Introduction: Cognitive impairment is a common symptom of Parkinson's disease (PD) associated with reduced quality of life and a more severe disease state. Previous research has shown an association between visuospatial dysfunction and worse disease course; however, it is not clear whether this is separable from executive dysfunction and/or dementia. This study sought to determine whether distinct cognitive factors could be measured in a large PD cohort, and if those factors were differentially associated with other PD-related features, specifically to provide insight into visuospatial dysfunction. Methods: Non-demented participants with PD from the Pacific Udall Center were enrolled (n = 197). Co-participants (n = 104) completed questionnaires when available. Principal components factor analysis (PCFA) was utilized to group the neuropsychological test scores into independent factors by considering those with big factor loading (≥.40). Linear and logistic regression analyses were performed to examine the relationship between the cognitive factors identified in the PCFA and other clinical features of PD. Results: Six factors were extracted from the PCFA: 1) executive/processing speed, 2) visual learning & memory/visuospatial, 3) auditory working memory, 4) contextual verbal memory, 5) semantic learning & memory, and 6) visuospatial. Motor severity (p = 0.001), mood (p < 0.001), and performance on activities of daily living scores (informant: p < 0.001, patient: p = 0.009) were primarily associated with frontal and executive factors. General sleep disturbance (p < 0.006) and hallucinations (p = 0.002) were primarily associated with visuospatial functioning and visual learning/memory. Conclusions: Motor symptoms, mood, and performance on activities of daily living were primarily associated with frontal/executive factors. Sleep disturbance and hallucinations were associated with visuospatial functioning and visual learning/memory only, over and above executive functioning and regardless of cognitive disease severity. These findings support that visuospatial function in PD may indicate a more severe disease course, and that symptom management should be guided accordingly.

Background

Clinicians and researchers commonly use global cognitive assessments to screen for impairment. Currently there are no published studies directly comparing the sensitivity and specificity of the Montreal Cognitive Assessment and Mattis Dementia Rating Scale-2 in PD. The objective of this study was to identify the relative sensitivity and specificity of the Montreal Cognitive Assessment and Mattis Dementia Rating Scale-2 in PD.

Methods

The Montreal Cognitive Assessment and Mattis Dementia Rating Scale-2 were administered to training and validation cohorts. Cutoff scores were determined within the training cohort (n = 85) to optimize sensitivity and specificity for cognitive impairment and were applied to an independent validation cohort (n = 521).

Results

The Montreal Cognitive Assessment was consistently sensitive across training and validation cohorts (90.0% and 80.3%, respectively), whereas the Mattis Dementia Rating Scale-2 was not (87.5% and 60.3%, respectively). In individual domains, the Montreal Cognitive Assessment remained sensitive to memory and visuospatial impairments (91.9% and 87.8%, respectively), whereas the Mattis Dementia Rating Scale-2 was sensitive to executive impairments (86.2%).

Conclusion

The Montreal Cognitive Assessment and Mattis Dementia Rating Scale-2 demonstrated individual strengths. Future work should focus on developing domain-specific cognitive screening tools for PD. © 2018 International Parkinson and Movement Disorder Society.

Introduction

Gait and balance impairments are cardinal features of Parkinson's disease (PD) that require cognitive input. However, the extent to which specific gait and balance characteristics relate to cognition in PD is unclear. In addition, independent models of gait and balance have not been developed from the same cohort. We aimed to i) develop models of gait and balance in a large PD cohort and ii) determine which gait and balance characteristics best related to cognition.

Methods

One hundred and ninety-eight people with PD were recruited to the Pacific Udall Center. Using six inertial sensors (APDM, Inc.), comprehensive gait measurements were collected over a 2-min continuous walk and comprehensive static balance measures were collected during a 60-second standing task. Six domains of cognition were assessed: global cognition, attention, executive function, language, memory, and visuospatial function. Correlations and hierarchical linear regression determined independent associations.

Results

Principal components analysis identified a gait model containing four domains accounting for 80.1% of total variance: pace/turning, rhythm, variability, and trunk. The balance model contained four independent domains accounting for 84.5% of total variance: sway area/jerkiness, sway velocity, sway frequency anteroposterior, and sway frequency mediolateral. Gait domains of pace/turning and variability were strongly associated with attention and executive function. Sway area and jerkiness of balance associated with attention and visuospatial function.

Conclusions

Gait and balance characteristics were associated with specific types of cognition. The specific relationships between gait or balance with cognitive functions suggests shared cerebral cortical circuitry for mobility and cognitive functions.

Objective

Parkinson's disease (PD) presents clinically with several motor subtypes that exhibit variable treatment response and prognosis. Here, we investigated genetic variants for their potential association with PD motor phenotype and progression.

Methods

We screened 10 SNPs, previously associated with PD risk, for association with tremor-dominant (TD) versus postural-instability gait disorder (PIGD) motor subtypes. SNPs that correlated with the TD/PIGD ratio in a discovery cohort of 251 PD patients were then evaluated in a multi-site replication cohort of 559 PD patients. SNPs associated with motor phenotype in both cross-sectional cohorts were next evaluated for association with (1) rates of motor progression in a longitudinal subgroup of 230 PD patients and (2) brain alpha-synuclein (SNCA) expression in the GTEx (Genotype-Tissue Expression project) consortium database.

Results

Genotype at rs356182, near SNCA, correlated with the TD/PIGD ratio in both the discovery (Bonferroni-corrected P = 0.04) and replication cohorts (P = 0.02). The rs356182 GG genotype was associated with a more tremor-predominant phenotype and predicted a slower rate of motor progression (1-point difference in annual rate of UPDRS-III motor score change, P = 0.01). The rs356182 genotype was associated with SNCA expression in the cerebellum (P = 0.005).

Interpretation

Our study demonstrates that the GG genotype at rs356182 provides molecular definition for a clinically important endophenotype associated with (1) more tremor-predominant motor phenomenology, (2) slower rates of motor progression, and (3) decreased brain expression of SNCA. Such molecularly defined endophenotyping in PD may benefit both clinical trial design and tailoring of clinical care as we enter the era of precision medicine.

Neuropsychiatric symptoms are common in Parkinson's disease (PD). We investigated the relationship between neuropsychiatric symptoms and current and future diagnosis of PD dementia (PDD). Individuals with PD who had a study partner were enrolled (n = 696). Study partners were administered the Neuropsychiatric Inventory or Neuropsychiatric Inventory Questionnaire at baseline. Participants were assigned a cognitive diagnosis at baseline and follow up visits. Hallucinations were significantly associated with a diagnosis of PDD cross-sectionally (p < 0.001) and with shortened time to dementia longitudinally among initially nondemented participants (n = 444; p = 0.005). Screening for hallucinations may be useful for assessing risk of dementia in participants with PD.

Introduction

Cognitive impairment is a common complication of Parkinson's disease (PD) and identifying risk factors for progression to Parkinson's disease dementia (PDD) is important. However, little research has been done comparing the utility of commonly used cognitive screening tests in predicting cognitive progression in PD.

Methods

We retrospectively reviewed data from patients with PD enrolled in the Pacific Udall Center who had baseline and longitudinal neuropsychological and global cognitive screening tests. The diagnostic accuracies of 3 common screening tests were compared: Montreal Cognitive Assessment (MoCA), Mattis Dementia Rating Scale (DRS-2), and Mini Mental Status Examination (MMSE). Cognitive diagnoses of PD with mild cognitive impairment (PD-MCI) and PDD were based on full neuropsychological testing and established Movement Disorder Society criteria. Logistic regression and Cox proportional hazards regression models were used to examine predictors of cognitive decline.

Results

Four hundred seventy patients for whom scores on all 3 screening tests were available from the same assessment were included in a cross-sectional analysis. The MoCA demonstrated the best overall diagnostic accuracy for PD-MCI (AUC= 0.79, sensitivity= 76.4%) and for PDD (AUC= 0.89, sensitivity= 81.0%) compared to the DRS-2 and MMSE. A longitudinal analysis was performed on the subset of patients (316/470; 67.2%) who were nondemented at baseline and had undergone two or more assessments. After controlling for covariates, the MoCA was the only test associated with progression to PDD (OR= 1.27 95% CI 1.1 - 1.5, p=0.001) and faster time to dementia (HR = 1.3, 95% CI 1.1 - 1.4, p<0.0001).

Conclusions

This study provides additional support for the use of the MoCA as a primary screening tool for cognitive impairment in PD and is the first to show that the MoCA is a predictor of conversion to PDD.

Recently, α-synuclein (α-syn) and DJ-1, 2 proteins critically involved in Parkinson's disease (PD), have been shown to be present in saliva, suggesting their potential utility as biomarkers of PD. However, the origin and influence of demographic characteristics (e.g., age or sex) on these proteins are unknown. We identified cheek epithelium, which forms the majority of the cellular component of saliva and is readily accessible clinically, as 1 of several potential sources of salivary α-syn and DJ-1. However, no PD-related trend in the cellular component was present. In the supernatant collected from 198 healthy subjects, no correlation was seen between salivary DJ-1 or α-syn with age. When male and female subjects were analyzed separately, a weak age-dependent increase in DJ-1 level was present in male subjects, along with slightly increased α-syn in female subjects. These results, albeit largely negative, provide critical information for understanding the salivary gland pathology and saliva as a PD biomarker source, and must be considered in future investigations of salivary changes in PD.

Cognitive impairment in Parkinson's disease (PD) is pervasive with potentially devastating effects. Identification of those at risk for cognitive decline is vital to identify and implement appropriate interventions. Robust multivariate approaches, including fixed-effect, mixed-effect, and multitask learning models, were used to study associations between biological, clinical, and cognitive factors and for predicting cognitive status longitudinally in a well-characterized prevalent PD cohort (n = 827). Age, disease duration, sex, and GBA status were the primary biological factors associated with cognitive status and progression to dementia. Specific cognitive tests were better predictors of subsequent cognitive status for cognitively unimpaired and dementia groups. However, these models could not accurately predict future mild cognitive impairment (PD-MCI). Data collected from a large PD cohort thus revealed the primary biological and cognitive factors associated with dementia, and provide clinicians with data to aid in the identification of risk for dementia. Sex differences and their potential relationship to genetic status are also discussed.

Introduction

Cognitive dysfunction is common in Parkinson's disease (PD) and associated with reduced functional abilities and increased dependence. To date, however, little is known about the relationship between performance of instrumental activities of daily living (IADLs) and cognitive stages in PD, and there are conflicting reports as to whether declines in specific cognitive domains predict IADL impairment.

Methods

Participants with PD were drawn from the Pacific Udall Center and included in the study if both participant and study partner IADL ratings and cognitive tests were completed (n = 192). Logistic regression analyses were performed to determine whether participant and/or study partner rating predicted mild cognitive impairment or dementia. Correlations are reported for the relationship between participant/study partner IADL reports as well as for specific cognitive tests.

Results

Although both participant and study partner ratings of IADL performance were associated with a diagnosis of PD with dementia, only participant self-rating of functional ability was significantly associated with a diagnosis of PD with mild cognitive impairment. Functional ability correlated most strongly with measures of processing speed, auditory working memory, and immediate verbal recall for both the participant and study partner ratings.

Conclusion

For participants with PD in the early stages of cognitive decline, self-rating may be more sensitive to the impact of cognitive changes on IADL function than ratings made by a knowledgeable study partner. Changes in executive function, processing speed, and learning may indicate a higher likelihood of IADL impairment. Careful assessment of cognition and IADL performance is recommended to permit individualized interventions prior to significant disability.

Mutations in the LRRK2 gene result in autosomal dominant, late onset Parkinson's disease (PD). Three such mutations (p.R1441C, p.R1441G, and p.R1441H) are known to occur within codon 1441, and haplotype analyses indicate that each one has arisen independently on multiple occasions. We sequenced the entire coding region of 18 casual genes for PD or other parkinsonian neurodegenerative disorders in the proband of a family with autosomal dominant PD. We discovered a new missense mutation in the LRRK2 gene, c.4321C>A (p.R1441S). The mutation was predicted to be highly deleterious in silico (Combined Annotation Dependent Depletion score of 25.5) and segregated with disease in the pedigree. The clinical characteristics of affected family members were similar to those described in PD families with other mutations in LRRK2 codon 1441 and included resting tremor, rigidity, bradykinesia, unilateral onset, and a good response to levodopa. Age at onset ranged from 41 to 76. Two of the affected members of the pedigree underwent detailed, longitudinal neuropsychological testing, and both displayed evidence of mild cognitive deficits at or slightly preceding the onset of motor symptoms. LRRK2 p.R1441S represents the fourth pathogenic mutation observed within codon 1441 and its discovery adds to the remarkable complexity of a mutational hotspot within the ROC domain of the LRRK2 protein. © 2016 Wiley Periodicals, Inc.