Parkinson's disease cerebrovascular reactivity pattern: A feasibility study.

A mounting body of research points to cerebrovascular dysfunction as a fundamental element in the pathophysiology of Parkinson's disease (PD). In the current feasibility study, blood-oxygen-level-dependent (BOLD) MRI was used to measure cerebrovascular reactivity (CVR) in response to hypercapnia in 26 PD patients and 16 healthy controls (HC), and aimed to find a multivariate pattern specific to PD. Whole-brain maps of CVR amplitude (i.e., magnitude of response to CO2) and latency (i.e., time to reach maximum amplitude) were computed, which were further analyzed using scaled sub-profile model principal component analysis (SSM-PCA) with leave-one-out cross-validation. A meaningful pattern based on CVR latency was identified, which was named the PD CVR pattern (PD-CVRP). This pattern was characterized by relatively increased latency in basal ganglia, sensorimotor cortex, supplementary motor area, thalamus and visual cortex, as well as decreased latency in the cerebral white matter, relative to HC. There were no significant associations with clinical measures, though sample size may have limited our ability to detect significant associations. In summary, the PD-CVRP highlights the importance of cerebrovascular dysfunction in PD, and may be a potential biomarker for future clinical research and practice.

Comparison of automated and manual quantification methods for neuromelanin-sensitive MRI in Parkinson's disease.

Neuromelanin-sensitive magnetic resonance imaging quantitative analysis methods have provided promising biomarkers that can noninvasively quantify degeneration of the substantia nigra in patients with Parkinson's disease. However, there is a need to systematically evaluate the performance of manual and automated quantification approaches. We evaluate whether spatial, signal-intensity, or subject specific abnormality measures using either atlas based or manually traced identification of the substantia nigra better differentiate patients with Parkinson's disease from healthy controls using logistic regression models and receiver operating characteristics. Inference was performed using bootstrap analyses to calculate 95% confidence interval bounds. Pairwise comparisons were performed by generating 10,000 permutations, refitting the models, and calculating a paired difference between metrics. Thirty-one patients with Parkinson's disease and 22 healthy controls were included in the analyses. Signal intensity measures significantly outperformed spatial and subject specific abnormality measures, with the top performers exhibiting excellent ability to differentiate patients with Parkinson's disease and healthy controls (balanced accuracy = 0.89; area under the curve = 0.81; sensitivity =0.86; and specificity = 0.83). Atlas identified substantia nigra metrics performed significantly better than manual tracing metrics. These results provide clear support for the use of automated signal intensity metrics and additional recommendations. Future work is necessary to evaluate whether the same metrics can best differentiate atypical parkinsonism, perform similarly in de novo and mid-stage cohorts, and serve as longitudinal monitoring biomarkers.

Longitudinal hippocampal subfields, CSF biomarkers, and cognition in patients with Parkinson disease.

Objective: Hippocampal atrophy is an indicator of emerging dementia in PD, though it is unclear whether cerebral spinal fluid (CSF) Abeta-42, t-tau, or alpha-syn predict hippocampal subfield atrophy in a de novo cohort of PD patients. To examine whether levels of CSF alpha-synuclein (alpha-syn), beta-amyloid 1-42 (Abeta-42), or total-tau (t-tau) are associated with hippocampal subfield volumes over time. Methods: We identified a subset of Parkinson's Progression Markers Initiative (PPMI) de novo PD patients with longitudinal T1-weighted imaging (baseline plus at least two additional visits across 12, 24, and 48 months) and CSF biomarkers available at baseline. We performed cross-sectional, regression, and linear mixed model analyses to evaluate the baseline and longitudinal CSF biomarkers, hippocampal subfields, and cognition. A false discovery rate (FDR) was used to correct for multiple comparisons. Results: 88 PD-CN and 21 PD-MCI had high quality longitudinal data. PD-MCI patients exhibited reduced bilateral CA1 volumes relative to PD-CN, though there were no significant differences in CSF biomarkers between these groups. Relationships between CSF biomarkers and hippocampal subfields changed over time, with a general pattern that lower CSF Abeta-42, higher t-tau and higher alpha-syn were associated with smaller hippocampal subfields, primarily in the right hemisphere. Conclusion: We replicated prior reports that demonstrated reduced CA1 volumes in PD-MCI in a de novo PD cohort. CSF biomarkers were associated with individual subfields, with evidence that the increased CSF t-tau was associated with smaller subiculum volumes at baseline and over time, though there was no clear indication that the subfields associated with cognition (CA1 and HATA) were associated with CSF biomarkers.

Reduced and Delayed Cerebrovascular Reactivity in Patients with Parkinson's Disease.

BACKGROUND: Cerebrovascular dysfunction in Parkinson's disease (PD) is heterogeneous and may contribute to disease pathophysiology or progression. There is a need to understand the mechanisms by which cerebrovascular dysfunction is altered in participants with PD. OBJECTIVES: The objective of this study is to test the hypothesis that participants with PD exhibit a significant reduction in the ability of the cerebral vessels to dilate in response to vasoactive challenges relative to healthy controls (HC). METHODS: The current study uses a vasodilatory challenge while participants undergo functional magnetic resonance imaging to quantify the amplitude and delay of cerebrovascular reactivity in participants with PD relative to age and sex-matched HC. An analysis of covariance was used to evaluate differences in cerebrovascular reactivity amplitude and latency between PD participants and HC. RESULTS: A significant main effect of group was observed for whole-brain cerebrovascular reactivity amplitude (F(1, 28) = 4.38, p = 0.046, Hedge's g = 0.73) and latency (F(1, 28) = 16.35, p < 0.001, Hedge's g = 1.42). Participants with PD exhibited reduced whole-brain amplitude and increased latencies in cerebrovascular reactivity relative to HC. The evaluation of regional effects indicates that the largest effects were observed in the cuneus, precuneus, and parietal regions. CONCLUSIONS: PD participants exhibited reduced and delayed cerebrovascular reactivity. This dysfunction may play an important role in chronic hypoxia, neuroinflammation, and protein aggregation, mechanisms that could lead to disease progression. Cerebrovascular reactivity may serve as an important biomarker and target for future interventions. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

GuitarPD: A Randomized Pilot Study on the Impact of Nontraditional Guitar Instruction on Functional Movement and Well-Being in Parkinson's Disease.

Playing musical instruments may have positive effects on motor, emotional, and cognitive deficits in patients with Parkinson's disease (PD). This pilot study examined the feasibility of a six-week nontraditional guitar instruction program for individuals with PD. Twenty-six participants with idiopathic PD (Age: 67.22 ± 8.07; 17 males) were randomly assigned to two groups (intervention first or 6 weeks of usual care control exposure) with stepwise exposure to the guitar intervention condition with cross-over at six weeks. Outcomes were assessed at baseline, 6, 12, and 18 weeks. Twenty-four participants completed the study. Combined analysis of the groups showed significant BDI-II improvement immediately after intervention completion (3.04 points, 95% CI [-5.2, -0.9], p = 0.04). PDQ-39 total quality of life scores improved from baseline to immediately postintervention 5.19 points (95% CI [-9.4, -1.0]) at trend significance (corrected p = 0.07). For Group 1 (exposed to the intervention first), MDS-UPDRS total scores improved by a mean of 8.04 points (95% CI [-12.4, -3.7], p = 0.004) and remained improved at 12 weeks by 10.37 points (95% CI [-14.7, -6.0], p < 0.001). This group also had significant improvements in mood and depression at weeks 6 and 12, remaining significant at week 18 (BDI-II: 3.75, 95% CI [-5.8, -1.7], p = 0.004; NeuroQoL-depression: 10.6, 95% CI [-4.9. -1.4], p = 0.004), and in anxiety at week 6 and week 18 (NeuroQoL; 4.42, 95% CI [-6.8, -2.1], p = 0.004; 3.58, 95% CI [-5.9, -1.2], p = 0.02, respectively). We found clinically and statistically significant improvements in mood/anxiety after 6 weeks of group guitar classes in individuals with PD. Group guitar classes can be a feasible intervention in PD and may improve mood, anxiety, and quality of life.

Movement Disorders in Multiple Sclerosis and Other Demyelinating Diseases: A Retrospective Review From a Tertiary Academic Center.

BACKGROUND: Movement disorders (MDs) have been described in demyelinating diseases (DDs). However, data is lacking in the effective treatment of these MD as well as in a potential correlation between DD lesions localization and the phenomenology of the MD and its response to treatment. METHODS: Retrospective review of 185 patients with MD and DD seen at our center over a period of 7 years. Clinical imaging, medications, and therapeutic responses to both MD and DD treatments were reviewed. RESULTS: Of the 185 patients, 62 were excluded because of a diagnosis of spasticity without any other MD. One hundred twenty three patients with DD (75% female, age 48.8±12.8 y) had one or more MD. The most common MD was ataxia followed by isolated tremor. Forty-two patients (34%) received any treatment for MD, 29 (69%) of which responded at least partially to a first MD agent and 78.6% responded at least partially to a second or third agent. Responders to the first MD therapy were more likely to have a lesion in the basal ganglia or the cerebellum, and less likely to have a lesion in the brainstem or the spinal cord, but these results could be biased by a lower-than-expected frequency of tonic spasms in our series. No correlation between DD lesions localization and the phenomenology of the MD was discovered. CONCLUSIONS: MD are common in DD and are frequently overlooked or undertreated. MD in this sample have a 69% therapeutic response to a first trial. Greater awareness of potential therapeutic options is needed to decrease disability.

Movement Disorders Virtual Fellowship Training in Times of Coronavirus Disease 2019: A Single-Center Experience.

Objective: To describe the impact a global pandemic has had on a teaching movement disorders program, as well as its subsequent transition to telemedicine. Methods: In the midst of the coronavirus disease 2019 (COVID-19) pandemic, we transitioned our movement disorders fellowship program virtually over the course of a few days. Here we describe the parameters used for the telemedicine fellow supervised clinic visit over the course of 2 months. Fellow's input was obtained from a brief survey at the end of the experience. Faculty's experience was collected upon independent faculty discussions. We also summarize the challenges and advantages of this teaching experience and its downsides. Results: A total of 130 patients (102 follow-up and 28 new patients) were seen over 22 clinic days with any of our 3 fellows being supervised by 1 of the 6 attending physicians. The main challenges were related to technical difficulties and lack of portions of the examination such as tone, reflexes, and sensory testing. The main advantages were related to increased patient access and a decrease in scheduling barriers. The overall satisfaction with the experience of the fellows was positive (69%). Conclusions: This sample shows the feasibility (despite lack of prior experience) of virtual clinical supervision of movement disorders fellows for follow-up and new complex patient encounters. This novel method for movement disorders training has implications for training locally, nationally, and internationally. Limitations and possible future directions such as the inclusion of nonsynchronous recordings and devices for tone and balance testing are also discussed.

Earlier Intervention with Deep Brain Stimulation for Parkinson's Disease.

Neuromodulation of subcortical areas of the brain as therapy to reduce Parkinsonian motor symptoms was developed in the mid-twentieth century and went through many technical and scientific advances that established specific targets and stimulation parameters. Deep Brain Stimulation (DBS) was approved by the FDA in 2002 as neuromodulation therapy for advanced Parkinson's disease, prompting several randomized controlled trials that confirmed its safety and effectiveness. The implantation of tens of thousands of patients in North America and Europe ignited research into its potential role in early disease stages and the therapeutic benefit of DBS compared to best medical therapy. In 2013 the EARLY-STIM trial provided Class I evidence for the use of DBS earlier in Parkinson's disease. This finding led to the most recent FDA approval in patients with at least 4 years of disease duration and 4 months of motor complications as an adjunct therapy for patients not adequately controlled with medications. This following review highlights the historical development and advances made overtime in DBS implantation, the current application, and the challenges that come with it.

DNAJB6 myopathy: a vacuolar myopathy with childhood onset.

INTRODUCTION: DNAJB6 mutations cause an autosomal dominant myopathy that can manifest as limb-girdle muscular dystrophy (LGMD1D/1E) or distal-predominant myopathy. In the majority of patients this myopathy manifests in adulthood and shows vacuolar changes on muscle biopsy. METHODS: Clinical, electrophysiological, pathological, and molecular findings are reported. RESULTS: We report a 56-year-old woman, who, like 3 other family members, became symptomatic in childhood with slowly progressive limb-girdle muscle weakness, normal serum creatine kinase (CK) values, and myopathic electromyographic findings. Muscle biopsy showed vacuolar changes and congophilic inclusions, and molecular analysis revealed a pathogenic mutation in the DNAJB6 gene. Differences and similarities with previously described cases are assessed. CONCLUSIONS: Childhood-onset of DNAJB6 myopathy is more frequent than previously believed; congophilic inclusions may be present in the muscle of these patients.

Using paraquat to generate anion free radicals and hydrogen peroxide in in vitro: Antioxidant effect of vitamin E: A procedure to teach theoretical and experimental principles of reactive oxygen species biochemistry.

The theoretical basis of reactive oxygen species and their impact on health issues are relatively easy to understand by biomedical students. The detection of reactive oxygen species requires expensive equipment, the procedures are time consuming and costly, and the results are hard to interpret. Moreover, cause-and-effect relationships in the living system are not so evident. In this report, we adapted a two-step procedure to detect anion superoxide radicals and hydrogen peroxide generation in lymphocytes exposed to paraquat by using nitroblue tetrazolium salt and dihydrorhodamine, respectively. Also, a two-step assay was performed to evaluate lymphocyte viability and nuclei morphologic changes on paraquat exposure for 1 and 24 hours incubation time by using trypan blue exclusion assay and acridine orange/ethidium bromide staining technique, respectively. Vitamin E was used as antioxidant to inhibit the deleterious effects of paraquat on cells. Students learned how to (i) design and perform experiments in the laboratory, (ii) read critical scientific literature, and (iii) discuss and contrast relevant information about reactive oxygen species as causative agents of cell death phenomenon.