Gut microbiota (GM) affects muscle homeostasis, and growing evidence indicates dysbiosis of GM may be a contributing factor in the pathogenesis of dystrophies. Furthermore, GM metabolites can interact with DNA methylation. Facioscapulohumeral muscular dystrophy (FSHD) is the second common dystrophy with hypomethylation of DR1 and 5P regions of D4Z4 repeat on 4qter.

Considering alteration of GM may be a contributing factor, we investigated (i) GM alterations and (ii) the correlation of microbial-derived free fatty acids (FFAs) with methylation of DR1 and 5P regions in FSHD.

Twenty-eight FSHD patients and 28 gender-age-matched controls were included. GM characterisation was performed through 16S-rRNA sequencing. Methylation levels of DR1 and 5P regions were assessed by bisulphite sequencing. Faecal and circulating FFAs including short-chain fatty acids (SCFAs), medium-chain fatty acids (MCFAs) and long-chain fatty acids (LCFAs) were analysed with gas chromatography-mass spectrometry.

Altered GM was observed in patients, along with distinct profiles of faecal and circulating SCFAs, MCFAs and LCFAs. DR1 and 5P regions exhibited significant hypomethylation in FSHD compared to control. Hypomethylation correlated with faecal and circulating FFAs in patients, while no correlation was identified in healthy controls. The severely affected patients exhibited a notable increase in the prevalence of Pasteurellaceae, while the FFA profile was similar among mild and severely affected patients. This is the first study revealing that FSHD patients showed compositional and functional GM dysbiosis. A strong association between proximal D4Z4 hypomethylation with microbial-derived SCFAs was identified.

These findings suggest that GM modulation with its metabolites could be a promising strategy for interventions in FSHD management.

Since cannabis was legalized in Canada in 2018, its use among older adults has increased. Although cannabis may exacerbate cognitive impairment, there are few studies on its use among older adults being evaluated for cognitive disorders.

We analyzed data from 238 patients who attended a cognitive clinic between 2019 and 2023 and provided data on cannabis use. Health professionals collected information using a standardized case report form.

Cannabis use was reported by 23 out of 238 patients (9.7%): 12 took cannabis for recreation, 8 for medicinal purposes and 3 for both purposes. Compared to non-users, cannabis users were younger (mean ± SD 62.0 ± 7.5 vs 68.9 ± 9.5 years; p = 0.001), more likely to have a mood disorder (p < 0.05) and be current or former cigarette smokers (p < 0.05). There were no significant differences in sex, race or education. The proportion with dementia compared with pre-dementia cognitive states did not differ significantly in users compared with non-users. Cognitive test scores were similar in users compared with non-users (Montreal Cognitive Assessment: 20.4 ± 5.0 vs 20.7 ± 4.5, p = 0.81; Folstein Mini-Mental Status Exam: 24.5 ± 5.1 vs 26.0 ± 3.6, p = 0.25). The prevalence of insomnia, obstructive sleep apnea, anxiety disorders, alcohol use or psychotic disorders did not differ significantly.

The prevalence of cannabis use among patients with cognitive concerns in this study was similar to the general Canadian population aged 65 and older. Further research is necessary to investigate patients’ motivations for use and explore the relationship between cannabis use and mood disorders and cognitive decline.

Epilepsy is a relatively common condition that affects approximately 4–5 per 1000 individuals in Ontario, Canada. While genetic testing is now prevalent in diagnostic and therapeutic care plans, optimal test selection and interpretation of results in a patient-specific context can be inconsistent and provider dependent.

The first of its kind, the Ontario Epilepsy Genetic Testing Program (OEGTP) was launched in 2020 to develop clinical testing criteria, curate gene content, standardize the technical testing criteria through a centralized testing laboratory, assess diagnostic yield and clinical utility and increase genetics literacy among providers.

Here we present the results of the first two years of the program, demonstrating the overall 20.8% diagnostic yield including pathogenic sequence and copy number variation detected by next-generation sequencing panels. Routine follow-up testing of family members enabled the resolution of ambiguous findings. Post-test outcomes were collected as reported by the ordering clinicians, highlighting the clinical benefits of genetic testing.

This programmatic approach to genetic testing in epilepsy by OEGTP, together with engagement of clinical and laboratory stakeholders, provided a unique opportunity to gather insight into province-wide implementation of a genetic testing program.

Cortical excitability has been proposed as a novel neurophysiological marker of neurodegeneration in Alzheimer’s dementia (AD). However, the link between cortical excitability and structural changes in AD is not well understood.

To assess the relationship between cortical excitability and motor cortex thickness in AD.

In 62 participants with AD (38 females, mean ± SD age = 74.6 ± 8.0) and 47 healthy control (HC) individuals (26 females, mean ± SD age = 71.0 ± 7.9), transcranial magnetic stimulation resting motor threshold (rMT) was determined, and T1-weighted MRI scans were obtained. Skull-to-cortex distance was obtained manually for each participant using MNI coordinates of the motor cortex (x = −40, y = −20, z = 52).

The mean skull-to-cortex distances did not differ significantly between participants with AD (22.9 ± 4.3 mm) and HC (21.7 ± 4.3 mm). Participants with AD had lower motor cortex thickness than healthy individuals (t(92) = −4.4, p = <0.001) and lower rMT (i.e., higher excitability) than HC (t(107) = −2.0, p = 0.045). In the combined sample, rMT was correlated positively with motor cortex thickness (r = 0.2, df = 92, p = 0.036); however, this association did not remain significant after controlling for age, sex and diagnosis.

Patients with AD have decreased cortical thickness in the motor cortex and higher motor cortex excitability. This suggests that cortical excitability may be a marker of neurodegeneration in AD.

The literature on cortical excitability, inhibitory and facilitatory properties of the brain in patients with primary dystonia is not well elucidated. We aimed to study the changes in these neurophysiological parameters in patients with dystonia using transcranial magnetic stimulation (TMS).

Patients with primary dystonia of presumed genetic etiology (n = 36) and an equal number of healthy controls (HC) (n = 36) were recruited from May 2021 to September 2022. TMS was done using single and paired pulse paradigms. The left motor cortex was stimulated, and responses were recorded from the contralateral first dorsal interosseus muscle. Resting motor threshold (RMT), central motor conduction time, contralateral silent period (cSP), ipsilateral silent period (iSP), short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) were recorded. All patients underwent whole exome sequencing.

The mean age of patients was 36.6 ± 13.5 years. There was a significant reduction of cSP (79.5 ± 33.8 vs 97.5 ± 25.4, p = 0.02) and iSP (42.3 ± 13.5 vs 53.8 ± 20.8, p = 0.003) in patients compared to HC. SICI was significantly enhanced in patients (0.38 ± 0.23) compared to HC (0.51 ± 0.24, p = 0.006). RMT was higher (42.1 ± 7.9 vs 37.1 ± 6.4%, p = 0.032) with enhanced SICI (0.36 ± 0.21 vs 0.56 ± 0.25, p = 0.004) in patients with generalized dystonia (n = 20) compared to HC. The genetically determined subgroup (n = 13) had significantly enhanced SICI compared to HC (0.23 ± 0.15 vs 0.51 ± 0.23, p = 0.001).

Patients with primary dystonia have altered cortical excitability and inhibition with significantly reduced silent period and enhanced intracortical inhibition suggestive of impaired GABAergic neurotransmission.

Canada’s National Microbiology Laboratory offers diagnostic testing of Creutzfeldt-Jakob disease (CJD) and related prion diseases. Since 2016, the highly sensitive and specific end-point quaking-induced conversion assay (EP-QuIC) of CSF samples has been used for antemortem CJD diagnostic testing alongside tests for surrogate biomarkers 14-3-3 and hTau. To assess EP-QuIC’s utility, we undertook a retrospective study of Canadian CJD diagnostic testing conducted between 2016 and 2024.

Using CJD CSF test results collected between 2016 and 2024, we analyzed the CJD incidence in Canada, estimated based on positive EP-QuIC tests. Multivariate regression models were used to further evaluate CJD CSF testing between CJD subtypes, genders, age groups and codon 129 genotypes.

From 2016 to 2024, the CJD incidence across Canada was estimated at 1.51 cases per million population per year. CJD incidence did not vary significantly across provinces, although a slight increase in CJD incidence was detected in New Brunswick due to increased sampling rates. EP-QuIC offered higher test sensitivity than both surrogate biomarker tests. Analysis of biomarker abundances and test positivity rates across biochemical subtypes revealed significant differences. We also detected variation in CSF test positivity rates across age groups and a trend of increasing biomarker abundance with age within EP-QuIC-negative cases. No significant variation was detected between males and females.

EP-QuIC exhibits exceptional specificity and sensitivity for antemortem diagnosis of CJD, providing a valuable tool for the diagnosis of human prion diseases and for improved surveillance.

The aim of this study is to assess the evolution of respiratory and feeding support in children with spinal muscular atrophy (SMA) type 1 after 24 months of nusinersen treatment.

Data on SMA type 1 children treated with nusinersen between 2017 and 2023 from the Canadian Neuromuscular Disease Registry were extracted. The cohort was divided into two groups based on age at treatment initiation: ≤2 years and >2 years. The primary outcome was the (i) time to death or needing full-time (≥16 hours/day) ventilation and (ii) time to needing feeding tube support. The secondary outcomes were differences in respiratory and feeding support requirements between the two groups at 24-month follow-up.

Thirty-two children were included, and the median age (range) for treatment initiation was 3.2 months (0.8– 13.1) in children who initiated treatment at ≤2 years and 51.2 (28.7–183.8) in those who initiated at >2 years of age. The median age of death or full-time ventilation was 8.6 months (6–22.4) and 10.5 months (4–24) for the two groups, respectively. The median age for initiation of feeding support was 5.1 (1.7–26.4) and 14.5 months (3.9–130.6), respectively. At 24 months (n = 23), there were no significant differences between the need for respiratory or feeding tube support between the two treatment groups.

Most children with SMA type 1 treated with nusinersen across Canada have continued need for respiratory and feeding support over time when initiated after symptom onset.

Noninvasive stimulation techniques are a promising therapy due to the ease of administration and minimal side effects. We investigated the clinical, electrophysiological and side effects of transcranial pulsed current stimulation (tPCS) in patients with Parkinson’s disease (PD).

Ten PD patients were called at monthly intervals in the OFF levodopa state. Patients received active tPCS for 20 minutes in the first visit and sham stimulation for 20 minutes in the second and were assessed for the levodopa response in the third. Clinical and bradykinesia scoring and gait and tremor analysis were done before and after stimulation/sham/levodopa in each visit. Scalp electroencephalography (EEG) was recorded for quantitative analysis during each visit. The interventions were compared between pre- and post-intervention.

A significant improvement with levodopa as compared to active and sham tPCS was seen in clinical scores. Upper limb postural tremor severity (z-score = −2.410, p = 0.016) and the stride velocity variability during post active stimulation improved by 20.7% compared to post sham stimulation though the difference was statistically non-significant. KINARM testing showed a statistically significant difference in the reaction time (p = 0.036) when comparing pre- and post-tPCS active stimulation. EEG recording showed a transitory increase of electrical activity after tPCS, with the most significant increase seen in alpha bandpower (p = 7.95*10-07; z score: −4.93).

tPCS was well tolerated in all patients. With minimal side effects, ease of administration and mild improvement in the electrophysiological parameters assessed, tPCS can be an alternative therapeutic option in patients with PD.

Huntington’s disease (HD) is an inherited, neurodegenerative disorder caused by the expansion of an unstable CAG repeat sequence in the Huntingtin (HTT) gene. The prevalence of HD, allelic diversity, rate of novel expansions and the clinical correlates vary across populations.

We analyzed the diversity of alleles and their clinical correlates and examined the inheritance patterns and the pattern of instability of CAG repeats in a few families.

Clinical history and pedigree structure were collected from records or through interviews between 2016 and 2019. Genetic testing at the HD locus was done on clinical suspicion, or relatedness, after counseling. Descriptive statistics and correlation analysis were used.

Expanded repeats were detected in 239 individuals, including 232 who were symptomatic and 7 presymptomatic relatives. The number of CAG repeats (mean = 45.6) and age at onset (mean = 39.2 years) showed a strong inverse correlation (r = -0.67). We found atypical alleles such as 8 intermediate alleles (IA), 12 reduced penetrance alleles and 14 large (>60) expansion alleles corresponding to juvenile HD. Three individuals carried biallelic expansions. Paternal inheritance was more common, and the mean increase in repeats in the available parent-child pairs was 14. Thirty-seven individuals had no family history of HD, with de novo expansion confirmed in three cases.

Novel mutations at the HTT locus may not be rare in India. A lack of family history should not exclude appropriate testing. The prevalence of IA and incidence of de novo expansions suggest that there may be a reservoir of alleles prone to expansion.

The outcomes of radiosurgery for trigeminal neuralgia (TN) in patients with multiple sclerosis (MS) are not as extensively assessed as those for idiopathic or classical TN cases.

Evaluate the safety and efficacy of radiosurgery for TN in MS patients and identify potential predictors of successful outcomes.

A retrospective single-institution cohort study with patients treated between 2009 and 2022 was performed. Fifty patients were included, and a total of 68 radiosurgical interventions were delivered. Outcomes included the maintenance of pain relief assessed using Kaplan–Meier curves and treatment-related complications. Cox regression analyses were used to identify potential predictors of better pain relief.

Following the first radiosurgical treatments, the initial pain relief rate was 86% after a median latency period of 14 days. Adequate pain relief rates at 6, 12, 36 and 60 months were 86%, 52%, 35% and 24%, respectively. Adequate pain relief was sustained for an actuarial median of 12.7 months. After initial relief, pain recurrence occurred in 68% of patients. No statistical difference was seen in the duration of pain relief after initial or repeat radiosurgery (p = 0.368). The most frequent complication was facial hypesthesia (Barrow Neurological Institute facial hypesthesia scale grade II: 10%; III: 6%; IV: 0%). Ipsilateral vascular compression was predictive of better efficacy (p = 0.024).

Radiosurgery for TN in patients with MS appears to be safe and to provide effective pain relief. Notably, radiological identification of vascular compression may predict more sustained pain relief.

Cerebellar ataxias are a heterogeneous group of disorders clinically manifest as impaired coordination during a voluntary motor task resulting from cortico-cerebellar brain network dysfunction, resulting in multiple motor systems including speech, upper limb dexterous movement and gait. Objective assessment of these dysfunctional motor domains provides vital clues in assessing the underlying pathophysiology.

In this study, speech, upper limb kinematics and gait were studied using acoustic software (Praat), upper limb robot (KINARM) and gait carpet (Zeno Walkway with PKMAS). Clinical assessment was conducted using the Scale for the Assessment and Rating of Ataxia (SARA).

In speech analysis, ataxia patients had slower and variable ‘tuh’ syllable repetition performance than healthy controls. In KINARM reaching tasks, ataxia patients displayed less accuracy and efficacy as measured by endpoint error (EE) and mean perpendicular error, along with slower mean and peak velocity of arm movements, prolonged reaction time and increased inter-trial variability. Moreover, there were more EEs while applying load during arm movement. Gait analysis revealed reduced cadence, reduced stride velocity, reduced step length, longer time in the double support phase and increased variability of step length, stride velocity, double support percentage and gait cycle time.

The study highlights the critical role played by the cerebellum during movement execution and has paved the way for more comprehensive future studies on degenerative cerebellar ataxia, incorporating kinematic measurements in multiple motor domains.