Introduction: Amantadine anecdotally improves gait in progressive supranuclear palsy (PSP) but definitive data is lacking. We investigated associations between amantadine usage, gait, cognition, and activities of daily living in 310 subjects with PSP using data from the davunetide trial. Method: We compared baseline demographics, PSP Rating Scale (PSPRS), Repeat Battery for the Assessment of Neuropsychological Status (RBANS), and Schwab and England Activities of Daily Living (SEADL) scores between subjects taking vs. not taking amantadine using chi-square tests for categorical variables and independent sample t-tests for continuous variables. Using the general linear model (GLM), we tested whether group status predicted total PSPRS, PSPRS-gait and midline, total RBANS, RBANS-attention, and SEADL before and after the 52-weeks follow-up. Results: Subjects taking vs. not taking amantadine were similar at baseline, except subjects taking amantadine had a higher Clinical Global Impression (CGI) Score (p = 0.01). However, the CGI change score did not differ between groups at week 52 (p = 0.10). Using GLM models (controlling for covariates), we found that subjects taking vs. not taking amantadine did not significantly predict total PSPRS, PSPRS-gait and midline, total RBANS, RBANS-attention, or SEADL at baseline, week 52, or the change score between baseline and week 52. Discussion: This post-hoc analysis of the davunetide trial did not find an association between amantadine and gait or cognitive measures in PSP, but was not powered to find such a difference. Future studies should still examine amantadine for symptomatic benefit in multiple PSP subtypes.

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.

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.

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.

Introduction

Increased plasma homocysteine (HC) is a risk factor for dementia in the general population. Levodopa therapy causes increased plasma HC, but it remains unclear whether elevated plasma HC is associated with cognitive impairment in Parkinson's disease (PD).

Methods

The study population includes all participants in the Pacific Northwest Udall Center (PANUC) Clinical cohort at the time of the study, consisting of 294 individuals with PD who had a standardized neuropsychological assessment and plasma collection for HC measurement. We tested the hypothesis that elevated plasma HC is inversely related to cognitive function in patients with PD.

Results

As expected, plasma HC was positively associated with age, disease duration, disease severity, and levodopa usage, while cognitive function was associated with age, education, gender, and APOE genotype, so subsequent analyses controlled for these covariates. When plasma HC was dichotomized as normal (<14 μmol/L) or elevated (≥14 μmol/L), subjects with hyper-homocysteinemia had lower scores on Digit Symbol (p = 0.031), Hopkins Verbal Learning Task (HVLT) Delayed Recall (p = 0.004), and semantic verbal fluency (p = 0.049). When examined as a continuous variable, plasma HC was inversely associated with HVLT Delayed Recall (p = 0.009)) and semantic verbal fluency (p = 0.004), but was not significantly related to Digit symbol, Trail-making test, Judgment of Line Orientation, phonemic verbal fluency, MMSE, or MOCA. When analysis was restricted to non-demented subjects (n = 231), the findings were unchanged.

Conclusions

We conclude that plasma HC is significantly associated with some aspects of cognitive function in PD, and may represent a treatable risk factor for cognitive decline in PD.

Introduction: Parkinson's disease (PD) is associated with a range of cognitive deficits. Few studies have carefully examined the subtle impacts of PD on cognition among patients who do not meet formal criteria for MCI or dementia. The aim of the current study was thus to describe the impact of PD on cognition in those without cognitive impairment in a well-characterized cohort.Methods: Non-cognitively impaired participants (122 with PD, 122 age- and sex-matched healthy volunteers) underwent extensive cognitive testing. Linear regression analyses compared diagnostic group performance across cognitive measures. For cognitive tasks that were significantly different between groups, additional analyses examined group differences restricting the group inclusion to PD participants with mild motor symptoms or disease duration less than 10 years.Results: Processing speed and semantic verbal fluency were significantly lower in the PD group (B = -3.77, 95% CIs [-5.76 to -1.77], p < .001, and B = -2.02, 95% CIs [-3.12, -0.92], p < .001, respectively), even after excluding those with moderate to severe motor symptoms (B = -2.73, 95% CIs [-4.94 to -0.53], p = .015 and B = -2.11, 95% CIs [-3.32 to -0.91], p < .001, respectively) or longer disease duration (B = -3.89, 95% CIs [-6.14 to -1.63], p < .001 and B = -1.58, 95% CIs [-2.78 to -0.37], p = .010, respectively). Semantic verbal fluency remained significantly negatively associated with PD diagnosis after controlling for processing speed (B = -1.66, 95% CIs [-2.79 to -0.53], p = .004).Conclusions: Subtle decline in specific cognitive domains may be present among people diagnosed with PD but without evidence to support a formal cognitive diagnosis. These results suggest the importance of early awareness of the potential for diminishing aspects of cognition in PD even among those without mild cognitive impairment or dementia.

INTRODUCTION:Identification of factors associated with progression of cognitive symptoms in Parkinson's disease (PD) is important for treatment planning, clinical care, and design of future clinical trials. The current study sought to identify whether prediction of cognitive progression is aided by examining baseline cognitive features, and whether this differs according to stage of cognitive disease. METHODS:Participants with PD in the Pacific Udall Center Clinical Consortium who had longitudinal data available and were nondemented at baseline were included in the study (n = 418). Logistic and Cox regression models were utilized to examine the relationship between cognitive, demographic, and clinical variables with risk and time to progression from no cognitive impairment to mild cognitive impairment (PD-MCI) or dementia (PDD), and from PD-MCI to PDD. RESULTS:Processing speed (OR = 1.05, p = 0.009) and working memory (OR = 1.01, p = 0.03) were associated with conversion to PDD among those with PD-MCI at baseline, over and above demographic variables. Conversely, the primary predictive factor in the transition from no cognitive impairment to PD-MCI or PDD was male sex (OR = 4.47, p = 0.004), and males progressed more rapidly than females (p = 0.01). Further, among females with shorter disease duration, progression was slower than for their male counterparts, and poor baseline performance on semantic verbal fluency was associated with shorter time to cognitive impairment in females but not in males. CONCLUSIONS:This study provides evidence for sex differences in the progression to cognitive impairment in PD, while specific cognitive features become more important indicators of progression with impending conversion to PDD.

Cognitive impairment is a common and disabling problem in Parkinson's disease (PD). Identification of genetic variants that influence the presence or severity of cognitive deficits in PD might provide a clearer understanding of the pathophysiology underlying this important nonmotor feature. We genotyped 1105 PD patients from the PD Cognitive Genetics Consortium for 249,336 variants using the NeuroX array. Participants underwent assessments of learning and memory (Hopkins Verbal Learning Test-Revised [HVLT-R]), working memory/executive function (Letter-Number Sequencing and Trail Making Test [TMT] A and B), language processing (semantic and phonemic verbal fluency), visuospatial abilities (Benton Judgment of Line Orientation [JoLO]), and global cognitive function (Montreal Cognitive Assessment). For common variants, we used linear regression to test for association between genotype and cognitive performance with adjustment for important covariates. Rare variants were analyzed using the optimal unified sequence kernel association test. The significance threshold was defined as a false discovery rate-corrected p-value (P_FDR) of 0.05. Eighteen common variants in 13 genomic regions exceeded the significance threshold for one of the cognitive tests. These included GBA rs2230288 (E326K; P_FDR = 2.7 × 10^-4) for JoLO, PARP4 rs9318600 (P_FDR = 0.006), and rs9581094 (P_FDR = 0.006) for HVLT-R total recall, and MTCL1 rs34877994 (P_FDR = 0.01) for TMT B-A. Analysis of rare variants did not yield any significant gene regions. We have conducted the first large-scale PD cognitive genetics analysis and nominated several new putative susceptibility genes for cognitive impairment in PD. These results will require replication in independent PD cohorts.