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Background: Cognitive reserve (CR) is considered a protective factor for cognitive function and may explain interindividual differences of cognitive performance given similar levels of neurodegeneration, e.g., in Alzheimer´s disease. Recent evidence suggests that CR is also relevant in Parkinson's disease (PD)., Objective: We aimed to explore the role of life-stage specific CR for overall cognition and specific cognitive domains cross-sectionally and longitudinally in PD., Methods: The cross-sectional analysis with data from the DEMPARK/LANDSCAPE study included 81 individuals without cognitive impairment (PD-N) and 87 individuals with mild cognitive impairment (PD-MCI). Longitudinal data covered 4 years with over 500 observations. CR was operationalized with the Lifetime of Experiences Questionnaire (LEQ), capturing the complexity of lifestyle activities across distinct life-stages. Cognition was assessed using a comprehensive neuropsychological test battery., Results: Higher LEQ scores, particularly from mid- and late-life, were observed in PD-N compared to PD-MCI [F(1,153) = 4.609, p = .033, η p 2  = 0.029]. They were significantly associated with better cognitive performance (0.200 ≤ β ≤ 0.292). Longitudinally, linear mixed effect models (0.236 ≤ marginal R 2  ≤ 0.441) revealed that LEQ scores were positively related to cognitive performance independent of time. However, the decline in overall cognition and memory over time was slightly more pronounced with higher LEQ scores., Conclusions: This study emphasizes the association between complex lifestyle activities and cognition in PD. Data indicate that while CR might be related to a delay of cognitive decline, individuals with high CR may experience a more pronounced drop in overall cognition and memory. Future studies will have to replicate these findings, particularly regarding domain-specific effects and considering reverse causal mechanisms., (© 2024. The Author(s).)

Background and Objectives: In Parkinson disease (PD), Alzheimer disease (AD) copathology is common and clinically relevant. However, the longitudinal progression of AD CSF biomarkers-β-amyloid 1-42 (Aβ 42 ), phosphorylated tau 181 (p-tau 181 ), and total tau (t-tau)-in PD is poorly understood and may be distinct from clinical AD. Moreover, it is unclear whether CSF p-tau 181 and serum neurofilament light (NfL) have added prognostic utility in PD, when combined with CSF Aβ 42 . First, we describe longitudinal trajectories of biofluid markers in PD. Second, we modified the AD β-amyloid/tau/neurodegeneration (ATN) framework for application in PD (ATN PD ) using CSF Aβ 42 (A), p-tau 181 (T), and serum NfL (N) and tested ATN PD prediction of longitudinal cognitive decline in PD., Methods: Participants were selected from the Parkinson's Progression Markers Initiative cohort, clinically diagnosed with sporadic PD or as controls, and followed up annually for 5 years. Linear mixed-effects models (LMEMs) tested the interaction of diagnosis with longitudinal trajectories of analytes (log transformed, false discovery rate [FDR] corrected). In patients with PD, LMEMs tested how baseline ATN PD status (AD [A+T+N±] vs not) predicted clinical outcomes, including Montreal Cognitive Assessment (MoCA; rank transformed, FDR corrected)., Results: Participants were 364 patients with PD and 168 controls, with comparable baseline mean (±SD) age (patients with PD = 62 ± 10 years; controls = 61 ± 11 years]; Mann-Whitney Wilcoxon: p = 0.4) and sex distribution (patients with PD = 231 male individuals [63%]; controls = 107 male individuals [64%]; χ 2 : p = 1). Patients with PD had overall lower CSF p-tau 181 (β = -0.16, 95% CI -0.23 to -0.092, p = 2.2e-05) and t-tau than controls (β = -0.13, 95% CI -0.19 to -0.065, p = 4e-04), but not Aβ 42 ( p = 0.061) or NfL ( p = 0.32). Over time, patients with PD had greater increases in serum NfL than controls (β = 0.035, 95% CI 0.022 to 0.048, p = 9.8e-07); slopes of patients with PD did not differ from those of controls for CSF Aβ 42 ( p = 0.18), p-tau 181 ( p = 1), or t-tau ( p = 0.96). Using ATN PD , PD classified as A+T+N± (n = 32; 9%) had worse cognitive decline on global MoCA (β = -73, 95% CI -110 to -37, p = 0.00077) than all other ATN PD statuses including A+ alone (A+T-N-; n = 75; 21%)., Discussion: In patients with early PD, CSF p-tau 181 and t-tau were low compared with those in controls and did not increase over 5 years of follow-up. Our study shows that classification using modified ATN PD (incorporating CSF Aβ 42 , CSF p-tau 181 , and serum NfL) can identify biologically relevant subgroups of PD to improve prediction of cognitive decline in early PD.

Introduction: Isolated/idiopathic rapid eye movement sleep behavior disorder (iRBD) is a powerful early predictor of dementia with Lewy bodies (DLB) and Parkinson's disease (PD). This provides an opportunity to directly observe the evolution of prodromal DLB and to identify which cognitive variables are the strongest predictors of evolving dementia., Methods: IRBD participants (n = 754) from 10 centers of the International RBD Study Group underwent annual neuropsychological assessment. Competing risk regression analysis determined optimal predictors of dementia. Linear mixed-effect models determined the annual progression of neuropsychological testing., Results: Reduced attention and executive function, particularly performance on the Trail Making Test Part B, were the strongest identifiers of early DLB. In phenoconverters, the onset of cognitive decline began up to 10 years prior to phenoconversion. Changes in verbal memory best differentiated between DLB and PD subtypes., Discussion: In iRBD, attention and executive dysfunction strongly predict dementia and begin declining several years prior to phenoconversion., Highlights: Cognitive decline in iRBD begins up to 10 years prior to phenoconversion. Attention and executive dysfunction are the strongest predictors of dementia in iRBD. Decline in episodic memory best distinguished dementia-first from parkinsonism-first phenoconversion., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Extracellular vesicles (EVs) may propagate and modulate Alzheimer's disease (AD) pathology. We aimed to comprehensively characterize the proteome of cerebrospinal fluid (CSF) EVs to identify proteins and pathways altered in AD., Methods: CSF EVs were isolated by ultracentrifugation (Cohort 1) or Vn96 peptide (Cohort 2) from non-neurodegenerative controls (n = 15, 16) and AD patients (n = 22, 20, respectively). EVs were subjected to untargeted quantitative mass spectrometry-based proteomics. Results were validated by enzyme-linked immunosorbent assay (ELISA) in Cohorts 3 and 4, consisting of controls (n = 16, n = 43, (Cohort3, Cohort4)), and patients with AD (n = 24, n = 100)., Results: We found > 30 differentially expressed proteins in AD CSF EVs involved in immune-regulation. Increase of C1q levels in AD compared to non-demented controls was validated by ELISA (∼ 1.5 fold, p (Cohort 3) = 0.03, p (Cohort 4) = 0.005)., Discussion: EVs may be utilized as a potential biomarker and may play a so far unprecedented role in immune-regulation in AD., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objective: We examine the trajectories of and the dynamic interplay between cognitive functioning and depressive symptoms in patients with Parkinson's disease (PD) in comparison to healthy controls (HC) from an intraindividual perspective., Method: The DeNoPa study is a single-center, observational, longitudinal study with biennial follow-ups over 8 years. The present analyses are based on 123 PD (79 male) and 107 HC (64 male) with a mean age of 64.1 years ( SD = 8.3). PD and HC completed a battery of neuropsychological tests and scales assessing depressive symptoms. We used a random-intercept cross-lagged panel model (RI-CLPM) to study their trajectories and the dynamic interplay., Results: Cognitive abilities of PD were on average d = -0.67 worse at baseline and d = -1.22 at 8-years follow-up in comparison to HC. Depressive symptoms in PD showed large variability and followed a U -shaped trajectory. From an intraindividual perspective, greater impairments in cognitive abilities were subsequently associated with increased depressive symptoms ( b = -0.60, p = .03), whereas the effect in the opposite direction was not significant., Conclusions: We found indication that a decline on a global composite scale of cognition can be seen as a precursor of depressive symptoms in patients with PD. To counter cognitive losses and the subsequent mood deterioration, patient education and early cognitive (and behavioral) enrichment seem promising candidates for treatment. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Importance: Plasma phosphorylated tau (p-tau) has proven to be an accurate biomarker for Alzheimer disease (AD) pathologic characteristics, offering a less expensive and less invasive alternative to cerebrospinal fluid (CSF) and positron emission tomography biomarkers for amyloid-β and tau. Alzheimer disease comorbid pathologic characteristics are common and are associated with more rapid cognitive decline in patients with dementia with Lewy bodies (DLB); therefore, it is anticipated that plasma p-tau concentrations may have utility in assessing cognitive impairment in individuals with this disorder., Objective: To measure the concentrations of plasma p-tau (p-tau181 and p-tau231) and evaluate their associations with cognitive decline in individuals with probable DLB., Design, Setting, and Participants: This multicenter longitudinal cohort study included participants from the European-DLB (E-DLB) Consortium cohort enrolled at 10 centers with harmonized diagnostic procedures from January 1, 2002, to December 31, 2020, with up to 5 years of follow-up. A total of 1122 participants with plasma samples were available. Participants with acute delirium or terminal illness and patients with other previous major psychiatric or neurologic disorders were excluded, leaving a cohort of 987 clinically diagnosed participants with probable DLB (n = 371), Parkinson disease (n = 204), AD (n = 207), as well as healthy controls (HCs) (n = 205)., Main Outcomes and Measures: The main outcome was plasma p-tau181 and p-tau231 levels measured with in-house single molecule array assays. The Mini-Mental State Examination (MMSE) was used to measure cognition., Results: Among this cohort of 987 patients (512 men [51.9%]; mean [SD] age, 70.0 [8.8] years), patients with DLB did not differ significantly regarding age, sex, or years of education from those in the AD group, but the DLB group was older than the HC group and included more men than the AD and HC groups. Baseline concentrations of plasma p-tau181 and p-tau231 in patients with DLB were significantly higher than those in the HC group but lower than in the AD group and similar to the Parkinson disease group. Higher plasma concentrations of both p-tau markers were found in a subgroup of patients with DLB with abnormal CSF amyloid-β42 levels compared with those with normal levels (difference in the groups in p-tau181, -3.61 pg/mL; 95% CI, -5.43 to -1.79 pg/mL; P = .049; difference in the groups in p-tau231, -2.51 pg/mL; 95% CI, -3.63 to -1.39 pg/mL; P = .02). There was no difference between p-tau181 level and p-tau231 level across confirmed AD pathologic characteristcs based on reduced Aβ42 level in CSF in individuals with DLB. In DLB, a significant association was found between higher plasma p-tau181 and p-tau231 levels and lower MMSE scores at baseline (for p-tau181, -0.092 MMSE points; 95% CI, -0.12 to -0.06 MMSE points; P = .001; for p-tau231, -0.16 MMSE points; 95% CI, -0.21 to -0.12 MMSE points; P < .001), as well as more rapid MMSE decline over time. Plasma p-tau181 level was associated with a decrease of -0.094 MMSE points per year (95% CI, -0.144 to -0.052 MMSE points; P = .02), whereas plasma p-tau231 level was associated with an annual decrease of -0.130 MMSE points (95% CI, -0.201 to -0.071 MMSE points; P = .02), after adjusting for sex and age., Conclusions and Relevance: This study suggests that plasma p-tau181 and p-tau231 levels may be used as cost-effective and accessible biomarkers to assess cognitive decline in individuals with DLB.

Background: Parkinson's disease (PD) is associated with various non-motor symptoms, including cognitive deterioration., Objective: Here, we used data from the DEMPARK/LANDSCAPE cohort to describe the association between progression of cognitive profiles and the PD motor phenotypes: postural instability and gait disorder (PIGD), tremor-dominant (TR-D), and not-determined (ND)., Methods: Demographic, clinical, and neuropsychological six-year longitudinal data of 711 PD-patients were included (age: M = 67.57; 67.4% males). We computed z-transformed composite scores for a priori defined cognitive domains. Analyses were controlled for age, gender, education, and disease duration. To minimize missing data and drop-outs, three-year follow-up data of 442 PD-patients was assessed with regard to the specific role of motor phenotype on cognitive decline using linear mixed modelling (age: M = 66.10; 68.6% males)., Results: Our study showed that in the course of the disease motor symptoms increased while MMSE and PANDA remained stable in all subgroups. After three-year follow-up, significant decline of overall cognitive performance for PIGD-patients were present and we found differences for motor phenotypes in attention (β= -0.08, SE = 0.003, p < 0.006) and memory functions showing that PIGD-patients deteriorate per months by -0.006 compared to the ND-group (SE = 0.003, p = 0.046). Furthermore, PIGD-patients experienced more often difficulties in daily living., Conclusion: Over a period of three years, we identified distinct neuropsychological progression patterns with respect to different PD motor phenotypes, with early executive deficits yielding to a more amnestic profile in the later course. Here, in particular PIGD-patients worsened over time compared to TR-D and ND-patients, highlighting the greater risk of dementia for this motor phenotype.

Introduction: The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) is a renowned cognitive test battery, which has been extended in its German version to the CERAD-Plus including tests of executive functions and processing speed. The most commonly used total score (TS) is based on the restricted CERAD version and reflects the sum of selected raw-values (Chandler et al., 2005). The CERAD-Plus extensions might be of particular diagnostic utility for cognitive assessments in Parkinson's Disease (PD), as executive functions and processing speed belong to the most vulnerable domains in PD., Objective: The aim was to develop a CERAD-TS based on the extended CERAD-Plus' age-, gender-, and education-corrected z-scores and to evaluate its diagnostic accuracy compared to the established CERAD-Chandler-TS., Methods: Baseline data of n = 679 patients with PD (69% male, n = 277 PD without cognitive impairment, n = 307 PD-MCI, n = 95 PD-D) from the multicenter, prospective DEMPARK/LANDSCAPE study were analyzed. ROC-analyses were conducted for four different TS that were either based on the original CERAD or CERAD-Plus, on raw-values or z-scores, and equally-weighted or based on factor scores. AUC-comparisons were conducted to determine the best yet most parsimonious TS., Results: The newly designed CERAD-Plus-TS based on equally-weighted z-scores outperformed both the CERAD-Chandler-TS and cognitive screening instruments when differentiating between individuals with PD of varying cognitive impairment (0.78 ≤ AUC ≤ 0.98)., Conclusion: Results suggest a high relevance of non-amnestic subscales for the cognitive assessment in PD populations. The proposed CERAD-Plus-TS needs further validation. The extensions might offer diagnostic potential for non-PD populations as well., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: In a multicenter cohort of probable dementia with Lewy bodies (DLB), we tested the hypothesis that β-amyloid and tau biomarker positivity increases with age, which is modified by APOE genotype and sex, and that there are isolated and synergistic associations with the clinical phenotype., Methods: We included 417 patients with DLB (age 45-93 years, 31% women). Positivity on β-amyloid (A+) and tau (T+) biomarkers was determined by CSF β-amyloid 1-42 and phosphorylated tau in the European cohort and by Pittsburgh compound B and AV-1451 PET in the Mayo Clinic cohort. Patients were stratified into 4 groups: A-T-, A+T-, A-T+, and A+T+., Results: A-T- was the largest group (39%), followed by A+T- (32%), A+T+ (15%), and A-T+ (13%). The percentage of A-T- decreased with age, and A+ and T+ increased with age in both women and men. A+ increased more in APOE ε4 carriers with age than in noncarriers. A+ was the main predictor of lower cognitive performance when considered together with T+. T+ was associated with a lower frequency of parkinsonism and probable REM sleep behavior disorder. There were no significant interactions between A+ and T+ in relation to the clinical phenotype., Conclusions: Alzheimer disease pathologic changes are common in DLB and are associated with the clinical phenotype. β-Amyloid is associated with cognitive impairment, and tau pathology is associated with lower frequency of clinical features of DLB. These findings have important implications for diagnosis, prognosis, and disease monitoring, as well as for clinical trials targeting disease-specific proteins in DLB., Classification of Evidence: This study provides Class II evidence that in patients with probable DLB, β-amyloid is associated with lower cognitive performance and tau pathology is associated with lower frequency of clinical features of DLB., (© 2020 American Academy of Neurology.)

Background: Small vessel disease and white matter hyperintensities (WMH) as its surrogate marker are known to predict cognitive decline in the elderly. However, the influence of vascular lesions on cognitive impairment in Parkinson's disease (PD) has been discussed controversial so far. The Aim of this study was to evaluate the predictive role of volume and location of white matter hyperintensities (WMH) on cognitive decline in de novo PD patients., Methods: 108 diagnosed drug-naïve PD patients (64 ± 9 years, 38% women) from the DeNoPa Cohort underwent extensive neuropsychological testing with re-testing in 24-month later. Movement Disorder Society criteria for the classification of mild cognitive impairment (MCI) and dementia in PD were applied. Participants that declined from normal cognition or MCI at baseline to MCI or dementia at 24-month follow-up (FU) or from MCI to dementia at 24-month FU were defined as "converters". Subjects with stable cognitive level or improved cognitive status were classified as "non-converters". Magnetic resonance imaging (MRI) was performed, and the extent of WMH was assessed as global volume and as WMH load within cholinergic pathways using the Cholinergic Pathways Hyperintensities Scale. We compared Parkinson's disease subjects with age-matched, neurologically healthy controls., Results: At total of 29 (27%) patients met the criteria for MCI at baseline, whereas 79 (73%) patients had no cognitive impairment. During the 24-month FU 33 patients showed cognitive decline ("converter") compared to 75 "non-converters". Multivariable logistic regression revealed no significant differences between "cognitively impaired" and "cognitively non-impaired" patients and participants of the control group at baseline or between "converter" and "non-converter" regarding the extent of WMH globally or within cholinergic pathways., Conclusions: We could not identify global or localized WMH load as predictive markers of cognitive decline in de novo PD patients indicating that cerebral small vessel disease is not a critical modifier of cognitive function in early PD., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Alzheimer's disease (AD) is the most common neurodegenerative disorder causing huge emotional and economic burden to our societies. An effective therapy has not been implicated yet, which is in part also due to the fact that pathological changes occur years before clinical symptoms manifest. Thus, there is a great need for the development of a translatable biomarker. Recent evidence highlights microRNAs as candidate biomarkers. In this study, we use next-generation sequencing to study the small noncoding RNAome (sncRNAome) in exosomes derived from human cerebrospinal fluid (CSF). We show that the sncRNAome from CSF-derived exosomes is dominated not only by microRNAs (miRNAs) but also by PIWI-interacting RNAs (piRNAs). We define a combined signature consisting of three miRNAs and three piRNAs that are suitable to detect AD with an AUC of 0.83 in a replication cohort and furthermore predict the conversion of mild-cognitive impaired (MCI) patients to AD dementia with an AUC of 0.86 for the piRNA signature. When combining the smallRNA signature with pTau and Aβ 42/40 ratio the AUC reaches 0.98. Our study reports a novel exosomal small noncoding RNA signature to detect AD pathology and provides the first evidence that in addition to miRNAs, piRNAs should also be considered as a candidate biomarker for AD.

Background: The International Parkinson and Movement Disorders Society criteria for mild cognitive impairment in PD need validation. The objectives of this present study were to evaluate prognostic validity of level I (abbreviated) International Parkinson and Movement Disorders Society mild cognitive impairment in PD criteria for development of PD dementia and compared them with level II (comprehensive) criteria., Methods: We analyzed data from 8 international studies (1045 patients) from our consortium that included baseline data on demographics, motor signs, depression, detailed neuropsychological testing, and longitudinal follow-up for conversion to Parkinson's disease dementia. Survival analysis evaluated their contribution to the hazard of Parkinson's disease dementia., Results: Level I mild cognitive impairment in PD, increasing age, male sex, and severity of PD motor signs independently increased the hazard of Parkinson's disease dementia. Level I and level II mild cognitive impairment in PD classification had similar discriminative ability with respect to the time to Parkinson's disease dementia., Conclusions: Level I mild cognitive impairment in PD classification independently contributes to the hazard of Parkinson's disease dementia. This finding supports the prognostic validity of the abbreviated mild cognitive impairment in PD criteria. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Objectives: Parkinson's disease (PD) is the second most common neurodegenerative disorder and is further associated with progressive cognitive decline. In respect to motor phenotype, there is some evidence that akinetic-rigid PD is associated with a faster rate of cognitive decline in general and a greater risk of developing dementia.The objective of this study was to examine cognitive profiles among patients with PD by motor phenotypes and its relation to cognitive function., Methods: Demographic, clinical and neuropsychological cross-sectional baseline data of the DEMPARK/LANDSCAPE study, a multicentre longitudinal cohort study of 538 patients with PD were analysed, stratified by motor phenotype and cognitive syndrome. Analyses were performed for all patients and for each diagnostic group separately, controlling for age, gender, education and disease duration., Results: Compared with the tremor-dominant phenotype, akinetic-rigid patients performed worse in executive functions such as working memory (Wechsler Memory Scale-Revised backward; p=0.012), formal-lexical word fluency (p=0.043), card sorting (p=0.006), attention (Trail Making Test version A; p=0.024) and visuospatial abilities (Leistungsprüfungssystem test 9; p=0.006). Akinetic-rigid neuropsychological test scores for the executive and attentive domain correlated negatively with non-tremor motor scores. Covariate-adjusted binary logistic regression analyses showed significant odds for PD-mild cognitive impairment for not-determined as compared with tremor-dominant (OR=3.198) and akinetic-rigid PD (OR=2.059). The odds for PD-dementia were significant for akinetic-rigid as compared with tremor-dominant phenotype (OR=8.314)., Conclusion: The three motor phenotypes of PD differ in cognitive performance, showing that cognitive deficits seem to be less severe in tremor-dominant PD. While these data are cross-sectional, longitudinal data are needed to shed more light on these differential findings., Competing Interests: Competing interests: GD has received lecture fees from Boston Scientific and has been serving as a consultant for Boston Scientific. He received royalties from Thieme Publishers. He is a government employee and receives through his institution funding for his research from the German Research Council, the German Ministry of Education and Research, and Medtronic. KW received reimbursement of congress fees from BIAL and Desitin; and grants from the Federal Ministry of Education and Research and the German Research Foundation., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The objectives of this study were to investigate (1) the annual rate of progression of motor and cognitive symptoms and (2) baseline predictors of different modalities for this progression in early Parkinson's disease (PD) when compared with healthy controls., Methods: A total of 135 de novo PD and 109 healthy controls (of the De Novo Parkinson cohort) were investigated at baseline and after 24 and 48 months. To delineate motor progression and cognitive decline, the Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS III) and the Mini-Mental Status Examination (MMSE) were selected. Baseline variables used to predict progression included sociodemographic factors, comorbidities, motor/nonmotor symptoms, polysomnography, MRI, and laboratory biomarkers in serum and CSF., Results: Symptoms worsened over 4 years in PD with an annual change of 1.8 points on the MDS-UPDRS III and 0.2 points on the MMSE. Baseline predictors of worse progression of motor symptoms in PD included male sex, orthostatic blood pressure drop, diagnosis of coronary artery disease, arterial hypertension, elevated serum uric acid, and CSF neurofilament light chain. Predictors of cognitive decline in PD included previous heavy alcohol abuse, current diagnoses of diabetes mellitus, arterial hypertension, elevated periodic limb movement index during sleep, decreased hippocampal volume by MRI, higher baseline levels of uric acid, C-reactive protein, high density lipoprotein (HDL) cholesterol, and glucose levels., Conclusion: Cardiovascular risk factors, deregulated blood glucose, uric acid metabolism, and inflammation were identified as risk markers for faster disease progression. Our panel of risk parameters needs validation during our continuing follow-up and also in independent patient cohorts. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

Background: Numerous neuropsychological tests and test versions are used in Parkinson's disease research, but their relative capacity to detect mild cognitive deficits and their comparability across studies are unknown. The objective of this study was to identify neuropsychological tests that consistently detect cognitive decline in PD across studies., Methods: Data from 30 normed neuropsychological tests across 20 international studies in up to 2908 nondemented PD patients were analyzed. A subset of 17 tests was administered to up to 1247 healthy controls. A 2-step meta-analytic approach using standardized scores compared performance in PD with normative data., Results: Pooled estimates of the differences between PD and site-specific healthy controls identified significant cognitive deficits in PD patients on 14 test scores across 5 commonly assessed cognitive domains (attention or working memory, executive, language, memory, and visuospatial abilities), but healthy control performance was statistically above average on 7 of these tests. Analyses based on published norms only, as opposed to direct assessment of healthy controls, showed high between-study variability that could not be accounted for and led to inconclusive results., Conclusions: Normed neuropsychological tests across multiple cognitive domains consistently detect cognitive deficits in PD when compared with site-specific healthy control performance, but relative PD performance was significantly affected by the inclusion and type of healthy controls versus the use of published norms only. Additional research is needed to identify a cognitive battery that can be administered in multisite international studies and that is sensitive to cognitive decline, responsive to therapeutic interventions, and superior to individual cognitive tests. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

Among the nonmotor symptoms in Parkinson's disease (PD), cognitive impairment is one of the most common and devastating. Over recent years, mild cognitive impairment (MCI) has become a recognized feature of PD (PD-MCI). The underlying mechanisms which influence onset, rate of decline, and conversion to dementia (PDD) are largely unknown. Adding to this uncertainty is the heterogeneity of cognitive domains affected. Currently there are no disease-modifying treatments that can slow or reverse this process. Identification of biomarkers that can predict rate and risk of cognitive decline is therefore an unmet need. Cerebrospinal fluid (CSF) is an ideal biomarker candidate as its constituents reflect the metabolic processes underlying the functioning of brain parenchyma. The pathological hallmark of PD is the presence of aggregated α-synuclein (α-Syn) in intracellular Lewy inclusions. In addition, there is concomitant Alzheimer's disease (AD) pathology. In AD, decreased CSF β-amyloid 1-42 (Aβ42) and increased CSF tau levels are predictive of future cognitive decline, setting a precedent for such studies to be carried out in PD. CSF studies in PD have focused on the classical AD biomarkers and α-Syn. Longitudinal studies indicate that low levels of CSF Aβ42 are predictive of cognitive decline; however, results for tau and α-Syn were not consistent. This chapter summarizes recent findings of CSF biomarker studies and cognitive dysfunction in PD., (© 2017 Elsevier Inc. All rights reserved.)

Objective: Inconsistent results exist regarding the cognitive profile in patients with Parkinson's disease with mild cognitive impairment (PD-MCI). We aimed at providing data on this topic from a large cohort of patients with PD-MCI., Methods: Sociodemographic, clinical and neuropsychological baseline data from patients with PD-MCI recruited in the multicentre, prospective, observational DEMPARK/LANDSCAPE study were analysed., Results: 269 patients with PD-MCI (age 67.8±7.4, Unified Parkinson's Disease Rating Scale (UPDRS-III) scores 23.2±11.6) were included. PD-MCI subtypes were 39.4% non-amnestic single domain, 30.5% amnestic multiple domain, 23.4% non-amnestic multiple domain and 6.7% amnestic single domain. Executive functions were most frequently impaired. The most sensitive tests to detect cognitive dysfunctions were the Modified Card Sorting Test, digit span backwards and word list learning direct recall. Multiple stepwise regression analyses showed that global cognition, gender and age, but not education or disease-related parameters predicted PD-MCI subtypes., Conclusions: This study with the so far largest number of prospectively recruited patients with PD-MCI indicates that non-amnestic PD-MCI is more frequent than amnestic PD-MCI; executive dysfunctions are the most typical cognitive symptom in PD-MCI; and age, gender and global cognition predict the PD-MCI subtype. Longitudinal data are needed to test the hypothesis that patients with PD-MCI with specific cognitive profiles have different risks to develop dementia., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Data on gender-specific profiles of cognitive functions in patients with Parkinson's disease (PD) are rare and inconsistent, and possible disease-confounding factors have been insufficiently considered., Method: The LANDSCAPE study on cognition in PD enrolled 656 PD patients (267 without cognitive impairment, 66% male; 292 with mild cognitive impairment, 69% male; 97 with PD dementia, 69% male). Raw values and age-, education-, and gender-corrected Z scores of a neuropsychological test battery (CERAD-Plus) were compared between genders. Motor symptoms, disease duration, l-dopa equivalent daily dose, depression - and additionally age and education for the raw value analysis - were taken as covariates., Results: Raw-score analysis replicated results of previous studies in that female PD patients were superior in verbal memory (word list learning, p = 0.02; recall, p = 0.03), while men outperformed women in visuoconstruction (p = 0.002) and figural memory (p = 0.005). In contrast, gender-corrected Z scores showed that men were superior in verbal memory (word list learning, p = 0.02; recall, p = 0.02; recognition, p = 0.04), while no difference was found for visuospatial tests. This picture could be observed both in the overall analysis of PD patients as well as in a differentiated group analysis., Conclusions: Normative data corrected for gender and other sociodemographic variables are relevant, since they may elucidate a markedly different cognitive profile compared to raw scores. Our study also suggests that verbal memory decline is stronger in women than in men with PD. Future studies are needed to replicate these findings, examine the progression of gender-specific cognitive decline in PD and define different underlying mechanisms of this dysfunction.

Background: Mild cognitive impairment and dementia are common, clinically important features of Parkinson's disease (PD). The underlying disease pathology is heterogeneous and not yet well characterized. Biomarkers for cognitive impairment in PD could aid in diagnostic and prognostic evaluation and in the development of new cognitive enhancing treatments., Objective: To examine the relationship between CSF markers and cognition in a large, multicenter, cohort study of early, untreated PD, and compare marker concentrations between PD patients with and without MCI and healthy, age-matched controls., Methods: 414 early, untreated PD (34% with mild cognitive impairment) and 189 healthy, cognitively intact controls with baseline neuropsychological testing and CSF abeta42, t-tau, p-tau181 and α-synuclein results were included. Multiple linear regression models were constructed with a composite cognition factor, or memory-, or visuospatial- or executive-attention domains as dependent variables, and CSF markers, demographic characteristics and MDS-UPDRS III score as predictors., Results: Lower α-synuclein was associated with reduced performance on the executive-attention domain and the composite cognition factor in the whole PD-group. Abeta42 was significantly decreased in PD with mild cognitive impairment compared with controls after adjusting for covariates, while values in PD without MCI were identical to healthy controls., Conclusions: The association between reduced CSF α-synuclein concentrations and cognition suggests that α-synuclein pathology contributes to early cognitive impairment in PD, in particular to executive-attentional dysfunction. Longitudinal analyses are needed to determine if this and other CSF biomarkers in early Parkinson's disease are associated with the risk of future cognitive decline and dementia.

Objective: To describe the frequency of mild cognitive impairment (MCI) in Parkinson disease (PD) in a cohort of newly diagnosed incident PD cases and the associations with a panel of biomarkers., Methods: Between June 2009 and December 2011, 219 subjects with PD and 99 age-matched controls participated in clinical and neuropsychological assessments as part of a longitudinal observational study. Consenting individuals underwent structural MRI, lumbar puncture, and genotyping for common variants of COMT, MAPT, SNCA, BuChE, EGF, and APOE. PD-MCI was defined with reference to the new Movement Disorder Society criteria., Results: The frequency of PD-MCI was 42.5% using level 2 criteria at 1.5 SDs below normative values. Memory impairment was the most common domain affected, with 15.1% impaired at 1.5 SDs. Depression scores were significantly higher in those with PD-MCI than the cognitively normal PD group. A significant correlation was found between visual Pattern Recognition Memory and cerebrospinal β-amyloid 1-42 levels (β standardized coefficient = 0.350; p = 0.008) after controlling for age and education in a linear regression model, with lower β-amyloid 1-42 and 1-40 levels observed in those with PD-MCI. Voxel-based morphometry did not reveal any areas of significant gray matter loss in participants with PD-MCI compared with controls, and no specific genotype was associated with PD-MCI at the 1.5-SD threshold., Conclusions: In a large cohort of newly diagnosed PD participants, PD-MCI is common and significantly correlates with lower cerebrospinal β-amyloid 1-42 and 1-40 levels. Future longitudinal studies should enable us to determine those measures predictive of cognitive decline.

Mild cognitive impairment is common in nondemented Parkinson's disease (PD) patients and may be a harbinger of dementia. In view of its importance, the Movement Disorder Society commissioned a task force to delineate diagnostic criteria for mild cognitive impairment in PD. The proposed diagnostic criteria are based on a literature review and expert consensus. This article provides guidelines to characterize the clinical syndrome and methods for its diagnosis. The criteria will require validation, and possibly refinement, as additional research improves our understanding of the epidemiology, presentation, neurobiology, assessment, and long-term course of this clinical syndrome. These diagnostic criteria will support future research efforts to identify at the earliest stage those PD patients at increased risk of progressive cognitive decline and dementia who may benefit from clinical interventions at a predementia stage., (Copyright © 2012 Movement Disorder Society.)

There is controversy regarding the definition and characteristics of mild cognitive impairment in Parkinson's disease. The Movement Disorder Society commissioned a Task Force to critically evaluate the literature and determine the frequency and characteristics of Parkinson's disease-mild cognitive impairment and its association with dementia. A comprehensive PubMed literature review was conducted using systematic inclusion and exclusion criteria. A mean of 26.7% (range, 18.9%-38.2%) of nondemented patients with Parkinson's disease have mild cognitive impairment. The frequency of Parkinson's disease-mild cognitive impairment increases with age, disease duration, and disease severity. Impairments occur in a range of cognitive domains, but single domain impairment is more common than multiple domain impairment, and within single domain impairment, nonamnestic is more common than amnestic impairment. A high proportion of patients with Parkinson's disease-mild cognitive impairment progress to dementia in a relatively short period of time. The primary conclusions of the Task Force are that: (1) Parkinson's disease-mild cognitive impairment is common, (2) there is significant heterogeneity within Parkinson's disease-mild cognitive impairment in the number and types of cognitive domain impairments, (3) Parkinson's disease-mild cognitive impairment appears to place patients at risk of progressing to dementia, and (4) formal diagnostic criteria for Parkinson's disease-mild cognitive impairment are needed., (Copyright © 2011 Movement Disorder Society.)

Background: Parkinson's disease (PD) is a progressive neurodegenerative motor disorder. However, non-motor complications frequently alter the course of the disease. A particularly disabling non-motor symptom is dementia., Methods/design: The study is designed as a multicentre prospective, observational cohort study of about 700 PD patients aged 45-80 years with or without dementia and PD-mild cognitive impairment (MCI). The patients will be recruited in eight specialized movement disorder clinics and will be followed for 36 months. Information about the patients' functional status will be assessed at baseline and 6-/12- month intervals. In addition, 120 patients with dementia with Lewy bodies (DLB) will be included. Well-established standardized questionnaires/tests will be applied for detailed neuropsychological assessment. In addition, patients will be asked to participate in modules including volumetric MRI, genetic parameters, and neuropsychology to detect risk factors, early diagnostic biomarkers and predictors for dementia in PD., Results: The study included 604 PD patients by March 2011; 56.3% were classified as having PD alone, with 30.6% of patients suffering from PD-MCI and 13.1% from PD with dementia. The mean age of the cohort was 68.6 ± 7.9 years, with a mean disease duration of 6.8 ± 5.4 years. There was a preponderance of patients in the earlier Hoehn and Yahr stages., Conclusion: The main aim of the study is to characterize the natural progression of cognitive impairment in PD and to identify factors which contribute to the evolution and/or progression of the cognitive impairment. To accomplish this aim we established a large cohort of PD patients without cognitive dysfunction, PD patients with MCI, and PD patients with dementia, to characterize these patients in a standardized manner, using imaging (serial structural MRI), genetic and proteomic methods in order to improve our understanding of the course of the PD process and the development of cognitive dysfunction and dementia in this disease. The inclusion of the DLB patients will start in the second quarter of 2011 in the BMBF-funded follow-up project LANDSCAPE., (Copyright © 2011 S. Karger AG, Basel.)