Cognition and Activity of Daily Living Function in people with Parkinson's disease.

The ability to perform activities of daily living (ADL) function is a multifaceted construct that reflects functionality in different daily life situations. The loss of ADL function due to cognitive impairment is the core feature for the diagnosis of Parkinson's disease dementia (PDD). In contrast to Alzheimer's disease, ADL impairment in PD can be compromised by various factors, including motor and non-motor aspects. This narrative review summarizes the current state of knowledge on the association of cognition and ADL function in people with PD and introduces the concept of "cognitive ADL" impairment for those problems in everyday life that are associated with cognitive deterioration as their primary cause. Assessment of cognitive ADL impairment is challenging because self-ratings, informant-ratings, and performance-based assessments seldomly differentiate between "cognitive" and "motor" aspects of ADL. ADL function in PD is related to multiple cognitive domains, with attention, executive function, and memory being particularly relevant. Cognitive ADL impairment is characterized by behavioral anomalies such as trial-and-error behavior or task step omissions, and is associated with lower engagement in everyday behaviors, as suggested by physical activity levels and prolonged sedentary behavior. First evidence shows that physical and multi-domain interventions may improve ADL function, in general, but the evidence is confounded by motor aspects. Large multicenter randomized controlled trials with cognitive ADL function as primary outcome are needed to investigate which pharmacological and non-pharmacological interventions can effectively prevent or delay deterioration of cognitive ADL function, and ultimately the progression and conversion to PDD.

Characteristics of behavioural addiction in Parkinson's disease patients with self-reported impulse control disorder and controls matched for levodopa equivalent dose: a matched case-control study.

Impulse control disorders (ICD) in Parkinson's disease (PD) frequently occur, not always as a direct consequence of dopaminergic medication. This study investigated premorbid personality traits and behavioural characteristics in non-demented PD patients with self-reported symptoms of ICD (PD-srICD). From a total of 200 non-demented PD patients who filled out questionnaires assessing symptoms and severity of ICD, those were classified as PD-srICD (n = 32) who reported current occurrence of at least one compulsive behaviour (gambling, sexual behaviour, buying behaviour, or eating). As a control group, 32 patients with no self-reported ICD symptoms were matched for levodopa equivalent daily dose. The demographic, clinical, and premorbid personality profiles were compared between both groups. Frequency of psychological characteristics indicating substance use disorder was evaluated in patients with PD-srICD. Patients with PD-srICD were more frequently male, younger at examination, had earlier PD onset, more depression, higher non-motor burden, less quality of life (p < 0.05, respectively), and more frequently reported premorbid sensation seeking/novelty orientation (p = 0.03) and joyful experience of stress (p = 0.04) than patients in the control group. Of patients with PD-srICD, 90.6% reported at least one behavioural characteristic of substance use disorder, most frequently positive expectations following ICD behaviour and illusional beliefs about its behavioural control. Signs of addiction were common among patients with PD-srICD. Therefore, the profile of psychological characteristics in patients with PD-srICD resembled that of patients with substance use disorder. It can be concluded that dopamine replacement therapy (DRT) alone does not account for PD-srICD and that thorough psychological diagnostics are recommended.

Effects of exergaming on hippocampal volume and brain-derived neurotrophic factor levels in Parkinson's disease.

BACKGROUND AND OBJECTIVE: Cognitive impairment is among the most burdensome non-motor symptoms in Parkinson's disease (PD) and has been associated with hippocampal atrophy. Exercise has been reported to enhance neuroplasticity in the hippocampus in correlation with an improvement of cognitive function. We present data from the Training-PD study, which was designed to evaluate effects of an "" training protocol on neuronal plasticity in PD. METHODS: We initiated a 6-week exergaming training program, combining visually stimulating computer games with physical exercise in 17 PD patients and 18 matched healthy controls. Volumetric segmentation of hippocampal subfields on T1- and T2-weighted magnetic resonance imaging and brain-derived neurotrophic factor (BDNF) serum levels were analyzed before and after the training protocol. RESULTS: The PD group showed a group-dependent significant volume increase of the left hippocampal subfields CA1, CA4/dentate gyrus (DG) and subiculum after the 6-week training protocol. The effect was most pronounced in the left DG of PD patients, who showed a significantly smaller percentage volume compared to healthy controls at baseline, but not at follow-up. Both groups had a significant increase in serum BDNF levels after training. CONCLUSIONS: The results of the present study indicate that exergaming might be a suitable approach to induce hippocampal volume changes in PD patients. Further and larger studies are needed to verify our findings.

Evaluation of the Dementia Apraxia Test in Parkinson's Disease Patients.

INTRODUCTION: Ideomotor apraxia, a disorder of skilled movements affecting limbs and/or face, can be seen in patients with Parkinson's disease (PD), yet tests of apraxia in PD are rare. The aim of this project was to evaluate the psychometric properties and validity of the Dementia Apraxia Test (DATE) in a PD sample. METHODS: 118 PD patients were included. Besides DATE performance, motor and non-motor burden, cognition, and activity of daily living (ADL) function were assessed. Patients were classified as cognitively impaired (n = 41) or non-cognitively impaired (n = 77). RESULTS: Interrater reliability of the DATE (sub-)scores between video ratings and on-site ratings by the investigator was good (0.81 ≤ rk ≤ 0.87). Items were mostly easy to perform, especially the buccofacial apraxia items, which had also low discriminatory power. DATE scores were associated with cognition and ADL function. DATE performance was confounded by motor impairment and patients' age; however, when analysed for both cognitive groups separately, the correlation between DATE and motor performance was not significant. DISCUSSION/CONCLUSION: The DATE seems to be an objective and predominantly valid apraxia screening tool for PD patients, with a few items needing revision. Due to the potential effect of motor impairment and age, standardized scores adjusting for these confounders are needed.

Quantifying activities of daily living impairment in Parkinson's disease using the Functional Activities Questionnaire.

OBJECTIVE: Cognitive-driven activity of daily living (ADL) impairment in Parkinson's disease (PD) is increasingly discussed as prodromal marker for dementia. Diagnostic properties of assessments for this specific ADL impairment are sparsely investigated in PD. The ability of the Functional Activities Questionnaire (FAQ) for differentiating between PD patients with normal cognition and with mild cognitive impairment (PD-MCI), according to informant and self-reports, was examined. Global cognitive function in groups with and without mild ADL impairment was compared according to different cut-offs. METHODS: Multicenter data of 589 patients of an international cohort (CENTRE-PD) were analyzed. Analyses were run separately for informant-rated and self-rated FAQ. Receiver operating characteristic (ROC) analysis was conducted to define the optimal FAQ cut-off for PD-MCI (≥ 1), and groups were additionally split according to reported FAQ cut-offs for PD-MCI in the literature (≥ 3, ≥ 5). Binary logistic regressions examined the effect of the Montreal Cognitive Assessment (MoCA) score in PD patients with and without mild ADL impairment. RESULTS: Two hundred and twenty-five (38.2%) patients were classified as PD-MCI. For all three cut-off values, sensitivity was moderate to low (< 0.55), but specificity was moderately high (> 0.54) with a tendency of higher values for self-reported deficits. For the self-report, the cut-off ≥ 3 showed a significant effect of the MoCA (B = - 0.31, p = 0.003), where FAQ ≥ 3 patients had worse cognition. No effect for group differences based on informant ratings was detected. CONCLUSION: Our data argue that self-reported ADL impairments assessed by the FAQ show a relation to the severity of cognitive impairment in PD.

Deficits in or preservation of basic number processing in Parkinson's disease? A registered report.

Neurodegenerative diseases such as Parkinson's disease (PD) have a huge impact on patients, caregivers, and the health-care system. To date, the diagnosis of mild cognitive impairments in PD has been established based on domain-general functions such as executive functions, attention, or working memory. However, specific numerical deficits observed in clinical practice have not yet been systematically investigated. PD-immanent deterioration of domain-general functions and domain-specific numerical areas suggests the mechanisms of both primary and secondary dyscalculia. The current study will systematically investigate basic number processing performance in PD patients for the first time, targeting domain-specific cognitive representations of numerosity and the influence of domain-general factors. The overall sample consists of patients with a diagnosis of PD, according to consensus guidelines, and healthy controls. PD patients will be stratified into patients with normal cognition or mild cognitive impairment (level I-PD-MCI based on cognitive screening). Basic number processing will be assessed using transcoding, number line estimation, and (non)symbolic number magnitude comparison tasks. Discriminant analysis will be employed to assess whether basic number processing tasks can differentiate between a healthy control group and both PD groups. All participants will be subjected to a comprehensive numerical and a neuropsychological test battery, as well as sociodemographic and clinical measures. Study results will give the first broad insight into the extent of basic numerical deficits in different PD patient groups and will help us to understand the underlying mechanisms of the numerical deficits faced by PD patients in daily life.

CSF Protein Level of Neurotransmitter Secretion, Synaptic Plasticity, and Autophagy in PD and DLB.

BACKGROUND: Molecular pathways associated with α-synuclein proteostasis have been detected in genetic studies and in cell models and include autophagy, ubiquitin-proteasome system, mitochondrial homeostasis, and synaptic plasticity. However, we lack biomarkers that are representative for these pathways in human biofluids. OBJECTIVE: The objective of this study was to evaluate CSF protein profiles of pathways related to α-synuclein proteostasis. METHODS: We assessed CSF protein profiles associated with neurotransmitter secretion, synapse plasticity, and autophagy in 2 monocentric cohorts with α-synucleinopathy (385 PD patients and 67 DLB patients). We included 80 PD patients and 17 DLB patients with variants in the glucocerebrosidase gene to serve as proxy for accelerated α-synuclein pathology with pronounced clinical trajectories. RESULTS: (1) Proteins associated with neurotransmitter secretion, synaptic plasticity, and endolysosomal autophagy were lower in PD and DLB patients compared with healthy controls. (2) These patterns were more pronounced in DLB than in PD patients, accentuated by GBA variant status in both entities. (3) CSF levels of these proteins were positively associated with CSF levels of total α-synuclein, with lower levels of proteostasis proteins related to lower levels of total α-synuclein. (4) These findings could be confirmed longitudinally. PD patients with low CSF profiles of proteostasis proteins showed lower CSF levels of α-synuclein longitudinally compared with PD patients with a normal proteostasis profile. CONCLUSION: CSF proteins associated with neurotransmitter secretion, synaptic plasticity, and endolysosomal autophagy might serve as biomarkers related to α-synuclein proteostasis in PD and DLB. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The Mutation Matters: CSF Profiles of GCase, Sphingolipids, α-Synuclein in PDGBA.

BACKGROUND: With pathway-specific trials in PD associated with variants in the glucocerebrosidase gene (PDGBA ) under way, we need markers that confirm the impact of genetic variants in patient-derived biofluids in order to allow patient stratification merely based on genetics and that might serve as biochemical read-out for target engagement. OBJECTIVE: To explore GBA-pathway-specific biomarker profiles cross-sectionally (TUEPAC-MIGAP, PPMI) and longitudinally (PPMI). METHODS: We measured enzyme activity of the lysosomal glucocerebrosidase, CSF levels of glucosylceramides (upstream substrate of glucocerebrosidase), CSF levels of ceramides (downstream product of glucocerebrosidase), lactosylceramides, sphingosines, sphingomyelin (by-products) and CSF levels of total α-synuclein in PDGBA patients compared to PDGBA_wildtype patients. RESULTS: Cross-sectionally in both cohorts and longitudinally in PPMI: (1) glucocerebrosidase activity was significantly lower in PDGBA compared to PDGBA_wildtype . (2) CSF levels of upstream substrates (glucosylceramides species) were higher in PDGBA compared to PDGBA_wildtype . (3) CSF levels of total α-synuclein were lower in PDGBA compared to PDGBA_wildtype . All of these findings were most pronounced in PDGBA with severe mutations (PDGBA_severe ). Cross-sectionally in TUEPAC-MIGAP and longitudinally in PPMI, CSF levels of downstream-products (ceramides) were higher in PDGBA_severe . Cross-sectionally in TUEPAC-MIGAP by-products sphinganine and sphingosine-1-phosphate and longitudinally in PPMI species of by-products lactosylceramides and sphingomyelin were higher in PDGBA_severe . INTERPRETATION: These findings confirm that GBA mutations have a relevant functional impact on biomarker profiles in patients. Bridging the gap between genetics and biochemical profiles now allows patient stratification for clinical trials merely based on mutation status. Importantly, all findings were most prominent in PDGBA with severe variants. © 2021 International Parkinson and Movement Disorder Society.

[Guidelines for the Neuropsychological Assessment of Patients with Parkinson's Disease]. / Empfehlungen zur neuropsychologischen Diagnostik beim Morbus Parkinson.

BACKGROUND: Presence of mild cognitive impairment is currently the best predictor for the development of Parkinson's disease dementia. Diagnostic criteria for both Parkinson's with mild cognitive impairment and Parkinson's disease dementia have been suggested by the Movement Disorder Society. However, not all cognitive tests recommended are available in the German language with proper standard values. OBJECTIVES: To define evidence-based guidelines for neuropsychological assessment of patients with Parkinson's disease in German. METHODS: Two systematic literature searches were conducted. First, articles that presented international guidelines (consensus papers or reviews) for the application of standardized neuropsychological assessments for the diagnosis of cognitive impairment in Parkinson's disease were selected. Of those, only neuropsychological assessments in German language with normative values referring either to a German, Austrian, or Swiss population were considered. Second, articles comparing test performances of healthy controls vs. Parkinson's disease and/or different cognitive Parkinson's disease subtypes (e.g. no cognitive impairment, Parkinson's with mild cognitive impairment, Parkinson's disease dementia) were selected. Effect sizes for group differentiation were calculated. RESULTS: Out of 127 full-text articles reviewed, 48 tests were identified during the first literature search. In the second search, 1716 articles were reviewed and 23 papers selected. The strongest effect sizes for group discrimination were revealed for tests assessing executive function, attention, and visuo-cognitive abilities. Based on the results of the two literature searches, consensus guidelines were defined by the authors, allowing for Level-II diagnosis for Parkinson's with mild cognitive impairment and Parkinson's disease dementia. CONCLUSIONS: The presented guidelines may have the potential to standardize and improve the neuropsychological assessment of Parkinson's disease patients in German speaking countries.

Longitudinal brain atrophy distribution in advanced Parkinson's disease: What makes the difference in "cognitive status" converters?

We investigated the brain atrophy distribution pattern and rate of regional atrophy change in Parkinson's disease (PD) in association with the cognitive status to identify the morphological characteristics of conversion to mild cognitive impairment (MCI) and dementia (PDD). T1-weighted longitudinal 3T MRI data (up to four follow-up assessments) from neuropsychologically well-characterized advanced PD patients (n = 172, 8.9 years disease duration) and healthy elderly controls (n = 85) enrolled in the LANDSCAPE study were longitudinally analyzed using a linear mixed effect model and atlas-based volumetry and cortical thickness measures. At baseline, PD patients presented with cerebral atrophy and cortical thinning including striatum, temporoparietal regions, and primary/premotor cortex. The atrophy was already observed in "cognitively normal" PD patients (PD-N) and was considerably more pronounced in cognitively impaired PD patients. Linear mixed effect modeling revealed almost similar rates of atrophy change in PD and controls. The group comparison at baseline between those PD-N whose cognitive performance remained stable (n = 42) and those PD-N patients who converted to MCI/PDD ("converter" cPD-N, n = 26) indicated suggested cortical thinning in the anterior cingulate cortex in cPD-N patients which was correlated with cognitive performance. Our results suggest that cortical brain atrophy has been already expanded in advanced PD patients without overt cognitive deficits while atrophy progression in late disease did not differ from "normal" aging regardless of the cognitive status. It appears that cortical atrophy begins early and progresses already in the initial disease stages emphasizing the need for therapeutic interventions already at disease onset.

Parkinson's Disease: Glucocerebrosidase 1 Mutation Severity Is Associated with CSF Alpha-Synuclein Profiles.

BACKGROUND: Mutations in the gene glucocerebrosidase (GBA1) are specifically associated with alpha-synucleinopathies, namely, Parkinson's disease (PD) and dementia with Lewy bodies. As disease-modifying treatment options such as alpha-synuclein lowering compounds are under way, patient stratification according to alpha-synuclein-specific enrichment strategies, possibly reflected by cerebrospinal fluid (CSF) profiles, is a much needed prerequisite. OBJECTIVE: Are GBA1 mutations associated with a CSF alpha-synuclein profile in PD? METHODS: Screening of the GBA1 gene and analysis of CSF levels of total alpha-synuclein were performed in 80 PDGBA , 80 PDGBA _wildtype and 39 healthy controls cross-sectionally. Subgroup analyses based on mutation severity was done for PDGBA . RESULTS: Patients carrying severe GBA1 mutations showed (1) an earlier age at onset, (2) more pronounced cognitive decline and higher prevalence of rapid eye movement sleep behavior disorder, and (3) reduced CSF levels of total alpha-synuclein. CONCLUSION: The effects of GBA1 mutations on CSF alpha-synuclein profiles and phenotypical characteristics seem dependent on GBA1 mutation severity. © 2019 International Parkinson and Movement Disorder Society.

Assessment of Cognitive-Driven Performance-Based Activities of Daily Living Dysfunction in Parkinson's Disease.

OBJECTIVES: Parkinson's disease (PD) patients with mild cognitive impairment (PD-MCI) have an increased risk of developing dementia (PDD). As activities of daily living (ADL) impairment is mandatory for the diagnosis of PDD, assessing early signs of instrumental ADL (iADL) dysfunction, especially in PD-MCI, is essential. In PD, self- and caregiver-reported iADL performance is often confounded by motor dysfunction and mood. Objective and time-efficient performance-based measurements are needed to screen for cognitive-related iADL dysfunction. We evaluated the Erlangen Test of Activities of Daily Living in Mild Dementia and Mild Cognitive Impairment (ETAM) in PD and determined its value for characterizing a subgroup of PD-MCI patients with mild performance-based iADL impairment. METHODS: Twenty-one cognitively normal PD patients (PD-NC), 24 PD-MCI patients, and 18 healthy controls (HC) were analyzed. Assessments included the ETAM, a comprehensive neuropsychological test battery, iADL, mood, and motor measurements. RESULTS: PD-MCI patients scored significantly lower on the ETAM total score compared to PD-NC patients (p = .002), whereas HC and PD-NC patients did not statistically differ. No HC scored lower than 27 points (diagnostic cutoff for mild iADL impairment); only PD-MCI patients scored below this cutoff (29.2%) suggesting the ETAM is able to characterize a PD-MCI subgroup with early iADL impairment. PD-MCI patients below the cutoff were more impaired in the attention domain (p = .04). CONCLUSIONS: The ETAM is a potentially valuable clinical assessment, able to detect first signs of iADL dysfunction in PD-MCI. Further studies in larger cohorts are needed to evaluate the prognostic ability for predicting PDD.

Cognitive decline in Parkinson's disease: the impact of the motor phenotype on cognition.

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.

Controls-based denoising, a new approach for medical image analysis, improves prediction of conversion to Alzheimer's disease with FDG-PET.

OBJECTIVE: The pattern expression score (PES), i.e., the degree to which a pathology-related pattern is present, is frequently used in FDG-brain-PET analysis and has been shown to be a powerful predictor of conversion to Alzheimer's disease (AD) in mild cognitive impairment (MCI). Since, inevitably, the PES is affected by non-pathological variability, our aim was to improve classification with the simple, yet novel approach to identify patterns of non-pathological variance in a separate control sample using principal component analysis and removing them from patient data (controls-based denoising, CODE) before calculating the PES. METHODS: Multi-center FDG-PET from 220 MCI patients (64 non-converter, follow-up ≥ 4 years; 156 AD converter, time-to-conversion ≤ 4 years) were obtained from the ADNI database. Patterns of non-pathological variance were determined from 262 healthy controls. An AD pattern was calculated from AD patients and controls. We predicted AD conversion based on PES only and on PES combined with neuropsychological features and ApoE4 genotype. We compared classification performance achieved with and without CODE and with a standard machine learning approach (support vector machine). RESULTS: Our model predicts that CODE improves the signal-to-noise ratio of AD-PES by a factor of 1.5. PES-based prediction of AD conversion improved from AUC 0.80 to 0.88 (p= 0.001, DeLong's method), sensitivity 69 to 83%, specificity 81% to 88% and Matthews correlation coefficient (MCC) 0.45 to 0.66. Best classification (0.93 AUC) was obtained when combining the denoised PES with clinical features. CONCLUSIONS: CODE, applied in its basic form, significantly improved prediction of conversion based on PES. The achieved classification performance was higher than with a standard machine learning algorithm, which was trained on patients, explainable by the fact that CODE used additional information (large sample of healthy controls). We conclude that the proposed, novel method is a powerful tool for improving medical image analysis that offers a wide spectrum of biomedical applications, even beyond image analysis.

Hypermetabolism in the cerebellum and brainstem and cortical hypometabolism are independently associated with cognitive impairment in Parkinson's disease.

PURPOSE: Cognitive impairment (CI) in Parkinson's disease (PD) is associated with a widespread reduction in cortical glucose metabolism and relative increases in the cerebellum and brainstem as measured using 18F-fluorodesoxyglucose (FDG) PET. We separately analysed CI-related hypermetabolism and hypometabolism in comparison with neuropsychological test performance and investigated whether increased FDG uptake is a true feature of the disease or a normalization effect. METHODS: The study included 29 subjects (12 patients with PD, 10 patients with PD dementia and 7 healthy controls") who underwent FDG PET and comprehensive neuropsychological testing. Test performance across various cognitive domains was summarized in a cognitive staging score. Metabolic indices reflecting associated changes in regional cerebral glucose metabolism (rCGM) were calculated: index(-) for CI-related hypometabolism, and index(+) for CI-related hypermetabolism. We tested whether index(+) offered additional value in predicting the severity of CI in multiple regression analysis. RESULTS: At higher stages of CI, increased rCGM was found in the posterior cerebellar vermis and pons, associated with impaired attention, executive function and memory. Reduced rCGM was found in various cortical regions in agreement with the literature. In multiple regression analysis, both indices independently predicted the severity of CI with a whole-model R2 of 0.68 (index(-), p = 0.0006; index(+), p = 0.013), confirmed by alternative analyses combining different reference tissues in the multiple regression. CONCLUSION: We found CI-related hypermetabolism in cerebellar regions that are known to be involved in several cognitive functions and in the pons. These alterations may represent compensatory activation of cognitive networks including cerebropontocerebellar tracts.

Polygenic load: Earlier disease onset but similar longitudinal progression in Parkinson's disease.

OBJECTIVES: In order to evaluate the influence of the genetic load of 49 genetic variants known to be associated with PD on the age at onset as well as on clinical outcome parameters. BACKGROUND: PD patients show a large variability in phenotype and progression reflecting interindividual heterogeneity. This might be influenced by a diverse genetic architecture. METHODS: Six hundred seventeen PD patients were included in this study and stratified by their "genetic load," which is based on the weighted odds ratios of 49 genetic variants known to be associated with PD from genome-wide association studies. Clinical parameters (H & Y, UPDRS-III, MMSE, and Beck's Depression Inventory) were evaluated cross-sectionally and in a subgroup longitudinally over 8 years. RESULTS: PD patients with the highest genetic load were younger at disease onset, whereas severity of clinical parameters were similar compared to patients with the lowest genetic load. These findings could be confirmed regarding progression to clinical endpoints in the longitudinal analysis. CONCLUSION: A high genetic load is associated with a younger age at onset, which, in turn, might possibly promote more effective compensatory mechanisms resulting in a similar rate of disease progression. © 2018 International Parkinson and Movement Disorder Society.

Movement disorder society criteria for clinically established early Parkinson's disease.

BACKGROUND: In 2015, the International Parkinson and Movement Disorder Society published clinical diagnostic criteria for Parkinson's disease (PD). Although recent validation studies suggest high accuracy, one unmet need is for highly specific criteria for clinical trials in early/de novo PD. OBJECTIVES: The objective of this study was to generate and test a PD diagnostic criteria termed "clinically established early PD." METHODS: We modified the Movement Disorder Society criteria to increase specificity for early PD by removing all disease duration components and changing red flags to absolute exclusions. We then estimated the sensitivity/specificity of clinically established early PD criteria in patients with disease duration <5 years, selected from a 626-patient validation study. RESULTS: After documentation of parkinsonism, 18 individual exclusion criteria are assessed that preclude the diagnosis of "clinically established early PD." Among 212 PD and 152 non-PD patients, the estimated specificity was 95.4%, with 69.8% sensitivity. CONCLUSIONS: We describe high-specificity criteria for de novo PD, which are freely available for use in clinical trials. © 2018 International Parkinson and Movement Disorder Society.

Psychometric Properties of an Abbreviated Version of the Apathy Evaluation Scale for Parkinson Disease (AES-12PD).

BACKGROUND: Apathy is a frequent symptom in Parkinson's disease (PD), substantially aggravating the course of PD. Regarding the accumulating evidence of the key role of apathy in PD, time-efficient assessments are useful for fostering progress in research and treatment. The Apathy Evaluation Scale (AES) is widely used for the assessment of apathy across different nosologies. OBJECTIVE: To facilitate the application of the AES in PD, we reduced the AES to two-thirds its length and validated this abbreviated version. DESIGN: Data sets of 339 PD patients of the DEMPARK/LANDSCAPE study without dementia and depression were randomly split into two samples. Data of sample 1 were used to develop a brief version of the AES (AES-12PD). A cross-validation was conducted in sample 2 and in a subsample of 42 PD patients with comorbid dementia and depressive symptomatology. Receiver operating characteristic analysis was applied to determine the optimal cutoff of the AES-12PD as an indicator of apathy. RESULTS: The AES-12PD featured high internal consistency that was better compared to the AES. The abbreviated scale was well differentiated from motor impairment and cognitive deficits. The AES-12PD cutoff of 27/28 was the optimal cutoff for apathy in PD patients without dementia and depression. The cutoff of 25/26 indicated apathy in PD patients with comorbid dementia and depression. CONCLUSION: Results confirm a high internal consistency and good discriminant validity of the AES-12PD. The AES-12PD represents a reliable tool for the efficient assessment of apathy that can be applied in PD patients with and without dementia and depression.

Hereditary spastic paraplegia: Clinicogenetic lessons from 608 patients.

OBJECTIVE: Hereditary spastic paraplegias (HSPs) are genetically driven disorders with the hallmark of progressive spastic gait disturbance. To investigate the phenotypic spectrum, prognostic factors, and genotype-specific differences, we analyzed baseline data from a continuous, prospective cohort. METHODS: We recruited 608 HSP cases from 519 families of mostly German origin. Clinical severity was assessed by the Spastic Paraplegia Rating Scale. Complicating symptoms were recorded by a standardized inventory. RESULTS: Family history indicated dominant (43%), recessive (10%), and simplex (47%) disease. We observed a significant male predominance, particularly in simplex cases without a genetic diagnosis. Disease severity increased with disease duration. Earlier disease onset was associated with less severe disease. Specific complicating features including cognitive impairment, extrapyramidal or peripheral motor involvement, and ataxia were associated with worse disease severity. Disease severity also depended on the genotype. HSP cases maintained the ability to walk independently for a median disease duration of 22 years. Early onset cases were able to maintain free walking significantly longer and were at less risk to become wheelchair dependent. INTERPRETATION: This cross-sectional cohort study provides the first large-scale data on disease manifestation, progression, and modifying factors, with relevance for counseling of HSP families and planning of future cross-sectional and natural history studies. Later age of onset, specific complicating features, and the SPG11 genotype are strongly associated with more severe disease. Future interventional studies will require stratification for modifiers of disease progression identified in this study. Prospective longitudinal studies will verify progression rates calculated in this baseline analysis.

Cognitive changes in prodromal Parkinson's disease: A review.

Although other nonmotor phenomena representing possible prodromal symptoms of Parkinson's disease have been described in some detail, the occurrence and characteristics of cognitive decline in this early phase of the disease are less well understood. The aim of this review is to summarize the current state of research on cognitive changes in prodromal PD. Only a small number of longitudinal studies have been conducted that examined cognitive function in individuals with a subsequent PD diagnosis. However, when we consider data from at-risk groups, the evidence suggests that cognitive decline may occur in a substantial number of individuals who have the potential for developing PD. In terms of specific cognitive domains, executive function in particular and, less frequently, memory scores are reduced. Prospective longitudinal studies are thus needed to clarify whether cognitive, and specifically executive, decline might be added to the prodromal nonmotor symptom complex that may precede motor manifestations of PD by years and may help to update the risk scores used for early identification of PD. © 2017 International Parkinson and Movement Disorder Society.