Qiong Yang

When conducting microscopy of human brain sections, the postmortem interval (PMI) introduces myelin‐related artifacts that can confound neuropathological interpretation, yet the extent and detectability of these changes remain poorly characterized. This study examined the impact of controlled PMI on myelin integrity in rhesus macaque brain tissue using advanced optical imaging approaches. Brains from five aged rhesus macaques (20.5–28.5 years) were maintained at 4°C and analyzed at 0, 24, and 72 h postmortem. Myelin integrity in white and gray matter was assessed using quantitative birefringence microscopy to measure relative retardance and polarization‐sensitive optical coherence tomography to quantify scattering coefficients, retardance, and volumetric features. Increasing PMI was associated with progressive myelin degradation, reflected by significant reductions in relative optical retardance in white matter ( p < 0.01) and gray matter ( p < 0.001), alongside increased scattering coefficients in both regions ( p < 0.001). Morphological analyses revealed a marked increase in myelin defects per mm ² with longer PMI ( p < 0.001), characterized by swellings, vesicles, and structural discontinuities. These findings demonstrate that PMI causes significant detectable myelin changes, which can be quantified using optical imaging techniques, providing critical implications for interpreting postmortem neuropathological studies (especially with human brain tissues) and establishing a need for standardized PMI considerations in research protocols to ensure accurate pathological assessment in neurological disease investigations.

Background and ObjectivesSleep is multidimensional, and it remains unclear which aspects are most relevant to cognition and dementia risk. We aimed to apply a data-driven approach to identify clust...

Low circulating vitamin D in later-life has been associated with increased risk of cognitive impairment and clinical dementia. However, whether serum vitamin D in early mid-life is associated with neuroimaging markers of preclinical dementia is unknown. We aimed to determine the association between early mid-life serum vitamin D and subsequent tau- and amyloid- burden on brain-PET, in a cohort of dementia-free adults. This was a prospective cohort study of Framingham Heart Study Generation 3 cohort participants who were dementia-free at time of PET, had serum 25-hydroxyvitamin D [25(OH)D] measured at examination cycle 1 (2002-2005) and had available 11C-Pittsburgh Compound-B (PiB)- and/or 18F-Flortaucipir (FTP)-PET completed between 2016 and 2019. Outcomes included global tau-PET deposition (across all 34 FreeSurfer defined cortical regions), composite tau (those regions most susceptible to early tau involvement in AD dementia, namely entorhinal cortex, parahippocampal gyrus, fusiform gyrus, amygdala and inferior and middle temporal cortices) and amyloid-PET deposition (composite region including the frontal, lateral temporal, parietal and retrosplenial cortices [FLR]). Data were analyzed using multivariable linear regression models adjusted for age, sex, time from blood sampling to PET, PET camera type, depression, season, current smoking, systolic blood pressure, use of antihypertensive medication, diabetes mellitus, cardiovascular disease, and body mass index. In our sample (n= 793, 53% women, mean age 39±8years) with available serum 25(OH)D and amyloid (n=424) and/or tau-PET (n=369), the mean time between blood sampling and PET was 16±2 years. On multivariable linear regression analysis, higher serum 25(OH)D was associated with lower global (β= -0.022; 95% CI: -0.040 to -0.004; p = 0.010]) and composite tau-PET deposition (β= -0.023; 95% CI: -0.043 to -0.003; p = 0.016]),but was not associated with amyloid-PET burden. In a group of dementia-free individuals, higher serum 25(OH)D at early mid-life was associated with lower tau deposition on brain PET a mean of 16 years later. Low vitamin D in mid-life may represent a potentially modifiable target to mitigate the risk of neuroimaging signs of preclinical dementia.

Background and ObjectivesThe aquaporin-4 (AQP4) water channel plays an integral role in clearing brain waste. However, little is known about whether variations in the AQP4 gene contributes to brain...

Background and Objectives: Identifying proteomic biomarkers associated with neuroimaging endophenotypes of cerebrovascular dysfunction and generalized neurodegeneration may provide insights into pre-Alzheimer disease pathological processes. This study aims to examine a broad panel of circulating proteins in relation to two diffusion tensor imaging (DTI) measures:free water (FW) and peak width of skeletonized mean diffusivity (PSMD), which are sensitive indicators of early white matter injury. Methods: Using data from the Framingham Heart Study (FHS) Offspring and Third Generation cohorts, who underwent proteomic profiling with SomaScan version 1.3K, we evaluated the associations between individual proteins and DTI measures. Proteins with p-values < 0.01 for associations with either FW or PSMD in the FHS cohort (exploratory phase) were selected for replication in the Age, Gene/Environment Susceptibility (AGES) - Reykjavik Study. AGES participants were profiled using a custom 5K SomaScan platform. For proteins that replicated, two-sample Mendelian randomization was conducted to explore potential causal relationships with neuroimaging traits, global cognitive function, stroke, and AD. Results: A total of 48 proteins were associated with either FW or PSMD in FHS (N=1,106, 56% female, mean age=48 at protein profiling) at an uncorrected p-value < 0.01. Of these, six proteins were validated in AGES (N=2,586, 58% female, mean age=76) at p-value < 0.05/48: TFF3 (beta=0.015), LG3BP (beta=0.0089), and heparin cofactor II (HCII, beta=0.0097) showed positive associations with FW, while CCL28 was positively associated with PSMD (beta=0.01). Conversely, BMPR1A (beta=-0.016) and gelsolin (beta=-0.011) were negatively associated with PSMD, all with SE=0.002. Mendelian randomization analyses further suggested potential causal effects (p-value<0.05), including positive effects of HCII, LG3BP, and TFF3 on WMH; HCII on small vessel stroke; LG3BP on any stroke and ischemic stroke; and a negative effect of gelsolin on large artery stroke. Conclusions and Relevance: This cohort and Mendelian randomization study identified several proteins significantly associated with FW and PSMD, which are potential imaging biomarkers of ischemia, neuroinflammation, and axonal degeneration. Mendelian randomization analyses suggested potential causal effects of certain proteins on white matter hyperintensities and stroke, highlighting the need for functional studies to explore whether elevated protein levels represent protective mechanisms or contribute to brain injury.

A polygenic score (PGS) for Alzheimer’s disease (AD) was derived recently from data on genome-wide significant loci in European ancestry populations. We applied this PGS to populations in 17 European countries and observed a consistent association with the AD risk, age at onset and cerebrospinal fluid levels of AD biomarkers, independently of apolipoprotein E locus (APOE). This PGS was also associated with the AD risk in many other populations of diverse ancestries. A cross-ancestry polygenic risk score improved the association with the AD risk in most of the multiancestry populations tested when the APOE region was included. Finally, we found that the PGS/polygenic risk score captured AD-specific information because the association weakened as the diagnosis was broadened. In conclusion, a simple PGS captures the AD-specific genetic information that is common to populations of different ancestries, although studies of more diverse populations are still needed to better characterize the genetics of AD.

Study Objectives: Poor sleep may play a role in the risk of dementia. However, few studies have investigated the association between polysomnography (PSG)-derived sleep architecture and dementia incidence. We examined the relationship between sleep architecture and dementia incidence across five US-based cohort studies from the Sleep and Dementia Consortium. Methods: Percent of time spent in stages of sleep (N1, N2, N3, rapid eye movement sleep), wake after sleep onset, sleep maintenance efficiency, apnea-hypopnea index, and relative delta power were derived from a single night home-based PSG. Dementia was ascertained in each cohort using its cohort-specific criteria. Each cohort performed Cox proportional hazard regressions for each sleep exposure and incident dementia, adjusting for age, sex, body mass index, antidepressant use, sedative use, and APOE e4 status. Results were then pooled in a random effects model. Results: The pooled sample comprised 4657 participants (30% women) aged ≥ 60 years (mean age was 74 years at sleep assessment). There were 998 (21.4%) dementia cases (median follow-up time of 5 to 19 years). Pooled effects of the five cohorts showed no association between sleep architecture and incident dementia. When pooled analysis was restricted to the three cohorts which had dementia case ascertainment based on DSM-IV/V criteria (n = 2374), higher N3% was marginally associated with an increased risk of dementia (hazard ratio (HR): 1.06; 95%CI: 1.00-1.12, per percent increase N3, p = .050). Conclusions: There were no consistent associations between sleep architecture measured and the risk of incident dementia. Implementing more nuanced sleep metrics and examination of associations with dementia subtypes remains an important next step for uncovering more about sleep-dementia associations.

White matter hyperintensities index structural abnormalities in the cerebral white matter, including axonal damage. The latter may promote atrophy of the cerebral cortex, a key feature of dementia. Here, we report a study of 51,065 individuals from 10 cohorts demonstrating that higher white matter hyperintensity volume associates with lower cortical thickness. The meta-GWAS of white matter hyperintensities-associated cortical ‘atrophy’ identifies 20 genome-wide significant loci, and enrichment in genes specific to vascular cell types, astrocytes, and oligodendrocytes. White matter hyperintensities-associated cortical ‘atrophy’ showed positive genetic correlations with vascular-risk traits and plasma biomarkers of neurodegeneration, and negative genetic correlations with cognitive functioning. 15 of the 20 loci regulated the expression of 54 genes in the cerebral cortex that, together with their co-expressed genes, were enriched in biological processes of axonal cytoskeleton and intracellular transport. The white matter hyperintensities-cortical thickness associations were most pronounced in cortical regions with higher expression of genes specific to excitatory neurons with long-range axons traversing through the white matter. The meta-GWAS-based polygenic risk score predicts vascular and all-cause dementia in an independent sample of 500,348 individuals. Thus, the genetics of white matter hyperintensities-related cortical atrophy involves vascular and neuronal processes and increases dementia risk.

Greedy search (GS) or exhaustive search plays a crucial role in decision trees and their various extensions. We introduce an alternative splitting method called smooth sigmoid surrogate (SSS) in which the indicator threshold function used in GS is approximated by a smooth sigmoid function. This approach allows for parametric smoothing or regularization of the erratic and discrete GS process, making it more effective in identifying the true cutoff point, particularly in the presence of weak signals, as well as less prone to the inherent end-cut preference problem. Additionally, SSS provides a convenient means of evaluating the best split by referencing a parametric nonlinear model. Moreover, in many variants of recursive partitioning, SSS can be reformulated as a one-dimensional smooth optimization problem, rendering it computationally more efficient than GS. Extensive simulation studies and real data examples are provided to evaluate and demonstrate its effectiveness.

Neurofilament light chain (NfL) levels in circulation have been established as a sensitive biomarker of neuro-axonal damage across a range of neurodegenerative disorders. Elucidation of the genetic architecture of blood NfL levels could provide new insights into molecular mechanisms underlying neurodegenerative disorders. In this meta-analysis of genome-wide association studies (GWAS) of blood NfL levels from eleven cohorts of European ancestry, we identify two genome-wide significant loci at 16p12 (UMOD) and 17q24 (SLC39A11). We observe association of three loci at 1q43 (FMN2), 12q14, and 12q21 with blood NfL levels in the meta-analysis of African-American ancestry. In the trans-ethnic meta-analysis, we identify three additional genome-wide significant loci at 1p32 (FGGY), 6q14 (TBX18), and 4q21. In the post-GWAS analyses, we observe the association of higher NfL polygenic risk score with increased plasma levels of total-tau, Aβ-40, Aβ-42, and higher incidence of Alzheimer’s disease in the Rotterdam Study. Furthermore, Mendelian randomization analysis results suggest that a lower kidney function could cause higher blood NfL levels. This study uncovers multiple genetic loci of blood NfL levels, highlighting the genes related to molecular mechanism of neurodegeneration.