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
Large-scale validation of skin prion seeding activity as a biomarker for diagnosis of prion diseases
AbstractDefinitive diagnosis of sporadic Creutzfeldt –Jakob disease (sCJD) relies on the examination of brain tissues for the pathological prion protein (PrPSc). Our previous study revealed that PrPSc-seeding activity (PrPSc-SA) is detectable in skin of sCJD patients by an ultrasensitive PrPSc seed amplification assay (PrPSc-SAA) known as real-time quaking-induced conversion (RT-QuIC). A total of 875 skin samples were collected from 2 cohorts (1 and 2) at autopsy from 2 –3 body areas of 339 cases with neuropathologically confirmed prion diseases and non-sCJD controls. The skin samples were analyzed for PrPSc-SA by RT-Q...
Source: Acta Neuropathologica - January 17, 2024 Category: Neurology Source Type: research
Pituitary neuroendocrine tumors with PIT1/SF1 co-expression show distinct clinicopathological and molecular features
In this study, we spotlight that DGST with co-expression of PIT1 a nd SF1 represent a common, yet underrecognized, distinct PitNET subtype. Our study questions the rationale of generally classifying such tumors as “plurihormonal”, and calls for a refinement of the WHO classification. We propose the term “somatogonadotroph PitNET”. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - January 16, 2024 Category: Neurology Source Type: research
Complement and MHC patterns can provide the diagnostic framework for inflammatory neuromuscular diseases
AbstractHistopathological analysis stands as the gold standard for the identification and differentiation of inflammatory neuromuscular diseases. These disorders continue to constitute a diagnostic challenge due to their clinical heterogeneity, rarity and overlapping features. To establish standardized protocols for the diagnosis of inflammatory neuromuscular diseases, the development of cost-effective and widely applicable tools is crucial, especially in settings constrained by limited resources. The focus of this review is to emphasize the diagnostic value of major histocompatibility complex (MHC) and complement patterns...
Source: Acta Neuropathologica - January 12, 2024 Category: Neurology Source Type: research
Distinct tau and alpha-synuclein molecular signatures in Alzheimer ’s disease with and without Lewy bodies and Parkinson’s disease with dementia
AbstractAlpha-synuclein (aSyn) pathology is present in approximately 50% of Alzheimer ’s disease (AD) cases at autopsy and might impact the age-of-onset and disease progression in AD. Here, we aimed to determine whether tau and aSyn profiles differ between AD cases with Lewy bodies (AD-LB), pure AD and Parkinson’s disease with dementia (PDD) cases using epitope-, post-translation al modification- (PTM) and isoform-specific tau and aSyn antibody panels spanning from the N- to C-terminus. We included the middle temporal gyrus (MTG) and amygdala (AMY) of clinically diagnosed and pathologically confirmed cases and performe...
Source: Acta Neuropathologica - January 10, 2024 Category: Neurology Source Type: research
Novel lissencephaly-associated NDEL1 variant reveals distinct roles of NDE1 and NDEL1 in nucleokinesis and human cortical malformations
This study identifies the first lissencephaly-associatedNDEL1 variant and sheds light on the distinct roles of NDE1 and NDEL1 in nucleokinesis and MCD pathogenesis. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - January 9, 2024 Category: Neurology Source Type: research
CSF p-tau205: a biomarker of tau pathology in Alzheimer ’s disease
In conclusion, we report the first high-throughput CSF p-tau205 immunoassay for the in vivo quantification of tau pathology in AD, and a potentially cost-effective alternative to tau-PET in clinical settings and clinical trials. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - January 6, 2024 Category: Neurology Source Type: research
Improved prognostic stratification of patients with isocitrate dehydrogenase-mutant astrocytoma
In conclusion, CNS WHO grade, global DNA methylation status, andCDKN2A homozygous deletion are prognostic in patients with IDH-mutant astrocytoma. Combination of these parameters allows for improved prediction of outcome. These data aid in designing upcoming trials using IDH inhibitors. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - January 6, 2024 Category: Neurology Source Type: research
New evidence suggests SARS-CoV-2 neuroinvasion along the nervus terminalis rather than the olfactory pathway
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - January 6, 2024 Category: Neurology Source Type: research
CSF p-tau205: a biomarker of tau pathology in Alzheimer ’s disease
In conclusion, we report the first high-throughput CSF p-tau205 immunoassay for the in vivo quantification of tau pathology in AD, and a potentially cost-effective alternative to tau-PET in clinical settings and clinical trials. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - January 6, 2024 Category: Neurology Source Type: research
Improved prognostic stratification of patients with isocitrate dehydrogenase-mutant astrocytoma
In conclusion, CNS WHO grade, global DNA methylation status, andCDKN2A homozygous deletion are prognostic in patients with IDH-mutant astrocytoma. Combination of these parameters allows for improved prediction of outcome. These data aid in designing upcoming trials using IDH inhibitors. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - January 6, 2024 Category: Neurology Source Type: research
