Amie Peterson

Treatment of Parkinson’s Disease with Trophic Factors

SummaryTrophic 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.

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.

Association of cognitive domains with postural instability/gait disturbance in Parkinson's disease

INTRODUCTION Research suggests an association between global cognition and postural instability/gait disturbance (PIGD) in Parkinson disease (PD), but the relationship between specific cognitive domains and PIGD symptoms is not clear. This study examined the association of cognition (global and specific cognitive domains) with PIGD symptoms in a large, well-characterized sample of individuals with PD. METHODS Cognitive function was measured with a detailed neuropsychological assessment, including global cognition, executive function, memory, visuospatial function, and language. PIGD symptoms were measured using the Movement Disorder Society Unified Parkinsons Disease Rating Scale (MDS-UPDRS) Part III, Motor Examination subscale. Multiple linear regression analyses were performed to assess the relationship between cognition and PIGD symptoms with models adjusting for age, sex, education, enrollment site, disease duration, and motor symptom severity. RESULTS The analysis included 783 participants, with mean (standard deviation) age of 67.3 (9.7) years and median (interquartile range) MDS-UPDRS Motor Subscale score of 26 (17, 35). Deficits in global cognition, executive function, memory, and phonemic fluency were associated with more severe PIGD symptoms. Deficits in executive function were associated with impairments in gait, freezing, and postural stability, while visuospatial impairments were associated only with more severe freezing, and poorer memory function was associated only with greater postural instability. DISCUSSION While impairments in global cognition and aspects of executive functioning were associated with more severe PIGD symptoms, specific cognitive domains were differentially related to distinct PIGD components, suggesting the presence of multiple neural pathways contributing to associations between cognition and PIGD symptoms in persons with PD.

Serum vitamin d concentrations are associated with falling and cognitive function in older adults

ObjectivesTo elucidate the mechanism through which vitamin D is associated with decreased falls.DesignThis was a convenience sample from a larger observational study examining correlations between vitamin D and 1) falls, 2) motor function, and 3) cognition (n=159).SettingFalls data were collected via weekly on-line surveys completed in the participants’ homes. Yearly evaluations of motor and cognitive function were conducted in an out-patient setting of a large tertiary medical center.ParticipantsParticipants from the Intelligent Systems for Assessment of Aging Changes Study (ISAAC), a community-based cohort study of independently living older adults over age 70, who had vitamin D concentration within 6 months of clinical evaluations were included in the analysis.ResultsParticipants mean age was 85 years and 74% were women. Fallers (n=37) had significantly lower vitamin D concentration (32.9ng/ml) compared to non-fallers (39.2ng/ml) (p<0.01). The relationship between vitamin D and falls remained significant after adjusting for age, health status (via CIRS), and supplement use (p=0.004). Vitamin D concentration were significantly associated with cognitive impairment (Clinical Dementia Rating = 0.5) (p=0.02) and MMSE (p<0.01) after adjusting for age, gender, and education. Vitamin D concentrations did not correlate with any motor measures.ConclusionVitamin D concentrations correlated with cognition and falls, but not with motor measures. Further research is needed to demonstrate a causal relationship between vitamin D and cognitive function and determine if cognition plays a role in falls reduction.

Cognitive profile of LRRK2-related Parkinson's disease.

Increasing evidence suggests that genetic factors play a role in the variability associated with cognitive performance in Parkinsons 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.

Evaluation of mild cognitive impairment subtypes in Parkinson's disease

Mild cognitive impairment in Parkinsons disease (PD‐MCI) is common and increases the risk for dementia. Establishing distinct PD‐MCI cognitive subtypes could be valuable for eventually predicting those most likely to convert to dementia. However, the study of PD‐MCI subtypes has not yielded consistent results among cohorts. To determine whether there are distinct cognitive subtypes among participants diagnosed with PD‐MCI in the Pacific Northwest Udall Center Clinical Consortium, we cognitively subtyped 95 patients with PD‐MCI, using the Movement Disorders Society Task Force diagnostic guidelines. Psychometric test scores were then subjected to principle components factor analysis to determine whether similar cognitive subgroups could be identified using statistical methodology. Multiple‐domain PD‐MCI was diagnosed in 95% of the sample, and a range of cognitive impairments were noted. Factor analysis yielded seven factors and demonstrated overlap of phonemic verbal fluency on two factors, as well as the loading of verbal fluency on the same factor as a visuospatial measure; however, these factors did not partition the sample into distinct cognitive subtypes. Separation of cognitive subtypes based on the current PD‐MCI criteria, or via statistical methods, may not provide sufficient information to describe distinct PD groups. Future efforts to validate the PD‐MCI criteria and identify combinations of genetic or other risk factors for cognitive impairment are warranted.

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

Balance problems and falls are a major source of morbidity and mortality in patients with Parkinsons disease. Vitamin D supplementation reduces falls and sway in neurologically intact elderly fallers, but effects in Parkinsons disease are not 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 Parkinsons 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 Parkinsons 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.

Pacific Northwest Udall Center of Excellence Clinical Consortium: Study Design and Baseline Cohort Characteristics

BACKGROUND The substantial proportion of individuals with Parkinsons disease (PD) who have or are expected to develop concomitant cognitive impairment emphasizes the need for large, well-characterized participant cohorts to serve as a basis for research into the causes, manifestations, and potential treatments of cognitive decline in those with PD. OBJECTIVE To establish a multi-site clinical core that cognitively and clinically characterizes patients with PD by obtaining quality longitudinal clinical, neuropsychological, and validated biomarker data. METHODS Six hundred nineteen participants with idiopathic PD (68.0 ± 9.1 years, 7.1 ± 6.2 years since diagnosis, 70% males) were enrolled in the Pacific Northwest Udall Center (PANUC), one of the Morris K. Udall Centers of Excellence for Parkinsons Research, Clinical Consortium and underwent comprehensive clinical and neuropsychological assessment. Participants were diagnosed with no cognitive impairment (PD-NCI), mild cognitive impairment (PD-MCI), or dementia (PDD) at a diagnostic consensus conference. RESULTS A substantial proportion of the overall sample was diagnosed with cognitive impairment at baseline: 22% with PDD and 59% with PD-MCI. A higher rate of cognitive impairment was observed in men than women (87% vs. 68%, p < 0.0001), despite a higher level of education. Most patients older than 50 years at the time of diagnosis and with disease duration greater than 10 years were cognitively impaired or demented. CONCLUSIONS The PANUC Clinical Consortium is a clinically and cognitively well-characterized cohort of patients with PD. Baseline cohort characteristics demonstrate a high rate of cognitive impairment in the sample, as well as potential sex differences with regard to cognitive diagnosis. The PANUC Clinical Consortium, with its access to biomarker, genetic, and autopsy data, provides an excellent foundation for detailed research related to cognitive impairment in 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.