Parkinsonism & Related Disorders

BackgroundThe Montreal Cognitive Assessment (MoCA) is a recommended brief screening tool to detect cognitive impairment in people with Parkinsons disease (PD). ObjectiveTo compare English and Bengali MoCA performance in Bangladeshi individuals with PD in East London. MethodsThis cross-sectional study involved participants completing both English and Bengali MoCA. Analyses included ANCOVA, paired and unpaired t-tests, and Bland-Altman methods in full and age-matched samples. ResultsFifty PD participants and 22 healthy controls (HC) were included in the full analysis. Both groups scored higher on Bengali than English MoCA (mean difference [~]4 points, p<0.001). Age-matched analyses (n= 29 PD and 22 HC) detected PD-control differences with the Bengali but not English version (p=0.02). Bengali scores aligned more closely with multidisciplinary assessments, though mean scores remained below normative cut-offs. ConclusionBengali MoCA improves detection of cognitive differences over English but still overestimates impairment, supporting the need for culturally adapted tools and population-specific cut-offs.

We describe the design of the first non-pharmacological prevention trials of Parkinsons Disease worldwide: the randomised controlled Slow-SPEED trials. The three trials examine the feasibility and preliminary efficacy of a gamified, remotely administered exercise intervention vs. active control program over 18-36 months in the Netherlands (n=110), United Kingdom (n=110) and United States (n=600). Each trial focuses on a complementary prodromal subgroup: isolated/idiopathic REM sleep behavioural disorder, hyposmia, or LRRK2/GBA1 mutation carriers. These trials will provide unique insights for large-scale Parkinsons Disease prevention studies.

Gait impairment (GI) and freezing of gait (FOG) affect 80% of patients with advanced Parkinsons disease. Continuous deep brain stimulation (cDBS) provides limited adaptability to address the episodic nature of FOG due to fixed parameters. Neural biomarkers for adaptive DBS are limited by signal artifacts and poor FOG classification. Wearable inertial measurement units (IMUs) offer a promising alternative by directly measuring signatures of GI&FOG. We developed Kinematic adaptive DBS (KaDBS), the first intelligent system to dynamically modulate stimulation in response to real-time gait metrics. KaDBS integrates bilateral shank-mounted IMUs with an investigational neurostimulator through a wireless architecture enabling step-detection, arrhythmicity calculation, and probabilistic FOG classification. Two control algorithms were implemented: an arrhythmicity model based on stride variability, and a P(FOG) classifier implementing tri-state control based on stepwise freezing probabilities. In the largest KaDBS cohort to date (n=8), we compared OFF, cDBS, KaDBS, and intermittent DBS during harnessed stepping and free walking. KaDBS was safe and well tolerated with no serious adverse events; symptom-free reports were 87.5% and 71.4% for arrhythmicity and P(FOG) models respectively, compared to 50.0% for cDBS. All symptoms were mild, transient, and resolved without intervention. KaDBS significantly reduced percent time freezing versus OFF during stepping-in-place (35.8%, P= 4.80 x 10-3) and free walking (33.4%, p = 9.00 x 10-). Therapeutic effects concentrated in baseline freezers: two participants with 100% time freezing during OFF achieved complete resolution with KaDBS, while non-freezers maintained stable gait. These findings establish KaDBS as a safe, effective approach to personalized neuromodulation for PD.

ATP1A3-related syndromes represent a continuously expanding clinical spectrum and present with an extraordinarily wide range of symptoms. New phenotypes continue to emerge, posing ongoing challenges for both diagnosis and development of treatments. In this context, telemedicine offers a unique opportunity to greatly expand outreach to patients. Remote, high-resolution assessments help refine phenotypic characterization and the identification of novel and intermediate phenotypes. In this study we aimed to determine completion rates and practicality of conducting motor, speech, and neuropsychological assessments entirely via virtual visits. Although the broader recruitment included several ATP1A3-related disorders, this virtual battery was specifically developed for subjects with RDP. Participants with other ATP1A3 phenotypes enrolled in the study contributed to evaluating the overall feasibility of the workflow but were not the target population for the full battery. We recruited individuals with suspected or confirmed diagnosis of ATP1A3-related disorders, along with familial controls, from three participant clinical sites. Participants completed all study procedures through scheduled telemedicine visits using their personal devices (tablets, laptops, smartphones). A total of 59 participants were enrolled, including 46 individuals with suspected or confirmed ATP1A3 variants and 13 family member controls. Among affected patients, 18 had RDP, 12 AHC (Alternating Hemiplegia of Childhood), 4 CAPOS (Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, Sensorineural hearing loss), 10 were categorized as "uncertain" and 2 with "mixed" phenotype (RDP/CAPOS and RDP/AHC). The virtual assessment battery included: (i) patient history questionnaire (PHQ), (ii) structured neurological examination adapted for virtual visits, (iii) speech recording, and (iv) extensive neuropsychological assessment. Feasibility was evaluated based on completion rates for each assessment component. Remote neurological, speech and neurocognitive/psychiatric assessments were completed by most participants with ATP1A3 phenotypes, with completion rates of 78% for motor examination and 87% for speech evaluation. The observed pattern of motor and speech impairments were consistent with prior in-person evaluations, supporting the validity and feasibility for both motor and nonmotor features of remote assessment in complex genetic neurological disease.

Importance: Dementia is common in Parkinson's disease (PD), causing greater disability than other symptoms, but varies in timing. Although visual deficits are linked with PD dementia, how these interact with genetic factors to predict PD dementia has not been characterised. Objective: To investigate whether visual deficits and genetic factors predict PD dementia. Design: Large prospective longitudinal case-control study, mean follow-up 32.7 (SD=12.3) months. Setting: Cases were recruited between 2017-2020 at 35 UK PD clinics. Participants: People with PD without dementia at baseline were included. Main outcomes and measures: Visual function was measured using a web-based platform. The main outcome measure was global cognition, measured as the Montreal Cognitive Assessment (MoCA). Blood samples were collected for genetics. Results: 450 patients with PD were included. Mean age of PD patients was 71.7 (SD=7.8), 68% male. Mean baseline MoCA was 27.7 (SD=1.7). 263 patients with PD were classed as poor-vision based on baseline visual tests: mean age 74.4 (SD=6.8) compared to 69.7 (SD=7.5) with good-vision. Poor-vision PD patients had higher rates of progression to mild cognitive impairment (PD-MCI) (HR=2.34, CI=1.58-3.48, pFDR=0.00062, age- and sex-corrected). The combination of genetic factors together with vision influenced outcomes. In good-vision PD patients, high-risk GBA1 gene variants were linked with greater progression to PD-MCI (HR=4.61, CI=1.73-12.28, pFDR=0.0068). Polygenic Risk Score (PRS) for both PD and Alzheimer's disease (AD) also modified cognitive survival when combined with vision status. High PD-PRS was associated with greater progression to PD-MCI in good-vision patients (HR=2.66, CI=1.21-5.81, pFDR=0.0381); and high AD-PRS with greater progression to PD-MCI in poor-vision PD patients (HR=1.91, CI=1.10-3.32, pFDR=0.04999). Combining high PD- and AD-PRS, compared to low PD- and AD-PRS in good-vision PD showed even higher progression to PD-MCI (HR=6.14, CI=1.36-27.83, pFDR=0.046). Simulations showed that adding visual and genetic stratification reduced sample size from n=705 to n=160 for clinical trials. Conclusions and relevance: Poor vision in PD predicts progression to PD-MCI and dementia. This combines with the effects of genetic factors including GBA risk variants and PD- and AD-PRS. These findings can enable enrichment of clinical trials for patients at higher risk of PD dementia, for more efficient trial design for interventions to slow progression.

Olfactory decline is a well-established aspect of Parkinsons disease (PD) and is considered one of its earliest signs, often preceding motor symptoms by years to decades. However, because olfactory impairment is also common in healthy aging and other medical conditions, current olfactory tests that score performance (odor detection, discrimination, and identification) lack disease specificity. In contrast to performance scores, olfactory perceptual fingerprints are derived from odor ratings and sniffing behavior, and provide a stable measure of how the world smells to an individual. To test the hypothesis that olfactory perceptual fingerprints may provide a disease-specific marker, we obtained them in three cohorts: Individuals with PD (n=33), healthy age-matched controls (n=33), and critically, in participants with non-PD olfactory dysfunction (n=28). Consistent with previous results, a standard clinical olfactory test detected impairment in both PD and non-PD olfactory dysfunction, but failed to distinguish between these two groups. In contrast, olfactory perceptual fingerprints detected impairment, and distinguished PD from non-PD olfactory dysfunction at 88% accuracy (SVM classification, leave-one-out cross validation, 90% sensitivity, 85% specificity, P=3.2x10-4), or 94% accuracy after matching age and sex (SVM classification, leave-one-out cross-validation, 100% sensitivity, 88% specificity, P=0.0047). The difference between PD related and unrelated olfactory decline was particularly evident in sniffing behavior: Whereas both healthy participants and non-PD olfactory decline groups decreased sniff duration in response to unpleasant odors (-12.5% and -11.36% respectively), individuals with PD paradoxically increased sniff duration (+1.69%; P=4.5x10-5). Thus, PD was marked not by loss of olfactory performance, but by a distinct shift in olfactory perception. These findings imply that olfactory perceptual fingerprints provide for a disease-specific marker in PD.

BackgroundDystonia is a debilitating movement disorder that is difficult to assess when co-existing with spasticity, as is typical in cerebral palsy (CP). Querying caregivers about their childrens movements is known to increase clinical dystonia identification. However, beyond identification, determining whether dystonia is the predominant vs. accompanying movement feature in a child with CP can guide clinical decision making, particularly regarding surgical candidacy. ObjectiveTo determine whether caregivers movement descriptions differed between children with predominant dystonia, predominant spasticity with accompanying dystonia, and predominant spasticity without dystonia. MethodsIn this cross-sectional study, we used conventional content analysis to codify caregivers descriptions of triggered involuntary movements in children with CP seen in a tertiary care CP center between 4/2023 and 12/2024. Movement feature frequencies were compared across tone types using Chi-square tests with Bonferroni corrections for multiple comparisons. ResultsOf 180 children with CP (mean age 9.2, 47.8% male), caregivers of children with predominant dystonia (50/180, 27.8%) more frequently described movements triggered by negative emotions (p<0.002) and affecting their back, trunk, and whole body (p<0.04). Caregivers of children with predominant spasticity with dystonia (99/180, 55.0%) more frequently described movements affecting a single limb (p<0.04). Caregivers of children without dystonia (31/180, 17.2%) described movements as being slight or small (p<0.008). These differences persisted even for caregivers unaware their child had dystonia (77/149, 51.6%). ConclusionsCaregivers movement descriptions differ between children with different combinations of dystonia and spasticity, which may help inform clinical management and guide communication with families about dystonia.

Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by reduced expression of the survival motor neuron (SMN) protein. In addition to affecting motor neuron survival, SMN deficiency impacts multisystem physiology and neurotransmission. Dopaminergic dysfunction has been reported in mouse models of SMA, leading to postural and locomotor impairments that improve upon treatment with L-DOPA and benserazide. However, whether altered dopamine metabolism contributes to clinical symptoms in SMA patients remains unclear. To investigate this issue, we conducted a real-world observational study involving pediatric patients with SMA1, SMA2, and SMA3. We performed a longitudinal measurement of the main dopamine-related catabolites - 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) - in cerebrospinal fluid (CSF) samples collected at baseline and after five intrathecal doses of Nusinersen, an SMN-enhancing therapy. No significant differences were observed in CSF DOPAC and HVA levels across SMA types or following treatment, and no association emerged with SMN2 copy number. In contrast, lower baseline DOPAC levels were detected in SMA1 patients requiring gastrostomy and tracheostomy, and were associated with reduced improvement on the CHOP-INTEND scale. These findings suggest that reduced central dopaminergic turnover reflects disease progression in SMA1 and is associated with more severe clinical impairment and limited functional recovery.

Background and objectives STXBP1-related disorder (STXBP1-RD), caused by pathogenic variants in the STXBP1 gene, is a rare neurodevelopmental condition, characterized by early-onset seizures, developmental delay, intellectual disability (ID), and prominent motor dysfunction. Despite the high prevalence of motor symptoms, systematic gait characterization remains limited. We therefore aimed to quantitively assess gait in individuals with STXBP1-RD. Methods In this cross-sectional study, we included ambulatory patients aged 6 years or older with genetically confirmed STXBP1-RD. Instrumented 3D Gait Analysis (i3DGA) was performed to objectively quantify gait. Functional mobility was assessed with the Functional mobility scale (FMS) and Mobility Questionnaire 28 (MobQues28). Caregiver health-related quality of life was evaluated using the PedsQL-Family Impact Module (PedsQL-FIM). We explored associations between gait, functional mobility, STXBP1-variant type and clinical features (ID, age at seizure onset, seizure frequency, age at onset of independent walking). Correspondence between i3DGA and the Edinburgh Visual Gait Score (EVGS), an observational gait assessment, was investigated. Results Eighteen participants were included. Compared to typically developing peers, individuals with STXBP1-RD had significantly reduced walking speed, step and stride length. Gait patterns were highly variable, with the most frequent pattern being an externally rotated foot progression angle (FPA), present in 11/18 participants. At home, 93.75% of the participants (16/18) walked independently, yet community mobility was more variable: 11/16 (68.75%) walked independently, 2/16 (12.50%) with aid and 3/16 (18.75%) used a wheelchair, indicating increasing limitations with distance and environmental complexity. Earlier acquisition of independent walking strongly predicted later unassisted ambulation at community level (p<0.001). Median MobQues28 score was 57.14% and median PedsQL-FIM score was 60.42%, indicating a moderate level of mobility limitations and reduced health-related quality of life of caregivers. EVGS was highly positive correlated with i3DGA (p= 0.001). Discussion Quantitative gait analysis in individuals with STXBP1-RD demonstrates heterogenous kinematic deviations, with an externally rotated FPA emerging as the most common pattern. Age at independent walking was a clinically relevant predictor of later functional mobility. EVGS showed strong correspondence with i3DGA and may offer a more practical, semi-quantitative assessment for broader use. These findings inform clinical decision-making and guide the selection of scalable outcome measures for natural history studies and interventional trials.

Amyotrophic Lateral Sclerosis (Lou Gehrigs disease) is a progressive neurodegenerative disease affecting hundreds of thousands of people worldwide. It is characterized by the degeneration of the neurons in the brain and spinal cord of the patients, leading to a loss of control of muscles. Over time, without nerves to stimulate them muscles tend to atrophy. ALS may occur sporadically or run in families; many mutations have been identified for the latter. Treatment of ALS is mostly limited to three approved therapeutic agents: riluzole, edaravone, and tauroursidiol/ sodium phenylbutyrate. Among these, riluzole remains the most effective despite its early discovery. There are no conclusive meta-analysis comparing riluzole monotherapy to all possible co-therapies present. In this work we have attempted to address such a concern and observed that no adjunct therapy significantly improved the performance of riluzole. However, mitochondrial/ oxidative stress modulator and neuroimmune/ neuroexcitability modulator co-therapy exhibited positive trends. Surprisingly, trials were mainly confined to the USA and European countries, indicating unequal demographic representation in ASL research. We have concluded that large double blinded inter-continental RCTs to be carried out for better understanding of the scenario.

BackgroundPrognosis and therapeutic management in Parkinsons disease remain challenging due to the diseases heterogeneous progression and symptom presentation and lack of reliable biomarkers to predict individual disease trajectories. ObjectiveTo determine whether baseline blood transcriptomes, analyzed through biologically defined pathway gene sets, contain signatures that distinguish distinct motor and non-motor progression trajectories in Parkinsons disease. MethodsUsing data from the Parkinsons Progression Markers Initiative cohort, we developed a pathway-based computational framework to derive individualized molecular severity scores from baseline blood transcriptomic profiles by integrating pathway-level gene expression with longitudinal clinical data. Severity indices for motor and non-motor features established domain-specific progression trajectories of sporadic Parkinsons disease. Machine learning models were trained to predict patient trajectory membership from baseline transcriptomics. Findings were validated in genetic subcohorts and externally in the Parkinsons Disease Biomarkers Program cohort. ResultsMolecular severity scores were associated with key clinical features. Analysis of score changes revealed two non-motor and two motor progression groups, each characterized by specific gene signatures (20 genes for non-motor; 121 for motor). From baseline transcriptomic data, we accurately predicted an individuals trajectory group (0.87 for motor progression). The framework demonstrated high generalizability across independent and genetic cohorts, producing clinically coherent profiles. ConclusionsOur analysis reveals that baseline blood transcriptomic profiles delineate motor and non-motor progression trajectories in sporadic Parkinsons disease. The results are consistent with prior findings and may contribute to the identification of novel biomarkers, thereby informing and potentially optimizing the design of clinical trials aimed at modifying disease progression.

BackgroundHuntingtons disease (HD) causes progressive loss of function, cognition, and motor control, with no approved therapy yet shown to slow disease progression. In the PROOF-HD phase 3 trial, pridopidine did not meet the primary or key secondary outcomes in the overall population, but participants who remained off antidopaminergic medications (ADMs) showed benefits compared to placebo during the double-blind phase. Whether such benefits continue with longer duration treatment and how they compare with expected natural-history trajectories remains unknown. MethodsWe evaluated outcomes through Week 104 from baseline in participants who received continuous pridopidine (45 mg twice daily) and remained off-ADMs throughout the double-blind and open-label extension period (n=90). External comparators from ENROLL-HD and TRACK-HD were constructed using propensity-score weighting methods. Least-squares mean changes from baseline to Week 104 were estimated using mixed-effects models for repeated measures across outcomes. ResultsAt two-years, pridopidine treatment was associated with benefits versus propensity-score weighted natural-history comparators across multiple outcomes. Relative to ENROLL-HD, participants receiving pridopidine showed slowing of progression over 104 weeks, expressed as percent slowing across cUHDRS, TFC, SWR, SDMT, and TMS outcomes (39.5-88.3% slowing). Similar patterns were observed relative to TRACK-HD across the same measures (48.5 - 81.5% slowing), including quantitative motor performance assessed by Q-Motor FT-IOI (77.8% slowing). Exploratory analyses including participants receiving concomitant ADMs showed similar directional patterns as the primary analyses. ConclusionsIn a two-year follow-up, continuous pridopidine treatment in participants remaining off-ADMs was associated with slower clinical progression relative to expected natural-history trajectories. (Clinical Trials Identifier: NCT04556656)

Lysosomal dysfunction is central to Parkinsons disease pathogenesis, with GBA1 as the strongest established genetic risk factor. Numerous other genes involved in lysosomal sphingolipid, glycosphingolipid and ceramide metabolism have been proposed as contributors to Parkinsons disease, underscoring the need for comprehensive genetic analyses across these pathways. We analysed rare variants (minor allele frequency < 0.01) across 36 lysosomal genes (excluding GBA1) in 8,267 individuals with Parkinsons disease and 68,208 controls, including a subset of 793 early-onset Parkinsons disease ([&le;]50 years) cases. Targeted sequencing was performed in four cohorts at McGill University (3,456 Parkinsons disease patients and 2,664 controls) and results were combined with whole-genome sequencing data from the UK Biobank (2,848 cases, 62,451 controls), and from the Accelerating Medicines Partnership - Parkinsons Disease (1,963 cases, 3,093 controls). We analysed the association of rare variants in these genes with Parkinsons disease using Sequence Kernel Association Test-Optimal (SKAT-O) across variant classes (all rare variants, nonsynonymous, loss-of-function and predicted damaging variants with a Combined Annotation Dependent Depletion (CADD) score >20), with meta-analysis across cohorts. We additionally performed per-domain analyses for variants in gene segments encoding functional domains. False discovery rate correction was applied. Meta-analysis identified a significant association between rare variants in ST3GAL3 and Parkinsons disease (Pfdr=0.04). Several additional lysosomal genes showed nominal associations (P<0.05), including HGSNAT, ASAH1, CTSD, HEXA, ST3GAL4 and SGPP1. Domain-based analyses identified a strong enrichment of nonsynonymous variants within the beta-acetyl-hexosaminidase-like domain of HEXA (P = 8.0 x 10), although this signal did not survive correction for multiple testing (Pfdr=0.154). In early-onset Parkinsons disease, domain-based analyses revealed significant associations in NAGLU (Pfdr=7.3x10) and ST3GAL5 (Pfdr=0.03). Together, these results provide genetic evidence that rare variants across multiple lysosomal pathways, particularly those related to sialylation, ganglioside metabolism, ceramide biology, and lysosomal proteolysis, may contribute to Parkinsons disease susceptibility beyond GBA1, highlighting biologically coherent pathways for future replication and functional investigation.

IntroductionNeurocognitive impairment (NCI) remains common among people living with HIV (PWH), particularly in low- and middle-income countries where accurate diagnostic tools are limited. In Peru, the lack of locally validated neuropsychological (NP) normative data in Spanish poses a major barrier to diagnosing HIV-associated NCI, especially among PWH who develop NCI at younger ages. This study aimed to develop regression-based NP norms for young and middle-aged Spanish-speaking adults in Lima, Peru and validate the norms in demographically similar PWH to improve diagnostic precision of HIV-associated NCI. MethodsA total of 164 healthy adults without HIV from Lima completed a comprehensive NP battery assessing memory, attention, executive function, and language, which are commonly affected in HIV-associated NCI. Multiple regression models were used to consider the influence of age, years of education, and sex on raw scores, yielding standardized demographically-adjusted norms for the population. The resulting norms were then applied to 310 PWH from Lima and then compared with previously published norms for Spanish speaking adults to evaluate performance differences. ResultsAge and education were the strongest predictors of performance across tests, while sex had minimal influence. Compared to people without HIV, PWH had significantly lower educational attainment (mean 12.6 vs. 13.7 years) and exhibited significantly worse performance on normed scores of Benson Figure Copy, Benson Figure Delayed Recall, Color Trails 1 and 2, Hopkins Verbal Learning Test - Revised, and WAIS-III Digit Symbol Coding, Digit Span, and Symbol Search. There were statistically significant differences between T-scores on nearly all tests between our population-specific norms and previously published norms in both directions, indicating potential over- and under-detection errors when applying norms from non-local samples. DiscussionOur findings highlight the utility of locally derived norms in detecting subtle cognitive changes among young and middle-aged PWH compared with previously published norms for Spanish-speakers. Application of these norms reveals significant between-group differences that may go undetected using non-local normative data or raw scores. Future efforts should focus on rural norm development and inclusion of individuals with lower educational backgrounds in Peru and other Latin American countries.

While 18F-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) is an established biomarker in amyotrophic lateral sclerosis (ALS), the metabolic correlates of motor neuron disease motor variants remain poorly defined. This is why we investigated patterns of cerebral glucose metabolism across the spectrum of motor neuron disorders (MND), including progressive muscular atrophy (PMA), primary lateral sclerosis (PLS) and amyotrophic lateral sclerosis (ALS). We retrospectively included 18 PMA, 25 PLS and 43 matched non-hereditary ALS patients according to most recent diagnostic criteria. FDG-PET imaging revealed similar widespread hypometabolism in PMA, as in ALS, whereas PLS showed a more focal motor cortical pattern of hypometabolism. Despite clinical differences between MND subtypes, PMA and ALS showed similar FDG-PET metabolic patterns, whereas PLS exhibited a more restricted cortical signature in this retrospective study.

Background/ObjectivesElectromyography (EMG), video-polysomnography (vPSG), and wrist actigraphy are each used to develop diagnostic algorithms for Rapid eye movement sleep behavior disorder (RBD). However, the extent to which they capture overlapping versus distinct motor phenomena remains unknown. We evaluated the respective contributions of actigraphy, EMG and vPSG to the measurement of REM-sleep motor activity. MethodsSeventeen adults with RBD (Mount Sinai n = 9; Stanford n = 8) and eight control participants from an open Newcastle dataset underwent vPSG and concomitant wrist actigraphy. Flexor digitorum superficialis EMG activity and video-detected movements were manually scored in 3-second mini epochs. Actigraphy was quantified using an acceleration-magnitude-based activity count model. Statistical and agreement analyses were performed to assess the motor events captured by all three, any two, or by each modality independently during REM sleep. ResultsIn participants with RBD, actigraphy-derived movement load was significantly higher during REM sleep than during non-REM stages, a pattern not observed in control participants. Across 12,941 3-second mini epochs, EMG, actigraphy, and video detected 1,703, 1,613, and 811 motor events, of which 413 were detected concurrently by all three modalities. Pairwise agreement was moderate and increased from EMG-actigraphy ({kappa} = 0.27 {+/-} 0.10) to actigraphy-video ({kappa} = 0.41 {+/-} 0.12) and EMG-video ({kappa} = 0.45 {+/-} 0.15). Of EMG-detected events, 49.0% were also detected by actigraphy; of actigraphy-detected events, 37.2% were detected by EMG and 34.9% by video. Actigraphy activity counts were highest for events detected by all three modalities and lowest for actigraphy-only events. ConclusionActigraphy-measured REM-related motor activity was elevated in RBD but not in controls. EMG, actigraphy, and video captured partially overlapping motor events in RBD patient, with actigraphy showing the highest sensitivity and manually scored video the lowest.

INTRODUCTIONConnected speech analyses can help characterize linguistic impairments in primary progressive aphasia (PPA) and classify variants, however, manual transcription of speech samples is time-consuming and expensive. Automated speech recognition (ASR) may be efficacious for transcribing PPA speech. METHODSTranscripts of picture descriptions (109 PPA, 32 healthy controls (HC)) were generated using a manual, automated (Whisper) or semi-automated approach including a quality control (QC) step. We evaluated transcript accuracy, the reliability of ASR-derived linguistic features, and classification performance. RESULTSWhisper demonstrated lowest error rates for HC, followed by semantic, logopenic and non-fluent PPA variants. Errors correlated with overall disease severity for semantic and logopenic variants. QC of Whisper outputs reduced errors and improved the reliability of linguistic features. Overall, ASR-derived features achieved better classification performance than manual transcription features. DISCUSSIONResults support the use of off-the-shelf ASR for scalable, cost-efficient transcription of PPA speech and classification.

BackgroundArtificial Intelligence (AI) based approaches to speech analysis have the potential to assist with objective speech error analysis in aphasia but off-the shelf tools often fail to detect speech errors due to prioritizing "fluent transcription." Speech production errors (dysfluencies) are hallmark diagnostic features of the nonfluent (nfvPPA) and logopenic (lvPPA) variants of primary progressive aphasia, yet they can be challenging to detect and characterize even by expert clinicians. This study aimed to evaluate whether the novel automated lightweight Scalable Speech Dysfluency Modeling system (SSDM-L), specifically designed to detect dysfluencies, could accurately distinguish PPA variants using voice recordings of individuals reading a brief passage. MethodParticipants included a total of 104 individuals, 40 with nfvPPA, 40 with lvPPA (matched on disease severity), and 24 healthy controls who read aloud the Grandfather Passage as part of a widely used motor speech evaluation (MSE). We automatically extracted ten speech error (dysfluency) variables using SSDM-L, including insertions, replacements, and deletions at both phoneme- and word-levels, and phoneme-level prolongations and repetitions. Group differences were assessed via ANCOVAs controlling for age, education, and disease severity (MMSE, CDR sum-of-boxes). To test clinical relevance, we performed correlation analyses with MSE ratings provided by experienced speech-language pathologists (i.e., gold standard) within the nfvPPA group. Classification performance was assessed by training random forest and XGBoost machine-learning models including 5-fold cross-validation. ResultsAll individuals read the entire passage in less than five minutes. SSDM-L detected eight of the ten predefined dysfluency features at sufficient frequency to include them in subsequent analyses. All eight features distinguished PPA from controls (p<.006). Individuals with nfvPPA made more errors than the lvPPA group on every feature (all p<.023). Each feature showed a moderate positive correlation with a global MSE apraxia/dysarthria score (r=.31-.56; p<.001-.053). Together, the eight features were able to classify nfvPPA versus lvPPA at AUC=.806 (random forest) and AUC=.776 (XGBoost). DiscussionAI-based automated speech error analysis accurately distinguished nfvPPA and lvPPA variants using a brief reading task. This quick error-sensitive scalable AI system has the potential of providing a practical tool to aid diagnosis in aphasia and motor speech disorders.

ObjectivesFunctional neurological symptoms which do not meet clinical definitions of functional neurological disorder (FND) are common in clinical practice. Understanding the distinction between these benign functional symptoms and FND is crucial in defining FND as an entity for study, and as a clinical syndrome. We aimed to measure the frequency of functional symptoms in people who do not have FND. MethodsA survey was administered to 95 clinicians who attended an international conference on FND. Participants were asked to report the occurrence and characteristics of experiences with features of functional sensory or motor symptoms, or dissociation. ResultsOf the 95 people who responded to the survey, 57.4% reported having experienced any functional symptoms, and 47.9% reported having experienced functional motor or sensory symptoms. The symptoms reported were generally short-lived and caused only mild distress and disruption. Most respondents who reported having experienced a functional symptom reported having had multiple events through their lives. InterpretationThe results suggest that the lifetime occurrence of functional neurological symptoms is at least two orders of magnitude higher than the prevalence of FND. The high prevalence of functional symptoms in people who have never had FND challenges the common assumption that the occurrence of functional neurological symptoms is synonymous with FND. We propose that FND is better conceived of as a failure of the mechanisms by which functional neurological symptoms resolve, rather than the occurrence of functional symptoms per se. This reconceptualization implies new research directions for the underlying aetiology of FND.

BackgroundOscillations underpin a large spectrum of brain function. Brain oscillations are altered by neuromodulation approaches including deep brain stimulation (DBS), but a mechanistic understanding of the brain oscillation - DBS interaction is missing. DBS is predominantly used in the treatment of Parkinsons disease. DBS can induce or alter pre-existing narrow frequency band gamma oscillations at half the stimulation frequency. Such half-harmonic responses have been interpreted as entrainment of endogenous oscillations by an exogenous oscillator with an associated Arnold tongue structure. However, half-harmonic responses are not exhibited by all patients. MethodsHere, a Wilson-Cowan model of subcortical neuronal populations is used to set out a broad theoretical framework explaining the heterogeneity of observed responses. ResultsIn the absence of stimulation, the model exhibited either damped oscillations or self-sustained oscillations, depending on parameter values. Off-stimulation behaviour determined observed stimulation response. When oscillations were strongly damped, the only observed response was a driven oscillation at the stimulation frequency. When off-stimulation oscillations were weakly damped, additional half-harmonic responses occurred for sufficiently large amplitude stimulation. When self-sustained oscillations were present they were entrained by the stimulation frequency leading to harmonic, half-harmonic and many other subharmonic responses. Varying stimulation amplitude highlighted hysteresis with the onset and offset of half-harmonic responses appearing at different thresholds. Such two-threshold systems present challenges for adaptive control systems. ConclusionsThis framework captures observed heterogeneity and will help guide future therapeutic practices and the development of adaptive neuromodulation techniques for more effective promotion of physiological rhythms and suppression of abnormal rhythms.