Similar brain proteomic signatures in Alzheimer ’s disease and epilepsy
AbstractThe prevalence of epilepsy is increased among Alzheimer ’s Disease (AD) patients and cognitive impairment is common among people with epilepsy. Epilepsy and AD are linked but the shared pathophysiological changes remain poorly defined. We aim to identify protein differences associated with epilepsy and AD using published proteomics datasets. We observe d a highly significant overlap in protein differences in epilepsy and AD: 89% (689/777) of proteins altered in the hippocampus of epilepsy patients were significantly altered in advanced AD. Of the proteins altered in both epilepsy and AD, 340 were altered in the s...
Source: Acta Neuropathologica - January 30, 2024 Category: Neurology Source Type: research
Mitochondrial damage and impaired mitophagy contribute to disease progression in SCA6
AbstractSpinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease that manifests in midlife and progressively worsens with age. SCA6 is rare, and many patients are not diagnosed until long after disease onset. Whether disease-causing cellular alterations differ at different disease stages is currently unknown, but it is important to answer this question in order to identify appropriate therapeutic targets across disease duration. We used transcriptomics to identify changes in gene expression at disease onset in a well-established mouse model of SCA6 that recapitulates key disease features. We observed both up- an...
Source: Acta Neuropathologica - January 29, 2024 Category: Neurology Source Type: research
Head-to-head comparison of [18F]-Flortaucipir, [18F]-MK-6240 and [18F]-PI-2620 postmortem binding across the spectrum of neurodegenerative diseases
AbstractWe and others have shown that [18F]-Flortaucipir, the most validated tau PET tracer thus far, binds with strong affinity to tau aggregates in Alzheimer's (AD) but has relatively low affinity for tau aggregates in non-AD tauopathies and exhibits off-target binding to neuromelanin- and melanin-containing cells, and to hemorrhages. Several second-generation tau tracers have been subsequently developed. [18F]-MK-6240 and [18F]-PI-2620 are the two that have garnered most attention. Our recent data indicated that the binding pattern of [18F]-MK-6240 closely parallels that of [18F]-Flortaucipir. The present study aimed at...
Source: Acta Neuropathologica - January 27, 2024 Category: Neurology Source Type: research
Molecular characteristics and improved survival prediction in a cohort of 2023 ependymomas
AbstractThe diagnosis of ependymoma has moved from a purely histopathological review with limited prognostic value to an integrated diagnosis, relying heavily on molecular information. However, as the integrated approach is still novel and some molecular ependymoma subtypes are quite rare, few studies have correlated integrated pathology and clinical outcome, often focusing on small series of single molecular types. We collected data from 2023 ependymomas as classified by DNA methylation profiling, consisting of 1736 previously published and 287 unpublished methylation profiles. Methylation data and clinical information we...
Source: Acta Neuropathologica - January 24, 2024 Category: Neurology Source Type: research
Transcriptomic and epigenetic dissection of spinal ependymoma (SP-EPN) identifies clinically relevant subtypes enriched for tumors with and without NF2 mutation
AbstractEpendymomas encompass multiple clinically relevant tumor types based on localization and molecular profiles. Tumors of the methylation class “spinal ependymoma” (SP-EPN) represent the most common intramedullary neoplasms in children and adults. However, their developmental origin is ill-defined, molecular data are scarce, and the potential heterogeneity within SP-EPN remains unexplored. The only known recurrent genetic events in SP-E PN are loss of chromosome 22q andNF2 mutations, but neither types and frequency of these alterations nor their clinical relevance have been described in a large, epigenetically def...
Source: Acta Neuropathologica - January 24, 2024 Category: Neurology Source Type: research
Clinically relevant molecular hallmarks of PFA ependymomas display intratumoral heterogeneity and correlate with tumor morphology
AbstractPosterior fossa type A (PF-EPN-A, PFA) ependymoma are aggressive tumors that mainly affect children and have a poor prognosis. Histopathology shows significant intratumoral heterogeneity, ranging from loose tissue to often sharply demarcated, extremely cell-dense tumor areas. To determine molecular differences in morphologically different areas and to understand their clinical significance, we analyzed 113 PF-EPN-A samples, including 40 corresponding relapse samples. Cell-dense areas ranged from 0 to 100% of the tumor area and displayed a higher proportion of proliferating tumor cells (p < 0.01). Clinically...
Source: Acta Neuropathologica - January 24, 2024 Category: Neurology Source Type: research
Molecular characteristics and improved survival prediction in a cohort of 2023 ependymomas
AbstractThe diagnosis of ependymoma has moved from a purely histopathological review with limited prognostic value to an integrated diagnosis, relying heavily on molecular information. However, as the integrated approach is still novel and some molecular ependymoma subtypes are quite rare, few studies have correlated integrated pathology and clinical outcome, often focusing on small series of single molecular types. We collected data from 2023 ependymomas as classified by DNA methylation profiling, consisting of 1736 previously published and 287 unpublished methylation profiles. Methylation data and clinical information we...
Source: Acta Neuropathologica - January 24, 2024 Category: Neurology Source Type: research
A familial missense variant in the Alzheimer ’s disease gene SORL1 impairs its maturation and endosomal sorting
AbstractTheSORL1 gene has recently emerged as a strong Alzheimer ’s Disease (AD) risk gene. Over 500 different variants have been identified in the gene and the contribution of individual variants to AD development and progression is still largely unknown. Here, we describe a family consisting of 2 parents and 5 offspring. Both parents were affected with dement ia and one had confirmed AD pathology with an age of onset > 75 years. All offspring were affected with AD with ages at onset ranging from 53 years to 74 years. DNA was available from the parent with confirmed AD and 5 offspring. We identified a coding ...
Source: Acta Neuropathologica - January 20, 2024 Category: Neurology Source Type: research
Temporal change of DNA methylation subclasses between matched newly diagnosed and recurrent glioblastoma
This study demonstrates a temporal heterogeneity of DNA methylation subclasses in 28.2% of glioblastomas, not impacting patient survival. Changes in cell state composition associated with subclass transition may be crucial for recurrent glioblastoma targe ted therapies. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - January 20, 2024 Category: Neurology Source Type: research
Multi-level profiling unravels mitochondrial dysfunction in myotonic dystrophy type 2
AbstractMyotonic dystrophy type 2 (DM2) is an autosomal-dominant multisystemic disease with a core manifestation of proximal muscle weakness, muscle atrophy, myotonia, and myalgia. The disease-causing CCTG tetranucleotide expansion within theCNBP gene on chromosome 3 leads to an RNA-dominated spliceopathy, which is currently untreatable. Research exploring the pathophysiological mechanisms in myotonic dystrophy type 1 has resulted in new insights into disease mechanisms and identified mitochondrial dysfunction as a promising therapeutic target. It remains unclear whether similar mechanisms underlie DM2 and, if so, whether ...
Source: Acta Neuropathologica - January 19, 2024 Category: Neurology Source Type: research
Performance of a seed amplification assay for misfolded alpha-synuclein in cerebrospinal fluid and brain tissue in relation to Lewy body disease stage and pathology burden
AbstractThe development of in vitro seed amplification assays (SAA) detecting misfolded alpha-synuclein ( αSyn) in cerebrospinal fluid (CSF) and other tissues has provided a pathology-specific biomarker for Lewy body disease (LBD). However, αSyn SAA diagnostic performance in early pathological stages or low Lewy body (LB) pathology load has only been assessed in small cohorts. Moreover, the relations hip between SAA kinetic parameters, the number of αSyn brain seeds and the LB pathology burden assessed by immunohistochemistry has never been systematically investigated. We tested 269 antemortem CSF samples and 138 seri...
Source: Acta Neuropathologica - January 19, 2024 Category: Neurology Source Type: research
