Cerebellum最新文献

This study characterizes in vivo glymphatic system alterations in spinocerebellar ataxia (SCA) using a structure-environment-function multimodal MRI framework and explores subtype-specific signatures and longitudinal progression. Twenty genetically confirmed SCA patients (SCA1 = 1, SCA2 = 11, SCA3 = 6, SCA7 = 2) and 23 matched healthy controls underwent MRI across two scanners. The framework included structural (perivascular space volume fraction, pPVS; choroid plexus volume, CPV), environmental (free water, FW), functional (DTI-ALPS index), and microstructural (fractional anisotropy, FA) metrics. Data were harmonized across sites. Cross-sectional, subtype, and longitudinal analyses were performed. SCA patients demonstrated significantly enlarged subcortical pPVS, elevated FW, and reduced FA compared to controls (all surviving FDR correction, q = 0.05), while CPV/rCPV showed non-significant trends and the ALPS index showed no group difference. Subtype analyses revealed higher white matter and total pPVS in SCA3 versus SCA2 (surviving FDR correction), but FW differences did not survive correction. Longitudinally, the SCA2 subset exhibited significant FA decline over time (p < 0.001), with robust group effects on FW and WM pPVS. Within a structure-environment-function framework, SCA exhibits prominent glymphatic-related abnormalities in perivascular and interstitial compartments, with preserved ALPS index. Distinct imaging signatures of SCA2 and SCA3 suggest divergent pathophysiologies. FW and FA emerge as promising complementary biomarkers for monitoring disease burden and progression in future trials.

The cerebellum has long been implicated in language processes, but its precise role in spelling subcomponents such as orthographic retrieval and phoneme-grapheme conversion planning remains underexplored. We used task-based fMRI and functional connectivity (FC) analyses to investigate cerebral-cerebellar cooperation during three in-scanner spelling conditions that differentially taxed print, and sound processes in 33 adults with and without reading impairments. ROI-to-ROI analyses identified robust cerebral-cerebellar connectivity across all conditions, with task-specific engagement of cerebellar regions in right lobule VI and Crus II. Despite marked behavioral differences between typical and impaired readers, including lower spelling accuracy and slower response times in the impaired group, no significant group differences in cerebral-cerebellar FC were observed. Generalized psychophysiological interaction (gPPI) analyses revealed unique cerebral-cerebellar connectivity patterns associated with sublexical processing (e.g., left supramarginal gyrus to right lobule VIb) in the phonological task, but not in the orthographic condition. These findings support a dynamic and context-dependent cerebellar role in language processing and suggest that cerebellar contributions to spelling involve integrative cooperation with cerebral language regions regardless of reading proficiency. This study reinforces the need to consider cerebellar-cortical networks in models of reading and dyslexia.

The number of known developmental disorders affecting the hindbrain is rapidly increasing due to advances in neuroimaging and genetic technologies. Nevertheless, it remains largely unknown why the development of the hindbrain is affected in many genetic disorders. We aim to unveil new insights into the biological pathways essential for hindbrain development by investigation of the pathogenetics of hindbrain abnormalities. In this work, an updated gene list of abnormalities of the hindbrain was generated, and genes were subsequently grouped according to most prevalent association in (1) predominantly cerebellar, (2) cerebellar and brainstem and (3) brainstem malformations. Brain-specific gene co-expression networks were generated to identify functional relationships and novel genes that were not yet linked to hindbrain malformations. The results showed that shared biological pathways underlie distinct hindbrain processes, even when cells originate from different primordia. Key players in hindbrain development include genes encoding transcription factors and extracellular signaling molecules. Notably, brainstem abnormalities are biologically distinct, with a smaller role for ciliogenesis. Through co-expression analysis, we identified candidate genes for hindbrain malformations including TRRAP and NCAM1. The identification of essential biological pathways in this study uncovers additional important challenges in genetic hindbrain malformations, such as how defects in apparently ubiquitous processes result in brain-specific phenotypes, and how timing and repair mechanisms influence the pathogenesis of affected pathways.

The diagnosis of hereditary ataxias caused by repeat expansions continue to present unique methodological challenges, especially for developing countries where genomic medicine services are not well established. The purpose of this work is to present a cohort of patients who presented with adult-onset ataxia of suspected genetic etiology, but had remained undiagnosed until now. They were analyzed for a set of repeat expansions including the genes causing the more recently identified types, SCA27BandRFC1-related CANVAS. Patients with a possible diagnosis of hereditary cerebellar ataxia with adult onset underwent genetic testing to detect a set of repeat expansions known to cause autosomal dominant ataxia. In selected cases, a complete vestibular function evaluation and brain magnetic resonance imaging was acquired. In 17 of the 56 studied cases (including 11 of 43 index cases) we established a genetic diagnosis, which demonstrates that this is a promising approach to adult-onset ataxias in a population that remains underrepresented in worldwide genomic studies. We identified 9 individuals with SCA27B and 7 with CANVAS, highlighting the epidemiological relevance of these newly recognized etiologies, an information useful for planning the allocation of resources towards improving the access to genomic medicine in in our region.

Aminopyridines (APs) enhance Purkinje cell excitability and are effective for several cerebellar and ocular motor syndromes, including downbeat nystagmus. Their use in anti-glutamic acid decarboxylase (GAD) cerebellar ataxia has not previously been described. A 69-year-old woman with confirmed anti-GAD cerebellar ataxia underwent clinical and videonystagmography (VNG) assessments at baseline, Day 7, and Day 30 after start of fampridine 20 mg/day. Baseline VNG showed pronounced downbeat nystagmus and frequent square-wave jerks. By Day 7, downbeat nystagmus had fully resolved with a marked reduction in square-wave jerks, accompanied by improvement in oscillopsia and diplopia. Findings remained stable at Day 30. SARA scores remained unchanged, with persistent gait, stance, and other cerebellar motor deficits. Fampridine was associated with rapid and sustained improvement in oculomotor dysfunction in this patient with anti-GAD cerebellar ataxia. APs may offer adjunctive symptomatic benefit in selected individuals with visually disabling downbeat nystagmus. Controlled studies are needed to confirm these observations.

To evaluate the efficacy and safety of repetitive Transcranial Magnetic Stimulation (rTMS) in Spinocerebellar Ataxia (SCA) patients. We conducted a systematic review and meta-analysis of nine Randomized Controlled Trials (RCTs). Searches covered major databases (Medline, Embase, CENTRAL, etc.) and trial registries (ICTRP, ClinicalTrials.gov). We included RCTs comparing rTMS with sham stimulation on outcomes for efficacy (ataxia severity, quality of life) and safety (adverse events, tolerability). Data were extracted, bias was assessed (RoB 2), and certainty of evidence was evaluated using the GRADE approach. All included studies used sham stimulation, with follow-ups up to four weeks. Pooled analyses showed significant differences favoring rTMS immediately post-intervention for global ataxia severity (International Cooperative Ataxia Rating Scale-ICARS-: MD -4.07, low certainty; Scale for the Assessment and Rating of Ataxia-SARA-: MD-1.55, very low certainty). Moderate-certainty evidence demonstrated significant improvements in the ICARS subdomains for posture and gait (MD -1.53, p<0.00001) and limb function (MD -3.59, p<0.00001). However, no significant effect was found for speech disorders. rTMS was well-tolerated; safety assessment showed no significant difference in adverse events or dropout rates (low certainty), and no serious adverse events were reported. Evidence was insufficient to assess the quality of life or long-term effects. Low to very-low certainty evidence suggests that rTMS, compared to sham, provides slight but clinically relevant short-term improvement in motor function and global ataxia severity in SCA patients, with comparable safety profiles. Our effect estimations are derived from small, highly heterogeneous RCTs conducted predominantly in Asian cohorts with SCA3. Rigorous studies with longer follow-up are needed to confirm the sustained utility of this intervention.

The latest tremor classification suggested to stratify patients with Essential Tremor (ET) into pure (pET) and plus (ET-plus) forms. Cognitive dysfunction in ET might reflect the Cerebellar Cognitive Affective Syndrome (CCAS), but there is no evidence in ET-plus. We aimed to evaluate the CCAS in ET-plus, further attempting to explore possible motor-cognitive associations.Thirty-nine patients with ET-plus and 19 matched healthy controls (HC) performed the CCAS-scale (CCAS-S). Patients were also assessed using the Tremor Research Group Essential Tremor Rating Scale and the Scale for the Assessment and Rating of Ataxia. Moreover, data about their soft signs were recorded. The obtained data were further compared to a published series of pET. Patients with ET-plus had worse CCAS-S performances than HC, with 69.4% of the former having a definite CCAS. Cognitive performances did not correlate with any of the clinical data, but with the presence of slowing. While the rate of definitive CCAS was similar between pET and ET-plus, they demonstrated different cognitive profiles. Poorer CCAS-S performance had a detrimental impact on activity of daily living beyond tremor severity. Our results demonstrate a pervasive cognitive impairment in ET-plus, possibly sustained by a cerebellar dysfunction. However, the association of cognitive deficits with the presence of slowing and the qualitative differences between ET-plus and pET might suggest a more widespread pathology with the involvement of extra-cerebellar brain areas, indicating that they reflect two different entities.