Explore the vast range of titles available.

Late-onset ataxia is common, often idiopathic, and can result from cerebellar, proprioceptive, or vestibular impairment; when in combination, it is also termed cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). We used non-parametric linkage analysis and genome sequencing to identify a biallelic intronic AAGGG repeat expansion in the replication factor C subunit 1 ( RFC1 ) gene as the cause of familial CANVAS and a frequent cause of late-onset ataxia, particularly if sensory neuronopathy and bilateral vestibular areflexia coexist. The expansion, which occurs in the poly(A) tail of an AluSx3 element and differs in both size and nucleotide sequence from the reference (AAAAG) 11 allele, does not affect RFC1 expression in patient peripheral and brain tissue, suggesting no overt loss of function. These data, along with an expansion carrier frequency of 0.7% in Europeans, implies that biallelic AAGGG expansion in RFC1 is a frequent cause of late-onset ataxia. Biallelic expansion of an intronic AAGGG repeat in RFC1 is identified here as a common cause of late-onset ataxia. This expansion occurs in the poly(A) tail of an AluSx3 element and is observed at a carrier frequency of 0.7% in populations of European ancestry.

Background Central Nervous System involvement in hereditary transthyretin amyloidosis (ATTRv) is present in liver transplanted patients with longstanding ATTRV30M amyloidosis, and in some rarer variants. The pathophysiology of brain involvement and its relationship with cognitive disturbances is unknown. This systematic review summarized the literature on brain and cognitive involvement in ATTRv amyloidosis and aimed to elucidate the reasons for such involvement. Methods The literature search was performed using the following databases: Medline/PubMed, Embase via Elsevier, Scopus, and Web of Science. Two assessors independently screened titles and abstracts, examined full texts, extracted data, and assessed the risk of bias. The risk of bias assessment was carried out using the JBI critical appraisal tools. This review included studies that applied any neuroimaging exam or cognitive assessment in humans with genetic confirmation of any TTR mutation. Results 59 studies met the inclusion criteria. Overall, the studies were of good quality. 57 studies reported at least one brain MRI technique. Only six studies reported a formal neuropsychological assessment. The studies included 1218 ATTRv patients (mean 45.7 ± 11.8 years) and 169 asymptomatic TTR variant carriers (mean 30.6 ± 7.5 years). The most common TTR variant was V30M (n = 936), followed by V122I (n = 74). 42.4% of ATTRv patients presented abnormalities in the neuroimaging exam and 19.7% presented cognitive dysfunction. Conclusion Based on the available evidence, brain involvement and cognitive symptoms can be present in ATTRv amyloidosis. Further research should explore the relationship of these symptoms with other complications (autonomic and cardiologic).

Neurological involvement occurs throughout the leprosy clinical spectrum and is responsible for the most feared consequences of the disease. Ultrasonography (US) provides objective measurements of nerve thickening and asymmetry. We examined leprosy patients before beginning multi-drug therapy aiming to describe differences in US measurements between classification groups and between patients with and without reactions. Eleven paucibacillary (PB) and 85 multibacillary (MB) patients underwent nerve US. Twenty-seven patients had leprosy reactions (type 1, type 2 and/or acute neuritis) prior to US. The ulnar (at the cubital tunnel-Ut-and proximal to the tunnel-Upt), median (M) and common fibular (CF) nerves were scanned to measure cross-sectional areas (CSAs) in mm2 and to calculate the asymmetry indexes ΔCSA (absolute difference between right and left CSAs) and ΔUtpt (absolute difference between Upt and Ut CSAs). MB patients showed greater (p<0.05) CSAs than PB at Ut (13.88±11.4/9.53±6.14) and M (10.41±5.4/6.36±0.84). ΔCSAs and ΔUtpt were similar between PB and MB. The CSAs, ΔCSAs and ΔUtpt were similar between PB patients with reactions compared to PB patients without reactions. MB patients with reactions showed significantly greater CSAs (Upt, Ut and M), ΔCSAs (Upt and Ut) and ΔUtpt compared to MB patients without reactions. PB and MB showed similar frequencies of abnormal US measurements. Patients with reactions had higher frequency of nerve thickening and similar frequency of asymmetry to those without reactions. This is the first study to investigate differences in nerve involvement among leprosy classification groups using US before treatment. The magnitude of thickening was greater in MB and in patients with reactions. Asymmetry indexes were greater in patients with reactions and did not significantly differ between PB and MB, demonstrating that asymmetry is a characteristic of leprosy neuropathy regardless of its classification.

Sleep restriction alters gut microbiota composition and intestinal barrier function in rodents, but whether similar effects occur in humans is unclear. This study aimed to determine the effects of severe, short-term sleep restriction on gut microbiota composition and intestinal permeability in healthy adults. Fecal microbiota composition, measured by 16S rRNA sequencing, and intestinal permeability were measured in 19 healthy men (mean ± SD; BMI 24.4 ± 2.3 kg/m 2 , 20 ± 2 years) undergoing three consecutive nights of adequate sleep (AS; 7–9 h sleep/night) and restricted sleep (SR; 2 h sleep/night) in random order with controlled diet and physical activity. α-diversity measured by amplicon sequencing variant (ASV) richness was 21% lower during SR compared to AS ( P  = 0.03), but α-diversity measured by Shannon and Simpson indexes did not differ between conditions. Relative abundance of a single ASV within the family Ruminococcaceae was the only differentially abundant taxon ( q  = 0.20). No between-condition differences in intestinal permeability or β-diversity were observed. Findings indicated that severe, short-term sleep restriction reduced richness of the gut microbiota but otherwise minimally impacted community composition and did not affect intestinal permeability in healthy young men.

Background The ATXN2 gene contains a polymorphic CAG-rich region encoding a polyglutamine tract in ataxin- 2. Normal alleles have fewer than 27 CAG repeats, 27–34 repeats pose a risk for ALS ( ATXN2 -ALS), and > 34 repeats cause spinocerebellar ataxia type 2 (SCA2). The striking phenotypic differences between these two ATXN2- related conditions are not yet fully understood. Objective To characterize and compare the distinguishing radiological signatures of ATXN2 -ALS, SCA2, sporadic ALS (sALS) and healthy controls in vivo using quantitative computational neuroimaging techniques. Methods Four groups were defined: healthy controls ( n  = 34), sALS ( n  = 17), ATXN2 -ALS ( n  = 16), and SCA2 ( n  = 17). Cortical, subcortical, brainstem, cerebellar and spinal regions were segmented based on T1-weighted data using validated segmentation tools and their volumes estimated. Group-specific morphometric data were correlated with cerebral ATXN2 expression maps from the Allen Human Brain Atlas. Results Study groups were age and sex-matched. sALS, ATXN2 -ALS and SCA2 have distinct structural CNS signatures, with disease burden restricted to the precentral gyri in the sALS group, to the spinal cord and brainstem in the ATXN2 -ALS group and more diffusely distributed in the subcortical structures in the SCA2 group. Brain ATXN2 expression correlated with the structural signature of SCA2, but not with that of ATXN2 -ALS. Conclusions Neuroimaging signatures differ in ATXN2 -ALS and SCA2, indicating distinct mechanisms of ATXN2 -mediated neurodegeneration. sALS and ATXN2 -ALS also exhibit distinct patterns of CNS involvement. The unique imaging signatures and clinical profiles along the spectrum of ATXN2-related disorders raise important questions regarding the pathophysiology of the disease and have practical clinical ramifications.

Previous studies have shown that leprosy multi-drug therapy (MDT) does not stop the progression of nerve function impairment. There are no prospective studies investigating the evolution of nerve anatomic abnormalities after treatment. We examined leprosy patients aiming to investigate the evolution of nerve ultrasonography (US) abnormalities and the risk factors for poor outcomes after MDT. We performed bilateral US of the ulnar (U), median (M) and common fibular (CF) nerves in 9 paucibacillary (PB) and 64 multibacillary (MB) patients before and after MDT. Forty-two patients had leprosy reactions (type 1, type 2, acute neuritis) during the study. We analyzed nerve maximum cross-sectional areas (CSA), echogenicity and Doppler signal. Poor outcomes included a post-treatment CSA above normal limits with a reduction of less than 30% (U, M) or 40% (CF) from the baseline, echogenicity abnormalities or intraneural Doppler in the post-treatment study. We found that PB and patients without reactions showed significant increases in CSA at CF, whereas MB and patients with reactions had CSA reduction in some nerves after treatment (p<0.05). Despite this reduction, we observed a greater frequency of poor CSA outcomes in the MB compared to the PB (77.8% and 40.6%; p>0.05) and in the patients with reactions compared to those without (66.7% and 38.7%; p<0.05). There was significantly higher odds ratio (7.75; 95%CI: 1.56-38.45) for poor CSA outcomes only for M nerve in patients with reactions. Poor echogenicity outcomes were more frequent in MB (59.4%) compared to PB (22.2%) (p<0.05). There was significant association between poor Doppler outcomes and neuritis. Gender, disease duration, and leprosy classification were not significant risk factors for poor outcomes in CSA, echogenicity or Doppler. US nerve abnormalities can worsen after treatment despite the leprosy classification or the presence of reactions.

Erythropoietin (EPO) administration stimulates haematological and non‐haematological adaptations that alter substrate oxidation and enhance aerobic performance. The effects of strenuous exercise and EPO on metabolites, and whether any effect is associated with haematological and non‐haematological adaptations, has not been assessed. The objective of this study was to examine changes in serum and skeletal muscle metabolomes and explore whether changes were associated with haematological and non‐haematological adaptations to strenuous exercise and EPO. Eight males (20 ± 3 years, 25 ± 3 kg/m2) completed this longitudinal study. Participants received 50 IU/kg body mass of EPO, 3×/week for 28 days, while exercise (energy expenditure of 1200–1500 kcals/day) and diet were controlled. Before (PRE) and after (POST) EPO, V̇O2peak ${{\\dot{V}}_{{{\\mathrm{O}}}_2}{\\mathrm{peak}}}$ , time trial (TT) performance, blood volume, iron homeostasis, and untargeted metabolomics profiles in rested/fasted muscle and serum were assessed. Weighted gene correlation network analysis (WGCNA) was used to identify plasticity of metabolite networks (POST/PRE) correlated with change in V̇O2peak ${{\\dot{V}}_{{{\\mathrm{O}}}_2}{\\mathrm{peak}}}$ , TT performance, blood volume and iron homeostasis. Four serum and 51 muscle metabolites were different (P ≤ 0.05, false discovery rate ≤ 0.10) at POST compared to PRE. Of the WGCNA networks identified, two serum modules were associated with aerobic performance (P = 0.05), while five skeletal muscle modules were associated with both aerobic performance and iron outcomes (P = 0.05). Changes to the serum and skeletal muscle metabolomes indicate altered carnitine, β‐alanine and glucose metabolism metabolites, likely depicting a shift to greater fat oxidation, buffering capacity and the alteration in iron homeostasis following 28 days of EPO administration and strenuous exercise. What is the central question of this study? What changes in serum and skeletal muscle metabolomes occur and are they associated with haematological and non‐haematological adaptations to strenuous exercise and exogenous erythropoietin (EPO) administration? What is the main finding and its importance? The skeletal muscle metabolome was more sensitive to 4 weeks of strenuous exercise and exogenous EPO administration than serum, and changes in carnitine, β‐alanine and glucose metabolism metabolites likely depict a shift to greater fat oxidation, buffering capacity and the alteration in iron homeostasis following 28 days of exogenous EPO administration and strenuous exercise training.

Background Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is a late-onset multisystem disorder related to the RFC1 gene. Despite evidence of dysautonomia and sleep disturbances, hypothalamic involvement is unknown. Objective We aimed to investigate hypothalamic volumetry in CANVAS/RFC1. Methods We analyzed 19 CANVAS/RFC1 patients and 19 healthy controls using automated hypothalamic segmentation from 3 T-MRI scans. Volumetric comparisons were performed using ANCOVA, while correlations with Scale for the Assessment and Rating of Ataxia (SARA) and Scales for Outcomes in Parkinson’s Disease-Autonomic questionnaire (SCOPA-AUT) scores were assessed by Pearson’s correlation. Results CANVAS/RFC1 group had a significantly lower total hypothalamic volume (RFC1: 734.84 ± 160.49 mm 3 vs Controls: 878.83 ± 136.55 mm 3 ; P  = 0.03; d = 0.99) and a reduced left tuberal superior (LTS) volume (RFC1: 71.21 ± 21.85 mm 3 vs Controls: 90.30 ± 15.67 mm 3 ; P = 0.02; d = 0.99). LTS volume inversely correlated with SARA score (R = -0.51, P = 0.049), but no associations were found with SCOPA-AUT. Conclusion This study reveals hypothalamic atrophy in CANVAS, suggesting its role in disease pathophysiology. Further research should investigate broader hypothalamic dysfunctions and clinical implications.

Charcot-Marie-Tooth disease type 1A (CMT1A) is the most prevalent hereditary neuropathy worldwide and classically has slow nerve conduction velocity (NCV), in most cases below 38 m/s. Two unrelated patients with motor NCVs in the upper limbs above 38 m/s are reported. Case report. Two genetically confirmed CMT1A patients are presented, from two unrelated families (one of British origin and the other of Brazilian origin). Both individuals had upper limb motor NCVs above 38 m/s, with values ranging from 41.9 to 45 m/s in the median nerve and from 42 to 42.3 m/s in the ulnar nerve. They presented with a very mild phenotype, with CMT Neuropathy Score version 2 (CMTNSv2) of 6 and 5, respectively. In contrast, affected family members within both kinships exhibited a classical phenotype with more severe disease manifestation (CMTNSv2 ranging from 12 to 20) and motor NCVs below 30 m/s. These cases, although very rare, highlight the importance of testing PMP22 duplication in patients with intermediate conduction velocities.

Background Central nervous system symptoms, such as cognitive dysfunction, have been reported in Hereditary Transthyretin Amyloidosis (ATTRv). However, there is a lack of neuroimaging studies investigating structural alterations in the brain related to cognition in ATTRv amyloidosis. This study aimed to investigate cognition and cortical morphology in a cohort of ATTRv patients. Methods 29 ATTRv patients and 26 healthy controls completed neuropsychological assessment. 21 of these patients underwent 3T brain MRI, and 23 healthy subjects constituted the control group for MRI. Cortical measures of volume, thickness, fractional anisotropy (FA), and mean diffusivity (MD) were obtained for both groups. Correlation analyses between brain and cognitive measurements were performed. Results Patients displayed worse performance than controls in executive functions, verbal and visual memory, visuospatial domains, and language tests. Our study indicated cortical thinning in ATTRv patients in the temporal, occipital, frontal, and parietal areas. The inferior temporal gyrus correlated with verbal memory. Insula and, pars opercularis correlated with both verbal memory and executive function. Conclusions Cortical thickness in the inferior temporal gyrus, pars opercularis, and insula were linked to memory and executive function. We observed no correlations between cortical volume measures and cognition. Further investigations are imperative to confirm these findings across different populations.