Vitamin B12 measurements across neurodegenerative disorders.

Background:Vitamin B12 deficiency causes a number of neurological features including cognitive and psychiatric disturbances, gait instability, neuropathy, and autonomic dysfunction. Clinical recognition of B12 deficiency in neurodegenerative disorders is more challenging because it causes defects that overlap with expected disease progression. We sought to determine whether B12 levels at the time of diagnosis in patients with Parkinson's disease (PD) differed from those in patients with other neurodegenerative disorders. Methods:We performed a cross-sectional analysis of B12 levels obtained around the time of diagnosis in patients with PD, Multiple System Atrophy (MSA), Dementia with Lewy Bodies (DLB), Alzheimer's disease (AD), Progressive Supranuclear Palsy (PSP), Frontotemporal Dementia (FTD), or Mild Cognitive Impairment (MCI). We also evaluated the rate of B12 decline in PD, AD, and MCI. Results:In multivariable analysis adjusted for age, sex, and B12 supplementation, we found that B12 levels were significantly lower at time of diagnosis in patients with PD than in patients with PSP, FTD, and DLB. In PD, AD, and MCI, the rate of B12 decline ranged from - 17 to - 47 pg/ml/year, much greater than that reported for the elderly population. Conclusions:Further studies are needed to determine whether comorbid B12 deficiency affects progression of these disorders

Toward understanding ambulatory activity decline in Parkinson disease

BACKGROUND: Declining ambulatory activity represents an important facet of disablement in Parkinson disease (PD). OBJECTIVE: The primary study aim was to compare the 2-year trajectory of ambulatory activity decline with concurrently evolving facets of disability in a small cohort of people with PD. The secondary aim was to identify baseline variables associated with ambulatory activity at 1- and 2-year follow-up assessments. DESIGN: This was a prospective, longitudinal cohort study. METHODS: Seventeen people with PD (Hoehn and Yahr stages 1-3) were recruited from 2 outpatient settings. Ambulatory activity data were collected at baseline and at 1- and 2-year annual assessments. Motor, mood, balance, gait, upper extremity function, quality of life, self-efficacy, and levodopa equivalent daily dose data and data on activities of daily living also were collected. RESULTS: Participants displayed significant 1- and 2-year declines in the amount and intensity of ambulatory activity concurrently with increasing levodopa equivalent daily dose. Worsening motor symptoms and slowing of gait were apparent only after 2 years. Concurrent changes in the remaining clinical variables were not observed. Baseline ambulatory activity and physical performance variables had the strongest relationships with 1- and 2-year mean daily steps. LIMITATIONS: The sample was small and homogeneous. CONCLUSIONS: Future research that combines ambulatory activity monitoring with a broader and more balanced array of measures would further illuminate the dynamic interactions among evolving facets of disablement and help determine the extent to which sustained patterns of recommended daily physical activity might slow the rate of disablement in PD.This study was funded primarily by the Davis Phinney Foundation and the Parkinson Disease Foundation. Additional funding was provided by Boston University Building Interdisciplinary Research Careers in Women's Health (K12 HD043444), the National Institutes of Health (R01NS077959), the Utah Chapter of the American Parkinson Disease Association (APDA), the Greater St Louis Chapter of the APDA, and the APDA Center for Advanced PD Research at Washington University. (Davis Phinney Foundation; Parkinson Disease Foundation; K12 HD043444 - Boston University Building Interdisciplinary Research Careers in Women's Health; R01NS077959 - National Institutes of Health; Utah Chapter of the American Parkinson Disease Association (APDA); Greater St Louis Chapter of the APDA; APDA Center for Advanced PD Research at Washington University

Cognitive-behavioral therapy for anxiety in Parkinson's disease

Parkinson's disease (PD) is characterized by motor symptoms, but nonmotor symptoms also significantly impair daily functioning and reduce quality of life. Anxiety is prevalent and debilitating in PD, but remains understudied and undertreated. Much affective research in PD focuses on depression rather than anxiety, and as such, there are no evidence-based treatments for anxiety in this population. Cognitive-behavioral therapy (CBT) has shown promise for treating depression in PD and may be efficacious for anxiety. This exploratory study implemented a multiple-baseline single-case experimental design to evaluate the utility and feasibility of CBT for individuals with PD who also met criteria for a DSM-5 anxiety disorder ( n = 9). Participants were randomized to a 2-, 4-, or 6-week baseline phase, followed by 12 CBT sessions, and two post treatment assessments (immediately post treatment and 6-week follow-up). Multiple outcome measures of anxiety and depression were administered weekly during baseline and intervention. Weekly CBT sessions were conducted in-person ( n = 5) or via secure videoconferencing ( n = 4). At post treatment, seven of the nine participants showed significant reductions in anxiety and/or depression, with changes functionally related to treatment and most improvements maintained at 6-week follow-up. Effects of CBT on secondary outcomes varied across participants, with preliminary evidence for reduction in fear of falling. Adherence and retention were high, as were treatment satisfaction and acceptability. The findings of this pilot study provide preliminary evidence for the utility of CBT as a feasible treatment for anxiety and comorbid depressive symptoms in PD and highlight the potential of telehealth interventions for mood in this population.Accepted manuscrip

Screening for Parkinson’s Disease with Response Time Barriers: A Pilot Study

Background: Although significant response time deficits (both reaction time and movement time) have been identified in numerous studies of patients with Parkinson’s disease (PD), few attempts have been made to evaluate the use of these measures in screening for PD. Methods: Receiver operator characteristic curves were used to identify cutoff scores for a unitweighted composite of two choice response tasks in a sample of 40 patients and 40 healthy participants. These scores were then cross-validated in an independent sample of 20 patients and 20 healthy participants. Results: The unit-weighted movement time composite demonstrated high sensitivity (90%) and specificity (90%) in the identification of PD. Movement time was also significantly correlated (r = 0.59, p \u3c 0.025) with the motor score of the Unified Parkinson’s Disease Rating Scale (UPDRS). Conclusions: Measures of chronometric speed, assessed without the use of biomechanically complex movements, have a potential role in screening for PD. Furthermore, the significant correlation between movement time and UPDRS motor score suggests that movement time may be useful in the quantification of PD severity

AN EXAMINATION OF CONCURRENT DISCRIMINATION LEARNING WITHIN INDIVIDUALS WITH PARKINSON’S DISEASE

The main focus of this research is to further understand memory formation by examining the role of the basal ganglia in learning. Broadly, this study examines how the basal ganglia may play a role in a task that has been associated with declarative memory mechanisms, in this case the concurrent discrimination task (CDT). Specifically, we examine how performance is affected on the CDT when structures of the basal ganglia are compromised by recruiting individuals with Parkinson’s disease (PD). Past work examining the performance of individuals with PD on a CDT have had contradicting results and have proposed that participants may adopt different strategies that rely variously either on declarative or non-declarative strategy (Moody et. al., 2010). We aimed to reduce strategy differences by making changes in stimuli, increasing the number of stimuli significantly, increasing the number of learning blocks, and making all participants explicitly aware of the task structure and goals. By making the goals explicit, we predicted that we would engage a declarative mechanism in both PD and control individuals. To examine declarative memory formation we used the Remember Know task (RK). However, since used a significantly larger set size of stimuli we hypothesized that individuals with PD would perform significantly worse on the CDT than control individuals. The current study reveals that there are no significant differences in performance between individuals with PD and control participants on both the CDT and RK task. We attribute these results to design of our paradigm and stimuli which may have influenced individuals to engage in declarative strategies to perform the CDT reasonably well

Predicting Progression in Parkinson's Disease Using Baseline and 1-Year Change Measures.

BackgroundImproved prediction of Parkinson's disease (PD) progression is needed to support clinical decision-making and to accelerate research trials.ObjectivesTo examine whether baseline measures and their 1-year change predict longer-term progression in early PD.MethodsParkinson's Progression Markers Initiative study data were used. Participants had disease duration ≤2 years, abnormal dopamine transporter (DAT) imaging, and were untreated with PD medications. Baseline and 1-year change in clinical, cerebrospinal fluid (CSF), and imaging measures were evaluated as candidate predictors of longer-term (up to 5 years) change in Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) score and DAT specific binding ratios (SBR) using linear mixed-effects models.ResultsAmong 413 PD participants, median follow-up was 5 years. Change in MDS-UPDRS from year-2 to last follow-up was associated with disease duration (β= 0.351; 95% CI = 0.146, 0.555), male gender (β= 3.090; 95% CI = 0.310, 5.869), and baseline (β= -0.199; 95% CI = -0.315, -0.082) and 1-year change (β= 0.540; 95% CI = 0.423, 0.658) in MDS-UPDRS; predictors in the model accounted for 17.6% of the variance in outcome. Predictors of percent change in mean SBR from year-2 to last follow-up included baseline rapid eye movement sleep behavior disorder score (β= -0.6229; 95% CI = -1.2910, 0.0452), baseline (β= 7.232; 95% CI = 2.268, 12.195) and 1-year change (β= 45.918; 95% CI = 35.994,55.843) in mean striatum SBR, and 1-year change in autonomic symptom score (β= -0.325;95% CI = -0.695, 0.045); predictors in the model accounted for 44.1% of the variance.ConclusionsBaseline clinical, CSF, and imaging measures in early PD predicted change in MDS-UPDRS and dopamine-transporter binding, but the predictive value of the models was low. Adding the short-term change of possible predictors improved the predictive value, especially for modeling change in dopamine-transporter binding

Prevalence and diagnosis of Parkinson's disease: a community study

Clinicopathological and community studies have demonstrated misdiagnosis in Parkinson’s disease (PD). Clinical trials of antiparkinson medication have also shown a subset of patients labelled as having PD have normal functional brain dopaminergic imaging. Conditions commonly misdiagnosed as PD include Essential tremor (ET), vascular Parkinsonism (VP) and dystonic tremor (DT). This thesis examines the accuracy of clinical diagnosis of PD in a community setting by identifying misdiagnosed cases and supervising antiparkinson medication withdrawal. Prescription database searches and GP case record review were carried out in 92 West Scotland GP practices within a population of 511,927. 610 patients on antiparkinson medication for a PD diagnosis were identified and age-adjusted prevalence was 129.5 per 100,000. Patients were invited for assessment if there was (a) no increase in dopaminergic drug dose or (b) no recorded progression of disease over time, suggestive of possible misdiagnosis. 64 patients were assessed and this was supplemented with FP-CIT SPECT scanning in 25 uncertain cases. Patients considered unlikely to have PD were advised to reduce and discontinue antiparkinson drugs, with repeat PD motor scoring over 6 months. 33 of 64 patients (51.6%) successfully completed antiparkinson medication withdrawal. An age, sex and disease duration matched control group was also assessed. The selection criteria allowed identification of a high proportion of misdiagnosed cases and FP-CIT SPECT was a useful diagnostic tool for assessing patients (previously diagnosed as PD) in whom there was diagnostic doubt

Doctor of Philosophy

dissertationParkinson disease (PD) is a progressive neurodegenerative disorder with selective damage of dopaminergic neurons within the Basal Ganglia (BG), leading to the most clearly recognized sequelae of motor deficits observed in PD. The BG have also been shown to be important during implicit motor sequence learning (IMSL), and individuals with BG lesions have demonstrated impairment in IMSL compared to healthy age matched controls. Additionally, individuals with PD are typically prescribed dopamine replacement or agonist medications, which have been found to reduce the observed movement deficits. However, it has been observed that dopamine addition may potentially impair IMSL. The primary purpose of this paper was to describe impairments in IMSL in individuals with PD, describe a neurobiological model for the observed deficits in IMSL, and to determine the impact of dopamine addition on acquisition performance and retention learning of repeated segments during a standing implicit continuous tracking task in individuals with PD. We hypothesized that IMSL would be impaired in individuals with PD on their usual dosage of dopamine. Secondarily, the impact of age, PD, and dopamine on sequence-specific integration was assessed, and it was hypothesized that there would be a graded deficit related to age, PD, and dopamine on sequencespecific integration. Finally, the relationship of spatial and temporal parameters within sequence learning was assessed as an exploratory aim. The results of this study supported an IMSL deficit primarily related to age and secondarily related to PD, but not dopamine replacement. Additionally, individuals with PD, regardless of medication, demonstrated impaired spatial integration compared to healthy young and elder participants. The type of task performed in this study was a demanding postural task compared to the traditional IMSL paradigms using the upper extremity and task difficulty could account for the lack of observed difference during acquisition. Longer time to practice the paradigm may be required to observe improved performance. Finally, although IMSL has been observed to be impaired in individuals with PD, a better understanding of the IMSL deficit related to the impact of medication and age during a standing motor task is warranted