CO2 cerebrovascular reactivity measured with CBF-MRI in older individuals: Association with cognition, physical function, amyloid, and tau proteins.

Vascular pathology is the second leading cause of cognitive impairment and represents a major contributing factor in mixed dementia. However, biomarkers for vascular cognitive impairment and dementia (VCID) are under-developed. Here we aimed to investigate the potential role of CO2 Cerebrovascular Reactivity (CVR) measured with phase-contrast quantitative flow MRI in cognitive impairment and dementia. Forty-five (69 ± 7 years) impaired (37 mild-cognitive-impairment and 8 mild-dementia by syndromic diagnosis) and 22 cognitively-healthy-control (HC) participants were recruited and scanned on a 3 T MRI. Biomarkers of AD pathology were measured in cerebrospinal fluid. We found that CBF-CVR was lower (p = 0.027) in the impaired (mean±SE, 3.70 ± 0.15%/mmHg) relative to HC (4.28 ± 0.21%/mmHg). After adjusting for AD pathological markers (Aß42/40, total tau, and Aß42/p-tau181), higher CBF-CVR was associated with better cognitive performance, including Montreal Cognitive Assessment, MoCA (p = 0.001), composite cognitive score (p = 0.047), and language (p = 0.004). Higher CBF-CVR was also associated with better physical function, including gait-speed (p = 0.006) and time for five chair-stands (p = 0.049). CBF-CVR was additionally related to the Clinical-Dementia-Rating, CDR, including global CDR (p = 0.026) and CDR Sum-of-Boxes (p = 0.015). CBF-CVR was inversely associated with hemoglobin A1C level (p = 0.017). In summary, CBF-CVR measured with phase-contrast MRI shows associations with cognitive performance, physical function, and disease-severity, independent of AD pathological markers.

Molecular Signatures of Normal Pressure Hydrocephalus: A Largescale Proteomic Analysis of Cerebrospinal Fluid.

Given the persistent challenge of differentiating idiopathic Normal Pressure Hydrocephalus (iNPH) from similar clinical entities, we conducted an in-depth proteomic study of cerebrospinal fluid (CSF) in 28 shunt-responsive iNPH patients, 38 Mild Cognitive Impairment (MCI) due to Alzheimer's disease, and 49 healthy controls. Utilizing the Olink Explore 3072 panel, we identified distinct proteomic profiles in iNPH that highlight significant downregulation of synaptic markers and cell-cell adhesion proteins. Alongside vimentin and inflammatory markers upregulation, these results suggest ependymal layer and transependymal flow dysfunction. Moreover, downregulation of multiple proteins associated with congenital hydrocephalus (e.g., L1CAM, PCDH9, ISLR2, ADAMTSL2, and B4GAT1) points to a possible shared molecular foundation between congenital hydrocephalus and iNPH. Through orthogonal partial least squares discriminant analysis (OPLS-DA), a panel comprising 13 proteins has been identified as potential diagnostic biomarkers of iNPH, pending external validation. These findings offer novel insights into the pathophysiology of iNPH, with implications for improved diagnosis.

The HOPE4MCI study: A randomized double-blind assessment of AGB101 for the treatment of MCI due to AD.

INTRODUCTION: In addition to the accumulation of amyloid plaques and neurofibrillary tangles, the presence of excess neural activity is a pathological hallmark of Alzheimer's disease (AD) and a prognostic indicator for progression of AD pathology and clinical/cognitive worsening in mild cognitive impairment due to Alzheimer's disease (MCI due to AD). The HOPE4MCI clinical study tested the efficacy of a therapeutic with demonstrated ability to normalize heightened neural activity in the hippocampus in a randomized controlled trial of 78 weeks duration in patients with MCI due to AD. METHODS: One hundred and sixty-four participants were randomized to placebo (n = 83) or AGB101 (n = 81), an extended-release formulation of low dose (220 mg) levetiracetam. The primary endpoint was the change in Clinical Dementia Rating Scale Sum of Boxes score (CDR-SB) comparing follow up at 18 months to baseline. The goal of the primary efficacy analysis was to estimate the difference between the AGB101 and placebo arms in the mean change of the primary endpoint. RESULTS: The mean change in CDR-SB was estimated to be 1.12 (95% confidence interval [CI]: 0.66, 1.69) for the AGB101 arm and 1.22 (95% CI: 0.75, 1.78) for the placebo arm. The estimated difference between arms is -0.10 (95% CI: -0.85, 0.58), which was not statistically significant. In a prespecified analysis, the difference was -0.45 (95% CI: -1.43, 0.53) for ApoE-4 noncarriers and -0.10 (95% CI: -0.92, 0.72) for apolipoprotein E (ApoE)-4 carriers. DISCUSSION: The possibility that ApoE-4 carriers and noncarriers will respond differently to therapeutic intervention is consistent with recently reported findings from biologics and the present results show further testing of AGB101 in patients with MCI due to AD who are noncarriers of the ApoeE-4 allele is warranted. Conclusions from the HOPE4MCI study are limited primarily due to the small sample size and results can only be regarded as a guide to future research.

Genetic and Clinical Correlates of AI-Based Brain Aging Patterns in Cognitively Unimpaired Individuals.

Importance: Brain aging elicits complex neuroanatomical changes influenced by multiple age-related pathologies. Understanding the heterogeneity of structural brain changes in aging may provide insights into preclinical stages of neurodegenerative diseases. Objective: To derive subgroups with common patterns of variation in participants without diagnosed cognitive impairment (WODCI) in a data-driven manner and relate them to genetics, biomedical measures, and cognitive decline trajectories. Design, Setting, and Participants: Data acquisition for this cohort study was performed from 1999 to 2020. Data consolidation and harmonization were conducted from July 2017 to July 2021. Age-specific subgroups of structural brain measures were modeled in 4 decade-long intervals spanning ages 45 to 85 years using a deep learning, semisupervised clustering method leveraging generative adversarial networks. Data were analyzed from July 2021 to February 2023 and were drawn from the Imaging-Based Coordinate System for Aging and Neurodegenerative Diseases (iSTAGING) international consortium. Individuals WODCI at baseline spanning ages 45 to 85 years were included, with greater than 50 000 data time points. Exposures: Individuals WODCI at baseline scan. Main Outcomes and Measures: Three subgroups, consistent across decades, were identified within the WODCI population. Associations with genetics, cardiovascular risk factors (CVRFs), amyloid ß (Aß), and future cognitive decline were assessed. Results: In a sample of 27 402 individuals (mean [SD] age, 63.0 [8.3] years; 15 146 female [55%]) WODCI, 3 subgroups were identified in contrast with the reference group: a typical aging subgroup, A1, with a specific pattern of modest atrophy and white matter hyperintensity (WMH) load, and 2 accelerated aging subgroups, A2 and A3, with characteristics that were more distinct at age 65 years and older. A2 was associated with hypertension, WMH, and vascular disease-related genetic variants and was enriched for Aß positivity (ages ≥65 years) and apolipoprotein E (APOE) ε4 carriers. A3 showed severe, widespread atrophy, moderate presence of CVRFs, and greater cognitive decline. Genetic variants associated with A1 were protective for WMH (rs7209235: mean [SD] B = -0.07 [0.01]; P value = 2.31 × 10-9) and Alzheimer disease (rs72932727: mean [SD] B = 0.1 [0.02]; P value = 6.49 × 10-9), whereas the converse was observed for A2 (rs7209235: mean [SD] B = 0.1 [0.01]; P value = 1.73 × 10-15 and rs72932727: mean [SD] B = -0.09 [0.02]; P value = 4.05 × 10-7, respectively); variants in A3 were associated with regional atrophy (rs167684: mean [SD] B = 0.08 [0.01]; P value = 7.22 × 10-12) and white matter integrity measures (rs1636250: mean [SD] B = 0.06 [0.01]; P value = 4.90 × 10-7). Conclusions and Relevance: The 3 subgroups showed distinct associations with CVRFs, genetics, and subsequent cognitive decline. These subgroups likely reflect multiple underlying neuropathologic processes and affect susceptibility to Alzheimer disease, paving pathways toward patient stratification at early asymptomatic stages and promoting precision medicine in clinical trials and health care.

Gene-SGAN: discovering disease subtypes with imaging and genetic signatures via multi-view weakly-supervised deep clustering.

Disease heterogeneity has been a critical challenge for precision diagnosis and treatment, especially in neurologic and neuropsychiatric diseases. Many diseases can display multiple distinct brain phenotypes across individuals, potentially reflecting disease subtypes that can be captured using MRI and machine learning methods. However, biological interpretability and treatment relevance are limited if the derived subtypes are not associated with genetic drivers or susceptibility factors. Herein, we describe Gene-SGAN - a multi-view, weakly-supervised deep clustering method - which dissects disease heterogeneity by jointly considering phenotypic and genetic data, thereby conferring genetic correlations to the disease subtypes and associated endophenotypic signatures. We first validate the generalizability, interpretability, and robustness of Gene-SGAN in semi-synthetic experiments. We then demonstrate its application to real multi-site datasets from 28,858 individuals, deriving subtypes of Alzheimer's disease and brain endophenotypes associated with hypertension, from MRI and single nucleotide polymorphism data. Derived brain phenotypes displayed significant differences in neuroanatomical patterns, genetic determinants, biological and clinical biomarkers, indicating potentially distinct underlying neuropathologic processes, genetic drivers, and susceptibility factors. Overall, Gene-SGAN is broadly applicable to disease subtyping and endophenotype discovery, and is herein tested on disease-related, genetically-associated neuroimaging phenotypes.

Actigraphy Estimated Sleep Moderates the Relationship between Physical Activity and Cognition in Older Adults.

Background and Aims: Physical inactivity and poor sleep are common in older adults and may interact to contribute to age- and disease-related cognitive decline. However, prior work regarding the associations among physical activity, and cognition in older adults is primarily limited to subjective questionnaires that are susceptible to inaccuracies and recall bias. Therefore, this study examined whether objectively measured physical activity and sleep characteristics, each estimated using actigraphy, are independently or interactively associated with cognitive performance. Methods: The study included 157 older adults free of dementia (136 cognitively unimpaired; 21 MCI; M age = 71.7) from the BIOCARD cohort. Results: Using multiple linear regression, cognition was regressed on estimated total volume of physical activity (TVPA), sleep efficiency (SE), wake after sleep onset (WASO), and total sleep time (TST) (adjusted for age, sex, education, diagnosis, vascular risk factors, and Apolipoprotein E (APOE)-e4 genetic status). Models were also run for domain-specific cognitive composite scores. TVPA and SE each were positively associated with a global cognitive composite score. TVPA was positively associated with executive function and language composites, and SE was positively related to executive function, visuospatial, and language composites. Importantly, a TVPA by SE interaction (p = 0.015) suggested that adults with the poorest SE experienced the greatest benefit from physical activity in relation to global cognition. The other sleep metrics were unrelated to cognitive performance. Conclusion: These results suggest that TVPA and SE may synergistically benefit cognition in older adults.

Differential methylation analysis in neuropathologically confirmed dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is a common form of dementia in the elderly population. We performed genome-wide DNA methylation mapping of cerebellar tissue from pathologically confirmed DLB cases and controls to study the epigenetic profile of this understudied disease. After quality control filtering, 728,197 CpG-sites in 278 cases and 172 controls were available for the analysis. We undertook an epigenome-wide association study, which found a differential methylation signature in DLB cases. Our analysis identified seven differentially methylated probes and three regions associated with DLB. The most significant CpGs were located in ARSB (cg16086807), LINC00173 (cg18800161), and MGRN1 (cg16250093). Functional enrichment evaluations found widespread epigenetic dysregulation in genes associated with neuron-to-neuron synapse, postsynaptic specialization, postsynaptic density, and CTCF-mediated synaptic plasticity. In conclusion, our study highlights the potential importance of epigenetic alterations in the pathogenesis of DLB and provides insights into the modified genes, regions and pathways that may guide therapeutic developments.

Automatic Rejection based on Tissue Signal (ARTS) for motion-corrected quantification of cerebral venous oxygenation in neonates and older adults.

OBJECTIVE: Cerebral venous oxygenation (Yv) is a key parameter for the brain's oxygen utilization and has been suggested to be a valuable biomarker in various brain diseases including hypoxic ischemic encephalopathy in neonates and Alzheimer's disease in older adults. T2-Relaxation-Under-Spin-Tagging (TRUST) MRI is a widely used technique to measure global Yv level and has been validated against gold-standard PET. However, subject motion during TRUST MRI scan can introduce considerable errors in Yv quantification, especially for noncompliant subjects. The aim of this study was to develop an Automatic Rejection based on Tissue Signal (ARTS) algorithm for automatic detection and exclusion of motion-contaminated images to improve the precision of Yv quantification. METHODS: TRUST MRI data were collected from a neonatal cohort (N = 37, 16 females, gestational age = 39.12 ± 1.11 weeks, postnatal age = 1.89 ± 0.74 days) and an older adult cohort (N = 223, 134 females, age = 68.02 ± 9.01 years). Manual identification of motion-corrupted images was conducted for both cohorts to serve as a gold-standard. 9.3% of the images in the neonatal datasets and 0.4% of the images in the older adult datasets were manually identified as motion-contaminated. The ARTS algorithm was trained using the neonatal datasets. TRUST Yv values, as well as the estimation uncertainty (ΔR2) and test-retest coefficient-of-variation (CoV) of Yv, were calculated with and without ARTS motion exclusion. The ARTS algorithm was tested on datasets of older adults: first on the original adult datasets with little motion, and then on simulated adult datasets where the percentage of motion-corrupted images matched that of the neonatal datasets. RESULTS: In the neonatal datasets, the ARTS algorithm exhibited a sensitivity of 0.95 and a specificity of 0.97 in detecting motion-contaminated images. Compared to no motion exclusion, ARTS significantly reduced the ΔR2 (median = 3.68 Hz vs. 4.89 Hz, P = 0.0002) and CoV (median = 2.57% vs. 6.87%, P = 0.0005) of Yv measurements. In the original older adult datasets, the sensitivity and specificity of ARTS were 0.70 and 1.00, respectively. In the simulated adult datasets, ARTS demonstrated a sensitivity of 0.91 and a specificity of 1.00. Additionally, ARTS significantly reduced the ΔR2 compared to no motion exclusion (median = 2.15 Hz vs. 3.54 Hz, P < 0.0001). CONCLUSION: ARTS can improve the reliability of Yv estimation in noncompliant subjects, which may enhance the utility of Yv as a biomarker for brain diseases.

Walking energetics and white matter hyperintensities in mid-to-late adulthood.

INTRODUCTION: White matter hyperintensities (WMHs) increase with age and contribute to cognitive and motor function decline. Energy costs for mobility worsen with age, as the energetic cost of walking increases and energetic capacity declines. We examined the cross-sectional associations of multiple measures of walking energetics with WMHs in mid- to late-aged adults. METHODS: A total of 601 cognitively unimpaired adults (mean age 66.9 ± 15.3 years, 54% women) underwent brain magnetic resonance imaging scans and completed standardized slow- and peak-paced walking assessments with metabolic measurement (V̇O2). T1-weighted scans and fluid-attenuated inversion recovery images were used to quantify WMHs. Separate multivariable linear regression models examined associations adjusted for covariates. RESULTS: Lower slow-paced V̇O2 (B = 0.07; P = 0.030), higher peak-paced V̇O2 (B = -0.10; P = 0.007), and lower cost-to-capacity ratio (B = .12; P < 0.0001) were all associated with lower WMH volumes. DISCUSSION: The cost-to-capacity ratio, which describes the percentage of capacity required for ambulation, was the walking energetic measure most strongly associated with WMHs.

Multi-Site Cross-Site Inter-Rater and Test-Retest Reliability and Construct Validity of the MarkVCID White Matter Hyperintensity Growth and Regression Protocol.

BACKGROUND: White matter hyperintensities (WMH) that occur in the setting of vascular cognitive impairment and dementia (VCID) may be dynamic increasing or decreasing volumes or stable over time. Quantifying such changes may prove useful as a biomarker for clinical trials designed to address vascular cognitive-impairment and dementia and Alzheimer's Disease. OBJECTIVE: Conducting multi-site cross-site inter-rater and test-retest reliability of the MarkVCID white matter hyperintensity growth and regression protocol. METHODS: The NINDS-supported MarkVCID Consortium evaluated a neuroimaging biomarker developed to track WMH change. Test-retest and cross-site inter-rater reliability of the protocol were assessed. Cognitive test scores were analyzed in relation to WMH changes to explore its construct validity. RESULTS: ICC values for test-retest reliability of WMH growth and regression were 0.969 and 0.937 respectively, while for cross-site inter-rater ICC values for WMH growth and regression were 0.995 and 0.990 respectively. Word list long-delay free-recall was negatively associated with WMH growth (p < 0.028) but was not associated with WMH regression. CONCLUSIONS: The present data demonstrate robust ICC validity of a WMH growth/regression protocol over a one-year period as measured by cross-site inter-rater and test-retest reliability. These data suggest that this approach may serve an important role in clinical trials of disease-modifying agents for VCID that may preferentially affect WMH growth, stability, or regression.

Cerebrospinal Fluid Alzheimer's Disease Biomarker Patterns of Change Prior to the Onset of Mild Cognitive Impairment.

BACKGROUND: Cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) are altered many years before the onset of clinical symptoms of mild cognitive impairment (MCI). Incorporating clinical symptom onset time into biomarker modeling may enhance our understanding of changes preceding MCI. OBJECTIVE: Using a new analytical approach, we examined patterns of biomarker change prior to MCI symptom onset among individuals who progressed from normal cognition to MCI, stratified based on the age of symptom onset. We also analyzed biomarker patterns of change among participants who remained cognitively normal, and examined potential modifiers of biomarker trajectories, including demographics and apolipoprotein E (APOE) status. METHODS: Analyses included 93 participants who progressed from normal cognition to MCI and 186 participants who remained cognitively normal, over an average follow-up period of 16.2 years. CSF biomarkers, including Aß42, Aß40, total tau (t-tau), and phosphorylated tau181 (p-tau181), were measured using the fully automated Lumipulse assays. RESULTS: Among participants who progressed to MCI, Aß42/Aß40 decreased, and t-tau and p-tau181 increased. For participants who did not progress to MCI, CSF biomarkers showed relatively stable patterns. In both progressors and non-progressors, APOE4 carriers showed lower Aß 42/Aß40 levels (compared to non-carriers) at each point of the mean curves. Among non-progressors, APOE4 carriers had higher levels of p-tau181, p-tau181/(Aß 42/Aß40), and t-tau/(Aß 42/Aß 40). Additionally, among those who did not progress, female sex was associated with higher levels of t-tau, p-tau181, t-tau/(Aß 42/Aß 40), and p-tau181/(Aß 42/Aß 40). CONCLUSIONS: These findings suggest that this analytic approach may provide additional insights into biomarker changes during early phases of AD.

Exploratory Assessment of Proteomic Network Changes in Cerebrospinal Fluid of Mild Cognitive Impairment Patients: A Pilot Study.

(1) Background: Despite the existence of well-established, CSF-based biomarkers such as amyloid-ß and phosphorylated-tau, the pathways involved in the pathophysiology of Alzheimer's disease (AD) remain an active area of research. (2) Methods: We measured 3072 proteins in CSF samples of AD-biomarker positive mild cognitive impairment (MCI) participants (n = 38) and controls (n = 48), using the Explore panel of the Olink proximity extension assay (PEA). We performed group comparisons, association studies with diagnosis, age, and APOE ε4 status, overrepresentation analysis (ORA), and gene set enrichment analysis (GSEA) to determine differentially expressed proteins and dysregulated pathways. (3) Results: GSEA results demonstrated an enrichment of granulocyte-related and chemotactic pathways (core enrichment proteins: ITGB2, ITGAM, ICAM1, SELL, SELP, C5, IL1A). Moreover, some of the well-replicated, differentially expressed proteins in CSF included: ITGAM, ITGB2, C1QA, TREM2, GFAP, NEFL, MMP-10, and a novel tau-related marker, SCRN1. (4) Conclusion: Our results highlight the upregulation of neuroinflammatory pathways, especially chemotactic and granulocyte recruitment in CSF of early AD patients.

Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies LRRC4C, LHX5-AS1 and nominates ancestry-specific loci PTPRK , GRB14 , and KIAA0825 as novel risk loci for Alzheimer's disease: the Alzheimer's Disease Genetics Consortium.

Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in non-European ancestry groups in genome-wide association studies (GWAS). We constructed and analyzed a multi-ancestry GWAS dataset in the Alzheimer's Disease (AD) Genetics Consortium (ADGC) to test for novel shared and ancestry-specific AD susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6,728 African American, 8,899 Hispanic (HIS), and 3,232 East Asian individuals, performing within-ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. We identified 13 loci with cross-ancestry associations including known loci at/near CR1 , BIN1 , TREM2 , CD2AP , PTK2B , CLU , SHARPIN , MS4A6A , PICALM , ABCA7 , APOE and two novel loci not previously reported at 11p12 ( LRRC4C ) and 12q24.13 ( LHX5-AS1 ). Reflecting the power of diverse ancestry in GWAS, we observed the SHARPIN locus using 7.1% the sample size of the original discovering single-ancestry GWAS (n=788,989). We additionally identified three GWS ancestry-specific loci at/near ( PTPRK ( P =2.4×10 -8 ) and GRB14 ( P =1.7×10 -8 ) in HIS), and KIAA0825 ( P =2.9×10 -8 in NHW). Pathway analysis implicated multiple amyloid regulation pathways (strongest with P adjusted =1.6×10 -4 ) and the classical complement pathway ( P adjusted =1.3×10 -3 ). Genes at/near our novel loci have known roles in neuronal development ( LRRC4C, LHX5-AS1 , and PTPRK ) and insulin receptor activity regulation ( GRB14 ). These findings provide compelling support for using traditionally-underrepresented populations for gene discovery, even with smaller sample sizes.

Hearing intervention versus health education control to reduce cognitive decline in older adults with hearing loss in the USA (ACHIEVE): a multicentre, randomised controlled trial.

BACKGROUND: Hearing loss is associated with increased cognitive decline and incident dementia in older adults. We aimed to investigate whether a hearing intervention could reduce cognitive decline in cognitively healthy older adults with hearing loss. METHODS: The ACHIEVE study is a multicentre, parallel-group, unmasked, randomised controlled trial of adults aged 70-84 years with untreated hearing loss and without substantial cognitive impairment that took place at four community study sites across the USA. Participants were recruited from two study populations at each site: (1) older adults participating in a long-standing observational study of cardiovascular health (Atherosclerosis Risk in Communities [ARIC] study), and (2) healthy de novo community volunteers. Participants were randomly assigned (1:1) to a hearing intervention (audiological counselling and provision of hearing aids) or a control intervention of health education (individual sessions with a health educator covering topics on chronic disease prevention) and followed up every 6 months. The primary endpoint was 3-year change in a global cognition standardised factor score from a comprehensive neurocognitive battery. Analysis was by intention to treat. This trial was registered at ClinicalTrials.gov, NCT03243422. FINDINGS: From Nov 9, 2017, to Oct 25, 2019, we screened 3004 participants for eligibility and randomly assigned 977 (32·5%; 238 [24%] from ARIC and 739 [76%] de novo). We randomly assigned 490 (50%) to the hearing intervention and 487 (50%) to the health education control. The cohort had a mean age of 76·8 years (SD 4·0), 523 (54%) were female, 454 (46%) were male, and most were White (n=858 [88%]). Participants from ARIC were older, had more risk factors for cognitive decline, and had lower baseline cognitive scores than those in the de novo cohort. In the primary analysis combining the ARIC and de novo cohorts, 3-year cognitive change (in SD units) was not significantly different between the hearing intervention and health education control groups (-0·200 [95% CI -0·256 to -0·144] in the hearing intervention group and -0·202 [-0·258 to -0·145] in the control group; difference 0·002 [-0·077 to 0·081]; p=0·96). However, a prespecified sensitivity analysis showed a significant difference in the effect of the hearing intervention on 3-year cognitive change between the ARIC and de novo cohorts (pinteraction=0·010). Other prespecified sensitivity analyses that varied analytical parameters used in the total cohort did not change the observed results. No significant adverse events attributed to the study were reported with either the hearing intervention or health education control. INTERPRETATION: The hearing intervention did not reduce 3-year cognitive decline in the primary analysis of the total cohort. However, a prespecified sensitivity analysis showed that the effect differed between the two study populations that comprised the cohort. These findings suggest that a hearing intervention might reduce cognitive change over 3 years in populations of older adults at increased risk for cognitive decline but not in populations at decreased risk for cognitive decline. FUNDING: US National Institutes of Health.

NPTX2 in Cerebrospinal Fluid Predicts the Progression From Normal Cognition to Mild Cognitive Impairment.

OBJECTIVE: This study examined whether cerebrospinal fluid (CSF) baseline levels of the synaptic protein NPTX2 predict time to onset of symptoms of mild cognitive impairment (MCI), both alone and when accounting for traditional CSF Alzheimer's disease (AD) biomarker levels. Longitudinal NPTX2 levels were also examined. METHODS: CSF was collected longitudinally from 269 cognitively normal BIOCARD Study participants (mean baseline age = 57.7 years; mean follow-up = 16.3 years; n = 77 progressed to MCI/dementia). NPTX2 levels were measured from 3 correlated peptides using quantitative parallel reaction monitoring mass spectrometry. Levels of Aß42 /Aß40 , p-tau181 , and t-tau were measured from the same CSF specimens using Lumipulse automated electrochemiluminescence assays. RESULTS: In Cox regression models, lower baseline NPTX2 levels were associated with an earlier time to MCI symptom onset (hazard ratio [HR] = 0.76, SE = 0.09, p = 0.023). This association was significant for progression within 7 years (p = 0.036) and after 7 years from baseline (p = 0.001). Baseline NPTX2 levels improved prediction of time to MCI symptom onset after accounting for baseline AD biomarker levels (p < 0.01), and NPTX2 did not interact with the CSF AD biomarkers or APOE-ε4 genetic status. In linear mixed effects models, higher baseline p-tau181 and t-tau levels were associated with higher baseline levels of NPTX2 (both p < 0.001) and greater rates of NPTX2 declines over time. INTERPRETATION: NPTX2 may be a valuable prognostic biomarker during preclinical AD that provides additive and independent prediction of MCI onset among individuals who are cognitively normal. We hypothesize that NPTX2-mediated circuit homeostasis confers resilience during the early phase of AD. ANN NEUROL 2023;94:620-631.

Genome-wide structural variant analysis identifies risk loci for non-Alzheimer's dementias.

We characterized the role of structural variants, a largely unexplored type of genetic variation, in two non-Alzheimer's dementias, namely Lewy body dementia (LBD) and frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS). To do this, we applied an advanced structural variant calling pipeline (GATK-SV) to short-read whole-genome sequence data from 5,213 European-ancestry cases and 4,132 controls. We discovered, replicated, and validated a deletion in TPCN1 as a novel risk locus for LBD and detected the known structural variants at the C9orf72 and MAPT loci as associated with FTD/ALS. We also identified rare pathogenic structural variants in both LBD and FTD/ALS. Finally, we assembled a catalog of structural variants that can be mined for new insights into the pathogenesis of these understudied forms of dementia.

Alzheimer's disease genetic risk and cognitive reserve in relationship to long-term cognitive trajectories among cognitively normal individuals.

BACKGROUND: Both Alzheimer's disease (AD) genetic risk factors and indices of cognitive reserve (CR) influence risk of cognitive decline, but it remains unclear whether they interact. This study examined whether a CR index score modifies the relationship between AD genetic risk factors and long-term cognitive trajectories in a large sample of individuals with normal cognition. METHODS: Analyses used data from the Preclinical AD Consortium, including harmonized data from 5 longitudinal cohort studies. Participants were cognitively normal at baseline (M baseline age = 64 years, 59% female) and underwent 10 years of follow-up, on average. AD genetic risk was measured by (i) apolipoprotein-E (APOE) genetic status (APOE-ε2 and APOE-ε4 vs. APOE-ε3; N = 1819) and (ii) AD polygenic risk scores (AD-PRS; N = 1175). A CR index was calculated by combining years of education and literacy scores. Longitudinal cognitive performance was measured by harmonized factor scores for global cognition, episodic memory, and executive function. RESULTS: In mixed-effects models, higher CR index scores were associated with better baseline cognitive performance for all cognitive outcomes. APOE-ε4 genotype and AD-PRS that included the APOE region (AD-PRSAPOE) were associated with declines in all cognitive domains, whereas AD-PRS that excluded the APOE region (AD-PRSw/oAPOE) was associated with declines in executive function and global cognition, but not memory. There were significant 3-way CR index score × APOE-ε4 × time interactions for the global (p = 0.04, effect size = 0.16) and memory scores (p = 0.01, effect size = 0.22), indicating the negative effect of APOE-ε4 genotype on global and episodic memory score change was attenuated among individuals with higher CR index scores. In contrast, levels of CR did not attenuate APOE-ε4-related declines in executive function or declines associated with higher AD-PRS. APOE-ε2 genotype was unrelated to cognition. CONCLUSIONS: These results suggest that APOE-ε4 and non-APOE-ε4 AD polygenic risk are independently associated with global cognitive and executive function declines among individuals with normal cognition at baseline, but only APOE-ε4 is associated with declines in episodic memory. Importantly, higher levels of CR may mitigate APOE-ε4-related declines in some cognitive domains. Future research is needed to address study limitations, including generalizability due to cohort demographic characteristics.

Early amygdala and ERC atrophy linked to 3D reconstruction of rostral neurofibrillary tau tangle pathology in Alzheimer's disease.

Previous research has emphasized the unique impact of Alzheimer's Disease (AD) pathology on the medial temporal lobe (MTL), a reflection that tau pathology is particularly striking in the entorhinal and transentorhinal cortex (ERC, TEC) early in the course of disease. However, other brain regions are affected by AD pathology during its early phases. Here, we use longitudinal diffeomorphometry to measure the atrophy rate from MRI of the amygdala compared with that in the ERC and TEC in cognitively unimpaired (CU) controls, CU individuals who progressed to mild cognitive impairment (MCI), and individuals with MCI who progressed to dementia of the AD type (DAT), using a dataset from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Our results show significantly higher atrophy rates of the amygdala in both groups of 'converters' (CU→MCI, MCI→DAT) compared to controls, with rates of volume loss comparable to rates of thickness loss in the ERC and TEC. We localize atrophy within the amygdala within each of these groups using fixed effects modeling. Controlling for the familywise error rate highlights the medial regions of the amygdala as those with significantly higher atrophy in both groups of converters than in controls. Using our recently developed method, referred to as Projective LDDMM, we map measures of neurofibrillary tau tangles (NFTs) from digital pathology to MRI atlases and reconstruct dense 3D spatial distributions of NFT density within regions of the MTL. The distribution of NFTs is consistent with the spatial distribution of MR measured atrophy rates, revealing high densities (and atrophy) in the amygdala (particularly medial), ERC, and rostral third of the MTL. The similarity of the location of NFTs in AD and shape changes in a well-defined clinical population suggests that amygdalar atrophy rate, as measured through MRI may be a viable biomarker for AD.

Test-retest reliability of 3D velocity-selective arterial spin labeling for detecting normal variations of cerebral blood flow.

Velocity-selective inversion (VSI) based velocity-selective arterial spin labeling (VSASL) has been developed to measure cerebral blood flow (CBF) with low susceptibility to the prolonged arterial transit time and high sensitivity to brain perfusion signal. The purpose of this magnetic resonance imaging study is to evaluate the test-retest reliability of a VSI-prepared 3D VSASL protocol with whole-brain coverage to detect baseline CBF variations among cognitively normal participants in different brain regions. Coefficients of variation (CoV) of both absolute and relative CBF across scans or sessions, subjects, and gray matter regions were calculated, and corresponding intraclass correlation coefficients (ICC) were computed. The higher between-subject CoV of absolute CBF (13.4 ± 2.0%) over within-subject CoV (within-session: 3.8 ± 1.1%; between-session: 4.9 ± 0.9%) yielded moderate to excellent ICC (within-session: 0.88±0.08; between-session: 0.77±0.14) to detect normal variations of individual CBF. The higher between-region CoV of relative CBF (11.4 ± 3.0%) over within-region CoV (within-session: 2.3 ± 0.9%; between-session: 3.3 ± 1.0%) yielded excellent ICC (within-session: 0.92±0.06; between-session: 0.85±0.12) to detect normal variations of regional CBF. Age, blood pressure, end-tidal CO2, and hematocrit partially explained the variability of CBF across subjects. Together these results show excellent test-retest reliability of VSASL to detect both between-subject and between-region variations supporting its clinical utility.

Regional White Matter Hyperintensities and Alzheimer's Disease Biomarkers Among Older Adults with Normal Cognition and Mild Cognitive Impairment.

BACKGROUND: Alzheimer's disease (AD) frequently co-occurs with other brain pathologies. Recent studies suggest there may be a mechanistic link between AD and small vessel cerebrovascular disease (CVD), as opposed to simply the overlap of two disorders. OBJECTIVE: We investigated the cross-sectional relationship between white matter hyperintensity (WMH) volumes (markers of CVD) and cerebrospinal fluid (CSF) biomarkers of AD. METHODS: WMH volumes were assessed globally and regionally (i.e., frontal, parietal, temporal, occipital, and limbic). CSF AD biomarkers (i.e., Aß 40, Aß 42, Aß 42/Aß 40 ratio, phosphorylated tau-181 [p-tau181], and total tau [t-tau]) were measured among 152 non-demented individuals (134 cognitively unimpaired and 18 with mild cognitive impairment (MCI)). RESULTS: Linear regression models showed that among all subjects, higher temporal WHM volumes were associated with AD biomarkers (higher levels of p-tau181, t-tau, and Aß 40), particularly among APOE ɛ 4 carriers (independent of Aß 42 levels). Higher vascular risk scores were associated with greater parietal and frontal WMH volumes (independent of CSF AD biomarker levels). Among subjects with MCI only, parietal WMH volumes were associated with a lower level of Aß 42/Aß 40. In addition, there was an association between higher global WMH volumes and higher CSF t-tau levels among younger participants versus older ones (∼<65 versus 65+ years), independent of Aß 42/Aß 40 and p-tau181. CONCLUSION: These findings suggest that although WMH are primarily related to systemic vascular risk and neurodegeneration (i.e., t-tau), AD-specific pathways may contribute to the formation of WMH in a regionally-specific manner, with neurofibrillary tangles (i.e., p-tau) playing a role in temporal WMHs and amyloid (i.e., Aß 42/Aß 40) in parietal WMHs.