Accumulation of amyloid-β in the cerebellar cortex of essential tremor patients

Béliveau, Éric; Tremblay, Cyntia; Aubry-Lafontaine, Émilie; Paris-Robidas, Sarah; Delay, Charlotte; Robinson, Chris; Ferguson, Les; Rajput, Ali H.; Rajput, Alex; Calon, Frédéric

doi:10.1016/j.nbd.2015.07.016

Cited by 19 publications

(11 citation statements)

References 90 publications

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“…The majority of ET experimentation has focused on cerebellar cortex, where unique pathological changes, such as Purkinje cell (PC) loss 7,8 and increased PC axonal changes, 7,9 have been observed in ET brains relative to age‐matched control brains. Other postmortem features associated with ET include reduced PC dendritic arborization and spine density, 10 increased number of heterotopic PCs, 11 basket cell axonal alterations around the PC body and initial axon segment, 12–14 abnormal arrangement of climbing fiber–PC synapses along the PC dendritic arbor, 15,16 changes in dentate γ‐aminobutyric acid (GABA) receptors 17 and accumulation of cerebellar β‐amyloid 18 …”

Section: Introductionmentioning

confidence: 99%

Dentate Nucleus Neuronal Density: A Postmortem Study of Essential Tremor Versus Control Brains

et al. 2020

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Background Essential tremor involves the cerebellum, yet quantitative analysis of dentate nucleus neurons has not been conducted. Objectives To quantitatively compare neuronal density or neuronal number in the dentate nucleus of essential tremor versus age‐matched controls. Methods Using a 7‐μm thick Luxol fast blue hematoxylin and eosin‐stained paraffin section, dentate nucleus neuronal density (neurons/mm2) was determined in 25 essential tremor cases and 25 controls. We also applied a stereological approach in a subset of four essential tremor cases and four controls to estimate total dentate nucleus neuronal number. Results Dentate nucleus neuronal density did not differ between essential tremor cases and controls (P = 0.44). Total dentate nucleus neuronal number correlated with neuronal density (P = 0.007) and did not differ between essential tremor cases and controls (P = 0.95). Conclusions Neuronal loss, observed in the Purkinje cell population in essential tremor, did not seem to similarly involve the dentate nucleus in essential tremor. © 2020 International Parkinson and Movement Disorder Society

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Section: Introductionmentioning

confidence: 99%

Dentate Nucleus Neuronal Density: A Postmortem Study of Essential Tremor Versus Control Brains

et al. 2020

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“…[54][55][56] Interestingly, a postmortem study has found increased levels of insoluble and soluble amyloid-β protein in the cerebellar and parietal cortex of patients with ET compared with control individuals and patients with PD. 57 Moreover, ET was found to be significantly genetically correlated with depression and PD, suggesting common variant overlap. Previous studies have found that ET is associated with both self-reported depression and antidepressant medication use, concordant with the genetic correlation results.…”

Section: Discussionmentioning

confidence: 99%

Association of Essential Tremor With Novel Risk Loci

et al. 2022

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IMPORTANCE Essential tremor (ET) is one of the most common movement disorders, affecting 5% of the general population older than 65 years. Common variants are thought to contribute toward susceptibility to ET, but no variants have been robustly identified. OBJECTIVE To identify common genetic factors associated with risk of ET. DESIGN, SETTING, AND PARTICIPANTS Case-control genome-wide association study. Inverse-variance meta-analysis was used to combine cohorts. Multicenter samples collected from European populations were collected from January 2010 to September 2019 as part of an ongoing study. Included patients were clinically diagnosed with or reported having ET. Control individuals were not diagnosed with or reported to have ET. Of 485 250 individuals, data for 483 054 passed data quality control and were used. MAIN OUTCOMES AND MEASURES Genotypes of common variants associated with risk of ET. RESULTS Of the 483 054 individuals included, there were 7177 with ET (3693 [51.46%] female; mean [SD] age, 62.66 [15.12] years), and 475 877 control individuals (253 785 [53.33%] female; mean [SD] age, 56.40 [17.6] years). Five independent genome-wide significant loci and were identified and were associated with approximately 18% of ET heritability. Functional analyses found significant enrichment in the cerebellar hemisphere, cerebellum, and axonogenesis pathways. Genetic correlation (r), which measures the degree of genetic overlap, revealed significant common variant overlap with Parkinson disease (r, 0.28; P = 2.38 × 10 −8 ) and depression (r, 0.12; P = 9.78 × 10 −4 ). A separate fine-mapping of transcriptome-wide association hits identified genes such as BACE2, LRRN2, DHRS13, and LINC00323 in disease-relevant brain regions, such as the cerebellum. CONCLUSIONS AND RELEVANCEThe results of this genome-wide association study suggest that a portion of ET heritability can be explained by common genetic variation and can help identify new common genetic risk factors for ET.

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“…Both Tau protein and amyloid-beta abnormalities have been observed in ET cerebellar tissues, with multiple findings pointing towards protein aggregation being a hallmark of the disease 38,39 .…”

Section: Discussionmentioning

confidence: 99%

Convergent transcriptomic targets of propranolol and primidone identify potential biomarkers for essential tremor

Castonguay

Liao

Khayachi

et al. 2021

Preprint

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Essential tremor (ET) is one of the most common movement disorders, affecting nearly 5% of individuals over 65 years old. Despite its high heritability, few genetic risk loci for ET have been identified. Recent advances in pharmacogenomics have generated a wealth of data that led to the identification of molecular signatures in response to hundreds of chemical compounds. Among the different forms of data, gene expression has proven to be quite successful for the inference of drug response in cell models. We sought to leverage this approach in the context of ET where many patients are responsive two drugs: propranolol and primidone. Propranolol- and primidone-specific transcriptomic drug targets, as well as convergent gene targets across both drugs, could provide insights into the pathogenesis of ET and identify possible targets of interest for future treatments. In this study, cerebellar DAOY and neural progenitor cells were treated for 5 days with clinical concentrations of propranolol and primidone, after which RNA-sequencing was used to identify differentially expressed genes. The expression of genes previously implicated in genetic and transcriptomic studies of ET and other movement disorders, such as TRAPPC11, were significantly upregulated by propranolol. Pathway enrichment analysis identified multiple terms related to calcium signalling, endosomal sorting, axon guidance, and neuronal morphology. Convergent differentially expressed genes across all treatments and cell types were also found to be significantly more mutationally constrained, implying that they might harbour rare deleterious variants implicated in disease. Furthermore, these genes were enriched within cell types having high expression of ET related genes in both cortical and cerebellar tissues. Altogether, our results highlight potential cellular and molecular mechanisms associated with tremor reduction and identify relevant genetic biomarkers for drug-responsiveness in ET.

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Accumulation of amyloid-β in the cerebellar cortex of essential tremor patients

Cited by 19 publications

References 90 publications

Dentate Nucleus Neuronal Density: A Postmortem Study of Essential Tremor Versus Control Brains

Dentate Nucleus Neuronal Density: A Postmortem Study of Essential Tremor Versus Control Brains

Association of Essential Tremor With Novel Risk Loci

Convergent transcriptomic targets of propranolol and primidone identify potential biomarkers for essential tremor

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