α-Synuclein molecular behavior and nigral proteomic profiling distinguish subtypes of Lewy body disorders.

Lewy body disorders (LBD), characterized by the deposition of misfolded α-synuclein (α-Syn), are clinically heterogeneous. Although the distribution of α-Syn correlates with the predominant clinical features, the burden of pathology does not fully explain the observed variability in clinical presentation and rate of disease progression. We hypothesized that this heterogeneity might reflect α-Syn molecular diversity, between both patients and different brain regions. Using an ultra-sensitive assay, we evaluated α-Syn seeding in 8 brain regions from 30 LBD patients with different clinical phenotypes and disease durations. Comparing seeding across the clinical phenotypes revealed that hippocampal α-Syn from patients with a cognitive-predominant phenotype had significantly higher seeding capacity than that derived from patients with a motor-predominant phenotype, whose nigral-derived α-Syn in turn had higher seeding capacity than that from cognitive-predominant patients. Interestingly, α-Syn from patients with rapid disease progression (< 3 years to development of advanced disease) had the highest nigral seeding capacity of all the patients included. To validate these findings and explore factors underlying seeding heterogeneity, we performed in vitro toxicity assays, and detailed neuropathological and biochemical examinations. Furthermore, and for the first time, we performed a proteomic-wide profiling of the substantia nigra from 5 high seeder and 5 low seeder patients. The proteomic data suggests a significant disruption in mitochondrial function and lipid metabolism in high seeder cases compared to the low seeders. These observations suggest that distinct molecular populations of α-Syn may contribute to heterogeneity in phenotypes and progression rates in LBD and imply that effective therapeutic strategies might need to be directed at an ensemble of differently misfolded α-Syn species, with the relative contribution of their differing impacts accounting for heterogeneity in the neurodegenerative process.

Gluteal compartment syndrome with neurologic impairment: Report of 2 cases and review of the literature.

INTRODUCTION: We describe two patients who developed gluteal compartment syndrome (GCS) in the context of drug overdose. One patient developed a sciatic neuropathy, and one patient developed a lumbosacral plexopathy. METHODS: We reviewed the literature of atraumatic GCS and resultant neurological impairment. RESULTS: We reviewed 26 cases (our two cases and 24 previously published cases) of GCS and neurological impairment. All patients developed GCS in the context of drug or alcohol overdose. Creatine kinase was markedly elevated in all patients in which it was tested, and most patients developed renal failure. Seventeen patients had a fasciotomy, and 9 patients were managed conservatively. There appeared to be a trend toward worse prognosis in the conservatively managed group. DISCUSSION: Neurologists should be aware of GCS. Immediate recognition facilitates consideration of further diagnostic testing, including intracompartmental pressure measurement and consideration of surgical decompression, which may influence outcome. Muscle Nerve, 57: 325-330, 2018.

Non-steroidal anti-inflammatory drug use and markers of Parkinson's disease progression: A retrospective cohort study.

BACKGROUND: Previous studies demonstrated reduced incidence of Parkinson's disease (PD) with regular non-steroidal anti-inflammatory drug (NSAID) exposure, particularly ibuprofen. No studies have investigated the impact of NSAID exposure on markers of disease progression for established PD. METHODS: This is a retrospective observational study using two cohorts. The Deprenyl and Tocopheral Anti-Oxidative Therapy of Parkinsonism (DATATOP) study enrolled 800 drug naïve people with PD with a median follow-up duration of 6.5 years. The DATATOP primary outcome measures were mortality at last study visit. The Parkinson's Progression Markers Initiative (PPMI) cohort was limited to drug naïve PD participants (423 at time of analysis). The PPMI primary outcome measure was annual rate of change in ipsilateral putamen 123I-ioflupane binding ratio at four years study duration. Regular NSAID exposure was defined as any scheduled NSAID use (as needed use was excluded). Analysis was performed separately for recent exposure and cumulative exposure time (CET). RESULTS: Total CET median and interquartile range (years) for ibuprofen, non-aspirin NSAID, and aspirin were respectively 0.9 (0.3-2.9), 1.1 (0.3-2.6), and 1.5 (0.4-2.8) for DATATOP and 0.4 (0.01-2.2), 1.4 (0.3-4.4), and 5.5 (2.6-7.1) for PPMI. Exposure was usually discontinuous. Exposure to ibuprofen was low in both cohorts. There was no significant association between NSAID recent exposure or CET and primary outcome measures in either cohort. CONCLUSIONS: NSAID exposure in established PD does not appear to provide protective effect although exposure may not have occurred continuously enough in these two cohorts to provide benefit. Statistical power for ibuprofen exposure analyses was limited.

A Phase Ib, Double Blind, Randomized Study of Cannabis Oil for Pain in Parkinson's Disease.

Background: Pain is common in Parkinson's disease (PD), but effective therapies are limited. Objectives: To determine the maximum tolerated dose (MTD) and safety of formulations of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) for pain in PD. Methods: In this phase 1b, double-blind, randomized, single-center study, participants were randomized to three formulations of THC/CBD (18:0, 10:10, and 1:20). The MTD, adverse events (AE), and tolerability are described for each formulation. Results: Eight participants were randomized. The MTD was similar among groups (0.8-0.9 mL/daily), and there were no serious AE or study drop-outs. The most common AE were drowsiness and dizziness (three participants). Epworth sleepiness scale scores were higher in the high CBD formulation (1:20). Conclusions: In patients with pain and PD, mixed formulations of THC/CBD were tolerated with no serious AE. Considering the safety profile, future phase II studies should be considered.

Amantadine-Induced Craniofacial Myoclonus: Distinctive Iatrogenic Dysarthria in Parkinson's Disease.

Background: Amantadine is a widely prescribed medication in Parkinson's disease (PD). A distinctive craniofacial distribution of myoclonus with speech impairment is an underrecognized iatrogenic complication in amantadine-treated patients with PD. Cases: We report 7 patients with idiopathic PD (disease duration, 6-21 years) who developed speech-induced craniofacial-predominant myoclonus with "stuttering-like" dysarthria and speech arrests days to months after amantadine initiation or dose increase. Renal insufficiency was identified as a risk factor in 4 cases. In all cases, reduction or discontinuation of amantadine markedly attenuated the myoclonus and restored speech intelligibility. Literature Review: Amantadine can induce subcortical segmental or generalized myoclonus. A report in 1996 of "vocal myoclonus" in an amantadine-treated patient with PD was the first observation of a focal distribution of myoclonus, particularly affecting speech. Since then, few cases of craniofacial myoclonus with speech impairment have been reported, none with accompanying video. With 1 exception, the craniofacial distribution was part of a generalized pattern of amantadine-induced myoclonus. Comorbid renal insufficiency is a recognized risk factor. Conclusions: Speech-induced craniofacial myoclonus, with marked "stuttering-like" dysarthria and speech arrests, is a disabling iatrogenic complication in PD that resolves upon amantadine discontinuation.

Spastic Paraplegia Type 7 and Movement Disorders: Beyond the Spastic Paraplegia.

Background: Spastic paraplegia type 7 (SPG7) mutations can present either as a pure form or a complex phenotype with movement disorders. Objective: Describe the main features of subjects with SPG7 mutations associated with movement disorders. Methods: We analyzed the clinical and paraclinical information of subjects with SPG7 mutations associated with movement disorders. Results: Sixteen affected subjects from 11 families were identified. Male sex predominated (10 of 16) and the mean age at onset was 41.25 ± 16.1 years. A cerebellar syndrome was the most frequent clinical movement disorder phenotype (7 of 16); however, parkinsonism (2 of 16), dystonia (1 of 16), and mixed phenotypes between them were also seen. The "ears of the lynx" sign was found in four subjects. A total of nine SPG7 variants were found, of which the most frequent was the c.1529C > T (p.Ala510Val). Conclusion: This case series expands the motor phenotype associated with SPG7 mutations. Clinicians must consider this entity in single or familial cases with combined movement disorders.

Predictors of health-related quality of life in Parkinson's disease.

BACKGROUND: Health-related quality of life in Parkinson's disease may be affected by a wide range of motor and non-motor symptoms. Identifying which symptoms are significant predictors of health-related quality of life in Parkinson's disease prioritizes symptoms for treatment, therapeutic development, and clinical outcomes. OBJECTIVES: To determine predictors of health-related quality of life in patients with Parkinson's disease. METHODS: We recruited 102 subjects into a prospective study to investigate neuropsychiatric symptoms in Parkinson's disease. Health-related quality of life was measured with the 39-item Parkinson's Disease Questionnaire. Subjects completed the Movement Disorder Society Unified Parkinson's Disease Rating Scale Parts I-IV as well as validated scales to assess anxiety, depression, apathy, cognition, psychosis, impulsive-compulsive disorder, autonomic dysfunction, sleep quality, excessive daytime sleepiness, and rapid eye movement sleep behavior disorder. We used univariate analyses to select clinical predictors to construct a multivariate regression model to determine which predictors were independently associated with worse health-related quality of life. RESULTS: In a multivariate linear regression model adjusted for age and gender, higher scores for the International Parkinson and Movement Disorder Society Unified Parkinson's Disease Rating Scale part II as well more severe symptoms of depression, anxiety, apathy, and excessive daytime sleepiness were associated with worse health-related quality of life. The model explained 78% of the variance of health-related quality of life, and the non-motor symptoms explained 49% of the variance. CONCLUSIONS: Anxiety, depression, excessive daytime sleepiness, apathy, and impairment in activities of daily living related to motor symptoms were independently associated with worse health-related quality of life.