Parkinson Disease: Emre M

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.

Lippa CF, Emre M. · No affiliation provided · Neurology. · Pubmed #17159092 No free full text.

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Emre M. · Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey. · Parkinsonism Relat Disord. · Pubmed #18267283 No free full text.

Abstract: Dementia affects approximately one-third of all patients with Parkinson's disease. Currently there is no treatment to halt or reverse the disease progression. Symptomatic treatment approaches are based on substituting neurotransmitter deficits or ameliorating associated behavioral symptoms. The most prominent deficits are cholinergic, and treatment with cholinesterase inhibitors (ChE-I) has been shown to provide some benefits in cognitive and behavioral symptoms without undue worsening in motor symptoms. Based on a large, randomized, placebo controlled trial, the ChE-I rivastigmine has been approved for the treatment of dementia associated with PD.

Dubois B, Burn D, Goetz C, Aarsland D, Brown RG, Broe GA, Dickson D, Duyckaerts C, Cummings J, Gauthier S, Korczyn A, Lees A, Levy R, Litvan I, Mizuno Y, McKeith IG, Olanow CW, Poewe W, Sampaio C, Tolosa E, Emre M. · INSERM-UPMC UMRS 610, Federation of Neurology, AP-HP, Salpêtrière Hospital; Université Paris6, Paris, France. · Mov Disord. · Pubmed #18098298 links to  free full text

Abstract: 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.

Emre M, Cummings JL, Lane RM. · Department of Neurology, Istanbul Faculty of Medicine, Istanbul, Turkey. · J Alzheimers Dis. · Pubmed #17656830 No free full text.

Abstract: Parkinson's disease dementia (PDD) and Alzheimer's disease (AD) are both characterized by cognitive abnormalities, neuropsychiatric symptoms, and cholinergic deficits. We reviewed data from large, placebo-controlled clinical trials conducted with rivastigmine in patients with PDD and AD to evaluate similarities and differences in response to treatment. In placebo groups, AD patients appeared to show more rapid cognitive decline than those with PDD. Treatment effects (rivastigmine versus placebo) on cognitive performance over 6 months were quantitatively similar in both populations, but qualitatively different: in AD, cognitive abilities were stabilized by rivastigmine compared to declines in placebo groups, whereas in PDD symptomatic improvements above baseline drove treatment effects while placebo patients had limited change. On activities of daily living, stabilization (rather than improvement) was observed in both dementia types. A more aggressive course of placebo decline, and greater treatment differences (rivastigmine versus placebo), were seen in sub-populations of both PDD and AD patients with hallucinations at baseline. The safety and adverse event profiles were comparable in the two populations. In conclusion, the magnitude of effect with rivastigmine versus placebo is quantitatively comparable in patients with AD and PD, but the treatment effect tended to be one of stabilization in AD, while in PDD improvements over baseline were seen. In both populations, hallucinations may identify patients who are likely to be more treatment-responsive.

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.

Lippa CF, Duda JE, Grossman M, Hurtig HI, Aarsland D, Boeve BF, Brooks DJ, Dickson DW, Dubois B, Emre M, Fahn S, Farmer JM, Galasko D, Galvin JE, Goetz CG, Growdon JH, Gwinn-Hardy KA, Hardy J, Heutink P, Iwatsubo T, Kosaka K, Lee VM, Leverenz JB, Masliah E, McKeith IG, Nussbaum RL, Olanow CW, Ravina BM, Singleton AB, Tanner CM, Trojanowski JQ, Wszolek ZK, Anonymous00243. · Department of Neurology, Drexel University College of Medicine, Philadelphia, PA 19102, USA. · Neurology. · Pubmed #17353469 No free full text.

Abstract: 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.

Hanagasi HA, Emre M. · Behavioral Neurology and Movement Disorders Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, 34390 Capa/Istanbul, Turkey. · Fundam Clin Pharmacol. · Pubmed #15810893 No free full text.

Abstract: Behavioural symptoms such as anxiety, depression and psychosis are common in Parkinson's disease (PD), and dementia occurs in about 90% of the patients. These symptoms can be more disabling than the motor dysfunction and they negatively impact quality of life, increase caregiver distress and are more frequently associated with nursing home placement. Depression can be treated with counselling and pharmacotherapy. Tricyclic antidepressants or selective serotonin reuptake inhibitors are widely used, but there is still need for controlled clinical trials. Management of psychosis in PD is complex and includes elimination of identifiable risk factors, reduction of polypharmacy and administration of atypical neuroleptics, which can alleviate psychotic symptoms without worsening motor functions. Clozapine is the best documented atypical neuroleptic shown to be effective against psychosis in PD patients. Cholinesterase inhibitors may prove additional benefit in psychotic PD patients. Recent evidence from small double-blind and open-label trials suggests that cholinesterase inhibitors may be effective in the treatment of dementia associated with PD.

Emre M. · Istanbul Faculty of Medicine, Department of Neurology, Behavioral Neurology and Movement Disorders Unit, Capa Istanbul, Turkey. · Curr Opin Neurol. · Pubmed #15247534 No free full text.

Abstract: PURPOSE OF REVIEW: Dementia in Parkinson's disease is increasingly being recognized. A number of studies have recently appeared on the epidemiology, clinical features, pathological correlations and treatment of dementia in Parkinson's disease. The purpose of this article is to provide an overview of recent findings on dementia associated with Parkinson's disease, from February 2003 to the present. RECENT FINDINGS: The cumulative prevalence of dementia in Parkinson's disease can be as high as 78%; dementia is especially prevalent in older patients. The profile of dementia seems to be different from that of Alzheimer's disease and similar to that of dementia with Lewy bodies. Clinicopathological correlation studies have suggested that dementia correlates best with Lewy bodies in certain limbic and cortical areas, but not all patients with sufficient Lewy bodies for a pathological diagnosis of dementia with Lewy bodies are demented. Cholinergic deficits in the cerebral cortex can be shown with in-vivo imaging studies, and seem to be more severe than in Alzheimer's disease. Several small studies with three different cholinesterase inhibitors suggest that these drugs can be effective in the treatment of PD dementia. SUMMARY: Dementia is highly prevalent in Parkinson's disease. The prototype of dementia in Parkinson's disease is a dysexecutive syndrome with impaired attention, executive functions and secondarily impaired memory. Neurochemically the most significant deficit seems to be cholinergic; dementia seems to correlate best with cortical and limbic Lewy bodies. Preliminary evidence suggests that cholinesterase inhibitors may be effective in Parkinson's disease dementia, and the results of large-scale, randomized and controlled studies are awaited to confirm these findings.

Emre M. · Istanbul Faculty of Medicine, Department of Neurology, Behavioral Neurology and Movement Disorders Unit, Istanbul University, Capa Istanbul, Turkey. · Mov Disord. · Pubmed #14502658 No free full text.

Abstract: Parkinson's disease (PD) is frequently associated with mental dysfunction. Domain-specific cognitive deficits are ubiquitous, and although they may not be clinically apparent in all patients, they are demonstrable by neuropsychological testing. Dementia is less frequent but is present significantly more in PD patients than in controls, with a cumulative prevalence rate up to 40% and up to six-fold increased incidence. Cognitive impairment mainly involves executive and visuospatial functions; memory is secondarily impaired with relatively preserved recognition. Qualitatively, the neuropsychological profile of dementia encompasses the same type of deficits found in nondemented PD patients. The dementia seen in PD, therefore, can be described as a dysexecutive syndrome combined with visuospatial dysfunction and behavioural symptoms. Dopaminergic, noradrenergic, serotoninergic, and cholinergic deficits have all been described as the underlying neurochemical impairment, but the strongest evidence exists for a cholinergic dysfunction. Involvement of brainstem nuclei, limbic structures, and cerebral cortex have been suggested as the site, and Lewy body (LB) degeneration and Alzheimer-type changes as the type of pathology underlying the mental dysfunction in PD. Although there is still some controversy as to the site and type of pathology, recent evidence suggests that LB-type degeneration in limbic structures and cerebral cortex, with consequent synaptic and cell loss, is the main pathological state associated with dementia in PD.

Emre M. · Department of Neurology, Istanbul Faculty of Medicine, Istanbul, Turkey. <> · Lancet Neurol. · Pubmed #12849211 No free full text.

Abstract: 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.

Burn D, Emre M, McKeith I, De Deyn PP, Aarsland D, Hsu C, Lane R. · Regional Neuroscience Center, Newcastle General Hospital, Newcastle-upon-Tyne, United Kingdom. · Mov Disord. · Pubmed #16960863 No free full text.

Abstract: 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.

Poewe W, Wolters E, Emre M, Onofrj M, Hsu C, Tekin S, Lane R, Anonymous00178. · Innsbruck Medical University, Innsbruck, Austria. · Mov Disord. · Pubmed #16229010 No free full text.

Abstract: In patients with dementia associated with Parkinson's disease (PD), the efficacy and safety of rivastigmine, an inhibitor of acetylcholinesterase and butyrylcholinesterase, were previously demonstrated in a 24-week double-blind placebo-controlled trial. Our objective was to determine whether benefits were sustained over the long term. Following the double-blind trial, all patients were permitted to enter an active treatment extension study, during which they received rivastigmine 3-12 mg/day. Standard safety assessments were performed. Efficacy assessments included the Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog) and other measures of cognition, daily function, neuropsychiatric symptoms, and executive function. Of 433 patients who completed the double-blind trial, 334 entered and 273 completed the active treatment extension. At 48 weeks, the mean ADAS-cog score for the whole group improved by 2 points above baseline. Placebo patients switching to rivastigmine for the active treatment extension experienced a mean cognitive improvement similar to that of the original rivastigmine group during the double-blind trial. The adverse event profile was comparable to that seen in the double-blind trial. Long-term rivastigmine treatment appeared well tolerated and may provide sustained benefits in dementia associated with PD patients who remain on treatment for up to 48 weeks.

Emre M, Aarsland D, Albanese A, Byrne EJ, Deuschl G, De Deyn PP, Durif F, Kulisevsky J, van Laar T, Lees A, Poewe W, Robillard A, Rosa MM, Wolters E, Quarg P, Tekin S, Lane R. · Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey. · N Engl J Med. · Pubmed #15590953 links to  free full text

Abstract: 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.

Goetz CG, Emre M, Dubois B. · Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA. · Ann Neurol. · Pubmed #19127578 No free full text.

Abstract: Cognitive impairment is common in Parkinson's disease (PD) and involves attentional, executive, visuospatial, and memory dysfunctions. Dementia is more frequently encountered in PD than in age-matched control populations, and whereas operational definitions of Alzheimer's disease and dementia with Lewy bodies have been developed, Parkinson's disease dementia (PD-D) has remained undefined. The Movement Disorder Society developed a task force to define and develop diagnostic guidelines for PD-D. This effort was based on existing descriptive studies with special emphasis on drawing distinction among Alzheimer's disease, dementia with Lewy bodies and PD-related cognitive impairment without dementia whenever possible. The second goal was to provide practical diagnostic procedures to diagnose PD-D. This effort emphasized available bedside tools that do not require neuropsychological expertise to administer or interpret. This work recently has been completed, and two primary articles have been published. The suggested clinical diagnostic criteria for PD-D involve four domains and are anchored in core features, associated clinical features, features that make the diagnosis uncertain, and features that are not compatible with the diagnosis of PD-D. When all four criteria are satisfactorily met, probable PD-D is designated; when the first and last criteria are met, but clinical characteristics are atypical or uncertainty factors exist, possible PD-D is designated. Whereas these definitions are operative and subject to change based on future data, they are based on widely available tests. The inclusion criteria can be applied internationally and in multicenter research on treatment interventions, clinicopathological correlations, and studies of cognitive and other nonmotor elements of PD.

Oertel W, Poewe W, Wolters E, De Deyn PP, Emre M, Kirsch C, Hsu C, Tekin S, Lane R. · Department of Neurology, Philipps University, Marburg, Germany. · Drug Saf. · Pubmed #18095748 No free full text.

Abstract: BACKGROUND AND AIM: Rivastigmine is now widely approved for the treatment of mild to moderately severe dementia in Parkinson's disease (PDD). However, since anticholinergic drugs have a role in the management of tremor in patients with Parkinson's disease (PD), concerns have been raised that the use of cholinergic drugs might worsen PD. The current analyses were performed to examine the potential of rivastigmine to affect tremor and other motor symptoms in patients with PDD. METHODS: The safety profile of rivastigmine was evaluated using a database from a 24-week, randomized, double-blind, placebo-controlled trial in 541 PDD patients (362 randomized to rivastigmine, 179 to placebo), and 334 PDD patients who subsequently entered an open-label 24-week extension on rivastigmine. RESULTS: During the double-blind trial, the adverse event (AE) of emerging or worsening tremor was reported in 10.2% of patients in the rivastigmine group, compared with 3.9% in the placebo group (p = 0.012). Tremor was most frequently reported during the titration phase of rivastigmine treatment, although this was not reflected in total motor Unified Parkinson's Disease Rating Scale (UPDRS) part III scores. Dose dependence of this AE was not observed. At the end of the double-blind phase, six (1.7%) rivastigmine-treated patients had discontinued the study because of tremor. In the open-label extension in which all patients received rivastigmine, tremor was reported by 6.9% of patients: 3.8% and 12.2% of whom had previously received double-blind rivastigmine and placebo, respectively (p = 0.006), suggesting that first exposure to rivastigmine leads to a transient increase in tremor. Three (0.9%) of the 334 patients who entered the open-label extension phase discontinued because of tremor. Incidences of worsening parkinsonism, bradykinesia and rigidity were all <5% in both treatment groups (all p-values not statistically significant, rivastigmine vs placebo). In the 48-week observation of rivastigmine treatment, there was no evidence of adverse long-term motor outcomes. Post-hoc analysis showed that similar improvements in the symptoms of dementia, including the ability to perform activities of daily living, were seen regardless of whether exacerbation of tremor was reported during the study. CONCLUSION: Rivastigmine did not induce clinically significant exacerbation of motor dysfunction in patients with PDD. Rest tremor incidence as an AE was a transient phenomenon during dose titration of rivastigmine. There was no indication that exposure to long-term rivastigmine was associated with a worsening of PD.

Ehrt U, Brønnick K, De Deyn PP, Emre M, Tekin S, Lane R, Aarsland D. · Norwegian Centre for Movement Disorders, Stavanger University Hospital, Norway. · Int J Geriatr Psychiatry. · Pubmed #17393542 No free full text.

Abstract: BACKGROUND: About 40% of the patients with Parkinson's disease (PD) have depressive symptoms, either major depression (MD) or subthreshold depression. Depression was found to be associated with age and age at onset of PD, female gender, more severe parkinsonism, in particular with left-sided and akinetic-rigid symptoms, more functional impairment and cognitive impairment.However, the findings are inconsistent and partly contradictory and most of the studies focused on major depression in PD without dementia.The aim of this study was to examine the relationship between subthreshold depression and other clinical features in 538 PD patients with dementia but without MD drawn from a randomized, placebo-controlled multicentre trial of rivastigmine in PD. RESULTS: One hundred and sixteen patients (21%) had subthreshold depression. Depression was associated with a younger age and age at onset and female gender, but not with severity of parkinsonism, cognition or activities of daily living or laterality of motor symptoms. However, in male patients, an association between depression and left-sided parkinsonism was found. CONCLUSION: In contrast to previous findings in PD patients with major depression but without dementia, we found no relationship between subthreshold depression and other clinical symptoms in patients with PDD.

Bronnick K, Emre M, Lane R, Tekin S, Aarsland D. · Norwegian Centre for Movement Disorders, Stavanger University Hospital, Helse Stavanger, Norway. · J Neurol Neurosurg Psychiatry. · Pubmed #17287236 No free full text.

Abstract: OBJECTIVE: To compare the profile of cognitive impairment in Alzheimer's disease (AD) with dementia associated with Parkinson's disease (PDD). METHODS: Neuropsychological assessment was performed in 488 patients with PDD and 488 patients with AD using the Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog). Logistic regression analysis was used to investigate whether the diagnosis could be accurately predicted from the cognitive profile. Additionally, the cognitive profiles were compared with a normative group using standardised effect sizes (Cohen's d). RESULTS: Diagnosis was predicted from the cognitive profile, with an overall accuracy of 74.7%. Poor performance of the AD patients on the orientation test in ADAS-cog best discriminated between the groups, followed by poor performance of the PDD patients on the attentional task in MMSE. Both groups showed memory impairment, AD patients performing worse than PDD patients. CONCLUSION: The cognitive profile in PDD differs significantly from that in AD. Performance on tests of orientation and attention are best in differentiating the groups.

Aarsland D, Brønnick K, Ehrt U, De Deyn PP, Tekin S, Emre M, Cummings JL. · Centre for Clinical Neuroscience Research, Stavanger University Hospital, Stavanger, Norway. · J Neurol Neurosurg Psychiatry. · Pubmed #16820421 No free full text.

Abstract: OBJECTIVE: To explore the profile of neuropsychiatric symptoms in patients with dementia associated with Parkinson's disease (PDD). METHODS: 537 patients with PDD drawn from an international multicentre clinical trial of rivastigmine were assessed using the 10-item Neuropsychiatric Inventory (NPI). A cluster analysis was used to investigate the inter-relationship of NPI items. Associations between the clusters and demographic and clinical variables were analysed. RESULTS: 89% of the patients presented at least one symptom on the NPI, 77% had two or more symptoms and 64% had at least one symptom with a score > or = 4. The most common symptoms were depression (58%), apathy (54%), anxiety (49%) and hallucinations (44%). Patients with more severe dementia and advanced Parkinson's disease had more neuropsychiatric symptoms. Nearly 60% of the care givers reported at least one NPI symptom to be of at least moderate severe distress. Five NPI clusters were identified: one group with few and mild symptoms (52%); a mood cluster (11%, high scores on depression, anxiety and apathy); apathy (24%; high apathy and low scores on other items); agitation (5%, high score on agitation and high total NPI score); and a psychosis cluster (8%; high scores on delusions and hallucinations). The psychosis and agitation clusters had the lowest Mini-Mental State Examination score and the highest Unified Parkinson's Disease Rating Scale and care giver distress scores. CONCLUSION: Neuropsychiatric symptoms are common in patients with PDD. The profile of these symptoms differs from that in other types of dementia. Subgroups with different neuropsychiatric profiles were identified. These subgroups may be associated with distinct neurobiological changes, which should be explored in future studies.

Bronnick K, Ehrt U, Emre M, De Deyn PP, Wesnes K, Tekin S, Aarsland D. · Psychiatric Clinic, Stavanger University Hospital, Helse Stavanger, Post Box 8100, 4068 Stavanger, Norway. · J Neurol Neurosurg Psychiatry. · Pubmed #16801351 No free full text.

Abstract: OBJECTIVE: To investigate the effects of attentional deficits on activities of daily living (ADL) in patients with dementia associated with Parkinson's disease (PDD). METHOD: 461 patients were assessed neuropsychologically. Factor analyses were used to differentiate attention from other cognitive functions and to differentiate different aspects of ADL functions. The effects of the attentional measure on ADL were examined using sequential multiple regression, controlling for age, sex, education, severity of motor symptoms and other cognitive functions. RESULTS: Three cognitive factors were identified, with one factor emerging as a measure of vigilance and focused attention. This factor predicted different aspects of ADL status even after controlling for motor functions and other cognitive factors. The attention factor was the single strongest cognitive predictor of ADL status, matching the strength of the effects of motor functions on ADL status. CONCLUSION: Impaired attention is an important determinant of ADL functions in patients with PDD.

Alves G, Larsen JP, Emre M, Wentzel-Larsen T, Aarsland D. · The Norwegian Center for Movement Disorders, Stavanger, Norway. · Mov Disord. · Pubmed #16637023 No free full text.

Abstract: The objective of this study was to assess the temporal relationship between changes in predominant motor symptoms and incident dementia in Parkinson's disease (PD). A community-based sample of 171 nondemented patients with PD was followed prospectively and examined at baseline and after 4 and 8 years. The motor subtype of Parkinsonism was classified into tremor-dominant (TD), indeterminate, or postural instability gait difficulty (PIGD) subtype at each visit, based on defined items in the Unified Parkinson's Disease Rating Scale, subscales II and III. Dementia was diagnosed according to DSM-III-R criteria, based on clinical interview, cognitive rating scales, and neuropsychological examination. Logistic regression was used to analyze the relationship between subtype of Parkinsonism and dementia. Transition from TD to PIGD subtype was associated with a more than threefold increase in the rate of Mini-Mental State Examination decline. Compared to patients with persistent TD or indeterminate subtype, the odds ratio for dementia was 56.7 (95% CI: 4.0-808.4; P = 0.003) for patients changing from TD or indeterminate subtype to PIGD subtype, and 80.0 (95% CI: 4.6-1400.1; P = 0.003) for patients with persistent PIGD subtype. Patients with TD subtype at baseline did not become demented until they developed PIGD subtype, and dementia did not occur among patients with persistent TD subtype of Parkinsonism. In a substantial proportion of PD patients who develop postural instability and gait disorder during the course of the disease, this transition is associated with accelerated cognitive decline and highly increased risk for subsequent dementia. These findings raise the question whether PIGD and dementia share common or parallel neuropathology.

Serdaroglu P, Hanagasi H, Tasli H, Emre M. · Department of Neurology, Faculty of Medicine, Istanbul University, Istanbul, Turkey. · Acta Myol. · Pubmed #16312141 No free full text.

Abstract: Absence of parkin has been shown to cause the downturned wing phenotype and severe disruption of myofibrils and mitochondrial abnormalities in parkin null mutant drosophila. The present report refers to studies on 3 patients with autosomal recessive Parkinson's disease with mild histopathological changes in muscle and a 'G' deletion at the exon9/intron9 junction or exon 3 deletion in the parkin gene. Using an antibody against a peptide corresponding to sequence number 305-323 of the human parkin protein it was demonstrated that parkin was expressed in skeletal muscle of these patients and that its distribution was similar to that in normal muscles. The mild nature of the histopathological changes, especially in the young patients, in the presence of parkin mutations may be due to residual E3-ubiquitin ligase activity of the mutant protein, to existence of muscle-specific splice-variants or to the relative functional insignificance of parkin in human muscle fibres. Further investigation of parkin expression in skeletal muscle is warranted.

Wesnes KA, McKeith I, Edgar C, Emre M, Lane R. · Cognitive Drug Research, Goring-on-Thames, United Kingdom. · Neurology. · Pubmed #16301500 No free full text.

Abstract: In a 24-week, randomized, double-blind, placebo-controlled, multicenter study of rivastigmine, 487 patients with dementia associated with Parkinson disease underwent assessment of attention on the Cognitive Drug Research computerized cognitive assessment system before dosing and 16 and 24 weeks later. Significant benefits of rivastigmine over placebo were seen on all aspects of attention assessed: sustained attention, focused attention, consistence of responding, and central processing speed.

Hanagasi HA, Ayribas D, Baysal K, Emre M. · Istanbul University, Istanbul Faculty of Medicine, Department of Neurology, Behavioral Neurology and Movement Disorders Unit, Istanbul, Turkey. · Int J Neurosci. · Pubmed #15809215 No free full text.

Abstract: A possible role of mitochondrial respiratory chain dysfunction in the pathogenesis of sporadic Parkinson's disease (PD) has been described. There are only a few reports concerning mitochondrial involvement in familial Parkinson's disease. The present study investigated mitochondrial complex I-IV activity in patients with sporadic and familial PD, compared to controls. Platelets were isolated from venous blood and platelet mitochondria were obtained through sonication and differential centrifugation. Complex I, II/III, and IV activities were measured in 17 patients with family history of Parkinson's disease (PDF), 15 patients with sporadic Parkinson disease (PDS), and 17 age-matched, healthy controls. The mitochondrial enzyme activities did not differ significantly between patient groups and controls. In addition, there was no correlation between mitochondrial complex activities and age, severity of disease, or age at onset of disease in the patient groups. In this study, the data indicate no significant differences in mitochondrial complex I-IV activities in PDF and PDS.

Gershanik O, Emre M, Bernhard G, Sauer D. · Hospital Frances La Rioja 951, Buenos Aires, Argentina. · Prog Neuropsychopharmacol Biol Psychiatry. · Pubmed #14499313 No free full text.

Abstract: The combination of entacapone with levodopa is effective in the treatment of Parkinson's disease (PD), providing significant improvements in 'on' time and Unified Parkinson's Disease Rating Scale (UPDRS) motor and ADL scores in controlled clinical trials. This multicentre, open-label study was designed to further evaluate the effectiveness of levodopa combined with entacapone 200 mg in routine clinical practice. Patients experiencing end-of-dose wearing-off were treated for 8 weeks (treatment phase), with an optional extension phase up to 20 weeks. The primary efficacy parameter was the Investigators' Global Assessment of Change; secondary efficacy parameters included UPDRS, 'off' time (from patient diaries), Patients' Global Assessment of Change, quality of life (QoL), SF-36 Health Assessment Questionnaire and Parkinson's Disease Questionnaire 39 (PDQ-39). Of the 479 patients who entered this study, 427 (89.1%) completed the treatment phase and 374 (78.1%) continued into the extension phase. Based on the Investigators' Assessment of Change, 380 (79.7%) patients showed an improvement with entacapone during the treatment phase. This improvement was maintained into the extension phase, and at Week 20, 301 (82.2%) patients continued to show an improvement. A positive treatment effect with entacapone was also seen with all secondary efficacy parameters, including QoL. Mean change in the total PDQ-39 scores showed improvements from baseline of -4.0 score points to the end of the treatment phase (n=182) and -3.1 score points at the end of the extension phase (n=152). Entacapone in combination with levodopa was generally well tolerated: 40 patients (8.4%) discontinued treatment due to adverse events (AEs) by the end of the extension phase. This study in a daily clinical practice setting confirmed the efficacy of coadministering entacapone with levodopa shown in controlled clinical trials and suggests that the combination is useful in improving the disability and QoL in patients with PD.