Multiple system atrophy with amyloid-ß-predominant Alzheimer's disease neuropathologic change.

Multiple system atrophy is a neurodegenerative disease with α-synuclein pathology predominating in the striatonigral and olivopontocerebellar systems. Mixed pathologies are considered to be of low frequency and mostly comprise primary age-related tauopathy or low levels of Alzheimer's disease-related neuropathologic change. Therefore, the concomitant presence of different misfolded proteins in the same brain region is less likely in multiple system atrophy. During the neuropathological evaluation of 21 consecutive multiple system atrophy cases, we identified four cases exhibiting an unusual discrepancy between high Thal amyloid-ß phase and low transentorhinal Braak neurofibrillary tangle stage. We mapped α-synuclein pathology, measured the size and number of glial cytoplasmic inclusions and compared the amyloid-ß peptides between multiple system atrophy and Alzheimer's disease. In addition, we performed α-synuclein seeding assay from the affected putamen samples. We performed genetic testing for APOE, MAPT, PSEN1, PSEN2 and APP. We refer to the four multiple system atrophy cases with discrepancy between amyloid-ß and tau pathology as 'amyloid-ß-predominant Alzheimer's disease neuropathologic change-multiple system atrophy' to distinguish these from multiple system atrophy with primary age-related tauopathy or multiple system atrophy with typical Alzheimer's disease neuropathologic change. As most multiple system atrophy cases with mixed pathologies reported in the literature, these cases did not show a peculiar clinical or MRI profile. Three amyloid-ß-predominant Alzheimer's disease neuropathologic change-multiple system atrophy cases were available for genetic testing, and all carried the APOE ɛ4 allele. The extent and severity of neuronal loss and α-synuclein pathology were not different compared with typical multiple system atrophy cases. Analysis of amyloid-ß peptides revealed more premature amyloid-ß plaques in amyloid-ß-predominant Alzheimer's disease neuropathologic change-multiple system atrophy compared with Alzheimer's disease. α-Synuclein seeding amplification assay showed differences in the kinetics in two cases. This study highlights a rare mixed pathology variant of multiple system atrophy in which there is an anatomical meeting point of amyloid-ß and α-synuclein, i.e. the striatum or cerebellum. Since biomarkers are entering clinical practice, these cases will be recognized, and the clinicians have to be informed that the prognosis is not necessarily different than in pure multiple system atrophy cases but that the effect of potential α-synuclein-based therapies might be influenced by the co-presence of amyloid-ß in regions where α-synuclein also aggregates. We propose that mixed pathologies should be interpreted not only based on differences in the clinical phenotype but also on whether protein depositions regionally overlap, potentially leading to a different response to α-synuclein-targeted therapies.

Using artificial intelligence to identify drugs for repurposing to treat l-DOPA-induced dyskinesia.

Repurposing regulatory agency-approved molecules, with proven safety in humans, is an attractive option for developing new treatments for disease. We identified and assessed the efficacy of 3 drugs predicted by an in silico screen as having the potential to treat l-DOPA-induced dyskinesia (LID) in Parkinson's disease. We analysed ∼1.3 million Medline abstracts using natural language processing and ranked 3539 existing drugs based on predicted ability to reduce LID. 3 drugs from the top 5% of the 3539 candidates; lorcaserin, acamprosate and ganaxolone, were prioritized for preclinical testing based on i) having a novel mechanism of action, ii) having not been previously validated for the treatment of LID, iii) being blood-brain-barrier penetrant and orally bioavailable and iv) being clinical trial ready. We assessed the efficacy of acamprosate, ganaxolone and lorcaserin in a rodent model of l-DOPA-induced hyperactivity, with lorcaserin affording a 58% reduction in rotational asymmetry (P < 0.05) compared to vehicle. Acamprosate and ganaxolone failed to demonstrate efficacy. Lorcaserin, a 5HT2C agonist, was then further tested in MPTP lesioned dyskinetic macaques where it afforded an 82% reduction in LID (P < 0.05), unfortunately accompanied by a significant increase in parkinsonian disability. In conclusion, although our data do not support the repurposing of lorcaserin, acamprosate or ganaxolone per se for LID, we demonstrate value of an in silico approach to identify candidate molecules which, in combination with an in vivo screen, can facilitate clinical development decisions. The present study adds to a growing literature in support of this paradigm shifting approach in the repurposing pipeline.

4R-Tau seeding activity unravels molecular subtypes in patients with Progressive Supranuclear Palsy.

Progressive Supranuclear palsy (PSP) is a 4-repeat (4-R) tauopathy. We hypothesized that the molecular diversity of tau could explain the heterogeneity seen in PSP disease progression. To test this hypothesis, we performed an extensive biochemical characterisation of the high molecular weight tau species (HMW-Tau) in 20 different brain regions of 25 PSP patients. We found a correlation between the HMW-Tau species and tau seeding capacity in the primary motor cortex, where we confirmed that an elevated 4R-Tau seeding activity correlates with a shorter disease duration. To identify factors that contribute to these differences, we performed proteomic and spatial transcriptomic analysis that revealed key mechanistic pathways, in particular those involving the immune system, that defined patients demonstrating high and low tau seeding capacity. These observations suggest that differences in the tau seeding activity may contribute to the considerable heterogeneity seen in disease progression of patients suffering from PSP.

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.

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.

The Pain in Dystonia Scale (PIDS)-Development and Validation in Cervical Dystonia.

BACKGROUND: A better understanding of pain in adult-onset idiopathic dystonia (AOID) is needed to implement effective therapeutic strategies. OBJECTIVE: To develop a new rating instrument for pain in AOID and validate it in cervical dystonia (CD). METHODS: Development and validation of the Pain in Dystonia Scale (PIDS) comprised three phases. In phase 1, international experts and participants with AOID generated and evaluated the preliminary items for content validity. In phase 2, the PIDS was drafted and revised by the experts, followed by cognitive interviews to ensure self-administration suitability. In phase 3, the PIDS psychometric properties were assessed in 85 participants with CD and retested in 40 participants. RESULTS: The final version of PIDS evaluates pain severity (by body-part), functional impact, and external modulating factors. Test-retest reliability showed a high-correlation coefficient for the total score (0.9, P < 0.001), and intraclass correlation coefficients were 0.7 or higher for all items in all body-parts subscores. The overall PIDS severity score showed high internal consistency (Cronbach's α, 0.9). Convergent validity analysis revealed a strong correlation between the PIDS severity score and the Toronto Western Spasmodic Torticollis Rating Scale pain subscale (0.8, P < 0.001) and the Brief Pain Inventory-short form items related to pain at time of the assessment (0.7, P < 0.001) and impact of pain on daily functioning (0.7, P < 0.001). CONCLUSION: The PIDS is the first specific questionnaire developed to evaluate pain in all patients with AOID, here, demonstrating high-level psychometric properties in people with CD. Future work will validate PIDS in other forms of AOID. © 2023 International Parkinson and Movement Disorder Society.

Measurement Properties of Clinical Scales Rating the Severity of Blepharospasm: A Multicenter Observational Study.

Background: Several scales have been proposed to clinically evaluate the Motor Severity of Blepharospasm (BSP) but information about their measurement properties as a multicenter instrument is limited. Objective: To compare the measurement properties of four clinical scales in rating the severity of BSP in a large sample of patients from multiple sites. Methods: The Burke-Fahn-Marsden Scale (BFMS), the Global Dystonia Severity Rating Scale (GDRS), the Jankovic Rating Scale (JRS), and the Blepharospasm Severity Rating Scale (BSRS) were administered to 211 patients across 10 sites who were also requested to self-complete the Blepharospasm Disability Index (BDI). Measurement properties to be assessed included inter-/intra-observer agreement, item-to-total correlation, internal consistency, floor and ceiling effect, convergent/discriminant validity, and adherence to the distribution of BDI. Results: The BFMS had unsatisfactory measurement properties, the GDRS had acceptable reliability but other properties could not be completely testable; the JRS had satisfactory measurement properties but the scale did not accurately reflect the distribution of disability parameter (BDI) in the sample, and the BSRS had satisfactory measurement properties and also showed the best adherence to the distribution of BDI in the assessed sample. Conclusion: The comparison of the measurement properties of four rating scales to assess the motor state of the BSP in a large sample of patients from multiple sites showed that the GDRS should be used to simultaneously assess BSP and dystonia in other body parts, while the JRS (easier to use) and BSRS (better to discriminate severity) should be used to assess BSP alone.

Motor and psychiatric features in idiopathic blepharospasm: A data-driven cluster analysis.

INTRODUCTION: Idiopathic blepharospasm is a clinically heterogeneous dystonia also characterized by non motor symptoms. METHODS: We used a k-means cluster analysis to assess 188 patients with idiopathic blepharospasm in order to identify relatively homogeneous subpopulations of patients, using a set of motor and psychiatric variables to generate the cluster solution. RESULTS: Blepharospasm patients reached higher scores on scales assessing depressive- and anxiety-related disorders than healthy/disease controls. Cluster analysis suggested the existence of three groups of patients that differed by type of spasms, overall motor severity, and presence/severity of psychiatric problems. The greater severity of motor symptoms was observed in Group 1, the least severity in Group 3, while the severity of blepharospasm in Group 2 was between that observed in Groups 1 and 3. The three motor subtypes also differed by psychiatric features: the lowest severity of psychiatric symptoms was observed in the group with least severe motor symptoms (group 3), while the highest psychiatric severity scores were observed in group 2 that carried intermediate motor severity rather than in the group with more severe motor symptoms (group 1). The three groups did not differ by disease duration, age of onset, sex or other clinical features. CONCLUSIONS: The present study suggests that blepharospasm patients may be classified in different subtypes according to the type of spasms, overall motor severity and presence/severity of depressive symptoms and anxiety.

Periodic Limb Movements while Awake (PLMA) as a Manifestation of Wearing-Off in Parkinson's Disease: A Case Series and Review of the Literature.

Background: Periodic limb movements while awake (PLMA) are similar to Periodic limb movements in sleep (PLMS) but occurring during wakefulness and seen in association with restless leg syndrome (RLS). Objectives: To describe PLMA as a wearing-off phenomenon in Parkinson's Disease (PD). Methods: We describe four individuals with PD and PLMS, who had associated similar periodic and stereotypic lower extremity movements during wakefulness, thought to be secondary to PLMA, and were highly responsive to dopaminergic treatment. Results: Despite the prevalence of RLS and PLMS in individuals with PD, the presence of similar movements during wakefulness has not been well characterized. The lack of a specific diagnostic criteria poses a significant diagnostic challenge. Conclusions: We describe, for the first time to our knowledge, PLMA as a wearing-off phenomenon in PD. This entity could be classified in the spectrum of "low-dose dyskinesia," as we found that it was highly responsive to dopaminergic treatment.

Newly Approved and Investigational Drugs for Motor Symptom Control in Parkinson's Disease.

Motor symptoms are a core feature of Parkinson's disease (PD) and cause a significant burden on patients' quality of life. Oral levodopa is still the most effective treatment, however, the motor benefits are countered by inherent pharmacologic limitations of the drug. Additionally, with disease progression, chronic levodopa leads to the appearance of motor complications including motor fluctuations and dyskinesia. Furthermore, several motor abnormalities of posture, balance, and gait may become less responsive to levodopa. With these unmet needs and our evolving understanding of the neuroanatomic and pathophysiologic underpinnings of PD, several advances have been made in defining new therapies for motor symptoms. These include newer levodopa formulations and drug delivery systems, refinements in adjunctive medications, and non-dopaminergic treatment strategies. Although some are in early stages of development, these novel treatments potentially widen the available options for the management of motor symptoms allowing clinicians to provide an individually tailored care for PD patients. Here, we review the existing and emerging interventions for PD with focus on newly approved and investigational drugs for motor symptoms, motor fluctuations, dyskinesia, and balance and gait dysfunction.

A Modified Progressive Supranuclear Palsy Rating Scale for Virtual Assessments.

BACKGROUND: The reliability of the Progressive Supranuclear Palsy Rating Scale (PSPRS) using teleneurology has not been assessed. OBJECTIVES: To test whether removing items inadequately assessed by video would impact measurement of PSP severity and progression. METHODS: We performed secondary analyses of two data sets: the phase 2/3 trial of Davunetide in PSP and a large single-center cohort. We examined two modifications of the PSPRS: (1) removing neck rigidity, limb rigidity, and postural stability (25 items; mPSPRS-25) and (2) also removing three ocular motor items and limb dystonia (21 items; mPSPRS-21). Proportional agreement relative to the possible total scores was measured using the intraclass correlation coefficient, compared to the original PSPRS baseline values and change over 6 and 12 months. We examined the ability of both scales to predict survival in the single-center cohort using proportional hazards models. RESULTS: The mPSPRS-25 showed excellent agreement (0.99; P < 0.001) with the original PSPRS at baseline, 0.98 (P < 0.001) agreement in measuring change over 6 months, and 0.98 (P < 0.001) over 12 months. The mPSPRS-21 showed agreement of 0.94 (P < 0.001) with the original PSPRS at baseline, 0.92 (P < 0.001) at 6 months, and 0.95 (P < 0.001) at 12 months. Baseline and 6-month change in both modified scales were highly predictive of survival in the single-center cohort. CONCLUSIONS: Modified versions of the PSPRS which can be administered remotely show excellent agreement with the original scale and predict survival in PSP. The mPSPRS-21 should facilitate clinical care and research in PSP via teleneurology. © 2022 International Parkinson and Movement Disorder Society.

Non-motor phenotypic subgroups in adult-onset idiopathic, isolated, focal cervical dystonia.

BACKGROUND: Non-motor symptoms are well established phenotypic components of adult-onset idiopathic, isolated, focal cervical dystonia (AOIFCD). However, improved understanding of their clinical heterogeneity is needed to better target therapeutic intervention. Here, we examine non-motor phenotypic features to identify possible AOIFCD subgroups. METHODS: Participants diagnosed with AOIFCD were recruited via specialist neurology clinics (dystonia wales: n = 114, dystonia coalition: n = 183). Non-motor assessment included psychiatric symptoms, pain, sleep disturbance, and quality of life, assessed using self-completed questionnaires or face-to-face assessment. Both cohorts were analyzed independently using Cluster, and Bayesian multiple mixed model phenotype analyses to investigate the relationship between non-motor symptoms and determine evidence of phenotypic subgroups. RESULTS: Independent cluster analysis of the two cohorts suggests two predominant phenotypic subgroups, one consisting of approximately a third of participants in both cohorts, experiencing increased levels of depression, anxiety, sleep impairment, and pain catastrophizing, as well as, decreased quality of life. The Bayesian approach reinforced this with the primary axis, which explained the majority of the variance, in each cohort being associated with psychiatric symptomology, and also sleep impairment and pain catastrophizing in the Dystonia Wales cohort. CONCLUSIONS: Non-motor symptoms accompanying AOIFCD parse into two predominant phenotypic sub-groups, with differences in psychiatric symptoms, pain catastrophizing, sleep quality, and quality of life. Improved understanding of these symptom groups will enable better targeted pathophysiological investigation and future therapeutic intervention.

An Open-Label Phase 2a Study to Evaluate the Safety and Tolerability of Perampanel in Cervical Dystonia.

BACKGROUND: Cervical dystonia (CD) is the most common focal isolated dystonia. Preclinical studies report that AMPA-selective glutamate receptor antagonists improve dystonia. Perampanel is a clinically available, AMPA receptor antagonist that has shown efficacy and safety in epilepsy. OBJECTIVES: To determine safety and tolerability of perampanel in CD. METHODS: We performed a phase 2a, open-label, multicenter study to evaluate tolerability and safety of perampanel in CD. Included subjects had primary CD; those on botulinum toxin were 8 weeks post last injection. All subjects received perampanel 2 mg/day, titrated 2 mg weekly over 6 weeks, to maximum 12 mg/day; maintenance phase was 4 weeks, ending at week 10. Primary endpoints included tolerability, defined as ability to remain on perampanel for the maintenance period, at any dose level and safety, determined from adverse events (AEs) collected at each visit. Secondary exploratory endpoints included Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), quality of life (cervical dystonia impact profile [CIDP]-58) and Clinical Global Impression of change (CGI). RESULTS: CD participants (n = 25) were recruited. Eight subjects withdrew; 4 because of AEs, 3 for other reasons and 1 lost to follow up. One subject tolerated 12 mg/day. Eight subjects (30.8%) tolerated 2 mg, whereas 19.2% tolerated 4 mg/day, and 15.4% tolerated 6 mg or 8 mg/day. All subjects experienced AEs. The most common AEs were dizziness, imbalance, and irritability. Exploratory endpoints of TWSTRS showed some improved pain scores and CIDP-58 improved sleep. CONCLUSIONS: Tolerability to perampanel was variable in CD subjects. Lower doses would be considered for future studies in this population.

A Multi-center Genome-wide Association Study of Cervical Dystonia.

BACKGROUND: Several monogenic causes for isolated dystonia have been identified, but they collectively account for only a small proportion of cases. Two genome-wide association studies have reported a few potential dystonia risk loci; but conclusions have been limited by small sample sizes, partial coverage of genetic variants, or poor reproducibility. OBJECTIVE: To identify robust genetic variants and loci in a large multicenter cervical dystonia cohort using a genome-wide approach. METHODS: We performed a genome-wide association study using cervical dystonia samples from the Dystonia Coalition. Logistic and linear regressions, including age, sex, and population structure as covariates, were employed to assess variant- and gene-based genetic associations with disease status and age at onset. We also performed a replication study for an identified genome-wide significant signal. RESULTS: After quality control, 919 cervical dystonia patients compared with 1491 controls of European ancestry were included in the analyses. We identified one genome-wide significant variant (rs2219975, chromosome 3, upstream of COL8A1, P-value 3.04 × 10-8 ). The association was not replicated in a newly genotyped sample of 473 cervical dystonia cases and 481 controls. Gene-based analysis identified DENND1A to be significantly associated with cervical dystonia (P-value 1.23 × 10-6 ). One low-frequency variant was associated with lower age-at-onset (16.4 ± 2.9 years, P-value = 3.07 × 10-8 , minor allele frequency = 0.01), located within the GABBR2 gene on chromosome 9 (rs147331823). CONCLUSION: The genetic underpinnings of cervical dystonia are complex and likely consist of multiple distinct variants of small effect sizes. Larger sample sizes may be needed to provide sufficient statistical power to address the presumably multi-genic etiology of cervical dystonia. © 2021 International Parkinson and Movement Disorder Society.