Cognitive profile of LRRK2-related Parkinson's disease.

BACKGROUND: Increasing evidence suggests that genetic factors play a role in the variability associated with cognitive performance in Parkinson's disease (PD). Mutations in the LRRK2 gene are the most common cause of monogenic PD; however, the cognitive profile of LRRK2-related PD is not well-characterized. METHODS: A cohort of 1,447 PD patients enrolled in the PD Cognitive Genetics Consortium was screened for LRRK2 mutations and completed detailed cognitive testing. Associations between mutation carrier status and cognitive test scores were assessed using linear regression models. RESULTS: LRRK2 mutation carriers (n = 29) demonstrated better performance on the Mini Mental State Examination (P = 0.03) and the Letter-Number Sequencing Test (P = 0.005). A smaller proportion of LRRK2 carriers were demented (P = 0.03). CONCLUSIONS: Our cross-sectional study demonstrates better performance on certain cognitive tests, as well as lower rates of dementia in LRRK2-related PD. Future longitudinal studies are needed to determine whether LRRK2 mutation carriers exhibit slower cognitive decline. © 2015 International Parkinson and Movement Disorder Society.

APOE, MAPT, and SNCA genes and cognitive performance in Parkinson disease.

IMPORTANCE: Cognitive impairment is a common and disabling problem in Parkinson disease (PD) that is not well understood and is difficult to treat. Identification of genetic variants that influence the rate of cognitive decline or pattern of early cognitive deficits in PD might provide a clearer understanding of the etiopathogenesis of this important nonmotor feature. OBJECTIVE: To determine whether common variation in the APOE, MAPT, and SNCA genes is associated with cognitive performance in patients with PD. DESIGN, SETTING, AND PARTICIPANTS: We studied 1079 PD patients from 6 academic centers in the United States who underwent assessments of memory (Hopkins Verbal Learning Test-Revised [HVLT-R]), attention and executive function (Letter-Number Sequencing Test and Trail Making Test), language processing (semantic and phonemic verbal fluency tests), visuospatial skills (Benton Judgment of Line Orientation test), and global cognitive function (Montreal Cognitive Assessment). Participants underwent genotyping for the APOE ε2/ε3/ε4 alleles, MAPT H1/H2 haplotypes, and SNCA rs356219. We used linear regression to test for association between genotype and baseline cognitive performance with adjustment for age, sex, years of education, disease duration, and site. We used a Bonferroni correction to adjust for the 9 comparisons that were performed for each gene. MAIN OUTCOMES AND MEASURES: Nine variables derived from 7 psychometric tests. RESULTS: The APOE ε4 allele was associated with lower performance on the HVLT-R Total Recall (P = 6.7 × 10(-6); corrected P [Pc] = 6.0 × 10(-5)), Delayed Recall (P = .001; Pc = .009), and Recognition Discrimination Index (P = .004; Pc = .04); a semantic verbal fluency test (P = .002; Pc = .02); the Letter-Number Sequencing Test (P = 1 × 10(-5); Pc = 9 × 10(-5)); and Trail Making Test B minus Trail Making Test A (P = .002; Pc = .02). In a subset of 645 patients without dementia, the APOE ε4 allele was associated with lower scores on the HVLT-R Total Recall (P = .005; Pc = .045) and the semantic verbal fluency (P = .005; Pc = .045) measures. Variants of MAPT and SNCA were not associated with scores on any tests. CONCLUSIONS AND RELEVANCE: Our data indicate that the APOE ε4 allele is an important predictor of cognitive function in PD across multiple domains. Among PD patients without dementia, the APOE ε4 allele was only associated with lower performance on word list learning and semantic verbal fluency, a pattern more typical of the cognitive deficits seen in early Alzheimer disease than PD.

A review of vitamin D and Parkinson's disease.

The role of vitamin D in bone health has been known for over a century. More recent research has suggested that vitamin D may play a role in the muscular, immune, endocrine, and central nervous systems. Animal research suggests that vitamin D may have some protective effects against toxic insults that are known to damage dopamine cells, the primary cells to degenerate in PD. Persons with PD tend to have lower vitamin D levels than persons of similar ages without PD. Vitamin D levels are generally associated with bone mineral density (BMD) in persons with PD, but simply giving vitamin D does not appear to improve BMD. Results of genetic studies examining polymorphism of the vitamin D receptor and PD risk, severity, or age at onset have shown variable results, with FokI CC seeming to possibly carry some increased risk of PD. Amount of sun exposure and vitamin D levels in earlier life may influence the risk of developing PD. Cross-sectional research suggests a relationship between vitamin D levels and severity of PD symptoms. A single intervention study did show some improvement in PD with vitamin D supplementation. Vitamin D may have effects on PD symptoms and perhaps even on the risk of disease development or disease progression. More well designed intervention studies are needed to confirm the effect of vitamin D on PD symptoms. Human neuroprotection studies are needed, but probably not feasible until better biomarkers are established.

Memory, mood, and vitamin D in persons with Parkinson's disease.

BACKGROUND: Research in recent years has suggested a role of vitamin D in the central nervous system. The final converting enzyme and the vitamin D receptor are found throughout the human brain. From animal studies vitamin D appears important in neurodevelopment, up-regulation of neurotrophic factors, stabilization of mitochondrial function, and antioxidation. OBJECTIVE: To examine the relationship between serum vitamin D and neuropsychiatric function in persons with Parkinson's disease (PD). METHODS: This is an add-on study to a longitudinal study following neuropsychiatric function in persons with PD. Baseline neuropsychiatric performance and serum 25-hydroxyvitamin D were examined for 286 participants with PD. Measures of global cognitive function (MMSE, MOCA, Mattis Dementia Scale), verbal memory (Hopkins Verbal Learning Test), fluency (animals, vegetables, and FAS words), visuospatial function (Benton Line Orientation), executive function (Trails Making Test and Digit-Symbol Substitution), PD severity (Hoehn & Yahr and Unified Parkinson's Disease Rating Scale) and depression (Geriatric Depression Scale (GDS)) were administered. Multivariate linear regression assessed the association between vitamin D concentration and neuropsychiatric function, in the entire cohort as well as the non-demented and demented subsets. RESULTS: Using a multivariate model, higher vitamin D concentrations were associated with better performance on numerous neuropsychiatric tests in the non-demented subset of the cohort. Significant associations were specifically found between vitamin D concentration and verbal fluency and verbal memory (t = 4.31, p < 0.001 and t = 3.04, p = 0.0083). Vitamin D concentrations also correlated with depression scores (t = -3.08, p = 0.0083) in the non-demented subset. CONCLUSIONS: Higher plasma vitamin D is associated with better cognition and better mood in this sample of PD patients without dementia. Determination of causation will require a vitamin D intervention study.

The relationship between balance control and vitamin D in Parkinson's disease-a pilot study.

BACKGROUND: Balance problems and falls are a major source of morbidity and mortality in patients with Parkinson's disease. Vitamin D supplementation reduces falls and sway in neurologically intact elderly fallers, but effects in Parkinson's disease are not established. METHODS: To study this relationship and select outcome measures for a vitamin D intervention study, balance function and vitamin D concentration were quantified in a series of Parkinson's patients in a cross-sectional, observational study. Participants underwent a battery of 5 balance tests. RESULTS: Serum vitamin D concentrations were correlated inversely with Parkinson's severity, as measured by the motor Unified Parkinson's Disease Rating Scale. Among the balance measures, vitamin D concentrations were correlated with automatic posture responses to backwards translation, specifically with response strength and stance weight asymmetry. CONCLUSIONS: These findings support the hypothesis that vitamin D plays a role in balance among patients with Parkinson's disease and identify specific outcome measures for detecting effects of vitamin D upon balance.

Treatment of Parkinson's disease with trophic factors.

Trophic factors are proteins that support and protect subpopulations of cells. A number have been reported to act on dopaminergic neurons in vitro and in vivo, making them potential therapeutic candidates for Parkinson's disease. All of these candidate factors protect dopaminergic neurons if given prior to, or with, selective neurotoxins. Fewer trophic factors, primarily glial-derived neurotrophic factor (GDNF) and its relative, neurturin (NRTN; also known as NTN), have been shown to restore function in damaged dopamine neurons after the acute effects of neurotoxins have subsided. A major barrier to clinical translation has been delivery. GDNF delivered by intracerebroventricular injection in patients was ineffective, probably because GDNF did not reach the target, the putamen, and intraputaminal infusion was ineffective, probably because of limited distribution within the putamen. A randomized clinical trial with gene therapy for NRTN is underway, in an attempt to overcome these problems with targeting and distribution. Other strategies are available to induce trophic effects in the CNS, but have not yet been the focus of human research. To date, clinical trials have focused on restoration of function (i.e., improvement of parkinsonism). Protection (i.e., slowing or halting disease progression and functional decline) might be a more robust effect of trophic agents. Laboratory research points to their effectiveness in protecting neurons and even restoring dopaminergic function after a monophasic neurotoxic insult. Utility for such compounds in patients with Parkinson's disease and ongoing loss of dopaminergic neurons remains to be proven.