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Background: Brain ageing is highly heterogeneous, as it is driven by a variety of normal and neuropathological processes. These processes may differentially affect structural and functional brain ageing across individuals, with more pronounced ageing (older brain age) during midlife being indicative of later development of dementia. Here, we examined whether brain-ageing heterogeneity in unimpaired older adults related to neurodegeneration, different cognitive trajectories, genetic and amyloid-beta (Aβ) profiles, and to predicted progression to Alzheimer's disease (AD)., Methods: Functional and structural brain age measures were obtained for resting-state functional MRI and structural MRI, respectively, in 3460 cognitively normal individuals across an age range spanning 42-85 years. Participants were categorised into four groups based on the difference between their chronological and predicted age in each modality: advanced age in both (n = 291), resilient in both (n = 260) or advanced in one/resilient in the other (n = 163/153). With the resilient group as the reference, brain-age groups were compared across neuroimaging features of neuropathology (white matter hyperintensity volume, neuronal loss measured with Neurite Orientation Dispersion and Density Imaging, AD-specific atrophy patterns measured with the Spatial Patterns of Abnormality for Recognition of Early Alzheimer's Disease index, amyloid burden using amyloid positron emission tomography (PET), progression to mild cognitive impairment and baseline and longitudinal cognitive measures (trail making task, mini mental state examination, digit symbol substitution task)., Findings: Individuals with advanced structural and functional brain-ages had more features indicative of neurodegeneration and they had poor cognition. Individuals with a resilient brain-age in both modalities had a genetic variant that has been shown to be associated with age of onset of AD. Mixed brain-age was associated with selective cognitive deficits., Interpretation: The advanced group displayed evidence of increased atrophy across all neuroimaging features that was not found in either of the mixed groups. This is in line with biomarkers of preclinical AD and cerebrovascular disease. These findings suggest that the variation in structural and functional brain ageing across individuals reflects the degree of underlying neuropathological processes and may indicate the propensity to develop dementia in later life., Funding: The National Institute on Aging, the National Institutes of Health, the Swiss National Science Foundation, the Kaiser Foundation Research Institute and the National Heart, Lung, and Blood Institute., Competing Interests: Declaration of interests TB has received investigator-initiated research awards from the NIH, the Alzheimer’s Association, the Foundation at Barnes-Jewish Hospital, Siemens Healthineers, Hyperfine and Avid Radiopharmaceuticals (a wholly-owned subsidiary of Eli Lilly and Company). She participates as a site investigator in clinical trials sponsored by Eli Lilly and Company, Biogen, Eisai, Jaansen, and Roche. She has served as a paid and unpaid consultant to Eisai, Siemens, Biogen, Janssen, Hyperfine, Merck Lilly, and Bristol-Myers Squibb. JCM has served as a paid consultant to the Barcelona Brain Research Center and the Native Alzheimer Disease-related Resource Center in Minority Aging Research. He also received payments for presentations at the AAIM meeting, Longer Life Foundation and the International Brain Health Symposium. JCM has received travel support to attend meetings including: AAIM, DIAN, AD/PD, ATRI/ADNI, ADRC, ADC, the International conference on Health Aging & Biomarkers and the International Brain Health Symposium. He has served on the advisory board for the Cure Alzheimer’s Fund and LEADS at Indiana University. IMN has received payments from Premier, Inc for participating in an advisory board, from Peerview for an educational talk, and from Subtle Medical, Inc for consulting. DW has served as a paid consultant to Qynapse, Beckman Coulter and Eli Lilly. He also received grants from the NIH and Biogen paid to his institution and received travel support from the Alzheimer's Association. SR is an NIA IRP employee and has served on the advisory board of Dementia Platforms, UK, the Canadian Consortium on Neurodegeneration in Aging and the Adult Aging Brain Connectome. She has received travel support from the McKnight Foundation to attend an annual meeting., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Anti-amyloid antibody therapies such as lecanemab are increasingly being used to treat Alzheimer's disease (AD). These therapies are associated with a high rate of amyloid-related imaging abnormalities (ARIA)., Methods: We review the case history of a patient who developed ARIA associated with lecanemab treatment., Results: In addition to microhemorrhages and cerebral edema that are recognized features of ARIA, the patient developed several ischemic strokes. The patient also experienced frequent electrographic seizures without overt clinical seizures. The patient demonstrated clinical and radiographic improvement after steroid treatment., Discussion: Our case suggests that ischemic strokes may be a feature of ARIA and highlights the importance of having a high clinical suspicion for seizures in ARIA. As anti-amyloid therapies are likely going to be increasingly used to treat AD, it is important to appreciate the spectrum of clinical and radiographic findings that can result as side effects from this class of therapies., Highlights: We report a patient who developed severe amyloid-related imaging abnormalities (ARIA) after treatment with lecanemab. Our report suggests that ischemic strokes may be a novel imaging feature of ARIA. Our report highlights the need for high clinical suspicion for seizures in ARIA., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Study Objectives: Obstructive sleep apnea (OSA) is associated with cognitive impairment; however, the underlying mechanisms remain incompletely understood. OSA is characterized by periods of interrupted ventilation ("ventilatory burden (VB)"), leading to hypoxemia ("hypoxic burden (HB)") and/or arousal ("arousal burden (AB)") from sleep. While hypoxemia is considered a key mechanism underlying white matter injury, its measurement has been limited. In our primary analysis, we assessed the association of HB, a quantitative measure of hypoxemia, with white matter hyperintensity volume (WMH v ), a marker of small vessel disease, and compared with that of VB and AB (quantitative measures of ventilatory deficit and arousals)., Methods: Data from participants in the Multi-Ethnic Study of Atherosclerosis with full polysomnograms (PSG) and brain MRI were analyzed. HB was defined as the total area under the oxygen desaturation curve per hour of sleep, while VB was defined as the event-specific area under the ventilation signal and AB was defined as the normalized cumulative duration of all arousals. The primary outcome was WMH v , with other MRI measures considered secondary outcomes., Results: The analysis included PSGs from 587 participants (age: 65.5±8.2 years). In the fully adjusted model, each 1 standard deviation (SD) increase in HB was associated with a 0.09 SD increase in WMH v (p=0.023), after adjusting for demographics, study site, and comorbidities. In contrast, VB, AB, and conventional OSA measures were not associated with outcomes., Conclusions: Hypoxic burden was associated with white matter hyperintensity volume in a racially/ethnically diverse cohort of older individuals with a high prevalence of OSA., (© 2024 American Academy of Sleep Medicine.)

Alzheimer's disease (AD) is associated with heterogeneous atrophy patterns. We employed a semi-supervised representation learning technique known as Surreal-GAN, through which we identified two latent dimensional representations of brain atrophy in symptomatic mild cognitive impairment (MCI) and AD patients: the "diffuse-AD" (R1) dimension shows widespread brain atrophy, and the "MTL-AD" (R2) dimension displays focal medial temporal lobe (MTL) atrophy. Critically, only R2 was associated with widely known sporadic AD genetic risk factors (e.g., APOE ε4) in MCI and AD patients at baseline. We then independently detected the presence of the two dimensions in the early stages by deploying the trained model in the general population and two cognitively unimpaired cohorts of asymptomatic participants. In the general population, genome-wide association studies found 77 genes unrelated to APOE differentially associated with R1 and R2. Functional analyses revealed that these genes were overrepresented in differentially expressed gene sets in organs beyond the brain (R1 and R2), including the heart (R1) and the pituitary gland, muscle, and kidney (R2). These genes were enriched in biological pathways implicated in dendritic cells (R2), macrophage functions (R1), and cancer (R1 and R2). Several of them were "druggable genes" for cancer (R1), inflammation (R1), cardiovascular diseases (R1), and diseases of the nervous system (R2). The longitudinal progression showed that APOE ε4, amyloid, and tau were associated with R2 at early asymptomatic stages, but this longitudinal association occurs only at late symptomatic stages in R1. Our findings deepen our understanding of the multifaceted pathogenesis of AD beyond the brain. In early asymptomatic stages, the two dimensions are associated with diverse pathological mechanisms, including cardiovascular diseases, inflammation, and hormonal dysfunction-driven by genes different from APOE-which may collectively contribute to the early pathogenesis of AD. All results are publicly available at https://labs-laboratory.com/medicine/ ., (© 2024. The Author(s).)

Brain aging process is influenced by various lifestyle, environmental and genetic factors, as well as by age-related and often coexisting pathologies. Magnetic resonance imaging and artificial intelligence methods have been instrumental in understanding neuroanatomical changes that occur during aging. Large, diverse population studies enable identifying comprehensive and representative brain change patterns resulting from distinct but overlapping pathological and biological factors, revealing intersections and heterogeneity in affected brain regions and clinical phenotypes. Herein, we leverage a state-of-the-art deep-representation learning method, Surreal-GAN, and present methodological advances and extensive experimental results elucidating brain aging heterogeneity in a cohort of 49,482 individuals from 11 studies. Five dominant patterns of brain atrophy were identified and quantified for each individual by respective measures, R-indices. Their associations with biomedical, lifestyle and genetic factors provide insights into the etiology of observed variances, suggesting their potential as brain endophenotypes for genetic and lifestyle risks. Furthermore, baseline R-indices predict disease progression and mortality, capturing early changes as supplementary prognostic markers. These R-indices establish a dimensional approach to measuring aging trajectories and related brain changes. They hold promise for precise diagnostics, especially at preclinical stages, facilitating personalized patient management and targeted clinical trial recruitment based on specific brain endophenotypic expression and prognosis., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: To evaluate associations between plasma biomarkers of brain injury and MRI and cognitive measures in participants with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study., Research Design and Methods: Plasma amyloid-β-40, amyloid-β-42, neurofilament light chain (NfL), phosphorylated Tau-181 (pTau-181), and glial fibrillary acidic protein (GFAP) were measured in 373 adults who participated in the DCCT/EDIC study. MRI assessments included total brain and white matter hyperintensity volumes, white matter mean fractional anisotropy, and indices of Alzheimer disease (AD)-like atrophy and predicted brain age. Cognitive measures included memory and psychomotor and mental efficiency tests and assessments of cognitive impairment., Results: Participants were 60 (range 44-74) years old with 38 (30-51) years' T1D duration. Higher NfL was associated with an increase in predicted brain age (0.51 years per 20% increase in NfL; P < 0.001) and a 19.5% increase in the odds of impaired cognition (P < 0.01). Higher NfL and pTau-181 were associated with lower psychomotor and mental efficiency (P < 0.001) but not poorer memory. Amyloid-β measures were not associated with study measures. A 1% increase in mean HbA1c was associated with a 14.6% higher NfL and 12.8% higher pTau-181 (P < 0.0001)., Conclusions: In this aging T1D cohort, biomarkers of brain injury did not demonstrate an AD-like profile. NfL emerged as a biomarker of interest in T1D because of its association with higher HbA1c, accelerated brain aging on MRI, and cognitive dysfunction. Our study suggests that early neurodegeneration in adults with T1D is likely due to non-AD/nonamyloid mechanisms., (© 2024 by the American Diabetes Association.)

Background: Arterial spin labeling (ASL) derived cerebral blood flow (CBF) maps are prone to artifacts and noise that can degrade image quality., Purpose: To develop an automated and objective quality evaluation index (QEI) for ASL CBF maps., Study Type: Retrospective., Population: Data from N = 221 adults, including patients with Alzheimer's disease (AD), Parkinson's disease, and traumatic brain injury., Field Strength/sequence: Pulsed or pseudocontinuous ASL acquired at 3 T using non-background suppressed 2D gradient-echo echoplanar imaging or background suppressed 3D spiral spin-echo readouts., Assessment: The QEI was developed using N = 101 2D CBF maps rated as unacceptable, poor, average, or excellent by two neuroradiologists and validated by 1) leave-one-out cross validation, 2) assessing if CBF reproducibility in N = 53 cognitively normal adults correlates inversely with QEI, 3) if iterative discarding of low QEI data improves the Cohen's d effect size for CBF differences between preclinical AD (N = 27) and controls (N = 53), 4) comparing the QEI with manual ratings for N = 50 3D CBF maps, and 5) comparing the QEI with another automated quality metric., Statistical Tests: Inter-rater reliability and manual vs. automated QEI were quantified using Pearson's correlation. P < 0.05 was considered significant., Results: The correlation between QEI and manual ratings (R = 0.83, CI: 0.76-0.88) was similar (P = 0.56) to inter-rater correlation (R = 0.81, CI: 0.73-0.87) for the 2D data. CBF reproducibility correlated negatively (R = -0.74, CI: -0.84 to -0.59) with QEI. The effect size comparing patients and controls improved (R = 0.72, CI: 0.59-0.82) as low QEI data was discarded iteratively. The correlation between QEI and manual ratings (R = 0.86, CI: 0.77-0.92) of 3D ASL was similar (P = 0.09) to inter-rater correlation (R = 0.78, CI: 0.64-0.87). The QEI correlated (R = 0.87, CI: 0.77-0.92) significantly better with manual ratings than did an existing approach (R = 0.54, CI: 0.30-0.72)., Data Conclusion: Automated QEI performed similarly to manual ratings and can provide scalable ASL quality control., Evidence Level: 2 TECHNICAL EFFICACY: Stage 1., (© 2024 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Introduction: We investigate pathological correlates of plasma phosphorylated tau 181 (p-tau 181 ), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) across a clinically diverse spectrum of neurodegenerative disease, including normal cognition (NormCog) and impaired cognition (ImpCog)., Methods: Participants were NormCog (n = 132) and ImpCog (n = 461), with confirmed β-amyloid (Aβ+/-) status (cerebrospinal fluid, positron emission tomography, autopsy) and single molecule array plasma measurements. Logistic regression and receiver operating characteristic (ROC) area under the curve (AUC) tested how combining plasma analytes discriminated Aβ+ from Aβ-. Survival analyses tested time to clinical dementia rating (global CDR) progression., Results: Multivariable models (p-tau+GFAP+NfL) had the best performance to detect Aβ+ in NormCog (ROCAUC = 0.87) and ImpCog (ROCAUC = 0.87). Survival analyses demonstrated that higher NfL best predicted faster CDR progression for both Aβ+ (hazard ratio [HR] = 2.94; p = 8.1e-06) and Aβ- individuals (HR = 3.11; p = 2.6e-09)., Discussion: Combining plasma biomarkers can optimize detection of Alzheimer's disease (AD) pathology across cognitively normal and clinically diverse neurodegenerative disease., Highlights: Participants were clinically heterogeneous, with autopsy- or biomarker-confirmed Aβ. Combining plasma p-tau 181 , GFAP, and NfL improved diagnostic accuracy for Aβ status. Diagnosis by plasma biomarkers is more accurate in amnestic AD than nonamnestic AD. Plasma analytes show independent associations with tau PET and post mortem Aβ/tau. Plasma NfL predicted longitudinal cognitive decline in both Aβ+ and Aβ- individuals., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

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 β (Aβ), 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 Aβ 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.

Objective: Subclinical brain infarcts (SBI) increase the risk for stroke and dementia, but whether they should be considered equivalent to symptomatic stroke when determining blood pressure targets remains unclear. We tested whether intensive systolic blood pressure (SBP) treatment reduced the risk of new SBI or stroke and determined the association between SBI and cognitive impairment., Methods: In this secondary analysis of SPRINT (Systolic Pressure Intervention Trial), participants ≥50 years old, with SBP 130-180mmHg and elevated cardiovascular risk but without known clinical stroke, dementia, or diabetes, were randomized to intensive (<120mmHg) or standard (<140mmHg) SBP treatment. Brain magnetic resonance images collected at baseline and follow-up were read for SBI. The occurrence of mild cognitive impairment (MCI) or probable dementia (PD) was evaluated., Results: For 667 participants at baseline, SBI were identified in 75 (11%). At median 3.9 years follow-up, 12 of 457 had new SBI on magnetic resonance imaging (5 intensive, 7 standard), whereas 8 had clinical stroke (4 per group). Baseline SBI (subhazard ratio [sHR] = 3.90; 95% CI 1.49 to 10.24; p = 0.006), but not treatment group, was associated with new SBI or stroke. For participants with baseline SBI, intensive treatment reduced their risk for recurrent SBI or stroke (sHR = 0.050; 95% CI 0.0031 to 0.79; p = 0.033). Baseline SBI also increased risk for MCI or PD during follow-up (sHR = 2.38; 95% CI 1.23 to 4.61; p = 0.010)., Interpretation: New cerebral ischemic events were infrequent, but intensive treatment mitigated the increased risk for participants with baseline SBI, indicating primary prevention SBP goals are still appropriate when SBI are present. ANN NEUROL 2024;95:866-875., (© 2024 American Neurological Association. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Left atrial (LA) myopathy is thought to be associated with silent brain infarctions (SBI) through changes in blood flow hemodynamics leading to thrombogenesis. 4D-flow MRI enables in-vivo hemodynamic quantification in the left atrium (LA) and LA appendage (LAA)., Purpose: To determine whether LA and LAA hemodynamic and volumetric parameters are associated with SBI., Study Type: Prospective observational study., Population: A single-site cohort of 125 Participants of the multiethnic study of atherosclerosis (MESA), mean age: 72.3 ± 7.2 years, 56 men., Field Strength/sequence: 1.5T. Cardiac MRI: Cine balanced steady state free precession (bSSFP) and 4D-flow sequences. Brain MRI: T1- and T2-weighted SE and FLAIR., Assessment: Presence of SBI was determined from brain MRI by neuroradiologists according to routine diagnostic criteria in all participants without a history of stroke based on the MESA database. Minimum and maximum LA volumes and ejection fraction were calculated from bSSFP data. Blood stasis (% of voxels <10 cm/sec) and peak velocity (cm/sec) in the LA and LAA were assessed by a radiologist using an established 4D-flow workflow., Statistical Tests: Student's t test, Mann-Whitney U test, one-way ANOVA, chi-square test. Multivariable stepwise logistic regression with automatic forward and backward selection. Significance level P < 0.05., Results: 26 (20.8%) had at least one SBI. After Bonferroni correction, participants with SBI were significantly older and had significantly lower peak velocities in the LAA. In multivariable analyses, age (per 10-years) (odds ratio (OR) = 1.99 (95% confidence interval (CI): 1.30-3.04)) and LAA peak velocity (per cm/sec) (OR = 0.87 (95% CI: 0.81-0.93)) were significantly associated with SBI., Conclusion: Older age and lower LAA peak velocity were associated with SBI in multivariable analyses whereas volumetric-based measures from cardiac MRI or cardiovascular risk factors were not. Cardiac 4D-flow MRI showed potential to serve as a novel imaging marker for SBI., Level of Evidence: 3 TECHNICAL EFFICACY: Stage 2., (© 2024 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Introduction: Variability in relationship of tau-based neurofibrillary tangles (T) and neurodegeneration (N) in Alzheimer's disease (AD) arises from non-specific nature of N, modulated by non-AD co-pathologies, age-related changes, and resilience factors., Methods: We used regional T-N residual patterns to partition 184 patients within the Alzheimer's continuum into data-driven groups. These were compared with groups from 159 non-AD (amyloid "negative") patients partitioned using cortical thickness, and groups in 98 patients with ante mortem MRI and post mortem tissue for measuring N and T, respectively. We applied the initial T-N residual model to classify 71 patients in an independent cohort into predefined groups., Results: AD groups displayed spatial T-N mismatch patterns resembling neurodegeneration patterns in non-AD groups, similarly associated with non-AD factors and diverging cognitive outcomes. In the autopsy cohort, limbic T-N mismatch correlated with TDP-43 co-pathology., Discussion: T-N mismatch may provide a personalized approach for determining non-AD factors associated with resilience/vulnerability in AD., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Vascular risk factors contribute to cognitive decline suggesting that maintaining cerebrovascular health could reduce dementia risk. The objective of this study is to evaluate the association of cerebrovascular reactivity (CVR), a measure of brain blood vessel elasticity, with mild cognitive impairment (MCI) and dementia., Methods: Participants were enrolled in the Systolic Blood Pressure Intervention Trial Memory and Cognition in Decreased Hypertension (SPRINT-MIND) magnetic resonance imaging substudy. Baseline CVR in Alzheimer's disease (AD) signature regions were primary variables of interest. The occipital pole and postcentral gyrus were included as control regions., Results: Higher AD composite CVR was associated with lower MCI risk. No significant associations between inferior temporal gyrus, occipital pole, or postcentral gyrus CVR and MCI risk, or any regional CVR-combined risk associations were observed., Discussion: CVR in AD signature regions is negatively associated with occurrence of MCI, implicating CVR in AD signature regions as a potential mechanism leading to cognitive impairment., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Heart rate (HR) fragmentation indices quantify breakdown of HR regulation and are associated with atrial fibrillation and cognitive impairment. Their association with brain magnetic resonance imaging (MRI) markers of small vessel disease is unexplored., Methods: In 606 stroke-free participants of the Multi-Ethnic Study of Atherosclerosis (mean age 67), HR fragmentation indices including percentage of inflection points (PIP) were derived from sleep study recordings. We examined PIP in relation to white matter hyperintensity (WMH) volume, total white matter fractional anisotropy (FA), and microbleeds from 3-Tesla brain MRI completed 7 years later., Results: In adjusted analyses, higher PIP was associated with greater WMH volume (14% per standard deviation [SD], 95% confidence interval [CI]: 2, 27%, P = 0.02) and lower WM FA (-0.09 SD per SD, 95% CI: -0.16, -0.01, P = 0.03)., Discussion: HR fragmentation was associated with small vessel disease. HR fragmentation can be measured automatically from ambulatory electrocardiogram devices and may be useful as a biomarker of vascular brain injury., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

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., (© 2024. The Author(s).)

Aim: The differentiation of paragangliomas, schwannomas, meningiomas, and other neuroaxis tumors in the head and neck remains difficult when conventional MRI is inconclusive. This study assesses the utility of 68 Ga-DOTATATE PET/CT as an adjunct to hone the diagnosis., Patients and Methods: This retrospective study considered 70 neuroaxis lesions in 52 patients with 68 Ga-DOTATATE PET/CT examinations; 22 lesions (31%) had pathologic confirmation. Lesions were grouped based on pathological diagnosis and best radiologic diagnosis when pathology was not available. Wilcoxon rank sum tests were used to test for differences in SUV max among paragangliomas, schwannomas, and meningiomas. Receiver operator characteristic curves were constructed., Results: Paragangliomas had a significantly greater 68 Ga-DOTATATE uptake (median SUV max , 62; interquartile range [IQR], 89) than nonparagangliomas. Schwannomas had near-zero 68 Ga-DOTATATE uptake (median SUV max , 2; IQR, 1). Intermediate 68 Ga-DOTATATE uptake was seen for meningiomas (median SUV max , 19; IQR, 6) and other neuroaxis lesions (median SUV max , 7; IQR, 9). Receiver operator characteristic analysis demonstrated an area under the curve of 0.87 for paragangliomas versus all other lesions and 0.97 for schwannomas versus all other lesions., Conclusions: Marked 68 Ga-DOTATATE uptake (>50 SUV max ) favors a diagnosis of paraganglioma, although paragangliomas exhibit a wide variability of uptake. Low to moderate level 68 Ga-DOTATATE uptake is nonspecific and may represent diverse pathophysiology including paraganglioma, meningioma, and other neuroaxis tumors but essentially excludes schwannomas, which exhibited virtually no uptake., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Normal and pathologic neurobiological processes influence brain morphology in coordinated ways that give rise to patterns of structural covariance (PSC) across brain regions and individuals during brain aging and diseases. The genetic underpinnings of these patterns remain largely unknown. We apply a stochastic multivariate factorization method to a diverse population of 50,699 individuals (12 studies and 130 sites) and derive data-driven, multi-scale PSCs of regional brain size. PSCs were significantly correlated with 915 genomic loci in the discovery set, 617 of which are newly identified, and 72% were independently replicated. Key pathways influencing PSCs involve reelin signaling, apoptosis, neurogenesis, and appendage development, while pathways of breast cancer indicate potential interplays between brain metastasis and PSCs associated with neurodegeneration and dementia. Using support vector machines, multi-scale PSCs effectively derive imaging signatures of several brain diseases. Our results elucidate genetic and biological underpinnings that influence structural covariance patterns in the human brain., Competing Interests: Competing interests statement:D.H.W. served as Site PI for studies by Biogen, Merck, and Eli Lilly/Avid. He has received consulting fees from GE Healthcare and Neuronix. He is on the DSMB for a trial sponsored by Functional Neuromodulation. A.J.S. receives support from multiple NIH grants (P30 AG010133, P30 AG072976, R01 AG019771, R01 AG057739, U01 AG024904, R01 LM013463, R01 AG068193, T32 AG071444, U01 AG068057, and U01 AG072177). He has also received support from Avid Radiopharmaceuticals, a subsidiary of Eli Lilly (in-kind contribution of PET tracer precursor); Bayer Oncology (Scientific Advisory Board); Eisai (Scientific Advisory Board); Siemens Medical Solutions, Inc. (Dementia Advisory Board); and Springer-Nature Publishing (Editorial Office Support as Editor-in-Chief, Brain Imaging, and Behavior). O.C. reports having received consulting fees from AskBio (2020) and Therapanacea (2022), having received payments for writing a lay audience short paper from Expression Santé (2019), and that his laboratory has received grants (paid to the institution) from Qynapse (2017 to present). Members of his laboratory have co-supervised a Ph.D. thesis with myBrainTechnologies (2016 to 2019) and with Qynapse (2017 to present). O.C.’s spouse is an employee and holds stock options of myBrainTechnologies (2015 to present). O.C. has a patent registered at the International Bureau of the World Intellectual Property Organization (PCT/IB2016/0526993, J.-B. Schiratti, S. Allassonniere, O.C., S. Durrleman, A method for determining the temporal progression of a biological phenomenon and associated methods and devices) (2017). M.E. receives support from multiple NIH grants, the Alzheimer’s Association, and the Alzheimer’s Therapeutic Research Institute. M.V.Z. serves as a consultant and/or speaker for the following pharmaceutical companies: Eurofarma, Lundbeck, Abbott, Greencare, Myralis, and Elleven Healthcare.

Incidence of opioid-related overdoses in the United States has increased dramatically over the past two decades. Despite public emphasis on overdose fatalities, most overdose cases are not fatal. Although there are case reports of amnestic syndromes and acute injury to the hippocampus following non-fatal opioid overdose, the effects of such overdoses on brain structure are poorly understood. Here, we investigated the neuroanatomical correlates of non-fatal opioid overdoses by comparing hippocampal volume in opioid use disorder (OUD) patients who had experienced an opioid overdose (OD; N = 17) with those who had not (NOD; N = 32). Voxel-based morphometry showed lower hippocampal volume in the OD group than in the NOD group, which on post hoc analysis was evident in the left but not the right hippocampus. These findings strengthen the evidence that hippocampal injury is associated with non-fatal opioid overdose, which is hypothesized to underlie overdose-related amnestic syndrome., (© 2023 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Introduction: Little is known about the epidemiology of brain microbleeds in racially/ethnically diverse populations., Methods: In the Multi-Ethnic Study of Atherosclerosis, brain microbleeds were identified from 3T magnetic resonance imaging susceptibility-weighted imaging sequences using deep learning models followed by radiologist review., Results: Among 1016 participants without prior stroke (25% Black, 15% Chinese, 19% Hispanic, 41% White, mean age 72), microbleed prevalence was 20% at age 60 to 64.9 and 45% at ≥85 years. Deep microbleeds were associated with older age, hypertension, higher body mass index, and atrial fibrillation, and lobar microbleeds with male sex and atrial fibrillation. Overall, microbleeds were associated with greater white matter hyperintensity volume and lower total white matter fractional anisotropy., Discussion: Results suggest differing associations for lobar versus deep locations. Sensitive microbleed quantification will facilitate future longitudinal studies of their potential role as an early indicator of vascular pathology., (© 2023 the Alzheimer's Association.)

Importance: Little is known about structural brain changes in type 1 diabetes (T1D) and whether there are early manifestations of a neurodegenerative condition like Alzheimer disease (AD) or evidence of premature brain aging., Objective: To evaluate neuroimaging markers of brain age and AD-like atrophy in participants with T1D in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study, identify which brain regions are associated with the greatest changes in patients with T1D, and assess the association between cognition and brain aging indices., Design, Setting, and Participants: This cohort study leveraged data collected during the combined DCCT (randomized clinical trial, 1983-1993) and EDIC (observational study, 1994 to present) studies at 27 clinical centers in the US and Canada. A total of 416 eligible EDIC participants and 99 demographically similar adults without diabetes were enrolled in the magnetic resonance imaging (MRI) ancillary study, which reports cross-sectional data collected in 2018 to 2019 and relates it to factors measured longitudinally in DCCT/EDIC. Data analyses were performed between July 2020 and April 2022., Exposure: T1D diagnosis., Main Outcomes and Measures: Psychomotor and mental efficiency were evaluated using verbal fluency, digit symbol substitution test, trail making part B, and the grooved pegboard. Immediate memory scores were derived from the logical memory subtest of the Wechsler memory scale and the Wechsler digit symbol substitution test. MRI and machine learning indices were calculated to predict brain age and quantify AD-like atrophy., Results: This study included 416 EDIC participants with a median (range) age of 60 (44-74) years (87 of 416 [21%] were older than 65 years) and a median (range) diabetes duration of 37 (30-51) years. EDIC participants had consistently higher brain age values compared with controls without diabetes, indicative of approximately 6 additional years of brain aging (EDIC participants: β, 6.16; SE, 0.71; control participants: β, 1.04; SE, 0.04; P < .001). In contrast, AD regional atrophy was comparable between the 2 groups. Regions with atrophy in EDIC participants vs controls were observed mainly in the bilateral thalamus and putamen. Greater brain age was associated with lower psychomotor and mental efficiency among EDIC participants (β, -0.04; SE, 0.01; P < .001), but not among controls., Conclusions and Relevance: The findings of this study suggest an increase in brain aging among individuals with T1D without any early signs of AD-related neurodegeneration. These increases were associated with reduced cognitive performance, but overall, the abnormal patterns seen in this sample were modest, even after a mean of 38 years with T1D.

Background and Objectives: Previous studies suggest that lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer disease (AD) and AD-related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN with cognitive function and MRI measures in community-based samples of middle-aged to older adults., Methods: We included dementia-free participants from 9 diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear DNA. Brain MRI markers included total brain, hippocampal, and white matter hyperintensity volumes. General cognitive function was derived from distinct cognitive domains. We performed cohort-specific association analyses of mtDNA CN with AD/ADRD endophenotypes assessed within ±5 years (i.e., cross-sectional analyses) or 5-20 years after blood draw (i.e., prospective analyses) adjusting for potential confounders. We further explored associations stratified by sex and age (<60 vs ≥60 years). Fixed-effects or sample size-weighted meta-analyses were performed to combine results. Finally, we performed mendelian randomization (MR) analyses to assess causality., Results: We included up to 19,152 participants (mean age 59 years, 57% women). Higher mtDNA CN was cross-sectionally associated with better general cognitive function (β = 0.04; 95% CI 0.02-0.06) independent of age, sex, batch effects, race/ethnicity, time between blood draw and cognitive evaluation, cohort-specific variables, and education. Additional adjustment for blood cell counts or cardiometabolic traits led to slightly attenuated results. We observed similar significant associations with cognition in prospective analyses, although of reduced magnitude. We found no significant associations between mtDNA CN and brain MRI measures in meta-analyses. MR analyses did not reveal a causal relation between mtDNA CN in blood and cognition., Discussion: Higher mtDNA CN in blood is associated with better current and future general cognitive function in large and diverse communities across the United States. Although MR analyses did not support a causal role, additional research is needed to assess causality. Circulating mtDNA CN could serve nevertheless as a biomarker of current and future cognitive function in the community., (Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Background and Purpose: The Systolic Blood Pressure Intervention (SPRINT) randomized trial demonstrated that intensive blood pressure management resulted in slower progression of cerebral white matter hyperintensities, compared with standard therapy. We assessed longitudinal changes in brain functional connectivity to determine whether intensive treatment results in less decline in functional connectivity and how changes in brain functional connectivity relate to changes in brain structure., Materials and Methods: Five hundred forty-eight participants completed longitudinal brain MR imaging, including resting-state fMRI, during a median follow-up of 3.84 years. Functional brain networks were identified using independent component analysis, and a mean connectivity score was calculated for each network. Longitudinal changes in mean connectivity score were compared between treatment groups using a 2-sample t test, followed by a voxelwise t test. In the full cohort, adjusted linear regression analysis was performed between changes in the mean connectivity score and changes in structural MR imaging metrics., Results: Four hundred six participants had longitudinal imaging that passed quality control. The auditory-salience-language network demonstrated a significantly larger decline in the mean connectivity score in the standard treatment group relative to the intensive treatment group ( P = .014), with regions of significant difference between treatment groups in the cingulate and right temporal/insular regions. There was no treatment group difference in other networks. Longitudinal changes in mean connectivity score of the default mode network but not the auditory-salience-language network demonstrated a significant correlation with longitudinal changes in white matter hyperintensities ( P = .013)., Conclusions: Intensive treatment was associated with preservation of functional connectivity of the auditory-salience-language network, while mean network connectivity in other networks was not significantly different between intensive and standard therapy. A longitudinal increase in the white matter hyperintensity burden is associated with a decline in mean connectivity of the default mode network., (© 2023 by American Journal of Neuroradiology.)

To learn multiscale functional connectivity patterns of the aging brain, we built a brain age prediction model of functional connectivity measures at seven scales on a large fMRI dataset, consisting of resting-state fMRI scans of 4186 individuals with a wide age range (22 to 97 years, with an average of 63) from five cohorts. We computed multiscale functional connectivity measures of individual subjects using a personalized functional network computational method, harmonized the functional connectivity measures of subjects from multiple datasets in order to build a functional brain age model, and finally evaluated how functional brain age gap correlated with cognitive measures of individual subjects. Our study has revealed that functional connectivity measures at multiple scales were more informative than those at any single scale for the brain age prediction, the data harmonization significantly improved the brain age prediction performance, and the data harmonization in the functional connectivity measures' tangent space worked better than in their original space. Moreover, brain age gap scores of individual subjects derived from the brain age prediction model were significantly correlated with clinical and cognitive measures. Overall, these results demonstrated that multiscale functional connectivity patterns learned from a large-scale multi-site rsfMRI dataset were informative for characterizing the aging brain and the derived brain age gap was associated with cognitive and clinical measures., Competing Interests: Competing Financial Interests Dr. Nasrallah was an educational speaker for Biogen. Dr. Wolk has received grant support from Merck, Biogen, and Eli Lilly/Avid and consultation fees from Neuronix and GE Healthcare and is on the Data and Safety Monitoring Board for a clinical trial run by Functional Neuromodulation., (Copyright © 2023. Published by Elsevier Inc.)

Deep learning has been demonstrated effective in many neuroimaging applications. However, in many scenarios, the number of imaging sequences capturing information related to small vessel disease lesions is insufficient to support data-driven techniques. Additionally, cohort-based studies may not always have the optimal or essential imaging sequences for accurate lesion detection. Therefore, it is necessary to determine which imaging sequences are crucial for precise detection. This study introduces a deep learning framework to detect enlarged perivascular spaces (ePVS) and aims to find the optimal combination of MRI sequences for deep learning-based quantification. We implemented an effective lightweight U-Net adapted for ePVS detection and comprehensively investigated different combinations of information from SWI, FLAIR, T1-weighted (T1w), and T2-weighted (T2w) MRI sequences. The experimental results showed that T2w MRI is the most important for accurate ePVS detection, and the incorporation of SWI, FLAIR and T1w MRI in the deep neural network had minor improvements in accuracy and resulted in the highest sensitivity and precision (sensitivity =0.82, precision =0.83). The proposed method achieved comparable accuracy at a minimal time cost compared to manual reading. The proposed automated pipeline enables robust and time-efficient readings of ePVS from MR scans and demonstrates the importance of T2w MRI for ePVS detection and the potential benefits of using multimodal images. Furthermore, the model provides whole-brain maps of ePVS, enabling a better understanding of their clinical correlates compared to the clinical rating methods within only a couple of brain regions., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Background: High blood pressure (BP) is a risk factor for late-life brain health; however, the association of elevated BP with brain health in mid-life is unclear., Methods: We identified 661 participants from the Coronary Artery Risk Development in Young Adults Study (age 18-30 at baseline) with 30 years of follow-up and brain magnetic resonance imaging at year 30. Cumulative exposure of BP was estimated by time-weighted averages (TWA). Ideal cardiovascular health was defined as systolic BP < 120 mm Hg, diastolic BP < 80 mm Hg. Brain age was calculated using previously validated high dimensional machine learning pattern analyses., Results: Every 5 mmHg increment in TWA systolic BP was associated with approximately 1-year greater brain age (95% confidence interval [CI]: 0.50-1.36) Participants with TWA systolic or diastolic BP over the recommended guidelines for ideal cardiovascular health, had on average 3-year greater brain age (95% CI: 1.00-4.67; 95% CI: 1.45-5.13, respectively)., Conclusion: Elevated BP from early to mid adulthood, even below clinical cut-offs, is associated with advanced brain aging in mid-life., (© 2022 the Alzheimer's Association.)

Background: Brain perivascular spaces (PVS) are part of the glymphatic system and facilitate clearance of metabolic byproducts. Since enlarged PVS are associated with vascular health, we tested whether intensive systolic blood pressure (SBP) treatment affects PVS structure., Methods: This is a secondary analysis of the Systolic PRessure INtervention Trial (SPRINT) MRI Substudy: a randomized trial of intensive SBP treatment to goal < 120 mm Hg vs < 140 mm Hg. Participants had increased cardiovascular risk, pre-treatment SBP 130-180, and no clinical stroke, dementia, or diabetes. Brain MRIs acquired at baseline and follow-up were used to automatically segment PVS in the supratentorial white matter and basal ganglia using a Frangi filtering method. PVS volumes were quantified as a fraction of the total tissue volume. The effects of SBP treatment group and major antihypertensive classes on PVS volume fraction were separately tested using linear mixed-effects models while covarying for MRI site, age, sex, Black race, baseline SBP, history of cardiovascular disease (CVD), chronic kidney disease, and white matter hyperintensities (WMH)., Results: For 610 participants with sufficient quality MRI at baseline (mean age 67 ± 8, 40 % female, 32 % Black), greater PVS volume fraction was associated with older age, male sex, non-Black race, concurrent CVD, WMH, and brain atrophy. For 381 participants with MRI at baseline and at follow-up (median ± IQR = 3.9 ± 0.4 years), intensive treatment was associated with decreased PVS volume fraction relative to standard treatment (interaction coefficient: -0.029 [-0.055 to -0.0029] p = 0.029). Reduced PVS volume fraction was also associated with exposure to calcium channel blockers (CCB)., Conclusions: PVS enlargement was partially reversed in the intensive SBP treatment group. The association with CCB use suggests that improved vascular compliance may be partly responsible. Improved vascular health may facilitate glymphatic clearance. Clincaltrials.gov: NCT01206062., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Clinton B. Wright reports a relationship with Wolters Kluwer UpToDate that includes: consulting or advisory.]., (Copyright © 2023. Published by Elsevier Inc.)

Objective: To determine if plasma tau phosphorylated at threonine 181 (p-tau181) distinguishes pathology-confirmed Alzheimer's disease (AD) from normal cognition (NC) adults, to test if p-tau181 predicts cognitive and functional decline, and to validate findings in an external cohort., Methods: Thirty-one neuropathology-confirmed AD cases, participants with clinical diagnoses of mild cognitive impairment (MCI, N = 91) or AD dementia (N = 64), and NC (N = 241) had plasma collected at study entry. The clinical diagnosis groups had annual cognitive (Mini-Mental State Examination, MMSE) and functional (Clinical Dementia Rating Scale, CDR) measures. NC (N = 70), MCI (N = 75), and AD dementia (N = 50) cases from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were used as a validation cohort. Plasma p-tau181 was measured using the Quanterix SiMoA HD-X platform., Results: Plasma p-tau181 differentiated pathology-confirmed AD from NC with negative amyloid PET scans with an AUC of 0.93. A cut point of 3.44 pg/mL (maximum Youden Index) had a sensitivity of 0.77, specificity of 0.96. p-Tau181 values above the cut point were associated with the faster rate of decline in MMSE in AD dementia and MCI and a shorter time to a clinically significant functional decline in all groups. In a subset of MCI cases from ADNI, p-tau181 values above the cut point associated with faster rate of decline in MMSE, and a shorter time to a clinically significant functional decline and conversion to dementia., Interpretation: Plasma p-tau181 differentiates AD pathology cases from NC with high accuracy. Higher levels of plasma p-tau181 are associated with faster cognitive and functional decline., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objective: To examine longitudinal race and sex differences in mid-life brain health and to evaluate whether cardiovascular health (CVH) or apolipoprotein E (APOE) ε4 explain differences., Methods: The study included 478 Black and White participants (mean age: 50 years). Total (TBV), gray (GMV), white (WMV), and white matter hyperintensity (WMH) volumes and GM-cerebral blood flow (CBF) were acquired with 3T-magnetic resonance imaging at baseline and 5-year follow-up. Analyses were based on general linear models., Results: There were race x sex interactions for GMV (P-interaction = .004) and CBF (P-interaction = .01) such that men showed more decline than women, and this was most evident in Blacks. Blacks compared to Whites had a significantly greater increase in WMH (P = .002). All sex-race differences in change were marginally attenuated by CVH and APOE ε4., Conclusion: Race-sex differences in brain health emerge by mid-life. Identifying new environmental factors beyond CVH is needed to develop early interventions to maintain brain health., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background Atrial fibrillation (AF) is associated with increased stroke risk and accelerated cognitive decline, but the association of early manifestations of left atrial (LA) impairment with subclinical changes in brain structure is unclear. We investigated whether abnormal LA structure and function, greater supraventricular ectopy, and intermittent AF are associated with small vessel disease on magnetic resonance imaging of the brain. Methods and Results In the Multi-Ethnic Study of Atherosclerosis, 967 participants completed 14-day ambulatory electrocardiographic monitoring, speckle tracking echocardiography and, a median 17 months later, magnetic resonance imaging of the brain. We assessed associations of LA volume index and reservoir strain, supraventricular ectopy, and prevalent AF with brain magnetic resonance imaging measures of small vessel disease and atrophy. The mean age of participants was 72 years; 53% were women. In multivariable models, LA enlargement was associated with lower white matter fractional anisotropy and greater prevalence of microbleeds; reduced LA strain, indicating worse LA function, was associated with more microbleeds. More premature atrial contractions were associated with lower total gray matter volume. Compared with no AF, intermittent AF (prevalent AF with <100% AF during electrocardiographic monitoring) was associated with lower white matter fractional anisotropy (-0.25 SDs [95% CI, -0.44 to -0.07]) and greater prevalence of microbleeds (prevalence ratio: 1.42 [95% CI, 1.12-1.79]). Conclusions In individuals without a history of stroke or transient ischemic attack, alterations of LA structure and function, including enlargement, reduced strain, frequent premature atrial contractions, and intermittent AF, were associated with increased markers of small vessel disease. Detailed assessment of LA structure and function and extended ECG monitoring may enable early identification of individuals at greater risk of small vessel disease.

Objective: Expression of glial fibrillary acidic protein (GFAP), a marker of reactive astrocytosis, colocalizes with neuropathology in the brain. Blood levels of GFAP have been associated with cognitive decline and dementia status. However, further examinations at a population-based level are necessary to broaden generalizability to community settings., Methods: Circulating GFAP levels were assayed using a Simoa HD-1 analyzer in 4338 adults without prevalent dementia from four longitudinal community-based cohort studies. The associations between GFAP levels with general cognition, total brain volume, and hippocampal volume were evaluated with separate linear regression models in each cohort with adjustment for age, sex, education, race, diabetes, systolic blood pressure, antihypertensive medication, body mass index, apolipoprotein E ε4 status, site, and time between GFAP blood draw and the outcome. Associations with incident all-cause and Alzheimer's disease dementia were evaluated with adjusted Cox proportional hazard models. Meta-analysis was performed on the estimates derived from each cohort using random-effects models., Results: Meta-analyses indicated that higher circulating GFAP associated with lower general cognition (ß = -0.09, [95% confidence interval [CI]: -0.15 to -0.03], p = 0.005), but not with total brain or hippocampal volume (p &gt; 0.05). However, each standard deviation unit increase in log-transformed GFAP levels was significantly associated with a 2.5-fold higher risk of incident all-cause dementia (Hazard Ratio [HR]: 2.47 (95% CI: 1.52-4.01)) and Alzheimer's disease dementia (HR: 2.54 [95% CI: 1.42-4.53]) over up to 15-years of follow-up., Interpretation: Results support the potential role of circulating GFAP levels for aiding dementia risk prediction and improving clinical trial stratification in community settings., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Neuroinflammation is implicated as a key pathologic mechanism in many neurodegenerative diseases and is thought to be mediated in large part by microglia, native phagocytic immune cells of the CNS. Abnormal aggregation of the protein α-synuclein after phagocytosis by microglia is one possible neuropathophysiological mechanism driving Parkinson's disease (PD). We conducted a human pilot study to evaluate the feasibility of targeting the inducible isoform of nitric oxide synthase using the [ 18 F]NOS radiotracer to measure neuroinflammation in idiopathic PD. Ten adults consisting of 6 PD patients and 4 healthy controls (HC) underwent one hour of dynamic [ 18 F]NOS positron emission tomography (PET) brain imaging with arterial blood sampling. We observed increased [ 18 F]NOS whole brain distribution volume (V T ) in PD patients compared to age-matched healthy controls ( p < 0.008) via a 1-tissue compartment (TC) model. The rate constant K1 for transport from blood into tissue did not differ between groups ( p = 0.72). These findings suggest elevated oxidative stress, a surrogate marker of inflammation, is present in early-stage idiopathic PD and indicate that [ 18 F]NOS PET imaging is a promising, non-invasive method to measure neuroinflammation.

Background: The SPRINT (Systolic Blood Pressure Intervention Trial) demonstrated reductions in major cardiovascular disease events and mortality with an intensive systolic blood pressure (SBP) goal intervention. However, a detailed description of the blood pressure intervention, antihypertensive medication usage, blood pressure levels, and rates and predictors of blood pressure control has not been reported previously., Methods: Hypertensive participants (n=9361) 50 years and older with elevated cardiovascular disease risk were randomized 1:1 to SBP goal <120 mm Hg or SBP goal <140 mm Hg. Guideline-recommended antihypertensive medications and dosing were provided at no cost. Intensive group participants were started on at least 2 medications, and medications were adjusted monthly until SBP goal was achieved, if feasible. Standard group participants were treated to achieve SBP 135 to 139 mm Hg., Results: Baseline blood pressure (median±interquartile range) was 138±19/78±16 mm Hg. For intensive group participants, percent at goal rose from 8.9% at baseline to 52.4% at 6 months and average antihypertensive medications rose from 2.2 to 2.7; SBP was <120 mm Hg in 61.6% and <130 mm Hg in 80.0% at their final visit. For the standard group participants, percent at goal rose from 53.0% at baseline to 68.6% at 6 months, while antihypertensive medications fell from 1.9 to 1.8. From 6 to 36 months, median SBP was stable at 119±14 mm Hg for intensive and 136±15 mm Hg for standard participants, with stable numbers of medications. Few predictors of SBP control were found in multiple regression models., Conclusions: These results may inform and help replicate the benefits of SPRINT in clinical practice., Registration: URL: http://www., Clinicaltrials: gov; Unique identifier: NCT01206062.

White matter hyperintensities (WMHs) are emblematic of cerebral small vessel disease, yet effects on the brain have not been well characterized at midlife. Here, we investigated whether WMH volume is associated with brain network alterations in midlife adults. Two hundred and fifty-four participants from the Coronary Artery Risk Development in Young Adults study were selected and stratified by WMH burden into Lo-WMH (mean age = 50 ± 3.5 years) and Hi-WMH (mean age = 51 ± 3.7 years) groups of equal size. We constructed group-level covariance networks based on cerebral blood flow (CBF) and gray matter volume (GMV) maps across 74 gray matter regions. Through consensus clustering, we found that both CBF and GMV covariance networks partitioned into modules that were largely consistent between groups. Next, CBF and GMV covariance network topologies were compared between Lo- and Hi-WMH groups at global (clustering coefficient, characteristic path length, global efficiency) and regional (degree, betweenness centrality, local efficiency) levels. At the global level, there were no between-group differences in either CBF or GMV covariance networks. In contrast, we found between-group differences in the regional degree, betweenness centrality, and local efficiency of several brain regions in both CBF and GMV covariance networks. Overall, CBF and GMV covariance analyses provide evidence that WMH-related network alterations are present at midlife., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Objective: Individuals with type 1 diabetes mellitus (T1DM) are living to ages when neuropathological changes are increasingly evident. We hypothesized that middle-aged and older adults with long-standing T1DM will show abnormal brain structure in comparison with control subjects without diabetes., Research Design and Methods: MRI was used to compare brain structure among 416 T1DM participants in the Epidemiology of Diabetes Interventions and Complications (EDIC) study with that of 99 demographically similar control subjects without diabetes at 26 U.S. and Canadian sites. Assessments included total brain (TBV) (primary outcome), gray matter (GMV), white matter (WMV), ventricle, and white matter hyperintensity (WMH) volumes and total white matter mean fractional anisotropy (FA). Biomedical assessments included HbA1c and lipid levels, blood pressure, and cognitive assessments of memory and psychomotor and mental efficiency (PME). Among EDIC participants, HbA1c, severe hypoglycemia history, and vascular complications were measured longitudinally., Results: Mean age of EDIC participants and control subjects was 60 years. T1DM participants showed significantly smaller TBV (least squares mean ± SE 1,206 ± 1.7 vs. 1,229 ± 3.5 cm3, P < 0.0001), GMV, and WMV and greater ventricle and WMH volumes but no differences in total white matter mean FA versus control subjects. Structural MRI measures in T1DM were equivalent to those of control subjects who were 4-9 years older. Lower PME scores were associated with altered brain structure on all MRI measures in T1DM participants., Conclusions: Middle-aged and older adults with T1DM showed brain volume loss and increased vascular injury in comparison with control subjects without diabetes, equivalent to 4-9 years of brain aging., (© 2022 by the American Diabetes Association.)

Community detection on graphs constructed from functional magnetic resonance imaging (fMRI) data has led to important insights into brain functional organization. Large studies of brain community structure often include images acquired on multiple scanners across different studies. Differences in scanner can introduce variability into the downstream results, and these differences are often referred to as scanner effects. Such effects have been previously shown to significantly impact common network metrics. In this study, we identify scanner effects in data-driven community detection results and related network metrics. We assess a commonly employed harmonization method and propose new methodology for harmonizing functional connectivity that leverage existing knowledge about network structure as well as patterns of covariance in the data. Finally, we demonstrate that our new methods reduce scanner effects in community structure and network metrics. Our results highlight scanner effects in studies of brain functional organization and provide additional tools to address these unwanted effects. These findings and methods can be incorporated into future functional connectivity studies, potentially preventing spurious findings and improving reliability of results., Competing Interests: Declaration of Competing Interest Authors declare that they have no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Lowering blood pressure (BP) reduces the risk for cognitive impairment and the progression of cerebral white matter lesions. It is unclear whether hypertension control also influences plasma biomarkers related to Alzheimer's disease and non-disease-specific neurodegeneration., Methods: We examined the effect of intensive (< 120 mm Hg) versus standard (< 140 mm Hg) BP control on longitudinal changes in plasma amyloid beta (Aβ) 40 and Aβ 42 , total tau, and neurofilament light chain (NfL) in a subgroup of participants from the Systolic Blood Pressure Intervention Trial (N = 517)., Results: Over 3.8 years, there were no significant between-group differences for Aβ 40, Aβ 42, Aβ 42 /Aβ 40, or total tau. Intensive treatment was associated with larger increases in NfL compared to standard treatment. Adjusting for kidney function, but not BP, attenuated the association between intensive treatment and NfL., Discussion: Intensive BP treatment was associated with changes in NfL, which were correlated with changes in kidney function associated with intensive treatment., Trial Registration: clinicaltrials.gov Identifier: NCT01206062., (© 2021 the Alzheimer's Association.)

Background: Episodic memory decline is a hallmark of Alzheimer's disease (AD). Subjective memory complaints (SMCs) may represent one of the earliest signs of impending cognitive decline. The degree to which self- or partner-reported SMCs predict cognitive change remains unclear., Objective: We aimed to evaluate the relationship between self- and partner-reported SMCs, objective cognitive performance, AD biomarkers, and risk of future decline in a well-characterized longitudinal memory center cohort. We also evaluated whether study partner characteristics influence reports of SMCs., Methods: 758 participants and 690 study partners were recruited from the Penn Alzheimer's Disease Research Center Clinical Core. Participants included those with Normal Cognition, Mild Cognitive Impairment, and AD. SMCs were measured using the Prospective and Retrospective Memory Questionnaire (PRMQ), and were evaluated for their association with cognition, genetic, plasma, and neuroimaging biomarkers of AD, cognitive and functional decline, and diagnostic progression over an average of four years., Results: We found that partner-reported SMCs were more consistent with cognitive test performance and increasing symptom severity than self-reported SMCs. Partner-reported SMCs showed stronger correlations with AD-associated brain atrophy, plasma biomarkers of neurodegeneration, and longitudinal cognitive and functional decline. A 10-point increase on baseline PRMQ increased the annual risk of diagnostic progression by approximately 70%. Study partner demographics and relationship to participants influenced reports of SMCs in AD participants only., Conclusion: Partner-reported SMCs, using the PRMQ, have a stronger relationship with the neuroanatomic and cognitive changes associated with AD than patient-reported SMCs. Further work is needed to evaluate whether SMCs could be used to screen for future decline., Competing Interests: IMN receives compensation as an educational speaker for Biogen. LX received personal consulting fees from Galileo CDS, Inc. All other authors have no relevant conflics of interest to report., (© 2022 – The authors. Published by IOS Press.)

Introduction: Longitudinal positron emission tomography (PET) studies of tau accumulation in Alzheimer's disease (AD) have noted reduced increases or frank decreases in tau signal. We investigated how such reductions related to analytical confounds and disease progression markers in atypical AD., Methods: We assessed regional and interindividual variation in longitudinal change on 18 F-flortaucipir PET imaging in 24 amyloid beta (Aβ)+ patients with atypical, early-onset amnestic or non-amnestic AD plus 62 Aβ- and 132 Aβ+ Alzheimer's Disease Neuroimaging Initiative (ADNI) participants., Results: In atypical AD, 18 F-flortaucipir uptake slowed or declined over time in areas with high baseline signal and older, more impaired individuals. ADNI participants had reduced longitudinal change in early Braak stage regions relative to late-stage areas., Discussion: Results suggested radioligand uptake plateaus or declines in advanced neurodegeneration. Further research should investigate whether results generalize to other radioligands and whether they relate to changes of the radioligand binding site structure or accessibility., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Workers are exposed to several risks in academic laboratories due to the presence of potentially hazardous substances. The main objective of this study was to assess the prevalence of accident occurrence and associated risk factors among laboratory workers at the scientific laboratories of the public university in Lebanon and the impact of safety measures training and availability ., Methods: In this observational study, a survey was conducted for one year in scientific laboratories at faculties of the public university., Results: Among the participants ( N = 220), 45.0% have had accidents; the main cause was exposure to chemicals (73.7%) and more specifically by inhalation (45.4%). Females (85.9%) were more exposed to accidents than males. Laboratory workers with a master's degree, a full-time schedule, and more than ten years of experience were significantly more exposed to accidents ( p  < 0.05). A significant association was found between accident occurrence and training on management of hazardous products ( p  = 0.044), risks related to workplace ( p  = 0.030), eyewash and emergency shower ( p  < 0.001), first aid ( p  = 0.012), and facial protection availability ( p  = 0.019). In spite of the lack of safety culture and efficient training on laboratory safety, participants have shown a very good perception regarding safety measures to be applied in case of work accidents., Conclusion: Based on our findings, the prevalence of accident occurrence is elevated among lab workers at the public university. The impact of regular training on laboratory safety preventive measures is of great importance to ensure the efficiency of occupational health and safety in scientific laboratories., Competing Interests: No potential conflicts of interest were disclosed., (© 2022 Occupational Safety and Health Research Institute.)

Neuroimaging biomarkers that distinguish between changes due to typical brain ageing and Alzheimer's disease are valuable for determining how much each contributes to cognitive decline. Supervised machine learning models can derive multivariate patterns of brain change related to the two processes, including the Spatial Patterns of Atrophy for Recognition of Alzheimer's Disease (SPARE-AD) and of Brain Aging (SPARE-BA) scores investigated herein. However, the substantial overlap between brain regions affected in the two processes confounds measuring them independently. We present a methodology, and associated results, towards disentangling the two. T 1 -weighted MRI scans of 4054 participants (48-95 years) with Alzheimer's disease, mild cognitive impairment (MCI), or cognitively normal (CN) diagnoses from the Imaging-based coordinate SysTem for AGIng and NeurodeGenerative diseases (iSTAGING) consortium were analysed. Multiple sets of SPARE scores were investigated, in order to probe imaging signatures of certain clinically or molecularly defined sub-cohorts. First, a subset of clinical Alzheimer's disease patients ( n  = 718) and age- and sex-matched CN adults ( n  = 718) were selected based purely on clinical diagnoses to train SPARE-BA1 (regression of age using CN individuals) and SPARE-AD1 (classification of CN versus Alzheimer's disease) models. Second, analogous groups were selected based on clinical and molecular markers to train SPARE-BA2 and SPARE-AD2 models: amyloid-positive Alzheimer's disease continuum group ( n  = 718; consisting of amyloid-positive Alzheimer's disease, amyloid-positive MCI, amyloid- and tau-positive CN individuals) and amyloid-negative CN group ( n  = 718). Finally, the combined group of the Alzheimer's disease continuum and amyloid-negative CN individuals was used to train SPARE-BA3 model, with the intention to estimate brain age regardless of Alzheimer's disease-related brain changes. The disentangled SPARE models, SPARE-AD2 and SPARE-BA3, derived brain patterns that were more specific to the two types of brain changes. The correlation between the SPARE-BA Gap (SPARE-BA minus chronological age) and SPARE-AD was significantly reduced after the decoupling ( r  = 0.56-0.06). The correlation of disentangled SPARE-AD was non-inferior to amyloid- and tau-related measurements and to the number of APOE ε4 alleles but was lower to Alzheimer's disease-related psychometric test scores, suggesting the contribution of advanced brain ageing to the latter. The disentangled SPARE-BA was consistently less correlated with Alzheimer's disease-related clinical, molecular and genetic variables. By employing conservative molecular diagnoses and introducing Alzheimer's disease continuum cases to the SPARE-BA model training, we achieved more dissociable neuroanatomical biomarkers of typical brain ageing and Alzheimer's disease., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Rationale & Objective: The safety of intensive blood pressure (BP) targets is controversial for persons with chronic kidney disease (CKD). We studied the effects of hypertension treatment on cerebral perfusion and structure in individuals with and without CKD., Study Design: Neuroimaging substudy of a randomized trial., Setting & Participants: A subset of participants in the Systolic Blood Pressure Intervention Trial (SPRINT) who underwent brain magnetic resonance imaging studies. Presence of baseline CKD was assessed by estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (UACR)., Intervention: Participants were randomly assigned to intensive (systolic BP <120 mm Hg) versus standard (systolic BP <140 mm Hg) BP lowering., Outcomes: The magnetic resonance imaging outcome measures were the 4-year change in global cerebral blood flow (CBF), white matter lesion (WML) volume, and total brain volume (TBV)., Results: A total of 716 randomized participants with a mean age of 68 years were enrolled; follow-up imaging occurred after a median 3.9 years. Among participants with eGFR <60 mL/min/1.73 m 2 (n = 234), the effects of intensive versus standard BP treatment on change in global CBF, WMLs, and TBV were 3.38 (95% CI, 0.32 to 6.44) mL/100 g/min, -0.06 (95% CI, -0.16 to 0.04) cm 3 (inverse hyperbolic sine-transformed), and -3.8 (95% CI, -8.3 to 0.7) cm 3 , respectively. Among participants with UACR >30 mg/g (n = 151), the effects of intensive versus standard BP treatment on change in global CBF, WMLs, and TBV were 1.91 (95% CI, -3.01 to 6.82) mL/100 g/min, 0.003 (95% CI, -0.13 to 0.13) cm 3 (inverse hyperbolic sine-transformed), and -7.0 (95% CI, -13.3 to -0.3) cm 3 , respectively. The overall treatment effects on CBF and TBV were not modified by baseline eGFR or UACR; however, the effect on WMLs was attenuated in participants with albuminuria (P = 0.04 for interaction)., Limitations: Measurement variability due to multisite design., Conclusions: Among adults with hypertension who have primarily early kidney disease, intensive versus standard BP treatment did not appear to have a detrimental effect on brain perfusion or structure. The findings support the safety of intensive BP treatment targets on brain health in persons with early kidney disease., Funding: SPRINT was funded by the National Institutes of Health (including the National Heart, Lung, and Blood Institute; the National Institute of Diabetes and Digestive and Kidney Diseases; the National Institute on Aging; and the National Institute of Neurological Disorders and Stroke), and this substudy was funded by the National Institutes of Diabetes and Digestive and Kidney Diseases., Trial Registration: SPRINT was registered at ClinicalTrials.gov with study number NCT01206062., (Published by Elsevier Inc.)

Background Cardiovascular risk factors are associated with cognitive decline and dementia. Magnetic resonance imaging provides sensitive measurement of brain morphology and vascular brain injury. However, associations of risk factors with brain magnetic resonance imaging findings have largely been studied in White participants. We investigated associations of race, ethnicity, and cardiovascular risk factors with brain morphology and white matter (WM) injury in a diverse population. Methods and Results In the Multi-Ethnic Study of Atherosclerosis, measures were made in 2018 to 2019 of total brain volume, gray matter and WM volume, and WM injury, including WM hyperintensity volume and WM fractional anisotropy. We assessed cross-sectional associations of race and ethnicity and of cardiovascular risk factors with magnetic resonance imaging measures. Magnetic resonance imaging data were complete in 1036 participants; 25% Black, 15% Chinese-American, 19% Hispanic, and 41% White. Mean (SD) age was 72 (8) years and 53% were women. Although WM injury was greater in Black than in White participants in a minimally adjusted model, additional adjustment for cardiovascular risk factors and socioeconomic status each attenuated this association, rendering it nonsignificant. Overall, greater average WM hyperintensity volume was associated with older age and current smoking (69% greater vs never smoking); lower fractional anisotropy was additionally associated with higher diastolic blood pressure, use of antihypertensive medication, and diabetes. Conclusions We found no statistically significant difference in measures of WM injury by race and ethnicity after adjustment for cardiovascular risk factors and socioeconomic status. In all racial and ethnic groups, older age, current smoking, hypertension, and diabetes were strongly associated with WM injury.