Parkinson Disease: Burn DJ

McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M, Anonymous00346. · Institute for Ageing and Health, University of Newcastle upon Tyne, UK. · Neurology. · Pubmed #16237129 No free full text.

Abstract: 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.

Burn DJ. · No affiliation provided · J Neurol Neurosurg Psychiatry. · Pubmed #17635975 No free full text.

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Burn DJ. · No affiliation provided · J Neurol Neurosurg Psychiatry. · Pubmed #17110742 No free full text.

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Burn DJ. · No affiliation provided · J Neurol Neurosurg Psychiatry. · Pubmed #14742580 links to  free full text

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Burn DJ. · No affiliation provided · J Neurol Neurosurg Psychiatry. · Pubmed #12185151 links to  free full text

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Ludolph AC, Kassubek J, Landwehrmeyer BG, Mandelkow E, Mandelkow EM, Burn DJ, Caparros-Lefebvre D, Frey KA, de Yebenes JG, Gasser T, Heutink P, Höglinger G, Jamrozik Z, Jellinger KA, Kazantsev A, Kretzschmar H, Lang AE, Litvan I, Lucas JJ, McGeer PL, Melquist S, Oertel W, Otto M, Paviour D, Reum T, Saint-Raymond A, Steele JC, Tolnay M, Tumani H, van Swieten JC, Vanier MT, Vonsattel JP, Wagner S, Wszolek ZK, Anonymous00107. · Department of Neurology, University of Ulm, Ulm, Germany. · Eur J Neurol. · Pubmed #19364361 No free full text.

Abstract: Tauopathies with parkinsonism represent a spectrum of disease entities unified by the pathologic accumulation of hyperphosphorylated tau protein fragments within the central nervous system. These pathologic characteristics suggest shared pathogenetic pathways and possible molecular targets for disease-modifying therapeutic interventions. Natural history studies, for instance, in progressive supranuclear palsy, frontotemporal dementia with parkinsonism linked to chromosome 17, corticobasal degeneration, and Niemann-Pick disease type C as well as in amyotrophic lateral sclerosis/Parkinson-dementia complex permit clinical characterization of the disease phenotypes and are crucial to the development and validation of biological markers for differential diagnostics and disease monitoring, for example, by use of neuroimaging or proteomic approaches. The wide pathologic and clinical spectrum of the tauopathies with parkinsonism is reviewed in this article, and perspectives on future advances in the understanding of the pathogenesis are given, together with potential therapeutic strategies.

Archibald NK, Clarke MP, Mosimann UP, Burn DJ. · Clinical Research Fellow, Clinical Ageing Research Unit, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, NE4 5PL, UK. · Brain. · Pubmed #19336464 No free full text.

Abstract: As a more complete picture of the clinical phenotype of Parkinson's disease emerges, non-motor symptoms have become increasingly studied. Prominent among these non-motor phenomena are mood disturbance, cognitive decline and dementia, sleep disorders, hyposmia and autonomic failure. In addition, visual symptoms are common, ranging from complaints of dry eyes and reading difficulties, through to perceptual disturbances (feelings of presence and passage) and complex visual hallucinations. Such visual symptoms are a considerable cause of morbidity in Parkinson's disease and, with respect to visual hallucinations, are an important predictor of cognitive decline as well as institutional care and mortality. Evidence exists of visual dysfunction at several levels of the visual pathway in Parkinson's disease. This includes psychophysical, electrophysiological and morphological evidence of disruption of retinal structure and function, in addition to disorders of 'higher' (cortical) visual processing. In this review, we will draw together work from animal and human studies in an attempt to provide an insight into how Parkinson's disease affects the retina and how these changes might contribute to the visual symptoms experienced by patients.

Emre M, Aarsland D, Brown R, Burn DJ, Duyckaerts C, Mizuno Y, Broe GA, Cummings J, Dickson DW, Gauthier S, Goldman J, Goetz C, Korczyn A, Lees A, Levy R, Litvan I, McKeith I, Olanow W, Poewe W, Quinn N, Sampaio C, Tolosa E, Dubois B. · Department of Neurology, Behavioral Neurology and Movement Disorders Unit, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey. · Mov Disord. · Pubmed #17542011 links to  free full text

Abstract: 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.

Warren NM, Burn DJ. · Institute for Ageing and Health, Newcastle General Hospital, Newcastle upon Tyne, UK. · Pract Neurol. · Pubmed #17430861 No free full text.

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Burn DJ. · Institute for Aging and Health, Wolfson Research Centre, Newcastle General Hospital, Newcastle, UK. · Curr Opin Neurol. · Pubmed #17102696 No free full text.

Abstract: PURPOSE OF REVIEW: The health and socioeconomic impacts of dementia with Lewy bodies and dementia associated with Parkinson's disease have become increasingly recognized. Whilst the nosological status of dementia with Lewy bodies has been better classified as 'Lewy body dementias', both conditions are now believed to represent a disease spectrum, characterized pathologically by synuclein protein and clinically by a variable admixture of cognitive, neuropsychiatric and extrapyramidal features. RECENT FINDINGS: Recent epidemiological studies are described and clinical and pathological similarities emphasized between dementia with Lewy bodies and Parkinson's disease. A number of investigational techniques are highlighted which have helped to better characterize dementia with Lewy bodies and discriminate it from Alzheimer's disease, whilst also shedding light upon the pathophysiology of both conditions. Finally, the therapeutic aspects of the Lewy body dementias will be considered, concentrating upon studies of the cholinesterase inhibitors. SUMMARY: The pathology underlying dementia with Lewy bodies and Parkinson's disease is heterogeneous, and is neither stereotyped in its topography nor its composition. Cholinesterase inhibitor drugs improve cognition and neuropsychiatric symptoms but the clinical response is unpredictable. Major future challenges are to better understand the pathophysiological basis underpinning the diseases, what determines clinical phenotypic expression and how disease-modifying therapies may best be developed and deployed.

Burn DJ. · Department of Neurology, Regional Neurosciences Centre, Newcastle General Hospital, University of Newcastle upon Tyne, United Kingdom. · J Neural Transm Suppl. · Pubmed #17017554 No free full text.

Abstract: This brief review deals with pathological aspects of dementia associated with Parkinson's disease (PDD). PDD has been variably linked with cortical Lewy body topography and density. alpha-Synuclein and Alzheimer-type pathology frequently co-exist, suggesting that a combination of pathology related to protein dysmetabolism, possibly with synergistic protein-protein interaction, underpins the cognitive impairment in PDD. Dementia may therefore ensue when a "toxic threshold" is reached, irrespective of the combination of pathologies involved in reaching that threshold. The nature of this putative protein-protein interaction needs to be further elucidated, and also whether there are specific clinical correlates of the pathological substrate. Serum and cerebrospinal fluid proteins or imaging techniques may be useful in future as biomarkers to identify the relative contribution of Lewy-related and Alzheimer-type pathology in a given case of PDD and to inform the rational use of drugs that can reduce alpha-synuclein aggregation and beta-amyloid production.

Burn DJ. · Regional Neurosciences Centre, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne, NE4 6BE, United Kingdom. · Curr Neurol Neurosci Rep. · Pubmed #16131416 No free full text.

Abstract: Dementia with Lewy bodies (DLB) presents to a range of specialists and involves a number of management challenges. The nosologic status of the disorder is controversial, especially its clinical overlap with Parkinson's disease-related dementia and its pathologic distinction from Alzheimer's disease. This article considers some of the controversies surrounding DLB with reference to recent literature. Emphasis is given to clinical topics, including the clinical phenomenology, differential diagnosis, and the treatment of core features of the disease.

Burn DJ, Tröster AI. · Department of Neurology, Regional Neurosciences Centre, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne NE4 6BE. · J Geriatr Psychiatry Neurol. · Pubmed #15312281 No free full text.

Abstract: This review deals with the range of neuropsychiatric problems that may arise from the use of medical and surgical therapies in the treatment of Parkinson's disease. As new approaches emerge, these problems are diversifying. Well-recognized drug-related complications include hallucinations and psychosis and the so-called dopamine-dysregulation syndrome. The etiology of these problems has not been fully established and is not clearly dose related, while the management can be difficult and needs to be tailored to the individual patient. Cholinergic and dopaminergic drugs may both influence cognitive function. The development of pharmacogenetics could improve the therapeutic ratio of medical approaches to PD in the future. The literature relating to the neuropsychiatric issues complicating the surgical treatment of Parkinson's disease is more recent and frequently suffers from methodological problems, lack of a systematic approach, and adequate patient follow-up. The emergence of neuropsychiatric problems in association with surgery has shed new light upon the pathophysiological mechanisms underpinning these symptoms. Depression, hypomania, euphoria, mirth, and hypersexuality have all been described following deep brain stimulation procedures, although most studies have concentrated upon the depressive features. Anxiety has been described only rarely to date. Fortunately, permanent cognitive complications appear to be rare. The optimal management approach for surgically related neuropsychiatric problems is unknown at present. Prospective multicenter studies would contribute significantly to resolving this therapeutic uncertainty.

Burn DJ, O'Brien JT. · Department of Neurology, Regional Neurosciences Centre, Newcastle General Hospital, United Kingdom. · Mov Disord. · Pubmed #14502661 No free full text.

Abstract: Neuropsychiatric symptoms, including dementia, frequently coexist with parkinsonian disorders and may cause diagnostic confusion as well as management problems. Functional imaging studies include single photon emission computerised tomography (SPECT), positron emission tomography (PET), proton magnetic resonance spectroscopy, diffusion tensor imaging, and functional magnetic resonance imaging. This review addresses the utility of these techniques, from the clinician's perspective, focusing on the most common causes of parkinsonism and cognitive impairment, Parkinson's disease with dementia, dementia with Lewy bodies, and Alzheimer's disease. The potential and limitations of these techniques for accurate and early diagnosis, monitoring disease progression, and establishing the pathophysiological basis underlying key clinical features are considered. The development of new probes for SPECT and PET cameras capable of labeling protein aggregates (e.g., beta-amyloid) will offer exciting new insights into the spatial and temporal pattern of pathophysiological processes. Longitudinal studies with clinicopathological correlation represent the "gold standard" for fully evaluating functional imaging techniques.

Burn DJ, McKeith IG. · Department of Neurology, Regional Neurosciences Centre, Newcastle General Hospital, United Kingdom. · Mov Disord. · Pubmed #14502659 No free full text.

Abstract: Dementia in Parkinson's disease (PDD) is a frequent and distressing complication with major consequences. Clinical and pathological features closely link PDD and dementia with Lewy bodies (DLB), suggesting they represent part of the same disease spectrum. Although dopaminergic deficiency primarily determines the akinetic-rigid symptoms of PDD and DLB, there is overwhelming evidence that cholinergic dysfunction underpins many of the cognitive impairments and psychotic features. Open-label studies have suggested that cholinesterase inhibitor drugs may exert positive effects upon all aspects of the neuropsychiatric syndrome in PDD and DLB but particularly apathy, anxiety, impaired attention, hallucinations, delusions, sleep disturbance, and cognitive test performance. Worsening of extrapyramidal motor features is reported only rarely. Initial double-blind, placebo-controlled studies in PDD and DLB have so far confirmed these encouraging results. Early identification of PD patients at greatest risk of developing dementia would permit early use of disease modifying treatments which represent the "golden fleece" management approach to these groups.

McKeith IG, Burn DJ, Ballard CG, Collerton D, Jaros E, Morris CM, McLaren A, Perry EK, Perry R, Piggott MA, O'Brien JT. · Institute for Ageing and Health, Wolfson Research Centre, Newcastle General Hospital, Newcastle, UK. · Semin Clin Neuropsychiatry. · Pubmed #12567332 No free full text.

Abstract: The objective was to summarize recent findings about the clinical features, diagnosis and investigation of dementia with Lewy (DLB) bodies, together with its neuropathology, neurochemistry and genetics. Dementia with Lewy bodies (DLB) is a primary, neurodegenerative dementia sharing clinical and pathological characteristics with both Parkinson's disease (PD) and Alzheimer's disease (AD). Antiubiquitin immunocytochemical staining, developed in the early 1990s, allowed the frequency and distribution of cortical LBs to be defined. More recently, alpha-synuclein antibodies have revealed extensive neuritic pathology in DLB demonstrating a neurobiological link with other "synucleinopathies" including PD and multiple system atrophy (MSA). The most significant correlates of cognitive failure in DLB appear to be with cortical LB and Lewy neurites (LNs) rather than Alzheimer type pathology. Clinical diagnostic criteria for DLB, published in 1996, have been subjected to several validation studies against autopsy findings. These conclude that although diagnostic specificity is high (range 79- 100%, mean 92%), sensitivity is lower (range 0- 83 %, mean, 49%). Improved methods of case detection are therefore required. Fluctuating impairments in attention, visual recognition and construction are more indicative of DLB than AD. Relative preservation of medial temporal lobe volume on structural MRI and the use of SPECT tracers for regional blood flow and the dopamine transporter are the most reliable current biomarkers for DLB. There are no genetic or CSF tests recommended for the diagnosis of DLB at present. Between 15 and 20% of all elderly demented cases reaching autopsy have DLB, making it the most common cause of degenerative dementia after AD. Exquisite, not infrequently fatal, sensitivity to neuroleptic drugs and encouraging reports of the effects of cholinesterase inhibitors on cognitive, psychiatric and neurological features, mean that an accurate diagnosis of DLB is more than merely of academic interest. Dementia developing late in the course of PD shares many of the same clinical and pathological characteristics.

Burn DJ. · Regional Neurosciences Centre, Newcastle General Hospital, Newcastle upon Tyne, UK. · Eur J Neurol. · Pubmed #12464121 No free full text.

Abstract: Depression in Parkinson's disease (PD) is a common complication, with a major impact on quality of life. Failure to recognize and treat depression can lead to premature and inappropriate discontinuation of antiparkinsonian therapies. Cited frequency for depression in PD varies between 2.7 and 70%. Methodological differences account for much of the disparity. The aetiology of depression in PD is complex, with 'tonic' (slowly changing and persistent) and 'phasic' (short-lived and fluctuating) components. Both depression and anxiety may predate the onset of the motor disorder by some years. Hedonistic homeostatic dysregulation is a cyclical mood disorder associated with excessive intake of dopaminergic therapies, inappropriate for the motor state. Negative affective symptoms occur on attempted reduction of medication, reinforcing the abnormal medication pattern. The Montgomery-Asberg Depression Rating Scale and the Hamilton Rating Scale for Depression have good diagnostic sensitivity and specificity for assessing depression in PD. There is a dearth of sizeable, placebo-controlled studies for evaluating drug treatment of depression in PD. Dopaminergic drugs have variable antidepressant properties. Selective serotonin reuptake inhibitors are currently the most commonly prescribed group of antidepressants in the depressed PD patient. Depression in the PD patient may be associated with a more rapid deterioration in cognitive and motor functions.

Burn DJ. · Neurology, Regional Neurosciences Centre, Newcastle General Hospital, and University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom. · Mov Disord. · Pubmed #12112190 No free full text.

Abstract: This review examines the frequency of depression complicating Parkinson's disease (PD), its aetiology and clinical features, and also how it may be recognised and treated. Studies investigating the frequency of depression in PD have yielded figures ranging between 2.7% and 70%. Methodological differences account for much of the disparity. The aetiology of depression in PD is complex, and probably relates to both biological and exogenous factors. Dysfunction of multiple neurotransmitter systems, including the serotonergic system, may be involved. Mood disturbances resulting from deep brain stimulation of the subthalamic nucleus may provide a fruitful area for future research, and assist our understanding of the neural networks involved in mediating depression. Several recent studies have confirmed that depression in the PD patient is a major determinant of quality of life and that this is closely related to dysfunction in other clinically important health areas. The validity for many existing scales in the screening, diagnosis, and monitoring of depression in the PD patient has not been established. The Montgomery-Asberg Depression Rating Scale and the Hamilton Rating Scale for Depression appear to have good diagnostic sensitivity and specificity when compared with DSM-IV criteria. Recommendations for the optimal drug treatment of depression in PD are difficult to give, due to an inexplicable dearth of sizeable, placebo-controlled studies. A majority of physicians would probably now opt for a selective serotonin reuptake inhibitor in the depressed PD patient. There is no good evidence that these drugs are associated with a worsening of motor features, but they should probably not be coprescribed with selegiline, because of the risk of causing a potentially serious serotonin syndrome. Several studies have suggested that depression in the PD patient is associated with a more rapid deterioration in cognitive and motor functions, perhaps as a surrogate marker for more extensive brainstem cell loss.

Bhatia K, Brooks DJ, Burn DJ, Clarke CE, Grosset DG, MacMahon DG, Playfer J, Schapira AH, Stewart D, Williams AC, Anonymous00286. · University Department of Clinical Neurology, Institute of Neurology, London. · Hosp Med. · Pubmed #11530583 No free full text.

Abstract: New data on diagnosis, drug therapy, surgery and psychosocial concerns have emerged since the publication of the 1998 Guidelines for the Management of Parkinson's Disease. This article reviews new data and addresses issues left unanswered in the previous guidelines.

Taylor JP, Rowan EN, Lett D, O'Brien JT, McKeith IG, Burn DJ. · Institute for Ageing and Health, Wolfson Research Centre, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne NE4 6BE, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #18586866 No free full text.

Abstract: BACKGROUND: Postural instability gait difficulty (PIGD) motor phenotype in Parkinson's disease (PD) is associated with a faster rate of cognitive decline than in tremor dominant cases and may be a risk factor for incident dementia. People with PD display attentional deficits; however, it is not clear whether attentional deficits in patients with non-demented PD are associated with (i) PIGD phenotype and/or (ii) subsequent cognitive decline. AIMS: (i) To examine rates of cognitive decline (Mini-Mental State Examination (MMSE) and Cambridge Cognitive Examination (CAMCOG)) over 3 years in subjects with non-demented PD aged over 65 years, (ii) using Cognitive Drug Research computerised assessment test battery, determine the rate of change in power of attention (PoA) scores over time (sum of mean choice reaction time, simple reaction time and digit vigilance reaction time scores), (iii) determine whether the PIGD phenotype is associated with changes in PoA and (iv) establish whether baseline PoA is associated with subsequent cognitive decline. RESULTS: 14 subjects (38%) were classified as PIGD motor phenotype at baseline. Cognitive decline was greater in PIGD compared with non-PIGD subjects (p < or = 0.02). PIGD phenotype was not associated with baseline PoA score although it was associated with subsequent worsening in PoA (mean PoA increase/year: non-PIGD subjects 11.4 ms; PIGD subjects 244.0 ms; p = 0.01). Higher baseline PoA scores were associated with greater cognitive decline (MMSE, p = 0.03; CAMCOG, p = 0.05) independent of PIGD status. CONCLUSION: PIGD phenotype and attention deficits are independently associated with a greater rate of cognitive decline in patients with non-demented PD. We propose that subtle attentional deficits in patients with non-demented PD predict subsequent cognitive impairment.

Barone P, Burn DJ, van Laar T, Hsu C, Poewe W, Lane RM. · Dipartimento di Scienze Neurologiche, Università Federico II di Napoli, Naples, Italy. · Mov Disord. · Pubmed #18581467 No free full text.

Abstract: The effects of rivastigmine versus placebo in Parkinson's disease dementia (PDD) patients with elevated or normal/low plasma homocysteine were determined. In this prospective analysis of a 24-week, randomly assigned, placebo-controlled study of rivastigmine in PDD, subpopulations comprised patients with plasma homocysteine >or=14 micromol/L (elevated) or <14 micromol/L (normal/low). Coprimary outcomes were the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Alzheimer Disease Cooperative Society-Clinical Global Impression of Change (ADCS-CGIC). Secondary outcomes included additional measures of cognition, including attention and executive function, daily function, and neuropsychiatric symptoms. Adverse events (AEs) were monitored. In total, 342 of 541 patients provided samples for analysis, from which 72% had elevated plasma homocysteine. Hyperhomocysteinemic patients showed treatment differences (rivastigmine vs. placebo) of 4.0 on ADAS-cog and 0.7 on ADCS-CGIC (both P < 0.01), and significant treatment differences on secondary outcomes. Rivastigmine- and placebo-treated hyperhomocysteinemic patients (16.5% and 14.6%) discontinued the study because of AEs. Patients with normal/low homocysteine showed no treatment differences on primary or secondary outcomes (1.4 on the ADAS-cog and 0.1 on ADCS-CGIC, both P = ns); 16.7% and 10.3% rivastigmine- and placebo-treated patients discontinued because of AEs. Elevated homocysteine was associated with greater rivastigmine treatment differences than normal/low homocysteine.

Molloy SA, Rowan EN, O'Brien JT, McKeith IG, Wesnes K, Burn DJ. · Institute of Ageing and Health, Wolfson Research Centre, Newcastle General Hospital, Newcastle upon Tyne, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #16952917 No free full text.

Abstract: BACKGROUND: Levodopa (L-dopa) is the gold standard treatment for Parkinson's disease, but a lack of clear efficacy combined with a perceived liability to neuropsychiatric side effects has limited L-dopa use in patients with parkinsonism and dementia. Therefore, the effect of L-dopa on the cognitive profile of dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD) is unclear. AIM: To ascertain the acute and long-term effects of L-dopa on aspects of attention and cognition in patients with DLB and PDD, and to compare these with the effects in Parkinson's disease. METHOD: Baseline cognitive and motor function was assessed off L-dopa in patients with Parkinson's disease (n = 22), PDD (n = 27) and DLB (n = 11) using standard "bedside" measures and a computerised programme detecting reaction times and accuracy. All patients then underwent an acute L-dopa challenge with subsequent subjective and objective analysis of alertness, verbal recall, reaction times and accuracy. The same parameters were measured after 3 months on L-dopa to assess the prolonged effect. RESULTS: Acute L-dopa challenge considerably improved motor function and subjective alertness in all patients without compromising either reaction times or accuracy, but increased fluctuations were noted in both groups with dementia. Neuropsychiatric scores improved in patients with Parkinson's disease both with and without dementia on L-dopa at 3 months. Although patients with Parkinson's disease also had better mean global cognitive function at this time, mean verbal attention and memory deteriorated, and patients with PDD had slower reaction times in some tests. No patient had a marked deterioration over this time. Patients with DLB did not experience any adverse cognitive or neuropsychiatric effects after 3 months of L-dopa treatment. CONCLUSION: The use of L-dopa in patients with parkinsonism with dementia does not adversely affect cognitive function.

Pakrasi S, Thomas A, Mosimann UP, Cousins DA, Lett D, Burn DJ, O'Brien JT, McKeith IG. · Institute for Ageing and Health, Wolfson Research Centre, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne, UK. · Int J Geriatr Psychiatry. · Pubmed #16858742 No free full text.

Abstract: INTRODUCTION: There is little data on stopping cholinesterase inhibitors in Dementia with Lewy bodies (DLB). Equally, it is not known if increasing the dose of cholinesterase inhibitors may help neuropsychiatric symptoms in advanced DLB. METHOD: We conducted an open label trial with donepezil involving 16 patients with LBD when the dose was reduced and treatment stopped over 4 weeks. Another 7 patients were given a trial of an increased dose of donepezil (15 mg) to resolve rehyphen;emergent neuropsychiatric symptoms. RESULTS: The slow discontinuation protocol was well tolerated in advanced DLB. Five of the seven patients given a trial of a higher dose of donepezil were rated as clinically improved after 12 weeks treatment. CONCLUSION: Cholinesterase inhibitors can be discontinued slowly in advanced DLB. Increasing the dose of donepezil may be of benefit to some patients with DLB who experience a recurrence in their neuropsychiatric symptoms.

Colloby SJ, O'Brien JT, Fenwick JD, Firbank MJ, Burn DJ, McKeith IG, Williams ED. · Institute for Ageing and Health, Newcastle University, Wolfson Research Centre, Newcastle General Hospital, Westgate Road, Newcastle- upon-Tyne NE4 6BE, UK. · Neuroimage. · Pubmed #15528096 No free full text.

Abstract: 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 <or= 0.05 corrected, the SPM[t] maps showed a significant bilateral reduced uptake in caudate, anterior and posterior putamen in DLB and PD subjects compared to AD subjects and controls. Significant reduction in binding was also observed bilaterally in the caudate nucleus in AD compared to controls. Striatal binding was indistinguishable between patients with DLB and PD. To investigate the usefulness of SPM as a decision aid in the evaluation of visually rated normal and abnormal patterns of uptake, receiver operator characteristic (ROC) curve analysis was performed using data from single-subject SPMs. The areas under the ROC curves were greater than 0.92, demonstrating comparable discriminatory power with visual rating. The automated voxel-based approach is a viable alternative to the subjective and often time-consuming method of ROI and, in addition, may have the potential to differentiate between normal and abnormal patterns of uptake in a manner similar to visual inspection.

Firbank MJ, Colloby SJ, Burn DJ, McKeith IG, O'Brien JT. · Institute for Ageing and Health, Newcastle University, Wolfson Research Centre, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne, NE4 6BE, UK. · Neuroimage. · Pubmed #14568499 No free full text.

Abstract: 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.