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Abstract 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/ .

Summary: Background: Perivascular spaces (PVS) on brain MRI are surrogates for small parenchymal blood vessels and their perivascular compartment, and may relate to brain health. However, it is unknown whether PVS can predict dementia risk and brain atrophy trajectories in participants without dementia, as longitudinal studies on PVS are scarce and current methods for PVS assessment lack robustness and inter-scanner reproducibility. Methods: We developed a robust algorithm to automatically assess PVS count and size on clinical MRI, and investigated 1) their relationship with dementia risk and brain atrophy in participants without dementia, 2) their longitudinal evolution, and 3) their potential use as a screening tool in simulated clinical trials. We analysed 46,478 clinical measurements of cognitive functioning and 20,845 brain MRI scans from 10,004 participants (71.1 ± 9.7 years-old, 56.6% women) from three publicly available observational studies on ageing and dementia (the Alzheimer’s Disease Neuroimaging Initiative, the National Alzheimer’s Coordinating Centre database, and the Open Access Series of Imaging Studies). Clinical and MRI data collected between 2004 and 2022 were analysed with consistent methods, controlling for confounding factors, and combined using mixed-effects models. Findings: Our fully-automated method for PVS assessment showed excellent inter-scanner reproducibility (intraclass correlation coefficients >0.8). Fewer PVS and larger PVS diameter at baseline predicted higher dementia risk and accelerated brain atrophy. Longitudinal trajectories of PVS markers differed significantly in participants without dementia who converted to dementia compared with non-converters. In simulated placebo-controlled trials for treatments targeting cognitive decline, screening out participants at low risk of dementia based on our PVS markers enhanced the power of the trial independently of Alzheimer’s disease biomarkers. Interpretation: These robust cerebrovascular markers predict dementia risk and brain atrophy and may improve risk-stratification of patients, potentially reducing cost and increasing throughput of clinical trials to combat dementia. Funding: US National Institutes of Health.

Summary: 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.

Abstract INTRODUCTION We investigated the feasibility and validity of the remotely‐administered neuropsychological battery from the National Alzheimer's Coordinating Center Uniform Data Set (UDS T‐Cog). METHODS Two hundred twenty Penn Alzheimer's Disease Research Center participants with unimpaired cognition, mild cognitive impairment, and dementia completed the T‐Cog during their annual UDS evaluation. We assessed administration feasibility and diagnostic group differences cross‐sectionally across telephone versus videoconference modalities, and compared T‐Cog to prior in‐person UDS scores longitudinally. RESULTS Administration time averaged 54 min and 79% of participants who initiated a T‐Cog completed all 12 subtests; completion time and rates differed by diagnostic group but not by modality. Performance varied expectedly across groups with moderate to strong associations between most T‐Cog measures and in‐person correlates, although select subtests demonstrated lower comparability. DISCUSSION The T‐Cog is feasibly administered and shows preliminary validity in a cognitively heterogeneous cohort. Normative data from this cohort should be expanded to more diverse populations to enhance utility and generalizability. Highlights This study examined the feasibility and validity of the remote Uniform Data Set (also known as the T‐Cog) and contributes key normative data for widespread use. A remote neuropsychological battery was feasibly administered with high overall engagement and completion rates, adequate reliability compared to in‐person testing, and evidence of validity across diagnostic groups. Typical barriers to administration included hearing impairment, technology issues, and distractions; hearing difficulties were particularly common among cognitively impaired groups. Certain tests were less closely related to their in‐person correlates and should be used with caution.

Abstract Background Synapse degeneration is an early event in pathological frontotemporal lobar degeneration (FTLD). Consequently, a surrogate marker of synapse loss could be used to monitor early pathologic changes in patients with underlying FTLD. The aim of this study was to evaluate the relationship of antemortem cerebrospinal fluid (CSF) levels of 8 synaptic proteins with postmortem global tau and TDP-43 burden and cognitive performance and to assess their diagnostic capacity in a neuropathological FTLD cohort. Methods We included patients with a neuropathological confirmation of FTLD-Tau (n = 24, mean age-at-CSF 67 years ± 11), FTLD-TDP (n = 25, 66 years ± 9) or AD (n = 25, 73 years ± 6) as well as cognitively normal controls (n = 35, 69 years ± 7) from the Penn FTD Center and ADRC. We used a semi-quantitative measure of tau and TDP-43 inclusions to quantify pathological burden across 16 brain regions. Statistical methods included Spearman rank correlations, one-way analysis of covariance, ordinal regression, step-wise multiple linear regression and receiver-operating characteristic curves. Result CSF calsyntenin-1 and neurexin-2a were correlated in all patient groups (r s = .55 to .88). In FTLD-TDP, we observed low antemortem CSF levels of calsyntenin-1 and neurexin-2a compared to AD (.72-fold, p = .001, .77-fold, p = .04, respectively) and controls (.80-fold, p = .02, .78-fold, p = .02, respectively), which were inversely associated with post-mortem global TDP-43 burden (regression r 2 = .56, p = .007 and r 2 = .57, p = .006, respectively). A multimarker panel including calsyntenin-1 was associated with TDP-43 burden (r 2 = .69, p = .003) and MMSE score (r 2 = .19, p = .03) in FTLD. A second multimarker synaptic panel, also including calsyntenin-1, was associated with MMSE score in FTLD-tau (r 2 = .49, p = .04) and improved diagnostic performance to discriminate FTLD-Tau and FTLD-TDP neuropathologic subtypes (AUC = .83). Conclusion These synaptic panels have potential in the differential diagnosis of FTLD neuropathologic subtypes and as surrogate markers of cognitive performance in future clinical trials targeting TDP-43 or tau.

PurposeTo assess the pathological aging effect on caudate functional connectivity among mild cognitive impairment (MCI) participants and examine whether and how sex and amyloid contribute to this process.Materials and MethodsTwo hundred and seventy-seven functional magnetic resonance imaging (fMRI) sessions from 163 cognitive normal (CN) older adults and 309 sessions from 139 participants with MCI were included as the main sample in our analysis. Pearson's correlation was used to characterize the functional connectivity (FC) between caudate nuclei and each brain region, then caudate nodal strength was computed to quantify the overall caudate FC strength. Association analysis between caudate nodal strength and age was carried out in MCI and CN separately using linear mixed effect (LME) model with covariates (education, handedness, sex, Apolipoprotein E4, and intra-subject effect). Analysis of covariance was conducted to investigate sex, amyloid status, and their interaction effects on aging with the fMRI data subset having amyloid status available. LME model was applied to women and men separately within MCI group to evaluate aging effects on caudate nodal strength and each region's connectivity with caudate nuclei. We then evaluated the roles of sex and amyloid status in the associations of neuropsychological scores with age or caudate nodal strength. An independent cohort was used to validate the sex-dependent aging effects in MCI.ResultsThe MCI group had significantly stronger age-related increase of caudate nodal strength compared to the CN group. Analyzing women and men separately revealed that the aging effect on caudate nodal strength among MCI participants was significant only for women (left: P = 6.23 × 10−7, right: P = 3.37 × 10−8), but not for men (P > 0.3 for bilateral caudate nuclei). The aging effects on caudate nodal strength were not significantly mediated by brain amyloid burden. Caudate connectivity with ventral prefrontal cortex substantially contributed to the aging effect on caudate nodal strength in women with MCI. Higher caudate nodal strength is significantly related to worse cognitive performance in women but not in men with MCI.ConclusionSex modulates the pathological aging effects on caudate nodal strength in MCI regardless of amyloid status. Caudate nodal strength may be a sensitive biomarker of pathological aging in women with MCI.

We used a virtual lesion DTI fiber tracking approach with healthy subject DTI data and simulated periventricular white matter (PVWM) lesion masks to predict the sequence of connectivity changes associated with progressive PVWM ischemia. We found that the optic radiations, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, corpus callosum, temporopontine tract and fornix were affected in early simulated ischemic injury, and that the connectivity of subcortical, cerebellar, and visual regions were significantly disrupted with increasing simulated lesion severity. The results of this study provide insights into the spatial-temporal changes of the brain structural connectome under progressive PVWM ischemia. The virtual lesion approach provides a meaningful proxy to the spatial-temporal changes of the brain's structural connectome and can be used to further characterize the cognitive sequelae of progressive PVWM ischemia in both normal aging and dementia.

Objective: Logopenic variant primary progressive aphasia (lvPPA) is commonly associated with Alzheimer's disease (AD) pathology. But lvPPA patients display different cognitive and anatomical profile from the common clinical AD patients, whose verbal episodic memory is primarily affected. Reports of verbal episodic memory difficulty in lvPPA are inconsistent, and we hypothesized that their lexical retrieval impairment contributes to verbal episodic memory performance and is associated with left middle temporal gyrus atrophy.Methods: We evaluated patients with lvPPA (n = 12) displaying prominent word-finding and repetition difficulties, and a demographically-matched cohort of clinical Alzheimer's disease (AD, n = 26), and healthy seniors (n = 16). We assessed lexical retrieval with confrontation naming and verbal episodic memory with delayed free recall. Whole-brain regressions related naming and delayed free recall to gray matter atrophy. Medial temporal lobe (MTL) subfields were examined using high in-plane resolution imaging.Results: lvPPA patients had naming and delayed free recall impairments, but intact recognition memory. In lvPPA, delayed free recall was related to naming; both were associated with left middle temporal gyrus atrophy but not MTL atrophy. Despite cerebrospinal fluid evidence consistent with AD pathology, examination of MTL subfields revealed no atrophy in lvPPA. While AD patients displayed impaired delayed free recall, this deficit did not correlate with naming. Regression analyses related delayed free recall deficits in clinical AD patients to MTL subfield atrophy, and naming to left middle temporal gyrus atrophy.Conclusion: Unlike amnestic AD patients, MTL subfields were not affected in lvPPA patients. Verbal episodic memory deficit observed in lvPPA was unlikely to be due to a hippocampal-mediated mechanism but appeared to be due to poor lexical retrieval. Relative sparing of MTL volume and intact recognition memory are consistent with previous reports of hippocampal-sparing variant cases of AD pathology, where neurofibrillary tangles are disproportionately distributed in cortical areas with relative sparing of the hippocampus. This suggests that AD neuropathology in lvPPA may originate in neuronal networks outside of the MTL, which deviates from the typical Braak staging pattern of spreading pathology in clinical AD.

Abstract Background One Health is defined as an integrated, unifying approach that aims to sustainably balance and optimize the health of people, animals and ecosystems; this approach attracts stakeholders from multiple sectors, academic disciplines, and professional practices. The diversity of expertise and interest groups is frequently and simultaneously framed as (1) a strength of the One Health approach in the process of understanding and solving complex problems associated with health challenges such as pathogen spillovers and pandemics and (2) a challenge regarding consensus on essential functions of One Health and the sets of knowledge, skills, and perspectives unique to a workforce adopting this approach. Progress in developing competency-based training in One Health has revealed coverage of various topics across fundamental, technical, functional, and integrative domains. Ensuring that employers value the unique characteristics of personnel trained in One Health will likely require demonstration of its usefulness, accreditation, and continuing professional development. These needs led to the conceptual framework of a One Health Workforce Academy (OHWA) for use as a platform to deliver competency-based training and assessment for an accreditable credential in One Health and opportunities for continuing professional development. Methods To gather information about the desirability of an OHWA, we conducted a survey of One Health stakeholders. The IRB-approved research protocol used an online tool to collect individual responses to the survey questions. Potential respondents were recruited from partners of One Health University Networks in Africa and Southeast Asia and international respondents outside of these networks. Survey questions collected demographic information, measured existing or projected demand and the relative importance of One Health competencies, and determined the potential benefits and barriers of earning a credential. Respondents were not compensated for participation. Results Respondents (N = 231) from 24 countries reported differences in their perspectives on the relative importance of competency domains of the One Health approach. More than 90% of the respondents would seek to acquire a competency-based certificate in One Health, and 60% of respondents expected that earning such a credential would be rewarded by employers. Among potential barriers, time and funding were the most cited. Conclusion This study showed strong support from potential stakeholders for a OHWA that hosts competency-based training with opportunities for certification and continuing professional development.

Abstract Background Bats provide important ecosystem services; however, current evidence supports that they host several zoonotic viruses, including species of the Coronaviridae family. If bats in close interaction with humans host and shed coronaviruses with zoonotic potential, such as the Severe Acute Respiratory Syndrome virus, spillover may occur. Therefore, strategies aiming to mitigate potential spillover and disease emergence, while supporting the conservation of bats and their important ecological roles are needed. Past research suggests that coronavirus shedding in bats varies seasonally following their reproductive cycle; however, shedding dynamics have been assessed in only a few species, which does not allow for generalization of findings across bat taxa and geographic regions. Methods To assess the generalizability of coronavirus shedding seasonality, we sampled hundreds of bats belonging to several species with different life history traits across East Africa at different times of the year. We assessed, via Bayesian modeling, the hypothesis that chiropterans, across species and spatial domains, experience seasonal trends in coronavirus shedding as a function of the reproductive cycle. Results We found that, beyond spatial, taxonomic, and life history differences, coronavirus shedding is more expected when pups are becoming independent from the dam and that juvenile bats are prone to shed these viruses. Conclusions These findings could guide policy aimed at the prevention of spillover in limited-resource settings, where longitudinal surveillance is not feasible, by identifying high-risk periods for coronavirus shedding. In these periods, contact with bats should be avoided (for example, by impeding or forbidding people access to caves). Our proposed strategy provides an alternative to culling – an ethically questionable practice that may result in higher pathogen levels – and supports the conservation of bats and the delivery of their key ecosystem services.

Abstract Recurring outbreaks of emerging and re-emerging zoonoses, such as Ebola virus disease, avian influenza, and Nipah virus, serve as a reminder that the health of humans, animals, and the environment are interconnected and that early response to emerging zoonotic pathogens requires a coordinated, interdisciplinary, cross-sectoral approach. As our world becomes increasingly connected, emerging diseases pose a greater threat, requiring coordination at local, regional, and global levels. One Health is a multisectoral, transdisciplinary, and collaborative approach promoted to more effectively address these complex health threats. Despite strong advocacy for One Health, challenges for practical implementation remain. Here we discuss the value of the One Health approach for addressing global health challenges. We also share strategies applied to achieve successful outcomes through the USAID Emerging Pandemic Threats Program PREDICT project, which serve as useful case studies for implementing One Health approaches. Lastly, we explore methods for promoting more formal One Health implementation to capitalize on the added value of shared knowledge and leveraged resources.

Free-ranging nonhuman primates are frequent sources of zoonotic pathogens due to their physiologic similarity and in many tropical regions, close contact with humans. Many high-risk disease transmission interfaces have not been monitored for zoonotic pathogens due to difficulties inherent to invasive sampling of free-ranging wildlife. Non-invasive surveillance of nonhuman primates for pathogens with high potential for spillover into humans is therefore critical for understanding disease ecology of existing zoonotic pathogen burdens and identifying communities where zoonotic diseases are likely to emerge in the future. We developed a non-invasive oral sampling technique using ropes distributed to nonhuman primates to target viruses shed in the oral cavity, which through bite wounds and discarded food, could be transmitted to people. Optimization was performed by testing paired rope and oral swabs from laboratory colony rhesus macaques for rhesus cytomegalovirus (RhCMV) and simian foamy virus (SFV) and implementing the technique with free-ranging terrestrial and arboreal nonhuman primate species in Uganda and Nepal. Both ubiquitous DNA and RNA viruses, RhCMV and SFV, were detected in oral samples collected from ropes distributed to laboratory colony macaques and SFV was detected in free-ranging macaques and olive baboons. Our study describes a technique that can be used for disease surveillance in free-ranging nonhuman primates and, potentially, other wildlife species when invasive sampling techniques may not be feasible.