Cerebellum最新文献

Oculomotor deficits are common in hereditary cerebellar ataxias (HCAs) and their quantitative assessment offers a sensitive and reliable manner to capture disease-severity and progression. As a group of experts of the Ataxia Global Initiative to support trial readiness, we previously established harmonized methodology for quantitative oculomotor assessments in HCAs. Here, we aimed to identify to most promising oculomotor/vestibular outcomes as endpoints for future trials. Through a systematic MEDLINE search we identified 130 articles reporting oculomotor/vestibular recordings in patients with HCAs. A total of 2,018 subjects were included: 1,776 with genetically-confirmed and 242 with clinically-defined HCAs. Studied diseases included spinocerebellar ataxias (SCA) 1/2/3/6/7/27B, episodic ataxia type 2, Friedreich ataxia, RFC1-related ataxia, fragile X-associated tremor/ataxia syndrome, cerebrotendinous xanthomatosis, ataxia-telangiectasia, ataxia with oculomotor apraxia types 1&2, and Niemann-Pick disease type C. We identified up to four oculomotor/vestibular outcomes per diagnostic entity, based on their ability to robustly discriminate patients from controls, correlate with disease-severity, detect longitudinal change, and represent different disease stages. For each parameter we provide recommendations for recordings. While the implementation of quantitative assessments into clinical trials offers a unique opportunity to track dysfunction of oculomotor/vestibular networks and to assess the impact of interventions, in some HCAs, endpoint qualification of available outcomes requires further validation to characterize their reliability, sensitivity to change, and minimally important change to patients. For all HCAs for which quantitative data are scarce or lacking, there is an urgent need for prospective studies covering a broader range of oculomotor/vestibular domains as approaching new treatments require harmonized and reliable endpoints.

Cadmium (Cd) is a widespread environmental pollutant with well-documented neurotoxic effects. The cerebellum, a key region for motor coordination, appears particularly vulnerable to Cd-induced damage. Numerous recent studies have investigated Cd-mediated cerebellar toxicity, yet an integrated interpretation of these findings remains limited.Here, we summarize current knowledge on histopathological and molecular alterations in the cerebellum following Cd exposure. Cadmium disrupts redox balance by generating reactive oxygen species (ROS) and depleting endogenous antioxidant defenses, including superoxide dismutase (SOD) and glutathione peroxidase (GPx). It also interferes with metal homeostasis, promoting accumulation of copper and manganese while reducing levels of zinc, selenium, and iron. Cd alters the expression of metal transporters and impairs synthesis of metallothioneins and heat shock proteins.Histologically, Cd exposure affects all three layers of the cerebellar cortex and leads to Purkinje and granular cell loss. Molecular markers of apoptosis (e.g., Bax, caspases, TUNEL-positive nuclei) and necrosis (e.g., RIPK1/3) are commonly elevated. Additionally, Cd impairs key signaling pathways such as PI3K/AKT and Sonic Hedgehog (Shh), and reduces neurotransmitter levels.Experimental evidence from multiple animal models (rats, piglets, chickens, etc.) consistently demonstrates cerebellar accumulation of Cd and associated pathological changes. Importantly, several interventions-including nano-selenium, soy-based diets, and natural antioxidants-have shown protective effects against Cd-induced cerebellar toxicity.

Introduction: The Cerebellar Cognitive Affective Syndrome (CCAS), also known as Schmahmann's syndrome, is increasingly recognized for its impact on cognitive and emotional functioning yet remains underdiagnosed. This study aimed to standardize the CCAS-Scale (CCAS-S) in the Italian population, enhancing its methodological and statistical validity.

Methods: A total of 671 healthy Italian volunteers (mean age = 46.19 years with SD 18.47, 58.88% females), were recruited from various geographical, educational and social backgrounds. Participants were assessed using the CCAS-S, alongside the Cognitive Reserve Index questionnaire, Raven's Colored Progressive Matrices and the Mini-Mental State Examination to ensure a comprehensive assessment and establish convergent validity. Moreover, the parallel CCAS-S version B was administered to 51 individuals.

Results: Statistical analyses on the Italian version of the CCAS-S revealed strong psychometric properties. Internal consistency was confirmed with Cronbach's alpha values of 0.70 and 0.74 for parallel forms A and B. Construct validity was supported by a moderate-to-high correlation (r = 0.453) with the Mini-Mental State Examination, suggesting both scales are related yet measure different cognitive functions, with the CCAS-S focusing on executive functions. Test-retest and inter-rater reliability were optimal (ICC = 0.902 and 0.989, respectively). Minimal practice effects were observed after 1 to 3 months, with further validation achieved using parallel version B.

Conclusions: The present work provides the first Italian standardization of CCAS-S. The results highlight the necessity for increased awareness and recognition of CCAS in clinical settings, advocating for the integration of the CCAS-S into routine assessments to improve diagnostic accuracy and patient care.

Spinocerebellar ataxia type 1 (SCA1) was the first autosomal dominant ataxia to have its genetic basis uncovered in 1993. It belongs to the group of polyglutamine SCAs, which are caused by abnormal (CAG) expansions within the coding regions of different genes. The disease has global, but not even distribution across the world. It seems to be particularly frequent in Northern Italy and Eastern Europe. There are few reports coming from Latin American countries. In the current review, we will cover epidemiological data from SCA1 in Brazilian patients, trying to compare the local genotypic and phenotypic profile with that from other countries. In addition, key contributions (phenotypic characterization and neuroimaging) to our understanding of this condition coming from Brazilian investigators will be addressed.

The Cerebellar Cognitive Affective / Schmahmann Syndrome scale (CCAS-S) detects cognitive and neuropsychiatric changes in cerebellar disease (CD). It has good sensitivity and specificity, but a false positive rate ~ 5%. We determined that healthy controls (HC) fail digit span tasks (DS) when presented with one repetition opportunity. We tested the hypothesis that providing participants a second attempt at DS would improve performance and decrease false positive rate. We also evaluated influence of age and education on CCAS-S scores. We administered the CCAS-S to 50 CD and 85 HC, providing a second attempt at forward / reverse DS for each failed number sequence, using either the same numbers, or a different set of numbers of the same length. Performance with same vs different digits was identical. After second DS attempt, raw score increased: HC, 106.1 ± 9.4 to 106.8 ± 9.2; CD, 89.2 ± 15.5 to 90.6 ± 15.8, and failed domains decreased: HC, 0.67 ± 0.89 to 0.4 ± 0.73; CD, 2.62 ± 1.9 to 2.24 ± 1.9. False positive definite CCAS (≥ 3 failed domains) decreased in HC, 4.7% to 1.2%. In CD, definite CCAS remained high, 48% to 38%. Some older HC failed ≥ 3 domains. Education (all ≥ 12 years) did not impact performance in HC; CD with more education failed fewer domains. False positive definite CCAS-S was reduced to 1.2% by second attempt at forward and backward DS. The CCAS-S detected incipient cognitive impairment in older individuals. Education effects were modest, but cohorts with education ≤ 11 years need further study.

The α2-adrenergic receptor (α2-AR) is involved in various forms of information transmission in the cerebellar cortex, but its role in modulating sensory stimulation-induced synaptic plasticity remains unclear. We investigated the role of the α2-AR in facial stimulation-evoked long-term synaptic plasticity within molecular layer interneuron-Purkinje cell (MLI-PC) circuitry in the cerebellum by electrophysiological, pharmacological and immunohistochemical methods, and used alongside the rotarod test to assess the impact of receptor activity on motor learning in mice. Facial stimulation at 1 Hz induced MLI-PC long-term depression (LTD), which was significantly enhanced by microinjection of noradrenaline (NA) into the cerebellar molecular layer. Blockade of the NMDA receptor abolished facial stimulation-induced MLI-PC LTD; However, the effect could be triggered in the absence of NMDA activity through NA or UK14304 α2-AR activation with concurrent stimulation. In the absence of NMDA receptor activity, α2-AR-mediated facial stimulation-induced MLI-PC LTD was abolished by blockade of α2A-, but not α2B- or α2C-ARs. Facial stimulation-induced MLI-PC LTD was triggered by a selective α2A-AR agonist, guanfacine, but it was completely prevented by inhibition of protein kinase A (PKA) activity with KT5720. The rotarod test indicated that microinjection of guanfacine into the cerebellar cortex to activate α2A-ARs significantly improved early motor learning. Immunochemistry revealed α2A-AR immunoreactivity throughout the mouse cerebellar cortex, mostly in the PC layer and MLIs. These results suggest that NA facilitates facial stimulation-induced, α2A-AR/PKA signaling cascade-dependent MLI-PC LTD and promotes the acquisition of motor learning in mice.

Hereditary ataxias are progressive neurodegenerative disorders primarily affecting the cerebellum. Since 2009, the Clinical Research Consortium for the Study of Cerebellar Ataxias (CRC-SCA) has studied the natural history of common types of spinocerebellar ataxias (SCAs). The CRC-SCA is a 17-site academic collaboration supported by the National Ataxia Foundation. In 2024, the CRC-SCA expanded its scope by incorporating newly identified late-onset ataxias, including repeat expansion mutations in RFC1 and FGF14 causing Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome (CANVAS) and SCA27B, respectively. These ongoing efforts have enriched the understanding of disease progression and facilitated access to biofluid and neuroimaging data for biomarker discovery, setting the stage for therapeutic development in hereditary ataxias. The CRC-SCA's natural history study and biomarker collection have validated several clinical outcome assessments (COAs) to capture important aspects of hereditary ataxias. We have also developed new COAs for cognitive and patient-reported outcome measures. A key component of the study includes biofluid collection-cerebrospinal fluid, plasma, and serum-to identify molecular biomarkers for disease progression and therapeutic response. Additionally, an incorporated magnetic resonance imaging (MRI) substudy provides critical imaging biomarkers, enhancing our ability to track macro- and microstructural, chemical and functional changes in the cerebellum and relate these to clinical presentations. The comprehensive, longitudinal dataset comprising COAs, biofluid biomarkers, and neuroimaging enhances clinical trial readiness in the field and accelerates therapeutic advancements for hereditary ataxias. This review highlights the collective efforts of CRC-SCA, details the study protocol, and emphasizes the integrity and specificity of the collected data elements.

Spinocerebellar Ataxia type 27B (SCA27B) is caused by an intronic GAA repeat expansion in the fibroblast growth factor 14 (FGF14) gene. The core clinical phenotype is a slowly progressive, adult-onset cerebellar ataxia, often with downbeat nystagmus (DBN) and episodic worsening. We tested whether clinical phenotyping could predict this genetic disorder. We screened the Massachusetts General Hospital Ataxia Center registry (n = 3,182) for patients with a) isolated DBN, b) DBN with ataxia, and c) autosomal dominant cerebellar ataxia (ADCA) that had eluded genetic diagnosis. Patient histories, examinations, and imaging were reviewed. Genetic analysis for FGF14 expansion was performed. Of 65 identified patients, 39 completed genetic testing. Among 14 with isolated DBN, 9 carried an FGF14 repeat expansion (GAA)_≥250 (range, 295-461), 1 had a potentially pathogenic allele (247 repeats), and 4 had normal alleles. Among 19 with DBN plus ataxia, 12 tested positive (276-431 repeats), 1 had a suspected pathogenic allele (228 repeats), and 6 had normal alleles. All 4 ADCA patients tested positive (320-483 repeats), as did 2 presymptomatic siblings. Our cohort enriched for suspicion of SCA27B had confirmed or suspected pathogenic FGF14-GAA expansion in 74.4% (29/39). Diagnostic success rate was 90.0% (27/30) in patients with onset > 45 years: 25/30 (GAA)_≥250, 2/30 (GAA)_200-249. Cerebellar atrophy was seen in 97.1% (34/35), mostly in the vermis/paravermis. Clinically meaningful improvement with 4-aminopyridine occurred in 71.0% (22/31) of patients. SCA27B can be reliably recognized from its core clinical phenotype in up to 90% of cases, enabling successful pharmacotherapy in 71.0%.

Background and objective: Degenerative cerebellar ataxia, a group of progressive neurodegenerative disorders, is characterised by cerebellar atrophy and impaired motor learning. Using CerebNet, a deep learning algorithm for cerebellar segmentation, this study investigated the relationship between cerebellar subregion volumes and motor learning ability.

Methods: We analysed data from 37 patients with degenerative cerebellar ataxia and 18 healthy controls. Using CerebNet, we segmented four cerebellar subregions: the anterior lobe, superior posterior lobe, inferior posterior lobe, and vermis. Regression analyses examined the associations between cerebellar volumes and motor learning performance (adaptation index [AI]) and ataxia severity (Scale for Assessment and Rating of Ataxia [SARA]).

Results: The inferior posterior lobe volume showed a significant positive association with AI in both single (B = 0.09; 95% CI: [0.03, 0.16]) and multiple linear regression analyses (B = 0.11; 95% CI: [0.008, 0.20]), an association that was particularly evident in the pure cerebellar ataxia subgroup. SARA scores correlated with anterior lobe, superior posterior lobe, and vermis volumes in single linear regression analyses, but these associations were not maintained in multiple linear regression analyses. This selective association suggests a specialised role for the inferior posterior lobe in motor learning processes.

Conclusion: This study reveals the inferior posterior lobe's distinct role in motor learning in patients with degenerative cerebellar ataxia, advancing our understanding of cerebellar function and potentially informing targeted rehabilitation approaches. Our findings highlight the value of advanced imaging technologies in understanding structure-function relationships in cerebellar disorders.