GPNMB Biomarker Levels in GBA1 Carriers with Lewy Body Disorders.

BACKGROUND: The GPNMB single-nucleotide polymorphism rs199347 and GBA1 variants both associate with Lewy body disorder (LBD) risk. GPNMB encodes glycoprotein nonmetastatic melanoma protein B (GPNMB), a biomarker for GBA1-associated Gaucher's disease. OBJECTIVE: The aim of this study was to determine whether GPNMB levels (1) differ in LBD with and without GBA1 variants and (2) associate with rs199347 genotype. METHODS: We quantified GPNMB levels in plasma and cerebrospinal fluid (CSF) from 124 individuals with LBD with one GBA1 variant (121 plasma, 14 CSF), 631 individuals with LBD without GBA1 variants (626 plasma, 41 CSF), 9 neurologically normal individuals with one GBA1 variant (plasma), and 2 individuals with two GBA1 variants (plasma). We tested for associations between GPNMB levels and rs199347 or GBA1 status. RESULTS: GPNMB levels associate with rs199347 genotype in plasma (P = 0.022) and CSF (P = 0.007), but not with GBA1 status. CONCLUSIONS: rs199347 is a protein quantitative trait locus for GPNMB. GPNMB levels are unaltered in individuals carrying one GBA1 variant. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Histopathology of the cerebellar cortex in essential tremor and other neurodegenerative motor disorders: comparative analysis of 320 brains.

In recent years, numerous morphologic changes have been identified in the essential tremor (ET) cerebellar cortex, distinguishing ET from control brains. These findings have not been fully contextualized within a broader degenerative disease spectrum, thus limiting their interpretability. Building off our prior study and now doubling the sample size, we conducted comparative analyses in a postmortem series of 320 brains on the severity and patterning of cerebellar cortex degenerative changes in ET (n = 100), other neurodegenerative disorders of the cerebellum [spinocerebellar ataxias (SCAs, n = 47, including 13 SCA3 and 34 SCA1, 2, 6, 7, 8, 14); Friedreich's ataxia (FA, n = 13); multiple system atrophy (MSA), n = 29], and other disorders that may involve the cerebellum [Parkinson's disease (PD), n = 62; dystonia, n = 19] versus controls (n = 50). We generated data on 37 quantitative morphologic metrics, grouped into 8 broad categories: Purkinje cell (PC) loss, heterotopic PCs, PC dendritic changes, PC axonal changes (torpedoes), PC axonal changes (other than torpedoes), PC axonal changes (torpedo-associated), basket cell axonal hypertrophy, and climbing fiber-PC synaptic changes. Principal component analysis of z scored raw data across all diagnoses (11,651 data items) revealed that diagnostic groups were not uniform with respect to pathology. Dystonia and PD each differed from controls in only 4/37 and 5/37 metrics, respectively, whereas ET differed in 21, FA in 10, SCA3 in 10, MSA in 21, and SCA1/2/6/7/8/14 in 27. Pathological changes were generally on the milder end of the degenerative spectrum in ET, FA and SCA3, and on the more severe end of that spectrum in SCA1/2/6/7/8/14. Comparative analyses across morphologic categories demonstrated differences in relative expression, defining distinctive patterns of changes in these groups. In summary, we present a robust and reproducible method that identifies somewhat distinctive signatures of degenerative changes in the cerebellar cortex that mark each of these disorders.

Essential Tremor versus "ET-plus": A Detailed Postmortem Study of Cerebellar Pathology.

Essential tremor (ET) is among the most prevalent movement disorders, and by some accounts, the most common form of cerebellar degeneration. Over the past 15 years, we have carefully documented a large number of postmortem changes within the cerebellum; these cerebellar changes differ significantly between ET and controls. A recent Consensus Classification of tremor proposed that ET patients with other neurological signs aside from action tremor (e.g., parkinsonism, ataxia, cognitive changes, dystonia) should be segregated off as "ET-plus". This diagnostic concept has raised considerable controversy and its validity is not yet established. Indeed, "ET-plus" has not been distinguished from ET based on differences in genetics, pathology or prognosis. Here we determine whether ET cases differ from "ET-plus" cases in underlying pathological changes in the postmortem brain. We examined postmortem brains from 50 ET cases (24 ET and 26 ET-plus), using a set of 14 quantitative metrics of cerebellar pathology determined by histologic and immunohistochemical methods. These metrics reflect changes across the Purkinje cell (PC) body (PC counts, empty baskets, heterotopias), PC dendrites (swellings), PC axon (torpedoes and associated axonal changes), basket cell axonal hypertrophy and climbing fiber-PC dendrite synaptic changes. ET and ET-plus were similar with respect to 13 of 14 cerebellar pathologic metrics (p > 0.05). Only one metric, the linear density of thickened PC axon profiles, differed between these groups (ET = 0.529 ± 0.397, ET-plus = 0.777 ± 0.477, p = 0.013), although after correcting for multiple comparisons, there were no differences. If ET-plus were indeed a different entity, then the underlying pathological basis should be distinct from that of ET. This study demonstrated there were no pathological differences in cerebellar cortex between ET versus ET-plus cases. These data do not support the notion that ET and ET-plus represent distinct clinical-pathological entities.

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

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.

Gene expression analysis of the cerebellar cortex in essential tremor.

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.