Dickson, Dennis W.

AbstractBackgroundGene expression changes have been identified in post‐mortem brain tissue of AD cases when compared with controls, implicating various genes and pathways. Such findings provide important insights into molecular dysregulation associated with this disease and nominate therapeutic targets. Here we investigate brain gene and co‐expression network changes in a cohort of AD cases to identify associations with degree of AD neuropathology including Braak stage (Tau), Thal phase (Amyloid beta) and brain tissue levels of five AD‐related proteins (apoE, Aβ40, Aβ42, tau, and p‐tau).MethodGene expression measures were collected from temporal cortex (TCX) tissue of 477 AD cases, available through the Mayo Clinic Brain Bank, using RNA sequencing (Illumina TruSeq mRNA) performed on the HiSeq4000. Following quality control 456 cases remained for analysis. Braak and Thal were provided by an experienced neuropathologist and TCX levels of five AD‐related proteins from three fractions (buffer‐soluble, detergent‐soluble, and insoluble) were measured by ELISA (Liu et al. 2020). Weighted gene coexpression network analysis (WGCNA) R package was used to build co‐expression networks. Genes and networks were tested for association with neuropathology and AD‐related protein levels, adjusting for relevant covariates.ResultA total of 57,353 genes were profiled, of which 19,044 were reliably expressed above background levels and formed 20 co‐expression modules. 36 genes were associated with Braak stage, 10 with Thal phase and up to 9,000 with the AD‐related protein fractions. Brain levels of pTau had the greatest number of associations, with an overrepresentation of genes involved in synaptic signalling and immune response gene ontology biological processes. 16 of the coexpression modules associated with at least one trait after Bonferroni correction for number of tests.ConclusionWe have identified a number of genes and networks associated with different aspects of AD neuropathology and associated proteins, further lending support to the involvement of synaptic and immune biology in AD. However it is not clear whether observed changes cause disease or are a consequence of the neurodegenerative process. Comparison of these findings across different proteins and fractions is expected to reveal common and distinct vulnerabilities associated with amyloid and tau, and different stages of protein aggregation.

Abstract This study explores the utility of the artificial intelligence model ChatGPT in predicting neuropathologic diagnoses from clinical summaries presented at clinicopathological conferences. Twenty-five cases of various neurodegenerative disorders were analyzed using ChatGPT versions 3.5 and 4. The primary neuropathological diagnoses predicted by the models aligned with the official neuropathologic diagnoses in 32% (ChatGPT-3.5) and 52% (ChatGPT-4) of cases. When considering all proposed diagnoses, accuracy increased to 76% and 84% for ChatGPT-3.5 and ChatGPT-4, respectively. These findings highlight the potential of artificial intelligence tools like ChatGPT in neuropathology, suggesting they may facilitate more comprehensive discussions in clinicopathological conferences.

Abstract Alpha‐synuclein (αsyn) aggregates are pathological features of several neurodegenerative conditions including Parkinson disease (PD), dementia with Lewy bodies, and multiple system atrophy (MSA). Accumulating evidence suggests that mitochondrial dysfunction and impairments of the autophagic‐lysosomal system can contribute to the deposition of αsyn, which in turn may interfere with health and function of these organelles in a potentially vicious cycle. Here we investigated a potential convergence of αsyn with the PINK1‐PRKN‐mediated mitochondrial autophagy pathway in cell models, αsyn transgenic mice, and human autopsy brain. PINK1 and PRKN identify and selectively label damaged mitochondria with phosphorylated ubiquitin (pS65‐Ub) to mark them for degradation (mitophagy). We found that disease‐causing multiplications of αsyn resulted in accumulation of the ubiquitin ligase PRKN in cells. This effect could be normalized by starvation‐induced autophagy activation and by CRISPR/Cas9‐mediated αsyn knockout. Upon acute mitochondrial damage, the increased levels of PRKN protein contributed to an enhanced pS65‐Ub response. We further confirmed increased pS65‐Ub‐immunopositive signals in mouse brain with αsyn overexpression and in postmortem human disease brain. Of note, increased pS65‐Ub was associated with neuronal Lewy body‐type αsyn pathology, but not glial cytoplasmic inclusions of αsyn as seen in MSA. While our results add another layer of complexity to the crosstalk between αsyn and the PINK1‐PRKN pathway, distinct mechanisms may underlie in cells and brain tissue despite similar outcomes. Notwithstanding, our finding suggests that pS65‐Ub may be useful as a biomarker to discriminate different synucleinopathies and may serve as a potential therapeutic target for Lewy body disease.

AbstractIntraneuronal accumulation of misfolded α-synuclein is the pathological hallmark of Parkinson’s disease and dementia with Lewy bodies, often co-occurring with variable degrees of Alzheimer’s disease related neuropathology. Genetic association studies have successfully identified common variants associated with disease risk and phenotypic traits in Lewy body disease, yet little is known about the genetic contribution to neuropathological heterogeneity.Using summary statistics from Parkinson’s disease and Alzheimer’s disease genome-wide association studies, we calculated polygenic risk scores and investigated the relationship with Lewy, amyloid-β and tau pathology. Associations were nominated in neuropathologically defined samples with Lewy body disease from the Netherlands Brain Bank (n = 217) and followed up in an independent sample series from the Mayo Clinic Brain Bank (n = 394). We also generated stratified polygenic risk scores based on single-nucleotide polymorphisms annotated to eight functional pathways or cell types previously implicated in Parkinson’s disease and assessed for association with Lewy pathology in subgroups with and without significant Alzheimer’s disease co-pathology.In an ordinal logistic regression model, the Alzheimer’s disease polygenic risk score was associated with concomitant amyloid-β and tau pathology in both cohorts. Moreover, both cohorts showed a significant association between lysosomal pathway polygenic risk and Lewy pathology, which was more consistent than the association with a general Parkinson’s disease risk score and specific to the subset of samples without significant concomitant Alzheimer’s disease related neuropathology.Our findings provide proof of principle that the specific risk alleles a patient carries for Parkinson’s and Alzheimer’s disease also influence key aspects of the underlying neuropathology in Lewy body disease. The interrelations between genetic architecture and neuropathology are complex, as our results implicate lysosomal risk loci specifically in the subset of samples without Alzheimer’s disease co-pathology. Our findings hold promise that genetic profiling may help predict the vulnerability to specific neuropathologies in Lewy body disease, with potential relevance for the further development of precision medicine in these disorders.

ABSTRACTBackgroundAs part of the CurePSP brain donation program, a questionnaire was developed to gather basic clinical information on donors; however, its usefulness has not been evaluated.ObjectiveTo assess the value of information obtained from the questionnaire in differentiating between parkinsonian disorders.MethodsWe reviewed 150 questionnaires, including 50 patients, each with a neuropathologic diagnosis of Lewy body disease (LBD), multiple system atrophy (MSA), or progressive supranuclear palsy. The frequency of clinical features recorded in the questionnaires was compared for the three disorders, and a machine learning algorithm was used to identify features predicting neuropathologic diagnosis.ResultsThe information from the questionnaires correlated with core clinical features for each disorder, such as hallucinations for LBD and autonomic dysfunction for MSA. Hallucinations and disorientations were identified as the key variables that contributed most to the prediction of neuropathology.ConclusionThe questionnaire provides useful clinical information for clinicopathological correlative studies.

AbstractBackgroundPerry disease (or Perry syndrome [PS]) is a hereditary neurodegenerative disorder inevitably leading to death within few years from onset. All previous cases with pathological confirmation were caused by mutations within the cytoskeleton‐associated protein glycine‐rich (CAP‐Gly) domain of the DCTN1 gene.ObjectivesThis paper presents the first clinicopathological report of PS due to a novel DCTN1 mutation outside the CAP‐Gly domain.MethodsClinical and pathological features of the new variant carrier are compared with another recently deceased PS case with a well‐known pathogenic DCTN1 mutation and other reported cases.Results and ConclusionsWe report a novel DCTN1 mutation outside the CAP‐Gly domain that we demonstrated to be pathogenic based on clinical and autopsy findings.