Dataset Information

Cerebellar pathology in childhood-onset vs. adult-onset essential tremor.

ABSTRACT: Although the incidence of ET increases with advancing age, the disease may begin at any age, including childhood. The question arises as to whether childhood-onset ET cases manifest the same sets of pathological changes in the cerebellum as those whose onset is during adult life. We quantified a broad range of postmortem features (Purkinje cell [PC] counts, PC axonal torpedoes, a host of associated axonal changes [PC axonal recurrent collateral count, PC thickened axonal profile count, PC axonal branching count], heterotopic PCs, and basket cell rating) in 60 ET cases (11 childhood-onset and 49 adult-onset) and 30 controls. Compared to controls, childhood-onset ET cases had lower PC counts, higher torpedo counts, higher heterotopic PC counts, higher basket cell plexus rating, and marginally higher PC axonal recurrent collateral counts. The median PC thickened axonal profile count and median PC axonal branching count were two to five times higher in childhood-onset ET than controls, but the differences did not reach statistical significance. Childhood-onset and adult-onset ET had similar PC counts, torpedo counts, heterotopic PC counts, basket cell plexus rating, PC axonal recurrent collateral counts, PC thickened axonal profile count and PC axonal branching count. In conclusion, we found that childhood-onset and adult-onset ET shared similar pathological changes in the cerebellum. The data suggest that pathological changes we have observed in the cerebellum in ET are a part of the pathophysiological cascade of events in both forms of the disease and that both groups seem to reach the same pathological endpoints at a similar age of death.

SUBMITTER: Louis ED

PROVIDER: S-EPMC5624847 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Cerebellar pathology in childhood-onset vs. adult-onset essential tremor.

Louis Elan D ED Kuo Sheng-Han SH Tate William J WJ Kelly Geoffrey C GC Faust Phyllis L PL

Neuroscience letters 20170901

Although the incidence of ET increases with advancing age, the disease may begin at any age, including childhood. The question arises as to whether childhood-onset ET cases manifest the same sets of pathological changes in the cerebellum as those whose onset is during adult life. We quantified a broad range of postmortem features (Purkinje cell [PC] counts, PC axonal torpedoes, a host of associated axonal changes [PC axonal recurrent collateral count, PC thickened axonal profile count, PC axonal ...[more]

PMID: 28867587

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Project description:Several morphological changes, centered in/around Purkinje cells (PCs), have been identified in the cerebellum of essential tremor (ET) patients. These changes have not been contextualized within a broader degenerative disease spectrum, limiting their interpretability. To address this, we compared the severity and patterning of degenerative changes within the cerebellar cortex in patients with ET, other neurodegenerative disorders of the cerebellum (spinocerebellar ataxias (SCAs), multiple system atrophy (MSA)], and other disorders that may involve the cerebellum [Parkinson's disease (PD), dystonia]. Using a postmortem series of 156 brains [50 ET, 23 SCA (6 SCA3; 17 SCA 1, 2 or 6), 15 MSA, 29 PD, 14 dystonia, 25 controls], we generated data on 37 quantitative morphologic metrics, which were grouped into 8 broad categories: (1) PC loss, (2) heterotopic PCs, (3) PC dendritic changes, (4) PC axonal changes (torpedoes), (5) PC axonal changes (other than torpedoes), (6) PC axonal changes (torpedo-associated), (7) basket cell axonal hypertrophy, (8) climbing fiber-PC synaptic changes. Our analyses used z scored raw data for each metric across all diagnoses (5772 total data items). Principal component analysis revealed that diagnostic groups were not uniform with respect to cerebellar pathology. Dystonia and PD each differed from controls in only 2/37 metrics, whereas ET differed in 21, SCA3 in 8, MSA in 19, and SCA1/2/6 in 26 metrics. Comparing ET with primary disorders of cerebellar degeneration (i.e., SCAs), we observed a spectrum of changes reflecting differences of degree, being generally mild in ET and SCA3 and more severe in SCA1/2/6. Comparative analyses across morphologic categories demonstrated differences in relative expression, defining distinctive patterns of changes in these groups. Thus, the degree of cerebellar degeneration in ET aligns it with a milder end in the spectrum of cerebellar degenerative disorders, and a somewhat distinctive signature of degenerative changes marks each of these disorders.

Project description:Essential tremor (ET) is one of the most common neurological diseases, with a central feature of an 8-12 Hz kinetic tremor. While previous postmortem studies have identified a cluster of morphological changes in the ET cerebellum centered in/around the Purkinje cell (PC) population, including a loss of PCs in some studies, the underlying molecular mechanisms for these changes are not clear. As genomic studies of ET patients have yet to identify major genetic contributors and animal models that fully recapitulate the human disease do not yet exist, the study of human tissue is currently the most applicable method to gain a mechanistic insight into ET disease pathogenesis. To begin exploration of an underlying molecular source of ET disease pathogenesis, we have performed the first transcriptomic analysis by direct sequencing of RNA from frozen cerebellar cortex tissue in 33 ET patients compared to 21 normal controls. Principal component analysis showed a heterogenous distribution of the expression data in ET patients that only partially overlapped with control patients. Differential expression analysis identified 231 differentially expressed gene transcripts ('top gene hits'), a subset of which has defined expression profiles in the cerebellum across neuronal and glial cell types but a largely unknown relationship to cerebellar function and/or ET pathogenesis. Gene set enrichment analysis (GSEA) identified dysregulated pathways of interest and stratified dysregulation among ET cases. By GSEA and mining curated databases, we compiled major categories of dysregulated processes and clustered string networks of known interacting proteins. Here we demonstrate that these 'top gene hits' contribute to regulation of four main biological processes, which are 1) axon guidance, 2) microtubule motor activity, 3) endoplasmic reticulum (ER) to Golgi transport and 4) calcium signaling/synaptic transmission. The results of our transcriptomic analysis suggest there is a range of different processes involved among ET cases, and draws attention to a particular set of genes and regulatory pathways that provide an initial platform to further explore the underlying biology of ET.

Dataset Information

Cerebellar pathology in childhood-onset vs. adult-onset essential tremor.

Publications

Cerebellar pathology in childhood-onset vs. adult-onset essential tremor.

Similar Datasets

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