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.

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.

Catatonia after deep brain stimulation successfully treated with lorazepam and right unilateral electroconvulsive therapy: a case report.

OBJECTIVES: The presence of a deep brain stimulator (DBS) in a patient who develops neuropsychiatric symptoms poses unique diagnostic challenges and questions for the treating psychiatrist. Catatonia has been described only once, during DBS implantation, but has not been reported in a successfully implanted DBS patient. METHODS: We present a case of a patient with bipolar disorder and renal transplant who developed catatonia after DBS for essential tremor. RESULTS: The patient was successfully treated for catatonia with lorazepam and electroconvulsive therapy after careful diagnostic workup. Electroconvulsive therapy has been successfully used with DBS in a handful of cases, and certain precautions may help reduce potential risk. CONCLUSIONS: Catatonia is a rare occurrence after DBS but when present may be safely treated with standard therapies such as lorazepam and electroconvulsive therapy.

Differential diagnosis of psychiatric symptoms after deep brain stimulation for movement disorders.

OBJECTIVES: The presence of a deep brain stimulator (DBS) in a patient with a movement disorder who develops psychiatric symptoms poses unique diagnostic and therapeutic challenges for the treating clinician. Few sources discuss approaches to diagnosing and treating these symptoms. MATERIALS AND METHODS: The authors review the literature on psychiatric complications in DBS for movement disorders and propose a heuristic for categorizing symptoms according to their temporal relationship with the DBS implantation process. RESULTS: Psychiatric symptoms after DBS can be categorized as preimplantation, intra-operative/perioperative, stimulation related, device malfunction, medication related, and chronic stimulation related/long term. Once determined, the specific etiology of a symptom guides the practitioner in treatment. CONCLUSIONS: A structured approach to psychiatric symptoms in DBS patients allows practitioners to effectively diagnose and treat them when they arise.

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.

Preoperative frailty risk in deep brain stimulation patients: Risk analysis index predicts Clavien-Dindo IV complications.

OBJECTIVE: Deep brain stimulation (DBS) improves patients' quality of life in multiple movement disorders and chronic neurodegenerative diseases. There are no published studies assessing frailty's impact on DBS outcomes. We evaluated frailty's impacts on DBS outcomes, comparing discriminative thresholds of the risk analysis index (RAI) to modified frailty index-5 (mFI-5) for predicting Clavien-Dindo complications (CDIV). METHODS: Patients who underwent DBS between 2015 and 2019 in the ACS-NSQIP registry were included. We employed receiver operating characteristic (ROC) curve to examine the discriminative thresholds of RAI and mFI-5 and multivariable analyses for postoperative outcomes. Our primary outcome was CDIV, and secondary outcomes were discharge to higher-level care facility, unplanned reoperation within 30 days, in any hospital, for any procedure related to the index procedure, and extended length of stay. RESULTS: A total of 3795 patients were included. In the ROC analysis for CDIV, RAI showed superior discriminative threshold (C-statistic = 0.70, 95% CI 0.61-0.80, <0.001) than mFI-5 (C-statistic = 0.60, 95% CI 0.49-0.70, P = 0.08). On multivariable analyses, frailty stratified by RAI, had independent associations with CDIV, i.e., pre-frail 2-fold increase OR 2.04 (95% CI: 1.94-2.14) p < 0.001, and frail 39% increase OR 1.39 (95% CI: 1.27-1.53), p < 0.001. CONCLUSION: Frailty was an independent risk-factor for CDIV. The RAI had superior discriminative thresholds than mFI-5 in predicting CDIV after DBS. Our ability to identify frail patients prior to DBS presents a novel clinical opportunity for quality improvement strategies to target this specific patient population. RAI may be a useful primary frailty screening modality for potential DBS candidates.

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.

Validity of spiral analysis in early Parkinson's disease.

Spiral analysis is an objective, easy to administer noninvasive test that has been proposed to measure motor dysfunction in Parkinson disease (PD). We compared overall Unified Parkinson Disease Rating Scale Part III scores to selected indices derived from spiral analysis in seventy-four patients with early PD (mean duration of disease 2.4 +/- 1.7 years, mean age 61.5 +/- 9.7 years). Of the spiral indices, degree of severity, first order zero crossing, second order smoothness, and mean speed were best correlated with total motor Unified Parkinson's Disease Rating Scale (UPDRS) score (all P < 0.01), and these indices showed a gradient across worsening tertiles of UPDRS (P < 0.05). Spiral indices also correlated with UPDRS ratings for the worst side and worst arm scores as well. The domains of bradykinesia, rigidity, and action tremor were correlated with first order crossing, second order smoothness, and mean speed, where as rest tremor was most highly correlated with degree of severity. This suggests that the spiral analysis may supplement motor assessment in PD, although further analysis of spiral metrics, a larger sample and longitudinal data should be evaluated.

Dystonia treatment: Patterns of medication use in an international cohort.

OBJECTIVE: To determine the frequency of medication use in patients with dystonia enrolled in an international biorepository study. METHODS: In a cross-sectional analysis, we included 2,026 participants enrolled at 37 sites in the United States, Canada, Europe, and Australia through Project 1 of the Dystonia Coalition, an international biorepository study. The primary aim was to assess the frequency of medication classes recommended for treating patients with dystonia, and the secondary aim was to compare characteristics (disease type, age, sex, duration of disease, comorbid conditions, severity). RESULTS: Querying the database for the presence of any medication for dystonia used (includes both injectable and oral therapy), we found 73% using medications (n = 1,488) and 27% using no dystonia medications (n = 538). Furthermore, 61% of the total sample used botulinum toxin (BoNT) therapy alone or in combination. Differences were found in medication use patterns by dystonia type, with the lowest oral medication use in focal dystonia and highest use in generalized dystonia; by region, with highest BoNT therapy rate reported in Italy and the lowest in the Northeast region of the United States; and by focal dystonia subtype, with highest BoNT therapy alone in blepharospasm and spasmodic dysphonia (49%) and lowest in other cranial dystonia (32%). CONCLUSIONS: The majority of patients with dystonia enrolled in the Dystonia Coalition Project 1 were using medications to treat their dystonia. Overall, a complex picture of medication use patterns emerged, with factors such as region, disease duration, type of dystonia, disease severity, and psychiatric comorbidities all playing a significant role.

Occupation and risk of parkinsonism: a multicenter case-control study.

BACKGROUND: We examined risk of parkinsonism in occupations (agriculture, education, health care, welding, and mining) and toxicant exposures (solvents and pesticides) putatively associated with parkinsonism. OBJECTIVE: To investigate occupations, specific job tasks, or exposures and risk of parkinsonism and clinical subtypes. DESIGN: Case-control. SETTING: Eight movement disorders centers in North America. PARTICIPANTS: Inclusion criteria were parkinsonism (>or=2 cardinal signs), diagnosis within 8 years of recruitment (to minimize survival bias), and ability to participate in detailed telephone interviews. Control subjects were primarily nonblood relatives or acquaintances of patients. MAIN OUTCOME MEASURES: This multicenter case-control study compared lifelong occupational and job task histories to determine associations with parkinsonism and certain clinical subtypes (postural instability and gait difficulty and age at diagnosis

Narrowing the DYT6 dystonia region and evidence for locus heterogeneity in the Amish-Mennonites.

The DYT6 gene for primary torsion dystonia (PTD) was mapped to chromosome 8p21-q22 in two Amish-Mennonite families who shared a haplotype of marker alleles across a 40 cM linked region. The objective of this study was to narrow the DYT6 region, clinically characterize DYT6 dystonia in a larger cohort, and to determine whether DYT6 is associated with dystonia in newly ascertained multiplex families. We systematically examined familial Amish-Mennonite dystonia cases, identifying five additional members from the original families, as well as three other multiplex Amish-Mennonite families, and evaluated the known DYT6 haplotype and recombination events. One of the three new families carried the shared haplotype, whereas the region was excluded in the two other families, suggesting genetic heterogeneity for PTD in the Amish-Mennonites. Clinical features in the five newly identified DYT6 carriers were similar to those initially described. In contrast, affected individuals from the excluded families had a later age of onset (46.9 years vs. 16.1 years in the DYT6), and the dystonia was both more likely to be of focal distribution and begin in the cervical muscles. Typing of additional markers in the DYT6-linked families revealed recombinations that now place the gene in a 23 cM region surrounding the centromere. In summary, the DYT6 gene is in a 23 cM region on chromosome 8q21-22 and does not account for all familial PTD in Amish-Mennonites.