Introduction: Parkinson’s disease (PD) reduces an individual’s capacity for automaticity which limits their ability to perform two tasks simultaneously, negatively impacting daily function. Understanding the neural correlates of dual tasks (DTs) may pave the way for targeted therapies. To better understand automaticity in PD, we aimed to explore whether individuals with differing DT performances possessed differences in brain morphologic characteristics. Methods: Data were obtained from 34 individuals with PD and 47 healthy older adults including (1) demographics (age, sex), (2) disease severity (Movement Disorder Society – Unified Parkinson’s Disease Rating Scale [MDS-UPDRS], Hoehn and Yahr, levodopa equivalent daily dose [LEDD]), (3) cognition (Montreal Cognitive Assessment), (4) LEDD, (5) single-task and DT performance during a DT-timed-up-and-go test utilizing a serial subtraction task, and (6) cortical thicknesses and subcortical volumes obtained from volumetric MRI. Participants were categorized as low or high DT performers if their combined DT effect was greater than the previously determined mean value for healthy older adults (μ = –74.2). Nonparametric testing using Quade’s ANCOVA was conducted to compare cortical thicknesses and brain volumes between the highDT and lowDT groups while controlling for covariates: age, sex, MDS-UPDRS part III, LEDD, and intracranial volume. Secondarily, similar comparisons were made between the healthy older adult group and the highDT and lowDT groups. Lastly, a hierarchical linear regression model was conducted regressing combined DT effect on covariates (block one) and cortical thicknesses (block 2) in stepwise fashion. Results: The highDT group had thicker cortices than the lowDT group in the right primary somatosensory cortex (p = 0.001), bilateral primary motor cortices (p ≤ 0.001, left; p = 0.002, right), bilateral supplementary motor areas (p = 0.001, left; p < 0.001, right), and mean of the bilateral hemispheres (p = 0.001, left; p < 0.001, right). Of note, left primary cortex thickness (p = 0.002), left prefrontal cortex thickness (p < 0.001), and right supplementary motor area thickness (p = 0.003) differed when adding a healthy comparison group. Additionally, the regression analysis found that the left paracentral lobule thickness explained 20.8% of the variability in combined DT effect (p = 0.011) beyond the influence of covariates. Conclusions: These results suggest regions underlying DT performance, specifically, a convergence of neural control relying on sensorimotor integration, motor planning, and motor activation to achieve higher levels of DT performance for individuals with PD. Introduction: Parkinson’s disease (PD) reduces an individual’s capacity for automaticity which limits their ability to perform two tasks simultaneously, negatively impacting daily function. Understanding the neural correlates of dual tasks (DTs) may pave the way for targeted therapies. To better understand automaticity in PD, we aimed to explore whether individuals with differing DT performances possessed differences in brain morphologic characteristics. Methods: Data were obtained from 34 individuals with PD and 47 healthy older adults including (1) demographics (age, sex), (2) disease severity (Movement Disorder Society – Unified Parkinson’s Disease Rating Scale [MDS-UPDRS], Hoehn and Yahr, levodopa equivalent daily dose [LEDD]), (3) cognition (Montreal Cognitive Assessment), (4) LEDD, (5) single-task and DT performance during a DT-timed-up-and-go test utilizing a serial subtraction task, and (6) cortical thicknesses and subcortical volumes obtained from volumetric MRI. Participants were categorized as low or high DT performers if their combined DT effect was greater than the previously determined mean value for healthy older adults (μ = –74.2). Nonparametric testing using Quade’s ANCOVA was conducted to compare cortical thicknesses and brain volumes between the highDT and lowDT groups while controlling for covariates: age, sex, MDS-UPDRS part III, LEDD, and intracranial volume. Secondarily, similar comparisons were made between the healthy older adult group and the highDT and lowDT groups. Lastly, a hierarchical linear regression model was conducted regressing combined DT effect on covariates (block one) and cortical thicknesses (block 2) in stepwise fashion. Results: The highDT group had thicker cortices than the lowDT group in the right primary somatosensory cortex (p = 0.001), bilateral primary motor cortices (p ≤ 0.001, left; p = 0.002, right), bilateral supplementary motor areas (p = 0.001, left; p < 0.001, right), and mean of the bilateral hemispheres (p = 0.001, left; p < 0.001, right). Of note, left primary cortex thickness (p = 0.002), left prefrontal cortex thickness (p < 0.001), and right supplementary motor area thickness (p = 0.003) differed when adding a healthy comparison group. Additionally, the regression analysis found that the left paracentral lobule thickness explained 20.8% of the variability in combined DT effect (p = 0.011) beyond the influence of covariates. Conclusions: These results suggest regions underlying DT performance, specifically, a convergence of neural control relying on sensorimotor integration, motor planning, and motor activation to achieve higher levels of DT performance for individuals with PD.

Introduction: Spinocerebellar ataxia type 36 (SCA36) is caused by large GGCCTG repeat expansion in the NOP56 gene. The genetic diagnosis based on Southern blot is expensive and time-consuming. This study aimed to evaluate the reliability and effectiveness of whole exome sequencing (WES) for routine genetic diagnosis of suspected SCA36 patients. Methods: Pathogenic repeat expansions for SCAs including SCA36 were first analyzed based on WES data using ExpansionHunter in five probands from SCA families, then the results were confirmed by triplet repeat primed polymerase chain reaction (TP-PCR) and Southern blot. Results: GGCCTG repeat expansion in NOP56 was indicated in all five probands by WES, then it was found in 11 SCA patients and three asymptomatic individuals by TP-PCR. The sizes of GGCCTG repeat expansions were confirmed to be 1,390–1,556 by Southern blot. The mean age at onset of the patients was 51.0 ± 9.3 (ranging from 41 to 71), and they presented slowly progressive cerebellar ataxia, atrophy and fasciculation in tongue or limb muscles. Conclusion: The patients were clinically and genetically diagnosed as SCA36. This study proposed that WES could be a rapid, reliable, and cost-effective routine test for the preliminarily detection of SCA36 and other ataxia diseases.

Introduction: Sleep disturbances have been associated with essential tremor (ET). However, their pathophysiological underpinnings remain unknown. In this exploratory study, we examined the association between subjective sleep disturbances and the presence of Lewy pathology (LP) on postmortem brain examination in ET cases. Methods: Fifty-two ET cases enrolled in a prospective, longitudinal study were assessed over an average period of 42 months. Cases completed the Pittsburgh Sleep Quality Index (PSQI), which yields seven component scores (e.g., sleep quality, sleep latency). For each component score, we calculated the difference between the last score and the baseline score. Brains were harvested at death. Each had a complete neuropathological assessment, including extensive α-synuclein immunostaining. We examined the associations between baseline PSQI scores and the change in PSQI scores (last – first), and LP on postmortem brain examination. Results: ET cases had a mean baseline age of 87.1 ± 4.8 years. LP was observed in 12 (23.1%) of 52 cases; in 7 of these 12, LP was observed in the locus coeruleus (LC). Change in time needed to fall asleep (last – first sleep latency component score) was associated with presence of LP on postmortem brain examination – greater increase in sleep latency was associated with higher odds of LP (odds ratio = 2.98, p = 0.02). The greatest increase in sleep latency was observed in cases with LP in the LC (p = 0.04). Conclusion: In ET cases, increases in sleep latency over time could be a marker of underlying LP, especially in the LC.

Background: Delirium disorder is a frequent neurological complication of SARS-CoV-2 infection and associated with increased disease severity and mortality. Cognitive impairment is a major risk factor for developing delirium disorder during COVID-19, which, in turn, increases the risk of subsequent neurological complications and cognitive decline. Summary: The bidirectional connection between delirium disorder and dementia likely resides at multiple levels, and its pathophysiological mechanisms during COVID-19 include endothelial damage, blood-brain barrier dysfunction, and local inflammation, with activation of microglia and astrocytes. Here, we describe the putative pathogenic pathways underlying delirium disorder during COVID-19 and highlight how they cross with the ones leading to neurodegenerative dementia. Key Messages: The analysis of the two-sided link can offer useful insights for confronting with long-term neurological consequences of COVID-19 and framing future prevention and early treatment strategies.

Objectives: This study aimed at testing whether CSF levels of amyloid β₄₂ (Aβ₄₂), Aβ₄₀, total tau, and phosphorylated tau (P-tau₁₈₁) individually contribute to the identification of atypical phenotypes among a retrospective cohort of probable Alzheimer’s disease (AD) patients diagnosed by means of the ratio between Aβ₄₂ and Aβ₄₀ (Aβ_42/40). Methods: The retrospective study cohort comprised 50 probable AD patients diagnosed by means of the ratio between Aβ₄₂ and Aβ₄₀ (Aβ_42/40) and for whom total tau and P-tau₁₈₁ values were also available. Patients were clinically classified as typical, amnestic-predominant AD (N = 39; 16 males; mean age: 73.4 ± 7.6 years; mean disease duration: 27.4 ± 24.7 months), or atypical phenotypes (N = 11; 6 males; mean age: 70.2 ± 6.5 years; mean disease duration: 35.5 ± 24.9 months) – i.e., posterior cortical atrophy (N = 4), logopenic-variant primary progressive aphasia (N = 4), and behavioural variant AD (N = 3). A logistic regression allowed predicting the occurrence of atypical versus typical phenotypes based on age, sex, and Aβ₄₂, Aβ₄₀, total tau, and P-tau₁₈₁ levels. Results: Atypical and typical AD patients were comparable for Aβ_42/40 values. Only Aβ₄₀ and P-tau₁₈₁ levels positively (p = 0.015) and negatively (p = 0.019) predicted the occurrence of atypical AD phenotypes, respectively. Classification precision was of 86%, yielding excellent specificity (94.9%) but poor sensitivity (54.5%). Conclusions: The present study delivers promising, albeit preliminary, evidence on the utility of Aβ₄₀ and P-tau₁₈₁ CSF biomarkers in differentiating atypical from typical Aβ_42/40-confirmed AD phenotypes, prompting further research and confirmation on larger cohorts.

Introduction: Previous studies reported increased plasma levels of cystatin C (Cys-C) in Parkinson’s disease (PD) and claimed for a possible association with disease severity and progression. The aim of this study was to evaluate plasma Cys-C in PD and healthy controls (HC) and test its association with markers of peripheral inflammation, neurodegeneration, and clinical progression in a longitudinal study. Methods: Plasma Cys-C, high-sensitive C-reactive protein, interleukin 6, and neurofilament light chain (NfL) were assessed at the baseline in 71 consecutive non-demented PD and 69 HC. PD patients underwent an extensive motor and cognitive assessment at baseline and after 2 years of follow-up. The association of Cys-C with disease severity was evaluated in a multilinear model adjusted for the effect of age, sex, disease duration, and peripheral inflammation. Results: Cys-C levels appeared to be higher in PD compared to controls and correlated with the plasma neuronal marker NfL (r = 0.204, p = 0.046). In longitudinal analyses, PD patients with higher Cys-C levels exhibited faster motor progression at 2 years of follow-up independently from the peripheral inflammatory profile. Conclusions: Cys-C was associated with higher NfL levels and a remarkably faster motor progression in PD independently from peripheral inflammation. Further studies are needed in order to understand the mechanisms underpinning the association of Cys-C with higher neuronal damage markers in neurodegenerative diseases.

Background: Alzheimer’s disease (AD) is the most frequent cause of dementia among the elderly. The accumulation of amyloid beta (Aβ) and its downstream pathological events such as oxidative stress play central roles in AD. Recent studies revealed that Aβ oligomer (AβO)-induced strong neurotoxicity in SH-SY5Y cells via the induction of oxidative stress. Objective: In the present study, we investigated the effect of two antioxidants, Tocovid and Twendee-X, on AβO-induced SH-SY5Y cell damage. Methods: AβOs (2.5 μM) were applied to induce cellular damage in the SH-SY5Y cell line. Cell viability following AβO toxicity, Tau protein phosphorylation, cell morphology, and intracellular reactive oxygen species were assayed with or without different concentrations of Tocovid or Twendee-X. Results: Tocovid (60 μg/mL) and Twendee-X (150 μg/mL) significantly recovered cell viability from AβO toxicity (**p < 0.01, vs. control), attenuated Tau protein phosphorylation (**p < 0.01, vs. AβOs), improved cell morphology (**p < 0.01, vs. AβOs), and suppressed intracellular ROS (**p < 0.01, vs. AβOs) in SH-SY5Y cells. Conclusion: These findings suggest the neuroprotective and therapeutic potential of Tocovid and Twendee-X for AD treatment.

Background: Sativex (USAN: nabiximols [NAB]) oromucosal spray is indicated for treatment of multiple sclerosis (MS) patients with moderate to severe spasticity and inadequate response to other antispasticity medications who demonstrate clinically significant improvement during an initial trial of therapy. This narrative review investigated the efficacy and effectiveness of NAB oromucosal spray for moderate to severe MS spasticity by examining spasticity 0–10 numerical rating scale (NRS) data from interventional and observational studies which featured a 4-week trial period as per the European Union-approved label. Summary: Across both study types, clinically relevant and statistically significant reductions in mean MS spasticity 0–10 NRS scores were measured soon after treatment start and were maintained in the mid- to long term in treatment responders. Initial responder rates (≥20% NRS improvement from baseline at week 4) ranged from 47.6% to 81.4%, tending lower in the randomized clinical trials setting. Clinically relevant responder rates (≥30% NRS improvement from baseline at week 12) were similar between study types (range 30–41%) except for one outlier (74% in an observational study). Two open studies reported treatment continuation for ≥18 months in approximately half of patients who initiated treatment. In most longer term studies, symptomatic improvement in MS spasticity was maintained at mean daily dosages of about 6–7 sprays/day. Safety was consistent with the known profile of NAB. Key Messages: Experimental and observational studies of NAB oromucosal spray recorded similar findings. About half to two-thirds of MS patients who begin treatment will perceive initial symptomatic relief of spasticity within the 4-week trial period. About 40% of patients who initiate treatment will reach the ≥30% NRS improvement threshold at 3 months, comprising the majority of patients who continue long-term treatment. A trial of therapy with NAB is useful to identify patients most likely to gain longer term improvement in spasticity symptoms and discontinue those with insufficient benefit.

Objectives: Excitotoxicity is thought to be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). One possible source of excitotoxicity is the presence of sulphur amino acids (SAAs). In the brain of subjects with ALS, there are increased levels of taurine. In the metabolism of methionine to taurine, excitatory sulphur amino acids (SAAs) are formed. These could potentially contribute to excitotoxicity in ALS. The present study has examined whether plasma levels of SAAs in 38 ALS patients differ from those of 30 healthy controls. Methods: Plasma levels of SAAs were measured by liquid chromatography mass spectrometry. Results: There were no significant changes in plasma cysteic acid, cysteine sulfinic acid, and homocysteic acid in ALS patients compared to healthy subjects. Significant elevations in plasma homocysteinesulfinic acid (HCSA) levels (p < 0.0001) were observed in the ALS patients (75.91 ± 15.38 nM) compared to healthy controls (54.06 ± 8.503 nM); 50% of the ALS patients had HCSA levels that were 1.5–2-folds higher than those of controls. Plasma levels of HCSA differed significantly (p = 0.0440) between patients with bulbar onset and spinal onset (68.57 ± 14.20 vs. 79.30 ± 14.95 nM, respectively). Conclusion: HCSA is elevated in the blood of subjects with ALS. Since HCSA can be transported from the blood to the CNS by active transport, has neurotransmitter properties, and can activate synaptic receptors including NMDAR and metabotropic glutamate receptor, it is possible that increases in HCSA could influence glutamatergic neurotransmission and potentially contribute to excitotoxicity in some ALS patients.