Neuropathology studies of dementia in US persons other than non-Hispanic whites

Nguyen, My-Le; Huie, Emily; Whitmer, Rachel A.; George, Kristen M; Dugger, Brittany N.

doi:10.17879/freeneuropathology-2022-3795

Cited by 9 publications

(9 citation statements)

References 81 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, autopsy- based collections have numerous selection biases. It is also imperative to denote race and ethnicity are social constructs and can have numerous intertwined variables of which may relate to differences found 58 . Nevertheless, when NHW were employed to train the machine learning algorithm and Hispanics for testing (Ethnicity-Aware model), we found the model to perform comparably to the Ethnicity-agnostic one.…”

Section: Discussionmentioning

confidence: 99%

MU-BRAIN: MUltiethnic Brain Rna-seq for Alzheimer INitiative

Yang,

Cieza,

Reyes-Dumeyer

et al. 2024

Preprint

View full text Add to dashboard Cite

BackgroundsAlzheimer’s Disease (AD) exhibits a complex molecular and phenotypic profile. Investigating gene expression plays a crucial role in unraveling the disease’s etiology and progression. Transcriptome data across ethnic groups lack, negatively impacting equity in intervention and research.MethodsWe employed 565 brains across six U.S. brain banks (N=399 non-Hispanic Whites, N=113 Hispanics, N=12 African Americans) to generated bulk RNA sequencing from prefrontal cortex. We sought to identify cross-ancestry and ancestry-specific differentially expressed genes (DEG) across Braak stages, adjusting for sex, age at death, and RNA quality metrics. We further validated our findings using the Religious Orders Study/Memory Aging Project brains (ROS/MAP; N=1,095). We conducted Gene Set and Variation and Enrichment analysis (GSVA; GSEA). We employed a machine-learning approach for phenotype prediction and gene prioritization to construct a polytranscriptomics risk score (PTRS) splitting our sample into training and testing sub-samples, either randomly or by ethnicity (“ancestry-agnostic” and “ancestry-aware”, respectively). Lastly, we validated top DEG using single-nucleus RNA sequencing (snRNAseq) data.ResultsWe identified DEG associated with Braak staging: AD-known genesVGF(padj=3.78E-07) andADAMTS2(padj=1.21E-04) were consistently differentially expressed across statistical models, ethnicities, and replicated in ROS/MAP. Genes from the heat shock protein (HSP) family, e.g.HSPB7(padj=3.78E-07), were the top differentially expressed genes and replicated in ROS/MAP. Ethnic-stratified analyses prioritizedTNFSF14andSPOCD1as top Hispanics DEG. GSEA highlighted “Alzheimer disease” (padj=4.24E-06) and “TYROBP causal network in microglia” (padj=1.68E-08) pathways. Up- and down-regulated genes were enriched in several pathways (e.g. “Immune response activation signal pathways”, “Vesicle-mediated transport in synapse”, “cognition”). Ancestry-agnostic and ancestry-aware PTRS effectively classified brains (AUC=0.77 and 0.73 respectively) and replicated in ROS/MAP. snRNAseq validated prioritized genes, includingVGF (downregulated in neurons; padj=1.1 E-07).ConclusionsThis is the largest diverse transcriptome for AD in post-mortem tissue to our knowledge. We identified perturbated genes, pathways and network expressions in AD brains resulting in cross-ethnic and ethnic-specific findings, ultimately highlighting the diversity within AD pathogenesis. The latter underscores the need for an integrative and personalized approach in AD studies.

show abstract

Section: Discussionmentioning

confidence: 99%

MU-BRAIN: MUltiethnic Brain Rna-seq for Alzheimer INitiative

Yang,

Cieza,

Reyes-Dumeyer

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Investigators within the neuropathology and ML core have published on ethno-racial differences across dementia as well as highlighted the paucity of minority representation in neuropathological research [ 50 , 72 , 73 ]. Hence, the team strives to include biospecimens from underrepresented groups and analyze data accordingly if the sample size permits.…”

Section: Thematic Approachmentioning

confidence: 99%

How cy pres promotes transdisciplinary convergence science: an academic health center for women’s cardiovascular and brain health

Villablanca,

Dugger,

Nuthikattu

et al. 2024

J. Clin. Trans. Sci.

View full text Add to dashboard Cite

show abstract

“…Observations in more diverse communities are critical, since socioeconomic, cultural, and/or ancestral aspects may influence clinical-pathological correlation [55,109,123,146]. (Some recent scholarship has evaluated LATE-NC in cohorts other than Whites [104,109,123,146].) It may be possible to discover molecular subtypes of LATE-NC using immunophenotyping, transcriptome profiling, and genotyping or other approaches, which has potential implications for prognosis and therapy.…”

Section: Future Directions and Knowledge Gaps Related To Late-ncmentioning

confidence: 99%

“…Additional pressing research is needed to define and stratify risk factors and interactions with other diseases, including various neurodegenerative and neurovascular disorders (see, for example, Refs [ 15 , 37 , 128 ]). Observations in more diverse communities are critical, since socioeconomic, cultural, and/or ancestral aspects may influence clinical–pathological correlation [ 55 , 109 , 123 , 146 ]. (Some recent scholarship has evaluated LATE-NC in cohorts other than Whites [ 104 , 109 , 123 , 146 ].)…”

Section: Future Directions and Knowledge Gaps Related To Late-ncmentioning

confidence: 99%

“…Observations in more diverse communities are critical, since socioeconomic, cultural, and/or ancestral aspects may influence clinical–pathological correlation [ 55 , 109 , 123 , 146 ]. (Some recent scholarship has evaluated LATE-NC in cohorts other than Whites [ 104 , 109 , 123 , 146 ].)…”

Section: Future Directions and Knowledge Gaps Related To Late-ncmentioning

confidence: 99%

See 1 more Smart Citation

LATE-NC staging in routine neuropathologic diagnosis: an update

et al. 2022

View full text Add to dashboard Cite

An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer’s disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.

show abstract

Neuropathology studies of dementia in US persons other than non-Hispanic whites

Cited by 9 publications

References 81 publications

MU-BRAIN: MUltiethnic Brain Rna-seq for Alzheimer INitiative

MU-BRAIN: MUltiethnic Brain Rna-seq for Alzheimer INitiative

How cy pres promotes transdisciplinary convergence science: an academic health center for women’s cardiovascular and brain health

LATE-NC staging in routine neuropathologic diagnosis: an update

Contact Info

Product

Resources

About