Variants in the MS4A cluster interact with soluble TREM2 expression on biomarkers of neuropathology.

Recent evidence suggests that Alzheimer's disease (AD) genetic risk variants (rs1582763 and rs6591561) of the MS4A locus are genome-wide significant regulators of soluble TREM2 levels such that the minor allele of the protective variant (rs1582763) is associated with higher sTREM2 and lower AD risk while the minor allele of (rs6591561) relates to lower sTREM2 and higher AD risk. Our group previously found that higher sTREM2 relates to higher Aß40, worse blood-brain barrier (BBB) integrity (measured with the CSF/plasma albumin ratio), and higher CSF tau, suggesting strong associations with amyloid abundance and both BBB and neurodegeneration complicate interpretation. We expand on this work by leveraging these common variants as genetic tools to tune the interpretation of high CSF sTREM2, and by exploring the potential modifying role of these variants on the well-established associations between CSF sTREM2 as well as TREM2 transcript levels in the brain with AD neuropathology. Biomarker analyses leveraged data from the Vanderbilt Memory & Aging Project (n = 127, age = 72 ± 6.43) and were replicated in the Alzheimer's Disease Neuroimaging Initiative (n = 399, age = 73 ± 7.39). Autopsy analyses were performed leveraging data from the Religious Orders Study and Rush Memory and Aging Project (n = 577, age = 89 ± 6.46). We found that the protective variant rs1582763 attenuated the association between CSF sTREM2 and Aß40 (ß = -0.44, p-value = 0.017) and replicated this interaction in ADNI (ß = -0.27, p = 0.017). We did not observe this same interaction effect between TREM2 mRNA levels and Aß peptides in brain (Aß total ß = -0.14, p = 0.629; Aß1-38, ß = 0.11, p = 0.200). In contrast to the effects on Aß, the minor allele of this same variant seemed to enhance the association with blood-brain barrier dysfunction (ß = 7.0e-4, p = 0.009), suggesting that elevated sTREM2 may carry a much different interpretation in carriers vs. non-carriers of this allele. When evaluating the risk variant (rs6591561) across datasets, we did not observe a statistically significant interaction against any outcome in VMAP and observed opposing directions of associations in ADNI and ROS/MAP on Aß levels. Together, our results suggest that the protective effect of rs1582763 may act by decoupling the associations between sTREM2 and amyloid abundance, providing important mechanistic insight into sTREM2 changes and highlighting the need to incorporate genetic context into the analysis of sTREM2 levels, particularly if leveraged as a clinical biomarker of disease in the future.

Evaluation of Mean Shift, ComBat, and CycleGAN for Harmonizing Brain Connectivity Matrices Across Sites.

Connectivity matrices derived from diffusion MRI (dMRI) provide an interpretable and generalizable way of understanding the human brain connectome. However, dMRI suffers from inter-site and between-scanner variation, which impedes analysis across datasets to improve robustness and reproducibility of results. To evaluate different harmonization approaches on connectivity matrices, we compared graph measures derived from these matrices before and after applying three harmonization techniques: mean shift, ComBat, and CycleGAN. The sample comprises 168 age-matched, sex-matched normal subjects from two studies: the Vanderbilt Memory and Aging Project (VMAP) and the Biomarkers of Cognitive Decline Among Normal Individuals (BIOCARD). First, we plotted the graph measures and used coefficient of variation (CoV) and the Mann-Whitney U test to evaluate different methods' effectiveness in removing site effects on the matrices and the derived graph measures. ComBat effectively eliminated site effects for global efficiency and modularity and outperformed the other two methods. However, all methods exhibited poor performance when harmonizing average betweenness centrality. Second, we tested whether our harmonization methods preserved correlations between age and graph measures. All methods except for CycleGAN in one direction improved correlations between age and global efficiency and between age and modularity from insignificant to significant with p-values less than 0.05.

Perivascular space burden interacts with APOE-ε4 status on cognition in older adults.

Enlarged perivascular spaces (ePVS) may adversely affect cognition. Little is known about how basal ganglia ePVS interact with apolipoprotein (APOE)-ε4 status. Vanderbilt Memory and Aging Project participants (n = 326, 73 ± 7, 59% male) underwent 3 T brain MRI at baseline to assess ePVS and longitudinal neuropsychological assessments. The interaction between ePVS volume and APOE-ε4 carrier status was related to baseline outcomes using ordinary least squares regressions and longitudinal cognition using linear mixed-effects regressions. ePVS volume interacted with APOE-ε4 status on cross-sectional naming performance (ß = -0.002, p = 0.002), and executive function excluding outliers (ß = 0.001, p = 0.009). There were no significant longitudinal interactions (p-values>0.10) except for Coding excluding outliers (ß = 0.002, p = 0.05). While cross-sectional models stratified by APOE-ε4 status indicated greater ePVS related to worse cognition mostly in APOE-ε4 carriers, longitudinal models stratified by APOE-ε4 status showed greater ePVS volume related to worse cognition among APOE-ε4 non-carriers only. Results indicated that greater ePVS volume interacts with APOE-ε4 status on cognition cross-sectionally. Longitudinally, the association of greater ePVS volume and worse cognition appears stronger in APOE-ε4 non-carriers, possibly due to the deleterious effects of APOE-ε4 on cognition across the lifespan.

Basic Mechanisms of Brain Injury and Cognitive Decline in Hypertension.

Dementia affects almost 50 million adults worldwide, and remains a major cause of death and disability. Hypertension is a leading risk factor for dementia, including Alzheimer disease and Alzheimer disease-related dementias. Although this association is well-established, the mechanisms underlying hypertension-induced cognitive decline remain poorly understood. By exploring the mechanisms mediating the detrimental effects of hypertension on the brain, studies have aimed to provide therapeutic insights and strategies on how to protect the brain from the effects of blood pressure elevation. In this review, we focus on the basic mechanisms contributing to the cerebrovascular adaptions to elevated blood pressure and hypertension-induced microvascular injury. We also assess the cellular mechanisms of neurovascular unit dysfunction, focusing on the premise that cognitive impairment ensues when the dynamic metabolic demands of neurons are not met due to neurovascular uncoupling, and summarize cognitive deficits across various rodent models of hypertension as a resource for investigators. Despite significant advances in antihypertensive therapy, hypertension remains a critical risk factor for cognitive decline, and several questions remain about the development and progression of hypertension-induced cognitive impairment.

Predicting Age from White Matter Diffusivity with Residual Learning.

Imaging findings inconsistent with those expected at specific chronological age ranges may serve as early indicators of neurological disorders and increased mortality risk. Estimation of chronological age, and deviations from expected results, from structural magnetic resonance imaging (MRI) data has become an important proxy task for developing biomarkers that are sensitive to such deviations. Complementary to structural analysis, diffusion tensor imaging (DTI) has proven effective in identifying age-related microstructural changes within the brain white matter, thereby presenting itself as a promising additional modality for brain age prediction. Although early studies have sought to harness DTI's advantages for age estimation, there is no evidence that the success of this prediction is owed to the unique microstructural and diffusivity features that DTI provides, rather than the macrostructural features that are also available in DTI data. Therefore, we seek to develop white-matter-specific age estimation to capture deviations from normal white matter aging. Specifically, we deliberately disregard the macrostructural information when predicting age from DTI scalar images, using two distinct methods. The first method relies on extracting only microstructural features from regions of interest (ROIs). The second applies 3D residual neural networks (ResNets) to learn features directly from the images, which are non-linearly registered and warped to a template to minimize macrostructural variations. When tested on unseen data, the first method yields mean absolute error (MAE) of 6.11 ± 0.19 years for cognitively normal participants and MAE of 6.62 ± 0.30 years for cognitively impaired participants, while the second method achieves MAE of 4.69 ± 0.23 years for cognitively normal participants and MAE of 4.96 ± 0.28 years for cognitively impaired participants. We find that the ResNet model captures subtler, non-macrostructural features for brain age prediction.

Sex-specific genetic architecture of late-life memory performance.

BACKGROUND: Women demonstrate a memory advantage when cognitively healthy yet lose this advantage to men in Alzheimer's disease. However, the genetic underpinnings of this sex difference in memory performance remain unclear. METHODS: We conducted the largest sex-aware genetic study on late-life memory to date (Nmales  = 11,942; Nfemales  = 15,641). Leveraging harmonized memory composite scores from four cohorts of cognitive aging and AD, we performed sex-stratified and sex-interaction genome-wide association studies in 24,216 non-Hispanic White and 3367 non-Hispanic Black participants. RESULTS: We identified three sex-specific loci (rs67099044-CBLN2, rs719070-SCHIP1/IQCJ-SCHIP), including an X-chromosome locus (rs5935633-EGL6/TCEANC/OFD1), that associated with memory. Additionally, we identified heparan sulfate signaling as a sex-specific pathway and found sex-specific genetic correlations between memory and cardiovascular, immune, and education traits. DISCUSSION: This study showed memory is highly and comparably heritable across sexes, as well as highlighted novel sex-specific genes, pathways, and genetic correlations that related to late-life memory. HIGHLIGHTS: Demonstrated the heritable component of late-life memory is similar across sexes. Identified two genetic loci with a sex-interaction with baseline memory. Identified an X-chromosome locus associated with memory decline in females. Highlighted sex-specific candidate genes and pathways associated with memory. Revealed sex-specific shared genetic architecture between memory and complex traits.

Longitudinal change in memory performance as a strong endophenotype for Alzheimer's disease.

INTRODUCTION: Although large-scale genome-wide association studies (GWAS) have been conducted on AD, few have been conducted on continuous measures of memory performance and memory decline. METHODS: We conducted a cross-ancestry GWAS on memory performance (in 27,633 participants) and memory decline (in 22,365 participants; 129,201 observations) by leveraging harmonized cognitive data from four aging cohorts. RESULTS: We found high heritability for two ancestry backgrounds. Further, we found a novel ancestry locus for memory decline on chromosome 4 (rs6848524) and three loci in the non-Hispanic Black ancestry group for memory performance on chromosomes 2 (rs111471504), 7 (rs4142249), and 15 (rs74381744). In our gene-level analysis, we found novel genes for memory decline on chromosomes 1 (SLC25A44), 11 (BSX), and 15 (DPP8). Memory performance and memory decline shared genetic architecture with AD-related traits, neuropsychiatric traits, and autoimmune traits. DISCUSSION: We discovered several novel loci, genes, and genetic correlations associated with late-life memory performance and decline. HIGHLIGHTS: Late-life memory has high heritability that is similar across ancestries. We discovered four novel variants associated with late-life memory. We identified four novel genes associated with late-life memory. Late-life memory shares genetic architecture with psychiatric/autoimmune traits.

Frontal and anterior temporal hypometabolism post chemoradiation in head and neck cancer: A real-world PET study.

BACKGROUND AND PURPOSE: Adverse neurological effects after cancer therapy are common, but biomarkers to diagnose, monitor, or risk stratify patients are still not validated or used clinically. An accessible imaging method, such as fluorodeoxyglucose positron emission tomography (FDG PET) of the brain, could meet this gap and serve as a biomarker for functional brain changes. We utilized FDG PET to evaluate which brain regions are most susceptible to altered glucose metabolism after chemoradiation in patients with head and neck cancer (HNCa). METHODS: Real-world FDG PET images were acquired as standard of care before and after chemoradiation for HNCa in 68 patients. Linear mixed-effects voxelwise models assessed changes after chemoradiation in cerebral glucose metabolism quantified with standardized uptake value ratio (SUVR), covarying for follow-up time and patient demographics. RESULTS: Voxelwise analysis revealed two large clusters of decreased glucose metabolism in the medial frontal and polar temporal cortices following chemoradiation, with decreases of approximately 5% SUVR after therapy. CONCLUSIONS: These findings provide evidence that standard chemoradiation for HNCa can lead to decreased neuronal glucose metabolism, contributing to literature emphasizing the vulnerability of the frontal and anterior temporal lobes, especially in HNCa, where these areas may be particularly vulnerable to indirect radiation-induced injury. FDG PET shows promise as a sensitive biomarker for assessing these changes.

A deep neural network estimation of brain age is sensitive to cognitive impairment and decline.

The greatest known risk factor for Alzheimer's disease (AD) is age. While both normal aging and AD pathology involve structural changes in the brain, their trajectories of atrophy are not the same. Recent developments in artificial intelligence have encouraged studies to leverage neuroimaging-derived measures and deep learning approaches to predict brain age, which has shown promise as a sensitive biomarker in diagnosing and monitoring AD. However, prior efforts primarily involved structural magnetic resonance imaging and conventional diffusion MRI (dMRI) metrics without accounting for partial volume effects. To address this issue, we post-processed our dMRI scans with an advanced free-water (FW) correction technique to compute distinct FW-corrected fractional anisotropy (FAFWcorr) and FW maps that allow for the separation of tissue from fluid in a scan. We built 3 densely connected neural networks from FW-corrected dMRI, T1-weighted MRI, and combined FW+T1 features, respectively, to predict brain age. We then investigated the relationship of actual age and predicted brain ages with cognition. We found that all models accurately predicted actual age in cognitively unimpaired (CU) controls (FW: r=0.66, p=1.62x10-32; T1: r=0.61, p=1.45x10-26, FW+T1: r=0.77, p=6.48x10-50) and distinguished between CU and mild cognitive impairment participants (FW: p=0.006; T1: p=0.048; FW+T1: p=0.003), with FW+T1-derived age showing best performance. Additionally, all predicted brain age models were significantly associated with cross-sectional cognition (memory, FW: ß=-1.094, p=6.32x10-7; T1: ß=-1.331, p=6.52x10-7; FW+T1: ß=-1.476, p=2.53x10-10; executive function, FW: ß=-1.276, p=1.46x10-9; T1: ß=-1.337, p=2.52x10-7; FW+T1: ß=-1.850, p=3.85x10-17) and longitudinal cognition (memory, FW: ß=-0.091, p=4.62x10-11; T1: ß=-0.097, p=1.40x10-8; FW+T1: ß=-0.101, p=1.35x10-11; executive function, FW: ß=-0.125, p=1.20x10-10; T1: ß=-0.163, p=4.25x10-12; FW+T1: ß=-0.158, p=1.65x10-14). Our findings provide evidence that both T1-weighted MRI and dMRI measures improve brain age prediction and support predicted brain age as a sensitive biomarker of cognition and cognitive decline.

Sex and Education Modify the Association Between Subjective Cognitive Decline and Amyloid Pathology.

Background: Subjective cognitive decline (SCD) may be an early risk factor for dementia, particularly in highly educated individuals and women. This study examined the effect of education and sex on the association between SCD and Alzheimer's disease (AD) biomarkers in non-demented older adults. Method: Vanderbilt Memory and Aging Project participants free of clinical dementia or stroke (n=156, 72±6 years, 37% mild cognitive impairment, 33% female) completed fasting lumbar puncture, SCD assessment, and Wide Range Achievement Test-III Reading subtest to assess reading level at baseline as a a proxy for educational quality. Cerebrospinal fluid (CSF) biomarkers for AD (ß-amyloid 42 (Aß42), Aß42/40 ratio, phosphorylated tau (p-tau), tau, and neurofilament light (NfL)) were analyzed in batch. Linear mixed effects models related SCD to CSF AD biomarkers and follow-up models assessed SCD x sex, SCD x reading level , and SCD x education interactions on AD biomarkers. Result: In main effect models, higher SCD was associated with lower Aß42 and Aß42/40 ratio (p-values<0.004). SCD was not associated with tau, p-tau, or NfL levels ( p- values>0.38). SCD score interacted with sex on Aß42/40 ratio ( p =0.03) but no other biomarkers ( p -values>0.10). In stratified models, higher SCD was associated with lower Aß42/40 ratio in men ( p =0.0003) but not in women ( p =0.48). SCD score interacted with education on Aß42 ( p =0.005) and Aß42/40 ratio ( p =0.001) such that higher education was associated with a stronger negative association between SCD and amyloid levels. No SCD score x reading level interaction was found (p-values> 0.51) though significant associations between SCD and amyloid markers were seen in the higher reading level group (p-values<0.004) but not the lower reading level group (p-values>0.12) when stratified by a median split in reading level. Conclusion: Among community-dwelling older adults free of clinical dementia, higher SCD was associated with greater cerebral amyloid accumulation, one of the earliest pathological AD changes. SCD appears most useful in detecting early AD-related brain changes in men and individuals with higher quantity and quality of education. SCD was not associated with CSF markers of tau pathology or neurodegeneration. These findings suggest that considering sex and education is important when assessing SCD in older adults.

Clinical and demographic factors modify the association between plasma phosphorylated tau-181 and cognition.

INTRODUCTION: Plasma phosphorylated tau181 (p-tau181) associations with global cognition and memory are clear, but the link between p-tau181 with other cognitive domains and subjective cognitive decline (SCD) across the clinical spectrum of Alzheimer's disease (AD) and how this association changes based on genetic and demographic factors is poorly understood. METHODS: Participants were drawn from the Alzheimer's Disease Neuroimaging Initiative and included 1185 adults aged >55 years with plasma p-tau181 and neuropsychological test data. Linear regression models related plasma p-tau181 to neuropsychological composite and SCD scores with follow-up models examining plasma p-tau181 interactions with cognitive diagnosis, APOE ε4 carrier status, age, and sex on cognitive outcomes. RESULTS: Higher plasma p-tau181 was associated with worse memory, executive functioning, and language abilities, and greater informant-reported SCD. Visuospatial abilities and self-report SCD were not associated with plasma p-tau181. Associations were generally stronger in MCI or dementia, APOE ε4 carriers, women, and younger participants. DISCUSSION: Higher levels of plasma p-tau181 are associated with worse neuropsychological test performance across multiple cognitive domains; however, these associations vary based on disease stage, genetic risk status, age, and sex.

Leveraging longitudinal diffusion MRI data to quantify differences in white matter microstructural decline in normal and abnormal aging.

Introduction: It is unclear how rates of white matter microstructural decline differ between normal aging and abnormal aging. Methods: Diffusion MRI data from several well-established longitudinal cohorts of aging (Alzheimer's Disease Neuroimaging Initiative [ADNI], Baltimore Longitudinal Study of Aging [BLSA], Vanderbilt Memory & Aging Project [VMAP]) were free-water corrected and harmonized. This dataset included 1723 participants (age at baseline: 72.8 ± 8.87 years, 49.5% male) and 4605 imaging sessions (follow-up time: 2.97 ± 2.09 years, follow-up range: 1-13 years, mean number of visits: 4.42 ± 1.98). Differences in white matter microstructural decline in normal and abnormal agers was assessed. Results: While we found a global decline in white matter in normal/abnormal aging, we found that several white matter tracts (e.g., cingulum bundle) were vulnerable to abnormal aging. Conclusions: There is a prevalent role of white matter microstructural decline in aging, and future large-scale studies in this area may further refine our understanding of the underlying neurodegenerative processes. HIGHLIGHTS: Longitudinal data were free-water corrected and harmonized.Global effects of white matter decline were seen in normal and abnormal aging.The free-water metric was most vulnerable to abnormal aging.Cingulum free-water was the most vulnerable to abnormal aging.

A deep neural network estimation of brain age is sensitive to cognitive impairment and decline.

The greatest known risk factor for Alzheimer's disease (AD) is age. While both normal aging and AD pathology involve structural changes in the brain, their trajectories of atrophy are not the same. Recent developments in artificial intelligence have encouraged studies to leverage neuroimaging-derived measures and deep learning approaches to predict brain age, which has shown promise as a sensitive biomarker in diagnosing and monitoring AD. However, prior efforts primarily involved structural magnetic resonance imaging and conventional diffusion MRI (dMRI) metrics without accounting for partial volume effects. To address this issue, we post-processed our dMRI scans with an advanced free-water (FW) correction technique to compute distinct FW-corrected fractional anisotropy (FAFWcorr) and FW maps that allow for the separation of tissue from fluid in a scan. We built 3 densely connected neural networks from FW-corrected dMRI, T1-weighted MRI, and combined FW+T1 features, respectively, to predict brain age. We then investigated the relationship of actual age and predicted brain ages with cognition. We found that all models accurately predicted actual age in cognitively unimpaired (CU) controls (FW: r=0.66, p=1.62×10-32; T1: r=0.61, p=1.45×10-26, FW+T1: r=0.77, p=6.48×10-50) and distinguished between CU and mild cognitive impairment participants (FW: p=0.006; T1: p=0.048; FW+T1: p=0.003), with FW+T1-derived age showing best performance. Additionally, all predicted brain age models were significantly associated with cross-sectional cognition (memory, FW: ß=-1.094, p=6.32×10-7; T1: ß=-1.331, p=6.52×10-7; FW+T1: ß=-1.476, p=2.53×10-10; executive function, FW: ß=-1.276, p=1.46×10-9; T1: ß=-1.337, p=2.52×10-7; FW+T1: ß=-1.850, p=3.85×10-17) and longitudinal cognition (memory, FW: ß=-0.091, p=4.62×10-11; T1: ß=-0.097, p=1.40×10-8; FW+T1: ß=-0.101, p=1.35×10-11; executive function, FW: ß=-0.125, p=1.20×10-10; T1: ß=-0.163, p=4.25×10-12; FW+T1: ß=-0.158, p=1.65×10-14). Our findings provide evidence that both T1-weighted MRI and dMRI measures improve brain age prediction and support predicted brain age as a sensitive biomarker of cognition and cognitive decline.

Associations of Sex, Race, and Apolipoprotein E Alleles With Multiple Domains of Cognition Among Older Adults.

Importance: Sex differences are established in associations between apolipoprotein E (APOE) ε4 and cognitive impairment in Alzheimer disease (AD). However, it is unclear whether sex-specific cognitive consequences of APOE are consistent across races and extend to the APOE ε2 allele. Objective: To investigate whether sex and race modify APOE ε4 and ε2 associations with cognition. Design, Setting, and Participants: This genetic association study included longitudinal cognitive data from 4 AD and cognitive aging cohorts. Participants were older than 60 years and self-identified as non-Hispanic White or non-Hispanic Black (hereafter, White and Black). Data were previously collected across multiple US locations from 1994 to 2018. Secondary analyses began December 2021 and ended September 2022. Main Outcomes and Measures: Harmonized composite scores for memory, executive function, and language were generated using psychometric approaches. Linear regression assessed interactions between APOE ε4 or APOE ε2 and sex on baseline cognitive scores, while linear mixed-effect models assessed interactions on cognitive trajectories. The intersectional effect of race was modeled using an APOE × sex × race interaction term, assessing whether APOE × sex interactions differed by race. Models were adjusted for age at baseline and corrected for multiple comparisons. Results: Of 32 427 participants who met inclusion criteria, there were 19 007 females (59%), 4453 Black individuals (14%), and 27 974 White individuals (86%); the mean (SD) age at baseline was 74 years (7.9). At baseline, 6048 individuals (19%) had AD, 4398 (14%) were APOE ε2 carriers, and 12 538 (38%) were APOE ε4 carriers. Participants missing APOE status were excluded (n = 9266). For APOE ε4, a robust sex interaction was observed on baseline memory (ß = -0.071, SE = 0.014; P = 9.6 × 10-7), whereby the APOE ε4 negative effect was stronger in females compared with males and did not significantly differ among races. Contrastingly, despite the large sample size, no APOE ε2 × sex interactions on cognition were observed among all participants. When testing for intersectional effects of sex, APOE ε2, and race, an interaction was revealed on baseline executive function among individuals who were cognitively unimpaired (ß = -0.165, SE = 0.066; P = .01), whereby the APOE ε2 protective effect was female-specific among White individuals but male-specific among Black individuals. Conclusions and Relevance: In this study, while race did not modify sex differences in APOE ε4, the APOE ε2 protective effect could vary by race and sex. Although female sex enhanced ε4-associated risk, there was no comparable sex difference in ε2, suggesting biological pathways underlying ε4-associated risk are distinct from ε2 and likely intersect with age-related changes in sex biology.

Leveraging longitudinal diffusion MRI data to quantify differences in white matter microstructural decline in normal and abnormal aging.

INTRODUCTION: It is unclear how rates of white matter microstructural decline differ between normal aging and abnormal aging. METHODS: Diffusion MRI data from several well-established longitudinal cohorts of aging [Alzheimer's Neuroimaging Initiative (ADNI), Baltimore Longitudinal Study of Aging (BLSA), Vanderbilt Memory & Aging Project (VMAP)] was free-water corrected and harmonized. This dataset included 1,723 participants (age at baseline: 72.8±8.87 years, 49.5% male) and 4,605 imaging sessions (follow-up time: 2.97±2.09 years, follow-up range: 1-13 years, mean number of visits: 4.42±1.98). Differences in white matter microstructural decline in normal and abnormal agers was assessed. RESULTS: While we found global decline in white matter in normal/abnormal aging, we found that several white matter tracts (e.g., cingulum bundle) were vulnerable to abnormal aging. CONCLUSIONS: There is a prevalent role of white matter microstructural decline in aging, and future large-scale studies in this area may further refine our understanding of the underlying neurodegenerative processes. HIGHLIGHTS: Longitudinal data was free-water corrected and harmonizedGlobal effects of white matter decline were seen in normal and abnormal agingThe free-water metric was most vulnerable to abnormal agingCingulum free-water was the most vulnerable to abnormal aging.

Linking self-perceived cognitive functioning questionnaires using item response theory: The subjective cognitive decline initiative.

OBJECTIVE: Self-perceived cognitive functioning, considered highly relevant in the context of aging and dementia, is assessed in numerous ways-hindering the comparison of findings across studies and settings. Therefore, the present study aimed to link item-level self-report questionnaire data from international aging studies. METHOD: We harmonized secondary data from 24 studies and 40 different questionnaires with item response theory (IRT) techniques using a graded response model with a Bayesian estimator. We compared item information curves to identify items with high measurement precision at different levels of the self-perceived cognitive functioning latent trait. Data from 53,030 neuropsychologically intact older adults were included, from 13 English language and 11 non-English (or mixed) language studies. RESULTS: We successfully linked all questionnaires and demonstrated that a single-factor structure was reasonable for the latent trait. Items that made the greatest contribution to measurement precision (i.e., "top items") assessed general and specific memory problems and aspects of executive functioning, attention, language, calculation, and visuospatial skills. These top items originated from distinct questionnaires and varied in format, range, time frames, response options, and whether they captured ability and/or change. CONCLUSIONS: This was the first study to calibrate self-perceived cognitive functioning data of geographically diverse older adults. The resulting item scores are on the same metric, facilitating joint or pooled analyses across international studies. Results may lead to the development of new self-perceived cognitive functioning questionnaires guided by psychometric properties, content, and other important features of items in our item bank. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Establishing Quality Control Procedures for Large-Scale Plasma Proteomics Analyses.

Proteomics research has been transformed due to high-throughput liquid chromatography (LC-MS/MS) tandem mass spectrometry instruments combined with highly sophisticated automated sample preparation and multiplexing workflows. However, scaling proteomics experiments to large sample cohorts (hundreds to thousands) requires thoughtful quality control (QC) protocols. Robust QC protocols can help with reproducibility, quantitative accuracy, and provide opportunities for more decisive troubleshooting. Our laboratory conducted a plasma proteomics study of a cohort of N = 335 patient samples using tandem mass tag (TMTpro) 16-plex batches. Over the course of a 10-month data acquisition period for this cohort we collected 271 pooled QC LC-MS/MS result files obtained from MS/MS analysis of a patient-derived pooled plasma sample, representative of the entire cohort population. This sample was tagged with TMTzero or TMTpro reagents and used to inform the daily performance of the LC-MS/MS instruments and to allow within and across sample batch normalization. Analytical variability of a number of instrumental and data analysis metrics including protein and peptide identifications, peptide spectral matches (PSMs), number of obtained MS/MS spectra, average peptide abundance, percent of peptides with a Δ m/z between ±0.003 Da, percent of MS/MS spectra obtained at the maximum injection time, and the retention time of selected tracking peptides were evaluated to help inform the design of a robust LC-MS/MS QC workflow for use in future cohort studies. This study also led to general tips for using selected metrics to inform real-time troubleshooting of LC-MS/MS performance issues with daily QC checks.

White matter microstructural metrics are sensitively associated with clinical staging in Alzheimer's disease.

Introduction: White matter microstructure may be abnormal along the Alzheimer's disease (AD) continuum. Methods: Diffusion magnetic resonance imaging (dMRI) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 627), Baltimore Longitudinal Study of Aging (BLSA, n = 684), and Vanderbilt Memory & Aging Project (VMAP, n = 296) cohorts were free-water (FW) corrected and conventional, and FW-corrected microstructural metrics were quantified within 48 white matter tracts. Microstructural values were subsequently harmonized using the Longitudinal ComBat technique and inputted as independent variables to predict diagnosis (cognitively unimpaired [CU], mild cognitive impairment [MCI], AD). Models were adjusted for age, sex, race/ethnicity, education, apolipoprotein E (APOE) ε4 carrier status, and APOE ε2 carrier status. Results: Conventional dMRI metrics were associated globally with diagnostic status; following FW correction, the FW metric itself exhibited global associations with diagnostic status, but intracellular metric associations were diminished. Discussion: White matter microstructure is altered along the AD continuum. FW correction may provide further understanding of the white matter neurodegenerative process in AD. Highlights: Longitudinal ComBat successfully harmonized large-scale diffusion magnetic resonance imaging (dMRI) metrics.Conventional dMRI metrics were globally sensitive to diagnostic status.Free-water (FW) correction mitigated intracellular associations with diagnostic status.The FW metric itself was globally sensitive to diagnostic status. Multivariate conventional and FW-corrected models may provide complementary information.

Baseline grey matter volumes and white matter hyperintensities predict decline in functional activities in older adults over a 5-year follow-up period.

INTRODUCTION: Functional independence is an essential predictor of quality of life in aging, yet few accessible predictors of functional decline have been identified. This study examined associations between baseline structural neuroimaging markers and longitudinal functional status. METHODS: Linear mixed effects models with follow-up time interaction terms related baseline grey matter volume and white matter hyperintensities (WMHs) to functional trajectory, adjusting for demographic and medical covariates. Subsequent models assessed interactions with cognitive status and apolipoprotein E (APOE) ε4 status. RESULTS: Smaller baseline grey matter volumes, particularly in regions commonly affected by Alzheimer's disease (AD), and greater baseline WMHs were associated with faster functional decline over a mean 5-year follow-up. Effects were stronger in APOE-ε4 carriers on grey matter variables. Cognitive status interacted with most MRI variables. DISCUSSION: Greater atrophy in AD-related regions and higher WMH burden at study entry were associated with faster functional decline, particularly among participants at increased risk of AD.

TREM2 gene expression associations with Alzheimer's disease neuropathology are region-specific: implications for cortical versus subcortical microglia.

Previous post-mortem assessments of TREM2 expression and its association with brain pathologies have been limited by sample size. This study sought to correlate region-specific TREM2 mRNA expression with diverse neuropathological measures at autopsy using a large sample size (N = 945) of bulk RNA sequencing data from the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP). TREM2 gene expression of the dorsolateral prefrontal cortex, posterior cingulate cortex, and caudate nucleus was assessed with respect to core pathology of Alzheimer's disease (amyloid-ß, and tau), cerebrovascular pathology (cerebral infarcts, arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy), microglial activation (proportion of activated microglia), and cognitive performance. We found that cortical TREM2 levels were positively related to AD diagnosis, cognitive decline, and amyloid-ß neuropathology but were not related to the proportion of activated microglia. In contrast, caudate TREM2 levels were not related to AD pathology, cognition, or diagnosis, but were positively related to the proportion of activated microglia in the same region. Diagnosis-stratified results revealed caudate TREM2 levels were inversely related to AD neuropathology and positively related to microglial activation and longitudinal cognitive performance in AD cases. These results highlight the notable changes in TREM2 transcript abundance in AD and suggest that its pathological associations are brain-region-dependent.