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Neuropsychological latent classes at enrollment and postmortem neuropathology.

ABSTRACT: INTRODUCTION:We classified individuals based on their baseline performance on cognitive measures and investigated the association between cognitive classifications and neuropathological findings ?7 years later, as an external validator. METHODS:Brain autopsies of 779 decedents were examined. Baseline latent class analysis on 10 neuropsychological measures was previously assigned: mixed-domains impairment (n = 39, 5%), memory-specific impairment (n = 210, 27%), frontal impairment (n = 113, 14.5%), average cognition (n = 360, 46.2%), and superior cognition (n = 57, 7.3%). Linear regressions and risks ratios were used to examine the relation of latent class assignment at enrollment with neuropathological indices. RESULTS:Amyloid ?, tau, and transactive response DNA-binding protein 43 were associated with mixed-domains impairment and memory-specific impairment classes ?7 years before death. Moderate arteriolosclerosis was associated with membership in the frontal impairment class. DISCUSSION:Our findings support the use of latent class models that incorporate more comprehensive neuropsychological measures to classify cognitive impairment.

SUBMITTER: Zammit AR

PROVIDER: S-EPMC6756968 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Neuropsychological latent classes at enrollment and postmortem neuropathology.

Zammit Andrea R AR Hall Charles B CB Bennett David A DA Ezzati Ali A Katz Mindy J MJ Muniz-Terrera Graciela G Lipton Richard B RB

Alzheimer's & dementia : the journal of the Alzheimer's Association 20190813 9

<h4>Introduction</h4>We classified individuals based on their baseline performance on cognitive measures and investigated the association between cognitive classifications and neuropathological findings ∼7 years later, as an external validator.<h4>Methods</h4>Brain autopsies of 779 decedents were examined. Baseline latent class analysis on 10 neuropsychological measures was previously assigned: mixed-domains impairment (n = 39, 5%), memory-specific impairment (n = 210, 27%), frontal impairment ( ...[more]

PMID: 31420203

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Project description:Progressive supranuclear palsy (PSP) is the second most common neurodegenerative Parkinsonian disorder after Parkinson's disease, and is characterized as a primary tauopathy. Leveraging the considerable clinical and neuropathologic heterogeneity associated with PSP, we measured tau neuropathology as quantitative traits to perform a genome-wide association study (GWAS) within PSP to identify genes and biological pathways that underlie the PSP disease process. In 882 PSP cases, semi-quantitative scores for phosphorylated tau-immunoreactive coiled bodies (CBs), neurofibrillary tangles (NFTs), tufted astrocytes (TAs), and tau threads were documented from 18 brain regions, and converted to latent trait (LT) variables using the R ltm package. LT analysis utilizes a multivariate regression model that links categorical responses to unobserved covariates allowing for a reduction of dimensionality, generating a single, continuous variable to account for the multiple lesions and brain regions assessed. We first tested for association with PSP LTs and the top PSP GWAS susceptibility loci. Significant SNP/LT associations were identified at rs242557 (MAPT H1c sub-haplotype) with hindbrain CBs and rs1768208 (MOBP) with forebrain tau threads. Digital microscopy was employed to quantify phosphorylated tau burden in midbrain tectum and red nucleus in 795 PSP cases and tau burdens were used as quantitative phenotypes in GWAS. Top associations were identified at rs1768208 with midbrain tectum and red nucleus tau burden. Additionally, we performed a PSP LT GWAS on an initial cohort, a follow-up SNP panel (37 SNPs, P < 10-5) in an extended cohort, and a combined analysis. Top SNP/LT associations were identified at SNPs in or near SPTBN5/EHD4, SEC13/ATP2B2, EPHB1/PPP2R3A, TBC1D8, IFNGR1/OLIG3, ST6GAL1, HK1, CALB1, and SGCZ. Finally, testing for SNP/transcript associations using whole transcriptome and whole genome data identified significant expression quantitative trait loci at rs3088159/SPTBN5/EHD4 and rs154239/GHRL. Modeling tau neuropathology heterogeneity using LTs as quantitative phenotypes in a GWAS may provide substantial insight into biological pathways involved in PSP by affecting regional tau burden.

Dataset Information

Neuropsychological latent classes at enrollment and postmortem neuropathology.

Publications

Neuropsychological latent classes at enrollment and postmortem neuropathology.

Similar Datasets

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