Measuring mild cognitive impairment in patients with Parkinson's disease

We examined the frequency of Parkinson disease with mild cognitive impairment (PD‐MCI) and its subtypes and the accuracy of 3 cognitive scales for detecting PD‐MCI using the new criteria for PD‐MCI proposed by the Movement Disorders Society. Nondemented patients with Parkinson's disease completed a clinical visit with the 3 screening tests followed 1 to 3 weeks later by neuropsychological testing. Of 139 patients, 46 met Level 2 Task Force criteria for PD‐MCI when impaired performance was based on comparisons with normative scores. Forty‐two patients (93%) had multi‐domain MCI. At the lowest cutoff levels that provided at least 80% sensitivity, specificity was 44% for the Montreal Cognitive Assessment and 33% for the Scales for Outcomes in Parkinson's Disease‐Cognition. The Mini‐Mental State Examination could not achieve 80% sensitivity at any cutoff score. At the highest cutoff levels that provided specificity of at least 80%, sensitivities were low (≤44%) for all tests. When decline from estimated premorbid levels was considered evidence of cognitive impairment, 110 of 139 patients were classified with PD‐MCI, and 103 (94%) had multi‐domain MCI. We observed dramatic differences in the proportion of patients who had PD‐MCI using the new Level 2 criteria, depending on whether or not decline from premorbid level of intellectual function was considered. Recommendations for methods of operationalizing decline from premorbid levels constitute an unmet need. Among the 3 screening tests examined, none of the instruments provided good combined sensitivity and specificity for PD‐MCI. Other tests recommended by the Task Force Level 1 criteria may represent better choices, and these should be the subject of future research. © 2013 Movement Disorder SocietyPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98243/1/mds25426.pd

Detection of emotions in Parkinson's disease using higher order spectral features from brain's electrical activity

Non-motor symptoms in Parkinson's disease (PD) involving cognition and emotion have been progressively receiving more attention in recent times. Electroencephalogram (EEG) signals, being an activity of central nervous system, can reflect the underlying true emotional state of a person. This paper presents a computational framework for classifying PD patients compared to healthy controls (HC) using emotional information from the brain's electrical activity

The effects of cognitive reserve and lifestyle on cognition and dementia in Parkinson's disease-a longitudinal cohort study

OBJECTIVE: Cognitive reserve theory seeks to explain the observed mismatch between the degree of brain pathology and clinical manifestations. Early-life education, midlife social and occupational activities and later-life cognitive and social interactions are associated with a more favourable cognitive trajectory in older people. Previous studies of Parkinson's disease (PD) have suggested a possible role for the effects of cognitive reserve, but further research into different proxies for cognitive reserve and longitudinal studies is required. This study examined the effects of cognitive lifestyle on cross-sectional and longitudinal measures of cognition and dementia severity in people with PD. METHODS: Baseline assessments of cognition, and of clinical, social and demographic information, were completed by 525 participants with PD. Cognitive assessments were completed by 323 participants at 4-year follow-up. Cognition was assessed using the measures of global cognition dementia severity. Cross-sectional and longitudinal serial analyses of covariance for cognition and binomial regression for dementia were performed. RESULTS: Higher educational level, socio-economic status and recent social engagement were associated with better cross-sectional global cognition. In those with normal cognition at baseline, higher educational level was associated with better global cognition after 4 years. Increasing age and low levels of a measure of recent social engagement were associated with an increased risk of dementia. CONCLUSIONS: Higher cognitive reserve has a beneficial effect on performance on cognitive tests and a limited effect on cognitive decline and dementia risk in PD

Diagnosis and management of Parkinson's disease dementia

Parkinson's disease (PD) has long been considered predominantly a motor disorder. However, its frequent association with dementia, which contributes significantly to the morbidity and mortality of the condition, is gaining increasing recognition. PD dementia (PDD) has a unique clinical profile and neuropathology, distinct from Alzheimer's disease (AD). Cholinergic deficits, a feature of both AD and PDD, underlie the rationale for cholinesterase inhibitor therapy in both conditions. In clinical practice, it is important that PDD should be recognised and appropriately treated. This review aims to outline the recently proposed clinical diagnostic criteria for PDD and to summarise the guidelines/recommendations published since 2006 on the use of cholinesterase inhibitors in the management of PDD. Although the cholinesterase inhibitor rivastigmine has recently been approved for the management of PDD, there remains a need for the development of novel therapies that can affect key mechanisms of the disease or prevent/delay patients with PD and mild cognitive impairment from progressing to PDD

In vivo cholinergic basal forebrain atrophy predicts cognitive decline in de novo Parkinson’s disease

Cognitive impairments are a prevalent and disabling non-motor complication of Parkinson’s disease, but with variable expression and progression. The onset of serious cognitive decline occurs alongside substantial cholinergic denervation, but imprecision of previously available techniques for in vivo measurement of cholinergic degeneration limit their use as predictive cognitive biomarkers. However, recent developments in stereotactic mapping of the cholinergic basal forebrain have been found useful for predicting cognitive decline in prodromal stages of Alzheimer’s disease. These methods have not yet been applied to longitudinal Parkinson’s disease data. In a large sample of people with de novo Parkinson’s disease (n = 168), retrieved from the Parkinson’s Progressive Markers Initiative database, we measured cholinergic basal forebrain volumes, using morphometric analysis of T1-weighted images in combination with a detailed stereotactic atlas of the cholinergic basal forebrain nuclei. Using a binary classification procedure, we defined patients with reduced basal forebrain volumes (relative to age) at baseline, based on volumes measured in a normative sample (n = 76). Additionally, relationships between the basal forebrain volumes at baseline, risk of later cognitive decline, and scores on up to 5 years of annual cognitive assessments were assessed with regression, survival analysis and linear mixed modelling. In patients, smaller volumes in a region corresponding to the nucleus basalis of Meynert were associated with greater change in global cognitive, but not motor scores after 2 years. Using the binary classification procedure, patients classified as having smaller than expected volumes of the nucleus basalis of Meynert had ∼3.5-fold greater risk of being categorized as mildly cognitively impaired over a period of up to 5 years of follow-up (hazard ratio = 3.51). Finally, linear mixed modelling analysis of domain-specific cognitive scores revealed that patients classified as having smaller than expected nucleus basalis volumes showed more severe and rapid decline over up to 5 years on tests of memory and semantic fluency, but not on tests of executive function. Thus, we provide the first evidence that volumetric measurement of the nucleus basalis of Meynert can predict early cognitive decline. Our methods therefore provide the opportunity for multiple-modality biomarker models to include a cholinergic biomarker, which is currently lacking for the prediction of cognitive deterioration in Parkinson’s disease. Additionally, finding dissociated relationships between nucleus basalis status and domain-specific cognitive decline has implications for understanding the neural basis of heterogeneity of Parkinson’s disease-related cognitive decline

Selective Molecular Alterations in the Autophagy Pathway in Patients with Lewy Body Disease and in Models of α-Synucleinopathy

Lewy body disease is a heterogeneous group of neurodegenerative disorders characterized by α-synuclein accumulation that includes dementia with Lewy bodies (DLB) and Parkinson's Disease (PD). Recent evidence suggests that impairment of lysosomal pathways (i.e. autophagy) involved in α-synuclein clearance might play an important role. For this reason, we sought to examine the expression levels of members of the autophagy pathway in brains of patients with DLB and Alzheimer's Disease (AD) and in α-synuclein transgenic mice.By immunoblot analysis, compared to controls and AD, in DLB cases levels of mTor were elevated and Atg7 were reduced. Levels of other components of the autophagy pathway such as Atg5, Atg10, Atg12 and Beclin-1 were not different in DLB compared to controls. In DLB brains, mTor was more abundant in neurons displaying α-synuclein accumulation. These neurons also showed abnormal expression of lysosomal markers such as LC3, and ultrastructural analysis revealed the presence of abundant and abnormal autophagosomes. Similar alterations were observed in the brains of α-synuclein transgenic mice. Intra-cerebral infusion of rapamycin, an inhibitor of mTor, or injection of a lentiviral vector expressing Atg7 resulted in reduced accumulation of α-synuclein in transgenic mice and amelioration of associated neurodegenerative alterations.This study supports the notion that defects in the autophagy pathway and more specifically in mTor and Atg7 are associated with neurodegeneration in DLB cases and α-synuclein transgenic models and supports the possibility that modulators of the autophagy pathway might have potential therapeutic effects

Mechanisms of Hybrid Oligomer Formation in the Pathogenesis of Combined Alzheimer's and Parkinson's Diseases

Background: Misfolding and pathological aggregation of neuronal proteins has been proposed to play a critical role in the pathogenesis of neurodegenerative disorders. Alzheimer’s disease (AD) and Parkinson’s disease (PD) are frequent neurodegenerative diseases of the aging population. While progressive accumulation of amyloid b protein (Ab) oligomers has been identified as one of the central toxic events in AD, accumulation of a-synuclein (a-syn) resulting in the formation of oligomers and protofibrils has been linked to PD and Lewy body Disease (LBD). We have recently shown that Ab promotes a-syn aggregation and toxic conversion in vivo, suggesting that abnormal interactions between misfolded proteins might contribute to disease pathogenesis. However the molecular characteristics and consequences of these interactions are not completely clear. Methodology/Principal Findings: In order to understand the molecular mechanisms involved in potential Ab/a-syn interactions, immunoblot, molecular modeling, and in vitro studies with a-syn and Ab were performed. We showed in vivo in the brains of patients with AD/PD and in transgenic mice, Ab and a-synuclein co-immunoprecipitate and form complexes. Molecular modeling and simulations showed that Ab binds a-syn monomers, homodimers, and trimers, forming hybrid ringlike pentamers. Interactions occurred between the N-terminus of Ab and the N-terminus and C-terminus of a-syn. Interacting a-syn and Ab dimers that dock on the membrane incorporated additional a-syn molecules, leading to th

Cognitive impairment in patients with Parkinson’s disease: profiles and implications for prognosis

Objectives: The main objective of the present thesis was to explore cognitive impairment in patients with Parkinson’s disease (PD), focussing on non-demented patients and elucidating cognitive profile, the course and predictive power of cognitive impairment for the development of dementia. Methods: The sample of 139 patients with PD was drawn from an epidemiological study of PD performed in Rogaland County, Norway in 1993. In 1997, the survivors performed a baseline evaluation consisting of neurological, psychiatric and neuropsychological assessments. They were re-assessed 4 years later with the same test-battery. A group of 38 healthy elderly controls performed the same neuropsychological test battery at baseline, in order to obtain normative data. PD was diagnosed according to explicit and generally accepted criteria based on clinical examination. The cognitive assessment consisted of a battery of neuropsychological tests assessing visual memory (Benton Visual Retention Test, multiple choice version), visuospatial abilities (Judgement of Line Orientation), and executive functions (Stroop Word Test), as well as of two screening instruments: the Mini Mental Status Examination (MMSE) and Dementia Rating Scale (DRS). Dementia in PD was diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised (DSM- III-R) criteria based on a semi-structured clinical caregiver-based interview and the results of the neuropsychological tests. The diagnosis of mild cognitive impairment (MCI) was made according to a modified version of the criteria proposed by Petersen et al 2001. Results: Fifty-five percent of the PD patients without dementia were cognitively impaired. Impairment on the Stroop Word Test was associated with an increased risk for incident dementia. Thirtyeight PD patients (52.7%) who fulfilled the criteria for MCI were identified. The progression rate to dementia after 4 years was 60% in subjects with MCI, compared to only 20% among the cognitively intact PD patients. Finally, cognitive heterogeneity was found both in patients with MCI and with dementia: In both groups, the majority exhibited a predominantly executive impairment (i.e. “subcortical” cognitive profile), although a considerable proportion had a predominantly memory impairment (i.e. “cortical” cognitive profile). Conclusions: These findings show that cognitive impairment is common even in non-demented patients with PD, and that MCI is an early manifestation of the dementia in PD. The cognitive profiles indicate that in most patients with PD, fronto-subcortical changes are the main contributing factor to dementia, whereas in other patients, cortical and hippocampal changes predominate