Cerebellum最新文献

Friedreich ataxia (FRDA) is an autosomal recessive disorder caused by GAA expansions in the FXN gene, which codes for the protein frataxin (FXN). These mutations reduce FXN expression, leading to mitochondrial dysfunction and multisystemic disease. Accumulating evidence suggests that neuronal dysfunction, rather than neuronal death, may drive the neurological phenotypes of FRDA, but the mechanisms underlying such neurological phenotypes remain unclear. To investigate the neural circuit basis of this dysfunction, we employed field recordings to measure Purkinje cell (PC) function and synaptic properties along with western blotting and immunohistochemistry to determine their density and structure in two established FRDA mouse models, the shRNA-frataxin (FRDAkd) and the frataxin knock in-knockout (KIKO) mice. Western blotting demonstrated subtle changes in mitochondrial proteins and only a modest reduction in the density of calbindin positive cells PCs in the cerebellar cortex of the FRDAkd mice, with no change in the density of PCs in the KIKO mice. Though PC density differed slightly in the two models, field recordings of parallel fiber-PC synapses in the molecular layer demonstrated concordant hypo-excitability of basal synaptic transmission and impairments of long-term plasticity using induction protocols associated with both potentiation and depression of synaptic strength. These results indicate that synaptic instability might be a common feature in FRDA mouse models.

Spinocerebellar ataxia type 25 (SCA25) is a rare autosomal dominant disorder caused by heterozygous pathogenic variants in the PNPT1 gene, primarily affecting the critical S1 RNA-binding domain. This study reports the first Brazilian and South American family with SCA25. To describe the clinical, genetic, and molecular findings in a family with a novel PNPT1 variant and compare them with previously reported cases. Clinical evaluation, neuroimaging, and genetic testing were performed on affected family members. The proband underwent clinical exome sequencing, with Sanger confirmation of the identified variant. Computational tools, including SpliceAI, were used to predict the molecular consequences of the variant. The proband, a 1-year-8-month-old girl, presented with progressive ataxia, cerebellar atrophy, and sensory neuropathy. Genetic testing identified a novel heterozygous truncating variant in PNPT1 (c.2068del; p.?), inherited from her father, who was mildly affected with polyneuropathy but no ataxia. SpliceAI predicted significant splicing disruptions, including intron retention or exon skipping, leading to a frameshift (p.(Arg690Glyfs*5)) and likely triggering nonsense-mediated decay or post-translational degradation. These findings align with previously reported PNPT1 variants associated with SCA25, which exhibit phenotypic variability and incomplete penetrance. This report expands the clinical and genetic spectrum of SCA25 and highlights the importance of considering this condition in the differential diagnosis of progressive ataxias. Further studies, including RNA and protein analyses, are required to confirm the molecular consequences of the PNPT1:c.2068del variant and to advance our understanding of the pathophysiology of SCA25.

Essential tremor (ET) is a common movement disorder, and while ventral intermediate nucleus deep brain stimulation (VIM-DBS) is a well-established treatment, its precise mechanisms or modulatory effects, particularly in relation to cerebellar oscillations, remain unclear. In this study, we hypothesized that VIM-DBS would modulate cerebellar oscillatory activity across both resting and motor task conditions, reflecting its impact on cerebello-thalamic pathways. Ten patients diagnosed with ET participated in this study. We examined the effects of VIM-DBS on mid-cerebellar oscillations during resting-state and lower-limb pedaling motor tasks. Frequency analysis was conducted on the resting-state signal and time-frequency analysis was performed on motor task-related signals. We explored the modulatory effects of VIM-DBS on oscillatory activity across delta, theta, alpha, beta, and gamma frequency bands. We found that ON VIM-DBS increased mid-cerebellar relative theta power during resting-state conditions, with no significant changes in other frequency bands. During a pedaling motor task, VIM-DBS led to significant reductions in theta, alpha, and gamma power, highlighting the frequency-specific effects of stimulation. VIM-DBS also increased peak acceleration of leg movements during the pedaling task. Furthermore, VIM-DBS selectively increased mid-frontal relative theta and beta power as well as mid-occipital relative theta power during resting condition, suggesting localized mid-cerebellar modulation. Moreover, similarity analyses between mid-cerebellar and nearby mid-occipital signals revealed differences in coherence, phase coherence, and cross-spectrum phase coherence. Overall, these results support the role of VIM-DBS in modulating mid-cerebellar oscillations in ET and provide new insights into the neural mechanisms underlying DBS efficacy.

The role of the cerebellum in the neurodevelopmental outcomes of preterm infants has often been neglected. However, accumulating evidence indicates that normal cerebellar development is disrupted by prematurity-associated complications causing cerebellar injury and by prematurity itself. This hampers not only the normal development of motor skills and gait, but also cognitive, language, and behavioral development, collectively referred to as "developmental cognitive affective syndrome." In this comprehensive narrative review, we provide the results of an extensive literature search in PubMed and Embase to summarize recent evidence on altered cerebellar development in premature infants, focusing on neuroimaging findings, its causative factors and its impact on long-term neurodevelopmental outcomes.

Deep brain stimulation (DBS) for essential tremor is remarkably effective, leading to over 80% reduction in standardized tremor ratings. However, for certain types of tremor, such as those accompanied by ataxia or dystonia, conventional DBS targets have shown poor efficacy. Various rationales for using cerebellar DBS stimulation to treat tremor have been advanced, but the varied approaches leave many questions unanswered: which anatomic target, stimulation settings, and indications seem most promising for this emerging approach. This article reviews the clinical experience published to date and explores some of the pre-clinical and human physiology data that might support a role for further systematic investigation of cerebellar DBS for clinical use. Four tremor disorders to date have been targeted with cerebellar DBS in humans: essential tremor, post-stroke tremor, dystonic tremor, and tremor associated with degenerative cerebellar ataxias, like spinocerebellar ataxia type 3. The dentate nucleus is the most frequently chosen target, but key stereotactic and imaging details are missing from many of the case reports. Interestingly, consensus on laterality has not been definitively established as there are conflicting models of the hypothesized mechanism of action of DBS of the dentate nuclei, and conflicting reports of benefit on the tremor ipsilateral to and contralateral toto the affected limb. Several points are highlighted, including the prediction from in vivo preclinical physiology studies and interventional studies, the remaining uncertainty regarding the preferred laterality of targets, and the lack of clear prioritization of tremor etiologies to be targeted in future rigorously designed interventional studies (e.g., preferably repeated n-of-1 or sham-controlled studies involving more than one patient).

Peripheral neuropathy (PN) identified as a significant contributor to disability in Spinocerebellar ataxia type 3 (SCA3) patients. This study seeks to assess the utility of current perception threshold (CPT) measurements in evaluating PN in individuals with SCA3 and aims to identify factors influencing CPT values in SCA3 and ascertain whether these values correlate with the severity of ataxia. Ninety-four patients diagnosed with SCA3 and 44 healthy controls were recruited for this investigation. All participants were performed standard CPT assessments. Comparative analysis was conducted on CPT variables between the groups. Multivariable linear regression models were employed to identify potential risk factors influencing CPT values, and to investigate the association between CPT values and the severity of ataxia in SCA3. The case group exhibited significantly higher values across all CPT variables compared to the control group (P < 0.01). Peripheral neuropathy was prevalent among SCA3 patients, with lower limb nerves demonstrating greater susceptibility than upper limb nerves. Increasing age (β = 1.813, P = 0.012) and heightened ataxia severity (β = 3.763, P = 0.013) as predictors of poorer CPT values. Gender also emerged as a predictor of CPT values. Furthermore, CPT values (β = 0.003, P = 0.013) and disease duration (β = 0.118, P < 0.001) were associated with more severe ataxia. Our findings suggest that the CPT test holds promise for assessing peripheral neuropathy in SCA3 patients and that CPT values may serve as indicators of disease severity in this population.

Essential Tremor (ET) is the most common movement disorder and has a worldwide prevalence of 1%, including 5% of the population over 65 years old. It is characterized by an active, postural or kinetic tremor, primarily affecting the upper limbs, and is diagnosed based on clinical characteristics. The pathological mechanisms of ET, however, are mostly unknown. Moreover, despite its high heritability, genetic studies of ET genetics have yielded mixed results. Transcriptomics is a field that has the potential to reveal valuable insights about the processes and pathogenesis of ET thus providing an avenue for the development of more effective therapies. With the emergence of techniques such as single-cell and single-nucleus RNA sequencing (scRNA-seq and snRNA-seq), molecular and cellular events can now be more closely examined, providing valuable insights into potential causal mechanisms. In this review, we review the growing literature on transcriptomic studies in ET, aiming to identify biological pathways involved and explore possible avenues for further ET research. We emphasized the convergence on shared of biological pathways across several studies, specifically axonal guidance and calcium signaling. These findings posit multiple hypotheses linking both pathways through the regulation of axonal and synaptic plasticity. We conclude that increasing the sample size is vital to uncover the subtleties of ET clinical and pathological heterogeneity. Additionally, integrating Multiomics approaches should provide a comprehensive understanding of the disease's pathophysiology.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare inherited condition described worldwide and characterized by a wide spectrum of heterogeneity in terms of genotype and phenotype. How sacsin loss leads to neurodegeneration is still unclear, and current knowledge indicates that sacsin is involved in multiple functional mechanisms. We hence hypothesized the existence of epigenetic factors, in particular alterations in methylation patterns, that could contribute to ARSACS pathogenesis and explain the pleiotropic effects of SACS further than pathogenic mutations. To investigate this issue, we recruited eight patients affected by ARSACS, four characterized by early onset of the disease and four with late onset. We performed Whole Genome Bisulfite Sequencing using DNA from peripheral blood to define the methylome of patients and compared them with a control group. Our analysis showed that patients with ARSACS exhibit an altered methylation pattern and that the observed differences exist also among affected individuals with different age of onset. Our study provides valuable insights for employing epigenetic biomarkers to assess the severity and progression of this disorder and propels further investigations into the role of epigenetic processes in ARSACS pathogenesis.

Alexander's law states that spontaneous nystagmus increases when looking in the direction of fast-phase and decreases during gaze in slow-phase direction. Disobedience to Alexander's law is occasionally observed in central nystagmus, but the underlying neural circuit mechanisms are poorly understood. In a retrospective analysis of 2,652 patients with posterior circulations stroke, we found a violation of Alexander's law in one or both directions of lateral gaze in 17 patients with lesions of unilateral lateral medulla affecting the vestibular nucleus. Patients with vestibular neuritis served as a control. When Alexander's law is violated, the time constant (Tc) was larger than that in the controls (median [interquartile range, IQR]: 14.4s [6.4-38.9] vs 9.0s [IQR 5.5-12.6], p = 0.036) while the Tc did not differ between the groups when Alexander' law is obeyed (9.6s [3.6-16.1] vs 9.0s [5.5-12.6], p = 0.924). To test the study hypothesis that an unstable neural integrator may generate nystagmus violating Alexander's law, we utilized the gaze-holding neural integrator model incorporating brainstem leaky neural integrator and negative velocity feedback loop via the cerebellum. The lesion-induced changes included false rotational cue, primarily attributed to central vestibular imbalance, and unstable neural integrator, examined in two ways: hyperexcitable brainstem neural integrator and paradoxical excitatory effect of Purkinje cells. With normal integrator function, the false rotational cue generated nystagmus consistent with Alexander's law. However, both types of unstable neural integrators tested produced nystagmus that violated Alexander's law. We propose that when the neural integrator is unstable with lesions in the brainstem neural integrator itself or the neural synapse between Purkinje cells and the brainstem vestibular nucleus, nystagmus violates Alexander's law. The spontaneous nystagmus violating Alexander's law may be the useful clue for identifying central vestibular syndrome.