M Farmer, D Galasko, J E Galvin, C G Goetz, J H Growdon, K A Gwinn-Hardy, J Hardy, P Heutink, T Iwatsubo, K Kosaka, V M-Y Lee, J B Leverenz, E Masliah, I G McKeith, R L Nussbaum, C W Olanow, B M Ravina, A B Singleton, C M Tanner, J Q Trojanowski, Z K Wszolek, DLB/PDD Working Group
DLB and PDD boundary issues: diagnosis, treatment, molecular pathology, and biomarkers.
Neurology. 2007 Mar 13;68(11):812-9. doi: 10.1212/01.wnl.0000256715.13907.d3.
Abstract/Text
For more than a decade, researchers have refined criteria for the diagnosis of dementia with Lewy bodies (DLB) and at the same time have recognized that cognitive impairment and dementia occur commonly in patients with Parkinson disease (PD). This article addresses the relationship between DLB, PD, and PD with dementia (PDD). The authors agreed to endorse "Lewy body disorders" as the umbrella term for PD, PDD, and DLB, to promote the continued practical use of these three clinical terms, and to encourage efforts at drug discovery that target the mechanisms of neurodegeneration shared by these disorders of alpha-synuclein metabolism. We concluded that the differing temporal sequence of symptoms and clinical features of PDD and DLB justify distinguishing these disorders. However, a single Lewy body disorder model was deemed more useful for studying disease pathogenesis because abnormal neuronal alpha-synuclein inclusions are the defining pathologic process common to both PDD and DLB. There was consensus that improved understanding of the pathobiology of alpha-synuclein should be a major focus of efforts to develop new disease-modifying therapies for these disorders. The group agreed on four important priorities: 1) continued communication between experts who specialize in PDD or DLB; 2) initiation of prospective validation studies with autopsy confirmation of DLB and PDD; 3) development of practical biomarkers for alpha-synuclein pathologies; 4) accelerated efforts to find more effective treatments for these diseases.
Murat Emre, Dag Aarsland, Richard Brown, David J Burn, Charles Duyckaerts, Yoshikino Mizuno, Gerald Anthony Broe, Jeffrey Cummings, Dennis W Dickson, Serge Gauthier, Jennifer Goldman, Christopher Goetz, Amos Korczyn, Andrew Lees, Richard Levy, Irene Litvan, Ian McKeith, Warren Olanow, Werner Poewe, Niall Quinn, Christina Sampaio, Eduardo Tolosa, Bruno Dubois
Clinical diagnostic criteria for dementia associated with Parkinson's disease.
Mov Disord. 2007 Sep 15;22(12):1689-707; quiz 1837. doi: 10.1002/mds.21507.
Abstract/Text
Dementia has been increasingly more recognized to be a common feature in patients with Parkinson's disease (PD), especially in old age. Specific criteria for the clinical diagnosis of dementia associated with PD (PD-D), however, have been lacking. A Task Force, organized by the Movement Disorder Study, was charged with the development of clinical diagnostic criteria for PD-D. The Task Force members were assigned to sub-committees and performed a systematic review of the literature, based on pre-defined selection criteria, in order to identify the epidemiological, clinical, auxillary, and pathological features of PD-D. Clinical diagnostic criteria were then developed based on these findings and group consensus. The incidence of dementia in PD is increased up to six times, point-prevelance is close to 30%, older age and akinetic-rigid form are associated with higher risk. PD-D is characterized by impairment in attention, memory, executive and visuo-spatial functions, behavioral symptoms such as affective changes, hallucinations, and apathy are frequent. There are no specific ancillary investigations for the diagnosis; the main pathological correlate is Lewy body-type degeneration in cerebral cortex and limbic structures. Based on the characteristic features associated with this condition, clinical diagnostic criteria for probable and possible PD-D are proposed.
(c) 2007 Movement Disorder Society.
Bruno Dubois, David Burn, Christopher Goetz, Dag Aarsland, Richard G Brown, Gerald A Broe, Dennis Dickson, Charles Duyckaerts, Jefferey Cummings, Serge Gauthier, Amos Korczyn, Andrew Lees, Richard Levy, Irene Litvan, Yoshikuni Mizuno, Ian G McKeith, C Warren Olanow, Werner Poewe, Cristina Sampaio, Eduardo Tolosa, Murat Emre
Diagnostic procedures for Parkinson's disease dementia: recommendations from the movement disorder society task force.
Mov Disord. 2007 Dec;22(16):2314-24. doi: 10.1002/mds.21844.
Abstract/Text
A preceding article described the clinical features of Parkinson's disease dementia (PD-D) and proposed clinical diagnostic criteria for "probable" and "possible" PD-D. The main focus of this article is to operationalize the diagnosis of PD-D and to propose practical guidelines based on a two level process depending upon the clinical scenario and the expertise of the evaluator involved in the assessment. Level I is aimed primarily at the clinician with no particular expertise in neuropsychological methods, but who requires a simple, pragmatic set of tests that are not excessively time-consuming. Level I can be used alone or in concert with Level II, which is more suitable when there is the need to specify the pattern and the severity on the dementia of PD-D for clinical monitoring, research studies or pharmacological trials. Level II tests can also be proposed when the diagnosis of PD-D remains uncertain or equivocal at the end of a Level I evaluation. Given the lack of evidence-based standards for some tests when applied in this clinical context, we have tried to make practical and unambiguous recommendations, based upon the available literature and the collective experience of the Task Force. We accept, however, that further validation of certain tests and modifications in the recommended cut off values will be required through future studies.
2007 Movement Disorder Society
Ian G McKeith, Tanis J Ferman, Alan J Thomas, Frédéric Blanc, Bradley F Boeve, Hiroshige Fujishiro, Kejal Kantarci, Cristina Muscio, John T O'Brien, Ronald B Postuma, Dag Aarsland, Clive Ballard, Laura Bonanni, Paul Donaghy, Murat Emre, James E Galvin, Douglas Galasko, Jennifer G Goldman, Stephen N Gomperts, Lawrence S Honig, Manabu Ikeda, James B Leverenz, Simon J G Lewis, Karen S Marder, Mario Masellis, David P Salmon, John Paul Taylor, Debby W Tsuang, Zuzana Walker, Pietro Tiraboschi, prodromal DLB Diagnostic Study Group
Research criteria for the diagnosis of prodromal dementia with Lewy bodies.
Neurology. 2020 Apr 28;94(17):743-755. doi: 10.1212/WNL.0000000000009323. Epub 2020 Apr 2.
Abstract/Text
The prodromal phase of dementia with Lewy bodies (DLB) includes (1) mild cognitive impairment (MCI), (2) delirium-onset, and (3) psychiatric-onset presentations. The purpose of our review is to determine whether there is sufficient information yet available to justify development of diagnostic criteria for each of these. Our goal is to achieve evidence-based recommendations for the recognition of DLB at a predementia, symptomatic stage. We propose operationalized diagnostic criteria for probable and possible mild cognitive impairment with Lewy bodies, which are intended for use in research settings pending validation for use in clinical practice. They are compatible with current criteria for other prodromal neurodegenerative disorders including Alzheimer and Parkinson disease. Although there is still insufficient evidence to propose formal criteria for delirium-onset and psychiatric-onset presentations of DLB, we feel that it is important to characterize them, raising the index of diagnostic suspicion and prioritizing them for further investigation.
Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
