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Abstract Positron Emission Tomography (PET) ligands have advanced Alzheimer’s disease (AD) diagnosis and treatment. Using autoradiography and cryo-EM, we identify AD brain tissue with elevated tau burden, purify filaments, and determine the structure of second-generation high avidity PET ligand MK-6240 at 2.31 Å resolution, which bound at a 1:1 ratio within the cleft of tau paired-helical filament (PHF), engaging with glutamine 351, lysine 353, and isoleucine 360. This information elucidates the basis of MK-6240 PET in quantifying PHF deposits in AD and may facilitate the structure-based design of superior ligands against tau amyloids.

Abstract Background Females represent approximately 70% of the Alzheimer’s disease (AD) cases and the literature has proposed a connection between the decreased estrogen levels during menopause and an increased AD risk. Previous investigations have predominantly focused on assessing how hormone therapy (HT) affects the likelihood of AD development and cognitive deterioration. However, as the research framework has shifted toward a biomarker-defined AD and alterations in specific biomarkers could take place years before cognitive decline becomes discernible, it is crucial to examine how HT influences AD biomarkers. The main goal of this study was to evaluate the impact of HT on AD biomarker-informed pathophysiology in both cognitively unimpaired (CU) and cognitively impaired (CI) post-menopausal females across the aging and AD spectrum. Methods This cross-sectional study included post-menopausal females without HT history (HT-) and with HT (HT+) at the time of PET imaging assessment from two cohorts: the Translational Biomarkers in Aging and Dementia (TRIAD) cohort, and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Participants underwent magnetic resonance imaging (MRI), positron emission tomography (PET) and biofluid collection. Voxel-based t-tests were performed to assess the differences in amyloid-β (Aβ) and tau neurofibrillary tangles (NFTs) loads between HT- and HT + females. Linear regression models with interaction terms were also conducted to examine the interactive effects of HT and Aβ-PET on regional tau-PET. Results HT + females demonstrated significantly lower tau-PET standardized uptake value ratio (SUVR) in Braak I-II ROIs (P

Abstract Alzheimer’s disease (AD) is a brain network disorder where pathological proteins accumulate through networks and drive cognitive decline. Yet, the role of network connectivity in facilitating this accumulation remains unclear. Using in-vivo multimodal imaging, we show that the distribution of tau and reactive microglia in humans follows spatial patterns of connectivity variation, the so-called gradients of brain organization. Notably, less distinct connectivity patterns (“gradient contraction”) are associated with cognitive decline in regions with greater tau, suggesting an interaction between reduced network differentiation and tau on cognition. Furthermore, by modeling tau in subject-specific gradient space, we demonstrate that tau accumulation in the frontoparietal and temporo-occipital cortices is associated with greater baseline tau within their functionally and structurally connected hubs, respectively. Our work unveils a role for both functional and structural brain organization in pathology accumulation in AD, and supports subject-specific gradient space as a promising tool to map disease progression.

Abstract The neuromodulatory subcortical nuclei within the isodendritic core (IdC) are the earliest sites of tauopathy in Alzheimer’s disease (AD). They project broadly throughout the brain’s white matter. We investigated the relationship between IdC microstructure and whole-brain white matter microstructure to better understand early neuropathological changes in AD. Using multiparametric quantitative magnetic resonance imaging we observed two covariance patterns between IdC and white matter microstructure in 133 cognitively unimpaired older adults (age 67.9 ± 5.3 years) with familial risk for AD. IdC integrity related to 1) whole-brain neurite density, and 2) neurite orientation dispersion in white matter tracts known to be affected early in AD. Pattern 2 was associated with CSF concentration of phosphorylated-tau, indicating AD specificity. Apolipoprotein-E4 carriers expressed both patterns more strongly than non-carriers. IdC microstructure variation is reflected in white matter, particularly in AD-affected tracts, highlighting an early mechanism of pathological development.

Summary: Biomarkers have been instrumental in population selection and disease monitoring in clinical trials of recently FDA-approved drugs targeting amyloid-β to slow the progression of Alzheimer's disease (AD). As new therapeutic strategies and biomarker techniques emerge, the importance of biomarkers in drug development is growing exponentially. In this emerging landscape, biomarkers are expected to serve a wide range of contexts of use in clinical trials focusing on AD and related dementias. The joint FDA-NIH BEST (Biomarkers, EndpointS, and other Tools) framework provides standardised terminology to facilitate communication among stakeholders in this increasingly complex field. This review explores various applications of biomarkers relevant to AD clinical trials, using the BEST resource as a reference. For simplicity, we predominantly provide contextual characterizations of biomarkers use from the perspective of drugs targeting amyloid-β and tau proteins. However, general definitions and concepts can be extrapolated to other targets.

Abstract Neuronal dysfunction and cognitive deterioration in Alzheimer’s disease (AD) are likely caused by multiple pathophysiological factors. However, mechanistic evidence in humans remains scarce, requiring improved non-invasive techniques and integrative models. We introduce personalized AD computational models built on whole-brain Wilson-Cowan oscillators and incorporating resting-state functional MRI, amyloid-β (Aβ) and tau-PET from 132 individuals in the AD spectrum to evaluate the direct impact of toxic protein deposition on neuronal activity. This subject-specific approach uncovers key patho-mechanistic interactions, including synergistic Aβ and tau effects on cognitive impairment and neuronal excitability increases with disease progression. The data-derived neuronal excitability values strongly predict clinically relevant AD plasma biomarker concentrations (p-tau217, p-tau231, p-tau181, GFAP) and grey matter atrophy obtained through voxel-based morphometry. Furthermore, reconstructed EEG proxy quantities show the hallmark AD electrophysiological alterations (theta band activity enhancement and alpha reductions) which occur with Aβ-positivity and after limbic tau involvement. Microglial activation influences on neuronal activity are less definitive, potentially due to neuroimaging limitations in mapping neuroprotective vs detrimental activation phenotypes. Mechanistic brain activity models can further clarify intricate neurodegenerative processes and accelerate preventive/treatment interventions.

Abstract Blood-based biomarkers for screening may guide tau positrion emissition tomography (PET) scan referrals to optimize prognostic evaluation in Alzheimer’s disease. Plasma Aβ42/Aβ40, pTau181, pTau217, pTau231, NfL, and GFAP were measured along with tau-PET in memory clinic patients with subjective cognitive decline, mild cognitive impairment or dementia, in the Swedish BioFINDER-2 study (n = 548) and in the TRIAD study (n = 179). For each plasma biomarker, cutoffs were determined for 90%, 95%, or 97.5% sensitivity to detect tau-PET-positivity. We calculated the percentage of patients below the cutoffs (who would not undergo tau-PET; “saved scans”) and the tau-PET-positivity rate among participants above the cutoffs (who would undergo tau-PET; “positive predictive value”). Generally, plasma pTau217 performed best. At the 95% sensitivity cutoff in both cohorts, pTau217 resulted in avoiding nearly half tau-PET scans, with a tau-PET-positivity rate among those who would be referred for a scan around 70%. And although tau-PET was strongly associated with subsequent cognitive decline, in BioFINDER-2 it predicted cognitive decline only among individuals above the referral cutoff on plasma pTau217, supporting that this workflow could reduce prognostically uninformative tau-PET scans. In conclusion, plasma pTau217 may guide selection of patients for tau-PET, when accurate prognostic information is of clinical value.

Summary: Background: Research in healthy young adults shows that characteristic patterns of brain activity define individual “brain-fingerprints” that are unique to each person. However, variability in these brain-fingerprints increases in individuals with neurological conditions, challenging the clinical relevance and potential impact of the approach. Our study shows that brain-fingerprints derived from neurophysiological brain activity are associated with pathophysiological and clinical traits of individual patients with Parkinson’s disease (PD). Methods: We created brain-fingerprints from task-free brain activity recorded through magnetoencephalography in 79 PD patients and compared them with those from two independent samples of age-matched healthy controls (N = 424 total). We decomposed brain activity into arrhythmic and rhythmic components, defining distinct brain-fingerprints for each type from recording durations of up to 4 min and as short as 30 s. Findings: The arrhythmic spectral components of cortical activity in patients with Parkinson’s disease are more variable over short periods, challenging the definition of a reliable brain-fingerprint. However, by isolating the rhythmic components of cortical activity, we derived brain-fingerprints that distinguished between patients and healthy controls with about 90% accuracy. The most prominent cortical features of the resulting Parkinson’s brain-fingerprint are mapped to polyrhythmic activity in unimodal sensorimotor regions. Leveraging these features, we also demonstrate that Parkinson’s symptom laterality can be decoded directly from cortical neurophysiological activity. Furthermore, our study reveals that the cortical topography of the Parkinson’s brain-fingerprint aligns with that of neurotransmitter systems affected by the disease’s pathophysiology. Interpretation: The increased moment-to-moment variability of arrhythmic brain-fingerprints challenges patient differentiation and explains previously published results. We outline patient-specific rhythmic brain signaling features that provide insights into both the neurophysiological signature and symptom laterality of Parkinson’s disease. Thus, the proposed definition of a rhythmic brain-fingerprint of Parkinson’s disease may contribute to novel, refined approaches to patient stratification. Symmetrically, we discuss how rhythmic brain-fingerprints may contribute to the improved identification and testing of therapeutic neurostimulation targets. Funding: Data collection and sharing for this project was provided by the Quebec Parkinson Network (QPN), the Pre-symptomatic Evaluation of Novel or Experimental Treatments for Alzheimer’s Disease (PREVENT-AD; release 6.0) program, the Cambridge Centre for Aging Neuroscience (Cam-CAN), and the Open MEG Archives (OMEGA). The QPN is funded by a grant from Fonds de Recherche du Québec - Santé (FRQS). PREVENT-AD was launched in 2011 as a $13.5 million, 7-year public-private partnership using funds provided by McGill University, the FRQS, an unrestricted research grant from Pfizer Canada, the Levesque Foundation, the Douglas Hospital Research Centre and Foundation, the Government of Canada, and the Canada Fund for Innovation. The Brainstorm project is supported by funding to SB from the NIH (R01-EB026299-05). Further funding to SB for this study included a Discovery grant from the Natural Sciences and Engineering Research Council of Canada of Canada (436355-13), and the CIHR Canada research Chair in Neural Dynamics of Brain Systems (CRC-2017-00311).

The molecular mechanisms underlying neuronal dysfunction in Alzheimer’s disease (AD) remain uncharacterized. Here, we identify genes, molecular pathways and cellular components associated with whole-brain dysregulation caused by amyloid-beta (Aβ) and tau deposits in the living human brain. We obtained in-vivo resting-state functional MRI (rs-fMRI), Aβ- and tau-PET for 47 cognitively unimpaired and 16 AD participants from the Translational Biomarkers in Aging and Dementia cohort. Adverse neuronal activity impacts by Aβ and tau were quantified with personalized dynamical models by fitting pathology-mediated computational signals to the participant’s real rs-fMRIs. Then, we detected robust brain-wide associations between the spatial profiles of Aβ-tau impacts and gene expression in the neurotypical transcriptome (Allen Human Brain Atlas). Within the obtained distinctive signature of in-vivo neuronal dysfunction, several genes have prominent roles in microglial activation and in interactions with Aβ and tau. Moreover, cellular vulnerability estimations revealed strong association of microglial expression patterns with Aβ and tau’s synergistic impact on neuronal activity (q

Abstract Background Antibody-based immunoassays have enabled quantification of very low concentrations of phosphorylated tau (p-tau) protein forms in cerebrospinal fluid (CSF), aiding in the diagnosis of AD. Mass spectrometry enables absolute quantification of multiple p-tau variants within a single run. The goal of this study was to compare the performance of mass spectrometry assessments of p-tau181, p-tau217 and p-tau231 with established immunoassay techniques. Methods We measured p-tau181, p-tau217 and p-tau231 concentrations in CSF from 173 participants from the TRIAD cohort and 394 participants from the BioFINDER-2 cohort using both mass spectrometry and immunoassay methods. All subjects were clinically evaluated by dementia specialists and had amyloid-PET and tau-PET assessments. Bland–Altman analyses evaluated the agreement between immunoassay and mass spectrometry p-tau181, p-tau217 and p-tau231. P-tau associations with amyloid-PET and tau-PET uptake were also compared. Receiver Operating Characteristic (ROC) analyses compared the performance of mass spectrometry and immunoassays p-tau concentrations to identify amyloid-PET positivity. Results Mass spectrometry and immunoassays of p-tau217 were highly comparable in terms of diagnostic performance, between-group effect sizes and associations with PET biomarkers. In contrast, p-tau181 and p-tau231 concentrations measured using antibody-free mass spectrometry had lower performance compared with immunoassays. Conclusions Our results suggest that while similar overall, immunoassay-based p-tau biomarkers are slightly superior to antibody-free mass spectrometry-based p-tau biomarkers. Future work is needed to determine whether the potential to evaluate multiple biomarkers within a single run offsets the slightly lower performance of antibody-free mass spectrometry-based p-tau quantification.

Summary: Background: Neuroimaging studies often quantify tau burden in standardized brain regions to assess Alzheimer disease (AD) progression. However, this method ignores another key biological process in which tau spreads to additional brain regions. We have developed a metric for calculating the extent tau pathology has spread throughout the brain and evaluate the relationship between this metric and tau burden across early stages of AD. Methods: 445 cross-sectional participants (aged ≥ 50) who had MRI, amyloid PET, tau PET, and clinical testing were separated into disease-stage groups based on amyloid positivity and cognitive status (older cognitively normal control, preclinical AD, and symptomatic AD). Tau burden and tau spatial spread were calculated for all participants. Findings: We found both tau metrics significantly elevated across increasing disease stages (p

Children who experienced moderate perinatal asphyxia (MPA) are at risk of developing long lasting subtle cognitive and behavioral deficits, including learning disabilities and emotional problems. The prefrontal cortex (PFC) regulates cognitive flexibility and emotional behavior. Neurons that release serotonin (5-HT) project to the PFC, and compounds modulating 5-HT activity influence emotion and cognition. Whether 5-HT dysregulations contribute to MPA-induced cognitive problems is unknown. We established a MPA mouse model, which displays recognition and spatial memory impairments and dysfunctional cognitive flexibility. We found that 5-HT expression levels, quantified by immunohistochemistry, and 5-HT release, quantified by in vivo microdialysis in awake mice, are reduced in PFC of adult MPA mice. MPA mice also show impaired body temperature regulation following injection of the 5-HT1A receptor agonist 8-OH-DPAT, suggesting the presence of deficits in 5-HT auto-receptor function on raphe neurons. Finally, chronic treatment of adult MPA mice with fluoxetine, an inhibitor of 5-HT reuptake transporter, or the 5-HT1A receptor agonist tandospirone rescues cognitive flexibility and memory impairments. All together, these data demonstrate that the development of 5-HT system function is vulnerable to moderate perinatal asphyxia. 5-HT hypofunction might in turn contribute to long-term cognitive impairment in adulthood, indicating a potential target for pharmacological therapies.

Summary: Background: Blood-based biomarkers of Alzheimer’s disease (AD) have become increasingly important as scalable tools for diagnosis and determining clinical trial eligibility. P-tau217 is the most promising due to its excellent sensitivity and specificity for AD-related pathological changes. Methods: We compared the performance of two commercially available plasma p-tau217 assays (ALZpath p-tau217 and Janssen p-tau217+) in 294 individuals cross-sectionally. Correlations with amyloid PET and tau PET were assessed, and Receiver Operating Characteristic (ROC) analyses evaluated both p-tau217 assays for identifying AD pathology. Findings: Both plasma p-tau217 assays were strongly associated with amyloid and tau PET. Furthermore, both plasma p-tau217 assays identified individuals with AD vs other neurodegenerative diseases (ALZpath AUC = 0.95; Janssen AUC = 0.96). Additionally, plasma p-tau217 concentrations rose with AD severity and their annual changes correlated with tau PET annual change. Interpretation: Both p-tau217 assays had excellent diagnostic performance for AD. Our study supports the future clinical use of commercially-available assays for p-tau217. Funding: This research is supported by the Weston Brain Institute, Canadian Institutes of Health Research (CIHR), Canadian Consortium on Neurodegeneration in Aging, the Alzheimer's Association, Brain Canada Foundation, the Fonds de Recherche du Québec - Santé and the Colin J. Adair Charitable Foundation.

Abstract Introduction Synaptic loss is closely associated with tau aggregation and microglia activation in later stages of Alzheimer’s disease (AD). However, synaptic damage happens early in AD at the very early stages of tau accumulation. It remains unclear whether microglia activation independently causes synaptic cleavage before tau aggregation appears. Methods We investigated 104 participants across the AD continuum by measuring 14-3-3 zeta/delta ( $$\upzeta /\updelta$$ ζ / δ ) as a cerebrospinal fluid biomarker for synaptic degradation, and fluid and imaging biomarkers of tau, amyloidosis, astrogliosis, neurodegeneration, and inflammation. We performed correlation analyses in cognitively unimpaired and impaired participants and used structural equation models to estimate the impact of microglia activation on synaptic injury in different disease stages. Results 14-3-3 $$\upzeta /\updelta$$ ζ / δ was increased in participants with amyloid pathology at the early stages of tau aggregation before hippocampal volume loss was detectable. 14-3-3 $$\upzeta /\updelta$$ ζ / δ correlated with amyloidosis and tau load in all participants but only with biomarkers of neurodegeneration and memory deficits in cognitively unimpaired participants. This early synaptic damage was independently mediated by sTREM2. At later disease stages, tau and astrogliosis additionally mediated synaptic loss. Conclusions Our results advertise that sTREM2 is mediating synaptic injury at the early stages of tau accumulation, underlining the importance of microglia activation for AD disease propagation.

Abstract In Parkinson’s disease (PD), motor dysfunctions only become apparent after extensive loss of DA innervation. This resilience has been hypothesized to be due to the ability of many motor behaviors to be sustained through a diffuse basal tone of DA; but experimental evidence for this is limited. Here we show that conditional deletion of the calcium sensor synaptotagmin-1 (Syt1) in DA neurons (Syt1 cKODA mice) abrogates most activity-dependent axonal DA release in the striatum and mesencephalon, leaving somatodendritic (STD) DA release intact. Strikingly, Syt1 cKODA mice showed intact performance in multiple unconditioned DA-dependent motor tasks and even in a task evaluating conditioned motivation for food. Considering that basal extracellular DA levels in the striatum were unchanged, our findings suggest that activity-dependent DA release is dispensable for such tasks and that they can be sustained by a basal tone of extracellular DA. Taken together, our findings reveal the striking resilience of DA-dependent motor functions in the context of a near-abolition of phasic DA release, shedding new light on why extensive loss of DA innervation is required to reveal motor dysfunctions in PD.

Introduction: Cerebral small vessel disease (SVD) is a common co-pathology in elderly and individuals with dementia. Neuroimaging markers of SVD include white matter hyperintensities (WMH) and MRI-visible perivascular spaces (PVS). However, the mechanisms underlying changes in these markers over time, whether ischemic or beta-amyloid (Aβ)-related, remain elusive. Here, we evaluated the effects of microstructural injury in the normal-appearing white matter and Aβ in the cerebral cortex on the progression of WMH and PVS over three years. Methods: Data was obtained from two independent cohorts: (i) TRIAD, comprising cognitively normal, MCI, and AD dementia participants (baseline: N=199, follow-up year 1 and 2: N=102 and 62); and (ii) MITNEC-C6, comprising “real-world” patients with mixed dementia and moderate-to- severe WMH burden (baseline: N=52, 2 years follow-up: N=25). We quantified global WMH and PVS volumes from FLAIR and T1w MRI. At baseline, we examined associations between these volumes and diffusion MRI-derived free water. Longitudinally, we employed linear [mixed-effect] models to investigate the relation of WMH or PVS volume changes over time with baseline free water, using cortical Aβ-PET, age, sex, and APOE-ε4 as covariates. Results: In TRIAD and MITNEC-C6 respectively, mean ages were 72±6 and 77±8 y, 60% and 42% were female, and 41% and 48% were Aβ-positive. At baseline, higher free water in normal- appearing white matter was associated with higher WMH volume (β_TRIAD=+0.34±0.06, P_TRIAD

Summary: Alzheimer’s disease (AD) is a multifactorial pathology, with most cases having a sporadic origin. Recently, knock-in (KI) mouse models, such as the novel humanized amyloid-β (hAβ)-KI, have been developed to better resemble sporadic human AD. METHODS: Here, we compared hippocampal publicly available transcriptomic profiles of transgenic (5xFAD and APP/PS1) and KI (hAβ-KI) mouse models with early- (EOAD) and late- (LOAD) onset AD patients. RESULTS: The three mouse models presented more Gene Ontology biological processes terms and enriched signaling pathways in common with LOAD than with EOAD individuals. Experimental validation of consistently dysregulated genes revealed five altered in mice (SLC11A1, S100A6, CD14, CD33, and C1QB) and three in humans (S100A6, SLC11A1, and KCNK). Finally, we identified 17 transcription factors potentially acting as master regulators of AD. CONCLUSION: Our cross-species analyses revealed that the three mouse models presented a remarkable similarity to LOAD, with the hAβ-KI being the more specific one.

BackgroundAlzheimer’s disease (AD) diagnosis in its early stages remains difficult with current diagnostic approaches. Though tau neurofibrillary tangles (NFTs) generally follow the stereotypical pattern described by the Braak staging scheme, the network degeneration hypothesis (NDH) has suggested that NFTs spread selectively along functional networks of the brain. To evaluate this, we implemented a Bayesian workflow to develop hierarchical multinomial logistic regression models with increasing levels of complexity of the brain from tau-PET and structural MRI data to investigate whether it is beneficial to incorporate network-level information into an ROI-based predictive model for the presence/absence of AD.MethodsThis study included data from the Translational Biomarkers in Aging and Dementia (TRIAD) longitudinal cohort from McGill University’s Research Centre for Studies in Aging (MCSA). Baseline and 1 year follow-up structural MRI and [18F]MK-6240 tau-PET scans were acquired for 72 cognitive normal (CN), 23 mild cognitive impairment (MCI), and 18 Alzheimer’s disease dementia subjects. We constructed the four following hierarchical Bayesian models in order of increasing complexity: (Model 1) a complete-pooling model with observations, (Model 2) a partial-pooling model with observations clustered within ROIs, (Model 3) a partial-pooling model with observations clustered within functional networks, and (Model 4) a partial-pooling model with observations clustered within ROIs that are also clustered within functional brain networks. We then investigated which of the models had better predictive performance given tau-PET or structural MRI data as an input, in the form of a relative annualized rate of change.ResultsThe Bayesian leave-one-out cross-validation (LOO-CV) estimate of the expected log pointwise predictive density (ELPD) results indicated that models 3 and 4 were substantially better than other models for both tau-PET and structural MRI inputs. For tau-PET data, model 3 was slightly better than 4 with an absolute difference in ELPD of 3.10 ± 1.30. For structural MRI data, model 4 was considerably better than other models with an absolute difference in ELPD of 29.83 ± 7.55 relative to model 3, the second-best model.ConclusionOur results suggest that representing the data generating process in terms of a hierarchical model that encompasses both ROI-level and network-level heterogeneity leads to better predictive ability for both tau-PET and structural MRI inputs over all other model iterations.

Abstract Background Behavioral variant frontotemporal dementia (bvFTD) is predominantly considered a dysfunction in cortico-cortical transmission, with limited direct investigation of cortical-subcortical transmission. Thus, we aimed to characterize the metabolic connectivity between areas of the limbic cortico-striato-thalamic-cortical (CSTC) circuit in presymptomatic and symptomatic bvFTD patients. Methods Thirty-three bvFTD patients and 33 unrelated healthy controls were recruited for this study. Additionally, six asymptomatic carriers of the MAPT P301L mutation were compared with 12 non-carriers who were all from the same family of bvFTD. Each participant underwent neuropsychological assessment, genetic testing, and a hybrid PET/MRI scan. Seed-based metabolic connectivity based on [18F]-fluorodeoxyglucose PET between the main components within the limbic CSTC circuit was explored according to the Oxford-GSK-Imanova Striatal Connectivity Atlas. Results BvFTD patients exhibited reduced metabolic connectivity between the relays in the limbic CSTC circuit, which included the frontal region (ventromedial prefrontal cortex, orbitofrontal cortex, rectus gyrus, and anterior cingulate cortex), the limbic striatum, and thalamus compared to controls. In the bvFTD patients, the involvement of the limbic CSTC circuit was associated with the severity of behavior disruption, as measured by the frontal behavior inventory, the disinhibition subscale, and the apathy subscale. Notably, asymptomatic MAPT carriers had weakened frontostriatal connectivity but enhanced striatothalamus and thalamofrontal connectivity within the limbic CSTC circuit compared with noncarriers. Conclusion These findings suggested that aberrant metabolic connectivity within the limbic CSTC circuit is present in symptomatic and even asymptomatic stages of bvFTD. Thus, metabolic connectivity patterns could be used as a potential biomarker to detect the presymptomatic stage and track disease progression.

Abstract Introduction Cerebrospinal fluid (CSF) tau biomarkers are reliable diagnostic markers for Alzheimer’s disease (AD). However, their strong association with amyloid pathology may limit their reliability as specific markers of tau neurofibrillary tangles. A recent study showed evidence that a ratio of CSF C-terminally truncated tau (tau368, a tangle-enriched tau species), especially in ratio with total tau (t-tau), correlates strongly with tau PET tracer uptake. In this study, we set to evaluate the performance of the tau368/t-tau ratio in capturing tangle pathology, as indexed by a high-affinity tau PET tracer, as well as its association with severity of clinical symptoms. Methods In total, 125 participants were evaluated cross-sectionally from the Translational Biomarkers of Aging and Dementia (TRIAD) cohort (21 young, 60 cognitively unimpaired [CU] elderly [15 Aβ+], 10 Aβ+ with mild cognitive impairment [MCI], 14 AD dementia patients, and 20 Aβ− individuals with non-AD cognitive disorders). All participants underwent amyloid and tau PET scanning, with [18F]-AZD4694 and [18F]-MK6240, respectively, and had CSF measurements of p-tau181, p-tau217, and t-tau. CSF concentrations of tau368 were quantified in all individuals with an in-house single molecule array assay. Results CSF tau368 concentration was not significantly different across the diagnostic groups, although a modest increase was observed in all groups as compared with healthy young individuals (all P < 0.01). In contrast, the CSF tau368/t-tau ratio was the lowest in AD dementia, being significantly lower than in CU individuals (Aβ−, P < 0.001; Aβ+, P < 0.01), as well as compared to those with non-AD cognitive disorders (P < 0.001). Notably, in individuals with symptomatic AD, tau368/t-tau correlated more strongly with [18F]-MK6240 PET SUVR as compared to the other CSF tau biomarkers, with increasing associations being seen in brain regions associated with more advanced disease (isocortical regions > limbic regions > transentorhinal regions). Importantly, linear regression models indicated that these associations were not confounded by Aβ PET SUVr. CSF tau368/t-tau also tended to continue to become more abnormal with higher tau burden, whereas the other biomarkers plateaued after the limbic stage. Finally, the tau368/t-tau ratio correlated more strongly with cognitive performance in individuals with symptomatic AD as compared to t-tau, p-tau217 and p-tau181. Conclusion The tau368/t-tau ratio captures novel aspects of AD pathophysiology and disease severity in comparison to established CSF tau biomarkers, as it is more closely related to tau PET SUVR and cognitive performance in the symptomatic phase of the disease.

Abstract Background Alzheimer’s disease is characterized by an abnormal increase of phosphorylated tau (pTau) species in the CSF. It has been suggested that emergence of different pTau forms may parallel disease progression. Therefore, targeting multiple specific pTau forms may allow for a deeper understanding of disease evolution and underlying pathophysiology. Current immunoassays measure pTau epitopes separately and may capture phosphorylated tau fragments of different length depending on the non-pTau antibody used in the assay sandwich pair, which bias the measurement. Methods We developed the first antibody-free mass spectrometric method to simultaneously measure multiple phosphorylated epitopes in CSF tau: pT181, pS199, pS202, pT205, pT217, pT231, and pS396. The method was first evaluated in biochemically defined Alzheimer’s disease and control CSF samples (n = 38). All seven pTau epitopes clearly separated Alzheimer’s disease from non-AD (p

Abstract The chromosome 9 open reading frame 72 (C9ORF72) has been proposed as the causative gene of frontotemporal dementia with parkinsonism (FTDP), but its pathophysiological mechanism of parkinsonism is poorly understood. To explore the roles of striatal motor subdivisions in the pathogenesis of parkinsonism resulting from C9ORF72 repeat expansions in the FTDP, two patients with FTDP from one pedigree and seventeen healthy controls were enrolled. The participants received clinical interviews, physical examinations, genetic testing, [18F]-fluorodeoxyglucose PET/MRI, and [18F]-dihydrotetrabenazine PET/CT. Voxel-wise and region of interest analysis were conducted with respect to gray matter volume, metabolism, and dopamine transport function between patients and controls, focusing on the motor part of the striatum according to the Oxford-GSK-Imanova Striatal Connectivity Atlas. Patient 1 presented with parkinsonism as the initial symptom, while patient 2 exhibited behavior disturbance as the first symptom, followed by parkinsonism within one year. Both patients had the hexanucleotide expansion detected in C9ORF72(>52 repeats). Gray matter volume atrophy, hypometabolism and dopamine dysfunction were observed in the motor areas of the striatum. Of the two patients, marked glucose hypometabolism within the striatal motor subregion was observed in patient 1, with corresponding gray matter atrophy. In addition, presynaptic dopaminergic integrity of patient 2 was deteriorated in the motor subregions which was consistent with gray matter atrophy. These findings imply that parkinsonism in FTDP may be associated with the degeneration and dopaminergic dysfunction of the striatal motor subregion, which might be attributed to C9orf72 repeat expansions.

Abstract Introduction [18F]AZD4694 is an amyloid beta (Aβ) imaging agent used in several observational studies and clinical trials. However, no studies have yet published data on longitudinal Aβ accumulation measured with [18F]AZD4694. Methods We assessed 146 individuals who were evaluated with [18F]AZD4694 at baseline and 2‐year follow‐up. We calculated annual rates of [18F]AZD4694 change for clinically defined and biomarker‐defined groups Results Cognitively unimpaired (CU) older adults displayed subtle [18F]AZD4694 standardized uptake value ratio (SUVR) accumulation over the follow‐up period. In contrast, Aβ positive CU older adults displayed higher annual [18F]AZD4694 SUVR increases. [18F]AZD4694 SUVR accumulation in Aβ positive mild cognitive impairment (MCI) and dementia was modest across the neocortex Discussion Larger increases in [18F]AZD4694 SUVR were observed in CU individuals who had abnormal amyloid positron emission tomography levels at baseline. [18F]AZD4694 can be used to monitor Aβ levels in therapeutic trials as well as clinical settings, particularly prior to initiating anti‐amyloid therapies.

BackgroundVirtual reality (VR) based meditation has been shown to help increase relaxation and decrease anxiety and depression in younger adults. However, this has not been studied in Randomized Controlled Trials (RCT) in the older adult population. The aim of this RCT is to assess the feasibility and acceptability of a VR-guided meditation intervention for community-dwelling older adults and its effect on stress and mental health.MethodsWe will recruit 30 participants aged ≥ 60 years, whose perceived stress score (PSS) is > 14 (moderate stress), and randomize them 1:1 to the intervention or control waitlist group. The intervention will involve exposure to eight 15-min VR-guided meditation sessions distributed twice weekly for 4-weeks. Two modalities will be offered: in-home and at the hospital.Data analysisBaseline and post-intervention assessments will evaluate perceived stress, anxiety, depression, sleep quality, quality of life, and mindfulness skills. Analyses will employ mixed methods repeated ANOVA tests. Qualitative analyses through semi-structured interviews and participant observation will be used to assess participants’ experiences. Study outcomes include: (A) feasibility and acceptability compared to a waitlist control (B) stress, using the Perceived Stress Scale (PSS); (C) anxiety, and depression, using the Generalized Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire-9 (PHQ-9); (D) insomnia, quality of life and mindfulness skills, using the Athens Insomnia Scale (AIS), Quality of Life Questionnaire (EQ-5D-5L) and Five Facets Mindfulness Questionnaire Short Forms (FFMQ-SF), respectively. We will also measure immersive tendencies, sickness and sense of presence using the Simulator Sickness Questionnaire (SSQ) and the Presence Questionnaire (PQ).DiscussionVirtual reality-guided meditation could be an acceptable, feasible, safe, and cost-effective novel alternative health intervention for improving older adults’ mental health.Clinical trial registration: NCT05315609 at https://clinicaltrials.gov.

The link between amyloid and tau proteins with Alzheimer’s disease progression remains unclear. Here, the authors propose HDACs I downregulation as an element linking the deleterious effects of brain proteinopathies with disease progression.

Abstract Background Synaptic dysfunction and degeneration are central to Alzheimer’s disease (AD) and have been found to correlate strongly with cognitive decline. Thus, studying cerebrospinal fluid (CSF) biomarkers reflecting synaptic degeneration, such as the presynaptic protein synaptosomal-associated protein 25 (SNAP-25), is of importance to better understand the AD pathophysiology. Methods We compared a newly developed Single molecule array (Simoa) immunoassay for SNAP-25 with an in-house immunoprecipitation mass spectrometry (IP-MS) method in a well-characterized clinical cohort (n = 70) consisting of cognitively unimpaired (CU) and cognitively impaired (CI) individuals with and without Aβ pathology (Aβ+ and Aβ−). Results A strong correlation (Spearman’s rank correlation coefficient (r s) > 0.88; p < 0.0001) was found between the Simoa and IP-MS methods, and no statistically significant difference was found for their clinical performance to identify AD pathophysiology in the form of Aβ pathology. Increased CSF SNAP-25 levels in CI Aβ+ compared with CU Aβ− (Simoa, p ≤ 0.01; IP-MS, p ≤ 0.05) and CI Aβ− (Simoa, p ≤ 0.01; IP-MS, p ≤ 0.05) were observed. In independent blood samples (n = 32), the Simoa SNAP-25 assay was found to lack analytical sensitivity for quantification of SNAP-25 in plasma. Conclusions These results indicate that the Simoa SNAP-25 method can be used interchangeably with the IP-MS method for the quantification of SNAP-25 in CSF. Additionally, these results confirm that CSF SNAP-25 is increased in relation to amyloid pathology in the AD continuum.

Background: Neurotransmitters deficits in Frontotemporal Dementia (FTD) are still poorly understood. Better knowledge of neurotransmitters impairment, especially in prodromal disease stages, might tailor symptomatic treatment approaches. Methods: In the present study, we applied JuSpace toolbox, which allowed for cross-modal correlation of Magnetic Resonance Imaging (MRI)-based measures with nuclear imaging derived estimates covering various neurotransmitter systems including dopaminergic, serotonergic, noradrenergic, GABAergic and glutamatergic neurotransmission.We included 392 mutation carriers (157 GRN, 164 C9orf72, 71 MAPT), together with 276 non-carrier cognitively healthy controls (HC). We tested if the spatial patterns of grey matter volume (GMV) alterations in mutation carriers (relative to HC) are correlated with specific neurotransmitter systems in prodromal (CDR® plus NACC FTLD = 0.5) and in symptomatic (CDR® plus NACC FTLD≥1) FTD. Results: In prodromal stages of C9orf72 disease, voxel-based brain changes were significantly associated with spatial distribution of dopamine and acetylcholine pathways; in prodromal MAPT disease with dopamine and serotonin pathways, while in prodromal GRN disease no significant findings were reported (p

Abstract Background Studies exploring topological properties of the metabolic network during the presymptomatic stage of genetic frontotemporal dementia (FTD) are scarce. However, such knowledge is important for understanding brain function and disease pathogenesis. Therefore, we aimed to explore FTD-specific patterns of metabolism topology reconfiguration in microtubule-associated protein tau (MAPT) mutation carriers before the onset of symptoms. Methods Six asymptomatic carriers of the MAPT P301L mutation were compared with 12 non-carriers who all belonged to the same family of FTD. For comparison, we included 32 behavioral variant FTD (bvFTD) patients and 33 unrelated healthy controls. Each participant underwent neuropsychological assessments, genetic testing, and a hybrid positron emission tomography (PET)/magnetic resonance imaging (MRI) scan. Voxel-wise gray matter volumes and standardized uptake value ratios were calculated and compared for structural MRI and fluorodeoxyglucose (FDG)-PET, separately. The sparse inverse covariance estimation method (SICE) was applied to topological properties and metabolic connectomes of brain functional networks derived from 18F-FDG PET/MRI data. Independent component analysis was used to explore the metabolic connectivity of the salience (SN) and default mode networks (DMN). Results The asymptomatic MAPT carriers performed normal global parameters of the metabolism network, whereas bvFTD patients did not. However, we revealed lost hubs in the ventromedial prefrontal, orbitofrontal, and anterior cingulate cortices and reconfigured hubs in the anterior insula, precuneus, and posterior cingulate cortex in asymptomatic carriers compared with non-carriers, which overlapped with the comparisons between bvFTD patients and controls. Similarly, significant differences in local parameters of these nodes were present between asymptomatic carriers and non-carriers. The reduction in the connectivity of lost hub regions and the enhancement of connectivity between reconfigured hubs and components of the frontal cortex were marked during the asymptomatic stage. Metabolic connectivity within the SN and DMN was enhanced in asymptomatic carriers compared with non-mutation carriers but reduced in bvFTD patients relative to controls. Conclusions Our findings showed that metabolism topology reconfiguration, characterized by the earliest involvement of medial prefrontal areas and active compensation in task-related regions, was present in the presymptomatic phase of genetic FTD with MAPT mutation, which may be used as an imaging biomarker of increased risk of FTD.

Background: Among a rapidly aging population, there is increased need for neuroprotective interventions promoting healthy neurological aging. Mind-body interventions, such as Kundalini yoga, are actively being explored as accessible means to encourage healthy aging. However, little remains known about the neurobiological effects of Kundalini yoga. Aims: This pilot randomized-controlled trial (RCT) examined the potential neuroprotective effects of Kundalini yoga in older adults. Methods: We conducted an RCT with 11 healthy meditation-naïve older adults. Participants were randomized to a Kundalini yoga or psychoeducation intervention. Structural magnetic resonance imaging data were obtained at baseline and 12-week follow-up. The primary outcome measure was gray matter volume of the bilateral hippocampi and bilateral posterior cingulate cortex. Results: We found significant right hippocampal volume increases specific to the Kundalini yoga group (P = 0.034, ηp2 = 0.408). Conclusions: These findings provide initial neurobiological support for the neuroprotective effects of Kundalini yoga.

BackgroundStudies have shown that prenatal maternal stress alters volumes of the amygdala and hippocampus, and alters functional connectivity between the amygdala and prefrontal cortex. However, it remains unclear whether prenatal maternal stress (PNMS) affects volumes and functional connectivity of these structures at their subdivision levels.MethodsT1-weighted MRI and resting-state functional MRI were obtained from 19-year-old young adult offspring with (n = 39, 18 male) and without (n = 65, 30 male) exposure to PNMS deriving from the 1998 ice storm. Volumes of amygdala nuclei, hippocampal subfields and prefrontal subregions were computed, and seed-to-seed functional connectivity analyses were conducted.ResultsCompared to controls, young adult offspring exposed to disaster-related PNMS had larger volumes of bilateral whole amygdala, driven by the lateral, basal, central, medial, cortical, accessory basal nuclei, and corticoamygdaloid transition; larger volumes of bilateral whole hippocampus, driven by the CA1, HATA, molecular layer, fissure, tail, CA3, CA4, and DG; and larger volume of the prefrontal cortex, driven by the left superior frontal. Inversely, young adult offspring exposed to disaster-related PNMS had lower functional connectivity between the whole amygdala and the prefrontal cortex (driven by bilateral frontal poles, the left superior frontal and left caudal middle frontal); and lower functional connectivity between the hippocampal tail and the prefrontal cortex (driven by the left lateral orbitofrontal).ConclusionThese results suggest the possibility that effects of disaster-related PNMS on structure and function of subdivisions of offspring amygdala, hippocampus and prefrontal cortex could persist into young adulthood.

Abstract Background The positron emission tomography (PET) radiotracer [18F]MK‐6240 exhibits high specificity for neurofibrillary tangles (NFTs) of tau protein in Alzheimer's disease (AD), high sensitivity to medial temporal and neocortical NFTs, and low within‐brain background. Objectives were to develop and validate a reproducible, clinically relevant visual read method supporting [18F]MK‐6240 use to identify and stage AD subjects versus non‐AD and controls. Methods Five expert readers used their own methods to assess 30 scans of mixed diagnosis (47% cognitively normal, 23% mild cognitive impairment, 20% AD, 10% traumatic brain injury) and provided input regarding regional and global positivity, features influencing assessment, confidence, practicality, and clinical relevance. Inter‐reader agreement and concordance with quantitative values were evaluated to confirm that regions could be read reliably. Guided by input regarding clinical applicability and practicality, read classifications were defined. The readers read the scans using the new classifications, establishing by majority agreement a gold standard read for those scans. Two naïve readers were trained and read the 30‐scan set, providing initial validation. Inter‐rater agreement was further tested by two trained independent readers in 131 scans. One of these readers used the same method to read a full, diverse database of 1842 scans; relationships between read classification, clinical diagnosis, and amyloid status as available were assessed. Results Four visual read classifications were determined: no uptake, medial temporal lobe (MTL) only, MTL and neocortical uptake, and uptake outside MTL. Inter‐rater kappas were 1.0 for the naïve readers gold standard scans read and 0.98 for the independent readers 131‐scan read. All scans in the full database could be classified; classification frequencies were concordant with NFT histopathology literature. Discussion This four‐class [18F]MK‐6240 visual read method captures the presence of medial temporal signal, neocortical expansion associated with disease progression, and atypical distributions that may reflect different phenotypes. The method demonstrates excellent trainability, reproducibility, and clinical relevance supporting clinical use. Highlights A visual read method has been developed for [18F]MK‐6240 tau positron emission tomography. The method is readily trainable and reproducible, with inter‐rater kappas of 0.98. The read method has been applied to a diverse set of 1842 [18F]MK‐6240 scans. All scans from a spectrum of disease states and acquisitions could be classified. Read classifications are consistent with histopathological neurofibrillary tangle staging literature.

Abstract Introduction The optimal combination of amyloid‐β/tau/neurodegeneration (A/T/N) biomarker profiles for the diagnosis of Alzheimer's disease (AD) dementia is unclear. Methods We examined the discriminative accuracy of A/T/N combinations assessed with neuroimaging biomarkers for the differentiation of AD from cognitively unimpaired (CU) elderly and non‐AD neurodegenerative diseases in the TRIAD, BioFINDER‐1 and BioFINDER‐2 cohorts (total n = 832) using area under the receiver operating characteristic curves (AUC). Results For the diagnosis of AD dementia (vs. CU elderly), T biomarkers performed as well as the complete A/T/N system (AUC range: 0.90–0.99). A and T biomarkers in isolation performed as well as the complete A/T/N system in differentiating AD dementia from non‐AD neurodegenerative diseases (AUC range; A biomarker: 0.84–1; T biomarker: 0.83–1). Discussion In diagnostic settings, the use of A or T neuroimaging biomarkers alone can reduce patient burden and medical costs compared with using their combination, without significantly compromising accuracy.

Alzheimer's disease and related dementias is a major public health burden-compounding over upcoming years due to longevity. Recently, clinical evidence hinted at the experience of social isolation in expediting dementia onset. In 502,506 UK Biobank participants and 30,097 participants from the Canadian Longitudinal Study of Aging, we revisited traditional risk factors for developing dementia in the context of loneliness and lacking social support. Across these measures of subjective and objective social deprivation, we have identified strong links between individuals' social capital and various indicators of Alzheimer's disease and related dementias risk, which replicated across both population cohorts. The quality and quantity of daily social encounters had deep connections with key aetiopathological factors, which represent 1) personal habits and lifestyle factors, 2) physical health, 3) mental health, and 4) societal and external factors. Our population-scale assessment suggest that social lifestyle determinants are linked to most neurodegeneration risk factors, highlighting them as promising targets for preventive clinical action.

Abstract Background Changes in soluble amyloid-beta (Aβ) levels in cerebrospinal fluid (CSF) are detectable at early preclinical stages of Alzheimer’s disease (AD). However, whether Aβ levels can predict downstream AD pathological features in cognitively unimpaired (CU) individuals remains unclear. With this in mind, we aimed at investigating whether a combination of soluble Aβ isoforms can predict tau pathology (T+) and neurodegeneration (N+) positivity. Methods We used CSF measurements of three soluble Aβ peptides (Aβ1 –38, Aβ1 –40 and Aβ1 –42) in CU individuals (n = 318) as input features in machine learning (ML) models aiming at predicting T+ and N+. Input data was used for building 2046 tuned predictive ML models with a nested cross-validation technique. Additionally, proteomics data was employed to investigate the functional enrichment of biological processes altered in T+ and N+ individuals. Results Our findings indicate that Aβ isoforms can predict T+ and N+ with an area under the curve (AUC) of 0.929 and 0.936, respectively. Additionally, proteomics analysis identified 17 differentially expressed proteins (DEPs) in individuals wrongly classified by our ML model. More specifically, enrichment analysis of gene ontology biological processes revealed an upregulation in myelinization and glucose metabolism-related processes in CU individuals wrongly predicted as T+. A significant enrichment of DEPs in pathways including biosynthesis of amino acids, glycolysis/gluconeogenesis, carbon metabolism, cell adhesion molecules and prion disease was also observed. Conclusions Our results demonstrate that, by applying a refined ML analysis, a combination of Aβ isoforms can predict T+ and N+ with a high AUC. CSF proteomics analysis highlighted a promising group of proteins that can be further explored for improving T+ and N+ prediction.

Abstract Alzheimer’s disease (AD) is characterised by a long preclinical phase. Although phosphorylated tau (p‐tau) species such as p‐tau217 and p‐tau231 provide accurate detection of early pathological changes, other biomarkers capable of staging disease progression during preclinical AD are still needed. Combining exploratory and targeted mass spectrometry methods in neuropathologically confirmed brain tissue, we observed that p‐tau235 is a prominent feature of AD pathology. In addition, p‐tau235 seemed to be preceded by p‐tau231, in what appeared to be a sequential phosphorylation event. To exploit its biomarker potential in cerebrospinal fluid (CSF), we developed and validated a new p‐tau235 Simoa assay. Using three clinical cohorts, we demonstrated that (i) CSF p‐235 increases early in AD continuum, and (ii) changes in CSF p‐tau235 and p‐tau231 levels during preclinical AD are consistent with the sequential phosphorylation evidence in AD brain. In conclusion, CSF p‐tau235 appears to be not only a highly specific biomarker of AD but also a promising staging biomarker for the preclinical phase. Thus, it could prove useful tracking disease progression and help enriching clinical trial recruitment.

Abstract Objective To investigate the relationship between the topography of amyloid‐β plaques, tau neurofibrillary tangles, and the overlap between the two, with cognitive dysfunction in individuals without dementia. Methods We evaluated 154 individuals who were assessed with amyloid‐β PET with [18F]AZD4694, tau‐PET with [18F]MK6240, structural MRI, and neuropsychological testing. We also evaluated an independent cohort of 240 individuals who were assessed with amyloid‐β PET with [18F]Florbetapir, tau‐PET with [18F]Flortaucipir, structural MRI, and neuropsychological testing. Using the VoxelStats toolbox, we conducted voxel‐wise linear regressions between amyloid‐PET, tau‐PET, and their interaction with cognitive function, correcting for age, sex, and years of education. Results In both cohorts, we observed that tau‐PET standardized uptake value ratio in medial temporal lobes was associated with clinical dementia rating Sum of Boxes (CDR‐SoB) scores independently of local amyloid‐PET uptake (FWE corrected at p

Background: Large-scale neuronal network breakdown underlies memory impairment in Alzheimer’s disease (AD). However, the differential trajectories of the relationships between network organisation and memory across pathology and cognitive stages in AD remain elusive. We determined whether and how the influences of individual-level structural and metabolic covariance network integrity on memory varied with amyloid pathology across clinical stages without assuming a constant relationship. Methods: Seven hundred and eight participants from the Alzheimer’s Disease Neuroimaging Initiative were studied. Individual-level structural and metabolic covariance scores in higher-level cognitive and hippocampal networks were derived from magnetic resonance imaging and [18F] fluorodeoxyglucose positron emission tomography using seed-based partial least square analyses. The non-linear associations between network scores and memory across cognitive stages in each pathology group were examined using sparse varying coefficient modelling. Results: We showed that the associations of memory with structural and metabolic networks in the hippocampal and default mode regions exhibited pathology-dependent differential trajectories across cognitive stages using sparse varying coefficient modelling. In amyloid pathology group, there was an early influence of hippocampal structural network deterioration on memory impairment in the preclinical stage, and a biphasic influence of the angular gyrus-seeded default mode metabolic network on memory in both preclinical and dementia stages. In non-amyloid pathology groups, in contrast, the trajectory of the hippocampus-memory association was opposite and weaker overall, while no metabolism covariance networks were related to memory. Key findings were replicated in a larger cohort of 1280 participants. Conclusions: Our findings highlight potential windows of early intervention targeting network breakdown at the preclinical AD stage. Funding: Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). We also acknowledge the funding support from the Duke NUS/Khoo Bridge Funding Award (KBrFA/2019-0020) and NMRC Open Fund Large Collaborative Grant (OFLCG09May0035), NMRC New Investigator Grant (MOH-CNIG18may-0003) and Yong Loo Lin School of Medicine Research funding.

This paper investigates the fragment performance of several composite panels for attaching to the inside walls of a building structure. These panels were developed using different types of fiber woven fabrics (W0, W90) combined with distinct layers orientations (angle-ply effect) of L0/0 and L0/15. Aramid, E-glass, and S-glass fiber fabrics impregnated with thermosetting epoxy resin, and a prepreg of Ultra High Molecular Weight Polyethylene (HB24) were employed. The panels are subjected to ballistic impact using different fragments under impact velocities in the range of 120 to 420 m/s. In order to measure the energy absorbed by the ballistic panels, the impact velocity and the residual velocity of the fragment were measured with laser chronographs placed before and after the laminated test specimens. The paper demonstrates quantitatively that the angle-ply laminates produced using L0/15 woven fabric orientation presented a higher impact energy absorption, promoting higher reductions on the fragment residual velocity compared to the L0/0 orientations. The laminates produced using UHMWPE fibers (HB24) presented better ballistic properties compared to the other fibers. Furthermore, it was noted that the energy dissipation rate is linearly correlated with the impact velocity and is independent of the fragment geometry.

Cerebrospinal fluid neurofilament light (NfL) is a biomarker for neurodegeneration that can also be assessed in blood. Here the authors show in a validation study the potential for plasma NfL as a biomarker for several neurodegenerative diseases.

Abnormalities in the expression of metabotropic glutamate receptor type 5 (mGluR5) have been observed in the hippocampus of patients with drug-resistant mesial Temporal Lobe Epilepsy (mTLE). Ex-vivo studies in mTLE hippocampal surgical specimens have shown increased mGluR5 immunoreactivity, while in vivo whole brain imaging using positron emission tomography (PET) demonstrated reduced hippocampal mGluR5 availability. To further understand mGluR5 abnormalities in mTLE, we performed a saturation autoradiography study with [3H]ABP688 (a negative mGluR5 allosteric modulator). We aimed to evaluate receptor density (Bmax) and dissociation constants (KD) in hippocampal mTLE surgical specimens and in non-epilepsy hippocampi from necropsy controls. mTLE specimens showed a 43.4% reduction in receptor density compared to control hippocampi, which was independent of age, sex and KD (multiple linear regression analysis). There was no significant difference in KD between the groups, which suggests that the decreased mGluR5 availability found in vivo with PET cannot be attributed to reduced affinity between ligand and binding site. The present study supports that changes within the epileptogenic tissue include mGluR5 internalization or conformational changes that reduce [3H]ABP688 binding, as previously suggested in mTLE patients studied in vivo.

Abstract Background Mitochondrial electron transport chain abnormalities have been reported in postmortem pathological specimens of Alzheimer’s disease (AD). However, it remains unclear how amyloid and tau are associated with mitochondrial dysfunction in vivo. The purpose of this study is to assess the local relationships between mitochondrial dysfunction and AD pathophysiology in mild AD using the novel mitochondrial complex I PET imaging agent [18F]BCPP-EF. Methods Thirty-two amyloid and tau positive mild stage AD dementia patients (mean age ± SD: 71.1 ± 8.3 years) underwent a series of PET measurements with [18F]BCPP-EF mitochondrial function, [11C]PBB3 for tau deposition, and [11C] PiB for amyloid deposition. Age-matched normal control subjects were also recruited. Inter and intrasubject comparisons of levels of mitochondrial complex I activity, amyloid and tau deposition were performed. Results The [18F]BCPP-EF uptake was significantly lower in the medial temporal area, highlighting the importance of the mitochondrial involvement in AD pathology. [11C]PBB3 uptake was greater in the temporo-parietal regions in AD. Region of interest analysis in the Braak stage I-II region showed significant negative correlation between [18F]BCPP-EF SUVR and [11C]PBB3 BPND (R = 0.2679, p = 0.04), but not [11C] PiB SUVR. Conclusions Our results indicated that mitochondrial complex I is closely associated with tau load evaluated by [11C]PBB3, which might suffer in the presence of its off-target binding. The absence of association between mitochondrial complex I dysfunction with amyloid load suggests that mitochondrial dysfunction in the trans-entorhinal and entorhinal region is a reflection of neuronal injury occurring in the brain of mild AD.

Abstract Alzheimer’s disease (AD) is associated with memory impairment and altered peripheral metabolism. Mounting evidence indicates that abnormal signaling in a brain-periphery metabolic axis plays a role in AD pathophysiology. The activation of pro-inflammatory pathways in the brain, including the interleukin-6 (IL-6) pathway, comprises a potential point of convergence between memory dysfunction and metabolic alterations in AD that remains to be better explored. Using T2-weighted magnetic resonance imaging (MRI), we observed signs of probable inflammation in the hypothalamus and in the hippocampus of AD patients when compared to cognitively healthy control subjects. Pathological examination of post-mortem AD hypothalamus revealed the presence of hyperphosphorylated tau and tangle-like structures, as well as parenchymal and vascular amyloid deposits surrounded by astrocytes. T2 hyperintensities on MRI positively correlated with plasma IL-6, and both correlated inversely with cognitive performance and hypothalamic/hippocampal volumes in AD patients. Increased IL-6 and suppressor of cytokine signaling 3 (SOCS3) were observed in post-mortem AD brains. Moreover, activation of the IL-6 pathway was observed in the hypothalamus and hippocampus of AD mice. Neutralization of IL-6 and inhibition of the signal transducer and activator of transcription 3 (STAT3) signaling in the brains of AD mouse models alleviated memory impairment and peripheral glucose intolerance, and normalized plasma IL-6 levels. Collectively, these results point to IL-6 as a link between cognitive impairment and peripheral metabolic alterations in AD. Targeting pro-inflammatory IL-6 signaling may be a strategy to alleviate memory impairment and metabolic alterations in the disease.

Abstract Background To investigate the association of plasma pTau181, assessed with a new immunoassay, with neurodegeneration of white matter and gray matter cross-sectionally and longitudinally, in aging and Alzheimer’s disease. Methods Observational data was obtained from the Alzheimer’s Disease Neuroimaging Initiative, in which participants underwent plasma assessment and magnetic resonance imaging. Based on their clinical diagnosis, participants were classified as cognitively unimpaired and cognitively impaired. Linear regressions and linear mixed-effect models were used to test the cross-sectional and longitudinal associations between baseline plasma pTau181 and neurodegeneration using voxel-based morphometry. Results We observed a negative correlation at baseline between plasma pTau181 and gray matter volume in cognitively unimpaired individuals. In cognitively impaired individuals, we observed a negative association between plasma pTau181 and both gray and white matter volume. In longitudinal analyses conducted in the cognitively unimpaired group, plasma pTau181 was negatively correlated with gray matter volume, starting 36 months after baseline assessments. Finally, in cognitively impaired individuals, plasma pTau181 concentrations were negatively correlated with both gray and white matter volume as early as 12 months after baseline, and neurodegeneration increased in an incremental manner until 48 months. Conclusions Higher levels of plasma pTau181 correlate with neurodegeneration and predict further brain atrophy in aging and Alzheimer’s disease. Plasma pTau181 may be useful in predicting AD-related neurodegeneration, comparable to positron emission tomography or cerebrospinal fluid assessment with high specificity for AD neurodegeneration.

Abstract The development of in vivo biomarkers of Alzheimer’s disease (AD) has advanced the diagnosis of AD from a clinical syndrome to a biological construct. The preclinical stage of AD continuum is defined by the identification of AD biomarkers crossing the pathological threshold in cognitively unimpaired individuals. While neuropsychiatric symptoms (NPS) are non-cognitive symptoms that are increasingly recognized as early manifestations of AD, the associations of NPS with AD pathophysiology in preclinical AD remain unclear. Here, we review the associations between NPS and AD biomarkers amyloid-β (Aβ), tau and neurodegeneration in preclinical AD and cognitively-unimpaired individuals in 19 eligible English-language publications (8 cross-sectional studies, 10 longitudinal, 1 both cross-sectional and longitudinal). The cross-sectional studies have consistently shown that NPS, particularly depressive and anxiety symptoms, are associated with higher Aβ. The longitudinal studies have suggested that greater NPS are associated with higher Aβ and cognitive decline in cognitively unimpaired subjects over time. However, most of the studies have either cross-sectionally or longitudinally shown no association between NPS and tau pathology. For the association of NPS and neurodegeneration, two studies have shown that the cerebrospinal fluid total-tau is linked to longitudinal increase in NPS and that the NPS may predict longitudinal metabolic decline in preclinical AD, respectively. However, evidence for the association between atrophy and NPS in preclinical AD is less consistent. Therefore, future longitudinal studies with well-designed methodologies and NPS measurements are required not only to determine the relationship among AT(N) biomarkers, NPS and cognitive decline, but also to elucidate the contribution of comorbid pathology to preclinical AD.

Abstract Background Neuropsychiatric symptoms (NPS) are increasingly recognized as early non-cognitive manifestations in the Alzheimer’s disease (AD) continuum. However, the role of NPS as an early marker of pathophysiological progression in AD remains unclear. Dominantly inherited AD (DIAD) mutation carriers are young individuals who are destined to develop AD in future due to the full penetrance of the genetic mutation. Hence, the study of DIAD mutation carriers enables the evaluation of the associations between pure AD pathophysiology and metabolic correlates of NPS without the confounding effects of co-existing pathologies. In this longitudinal study, we aimed to identify regional brain metabolic dysfunctions associated with NPS in cognitively intact DIAD mutation carriers. Methods We stratified 221 cognitively intact participants from the Dominantly Inherited Alzheimer’s Network according to their mutation carrier status. The interactions of NPS measured by the Neuropsychiatric Inventory-Questionnaire (NPI-Q), age, and estimated years to symptom onset (EYO) as a function of metabolism measured by [18F]flurodeoxyglucose ([18F]FDG) positron emission tomography, were evaluated by the mixed-effects regression model with family-level random effects in DIAD mutation carriers and non-carriers. Exploratory factor analysis was performed to identify the neuropsychiatric subsyndromes in DIAD mutation carriers using the NPI-Q sub-components. Then the effects of interactions between specific neuropsychiatric subsyndromes and EYO on metabolism were evaluated with the mixed-effects regression model. Results A total of 119 mutation carriers and 102 non-carriers were studied. The interaction of higher NPI-Q and shorter EYO was associated with more rapid declines of global and regional [18F]FDG uptake in the posterior cingulate and ventromedial prefrontal cortices, the bilateral parietal lobes and the right insula in DIAD mutation carriers. The neuropsychiatric subsyndromes of agitation, disinhibition, irritability and depression interacted with the EYO to drive the [18F]FDG uptake decline in the DIAD mutation carriers. The interaction of NPI and EYO was not associated with [18F]FDG uptake in DIAD mutation non-carriers. Conclusions The NPS in cognitively intact DIAD mutation carriers may be a clinical indicator of subsequent metabolic decline in brain networks vulnerable to AD, which supports the emerging conceptual framework that NPS represent early manifestations of neuronal injury in AD. Further studies using different methodological approaches to identify NPS in preclinical AD are needed to validate our findings.

Objectives Studies have shown that demand-side interventions, such as conditional cash transfers and vouchers, can increase the proportion of women giving birth in a health facility in low-income and middle-income countries, but there is limited evidence of the effectiveness of supply-side interventions. We evaluated the impact of the Subsidy Reinvestment and Empowerment Programme Maternal and Child Health Project (SURE-P MCH) on rates of institutional delivery and antenatal care.Design, setting and participants We used a differences-in-differences study design that compared changes in rates of institutional delivery and antenatal care in areas that had received additional support through the SURE-P MCH programme relative to areas that did not. Data on outcomes were obtained from the 2013 Nigerian Demographic and Health Survey.Results We found that the programme significantly increased the proportion of women giving birth in a health facility by approximately 7 percentage points (p=0.069) or approximately 10% relative to the baseline after 9 months of implementation. The programme, however, did not significantly increase the use of antenatal care.Conclusion The findings of this study suggest there could be important improvements in institutional delivery rates through greater investment in supply-side interventions.

Summary: Background: Tau in Alzheimer's disease (AD) is assessed via cerebrospinal fluid (CSF) and Positron emission tomography (PET). Novel methods to detect phosphorylated tau (pTau) in blood have been recently developed. We aim to investigate agreement of tau status as determined by [18F]MK6240 tau-PET, plasma pTau181 and pTau231. Methods: We assessed cognitively unimpaired young, cognitively unimpaired, mild cognitive impairment and AD individuals with [18F]MK6240, plasma pTau181, pTau 231, [18F]AZD4694 amyloid-PET and MRI. A subset underwent CSF assessment.We conducted ROC curves to obtain cut-off values for plasma pTau epitopes. Individuals were categorized as positive or negative in all biomarkers. We then compared the distribution among concordant and discordant groups in relation to diagnosis, Aβ status, APOEε4 status, [18F]AZD4694 global SUVR, hippocampal volume and CSF pTau181. Findings: The threshold for positivity was 15.085 pg/mL for plasma pTau181 and 17.652 pg/mL for plasma pTau231. Most individuals had concordant statuses, however, 18% of plasma181/PET, 26% of plasma231/PET and 25% of the pTau231/pTau181 were discordant. Positivity to at least one biomarker was often accompanied by diagnosis of cognitive impairment, Aβ positivity, APOEε4 carriership, higher levels of [18F]AZD4694 global SUVR, hippocampal atrophy and CSF pTau181. Interpretation: Plasma pTau181, pTau231 and [18F]MK6240 seem to reflect different stages of tau progression. Plasma biomarkers can be useful in the context of diagnostic information and clinical trials, to evaluate the disease stage. Moreover, they seem to confidently evaluate tau-PET positivity. Funding: Moreover, this study was supported by Weston Brain Institute, Canadian Institute of Health Research and Fonds de Recherche du Québec.

Summary: Background: Phosphorylated tau (p-tau) epitopes in cerebrospinal fluid (CSF) are accurate biomarkers for a pathological and clinical diagnosis of Alzheimer's disease (AD) and are seen to be increased in preclinical stage of the disease. However, it is unknown if these increases transpire earlier, prior to amyloid-beta (Aβ) positivity as determined by position emission tomography (PET), and if an ordinal sequence of p-tau epitopes occurs at this incipient phase Methods: We measured CSF concentrations of p-tau181, p-tau217 and p-tau231 in 171 participants across the AD continuum who had undergone Aβ ([18F]AZD4694) and tau ([18F]MK6240) position emission tomography (PET) and clinical assessment Findings: All CSF p-tau biomarkers were accurate predictors of cognitive impairment but CSF p-tau217 demonstrated the largest fold-changes in AD patients in comparison to non-AD dementias and cognitively unimpaired individuals. CSF p-tau231 and p-tau217 predicted Aβ and tau to a similar degree but p-tau231 attained abnormal levels first. P-tau231 was sensitive to the earliest changes of Aβ in the medial orbitofrontal, precuneus and posterior cingulate before global Aβ PET positivity was reached Interpretation: We demonstrate that CSF p-tau231 increases early in development of AD pathology and is a principal candidate for detecting incipient Aβ pathology for therapeutic trial application Funding: Canadian Institutes of Health Research (CIHR), Canadian Consortium of Neurodegeneration and Aging, Weston Brain Institute, Brain Canada Foundation, the Fonds de Recherche du Québec.

Abstract Introduction Alzheimer's disease consensus recommends biomarker dichotomization, a practice with well‐described clinical strengths and methodological limitations. Although neuroimaging studies have explored alternative biomarker interpretation strategies, a formally defined three‐range approach and its prognostic impact remains under‐explored for cerebrospinal fluid (CSF) biomarkers . Methods With two‐graph receiver‐operating characteristics based on different reference schemes, we derived three‐range cut‐points for CSF Elecsys biomarkers. According to baseline CSF status, we assessed the prognostic utility of this in predicting risk of clinical progression and longitudinal trajectories of cognitive decline and amyloid–beta (Aβ) positron emission tomography (PET) accumulation in non‐demented individuals (Alzheimer's Disease Neuroimaging Initiative [ADNI]; n = 1246). In all analyses, we compared herein‐derived three‐range CSF cut‐points to previously described binary ones. Results In our main longitudinal analyses, we highlight CSF p‐tau181/Aβ1‐42 three‐range cut‐points derived based on the cognitively normal Aβ‐PET negative versus dementia Aβ‐PET positive reference scheme for best depicting a prognostically relevant biomarker abnormality range. Longitudinally, our approach revealed a divergent intermediate cognitive trajectory undetected by dichotomization and a clearly abnormal group at higher risk for cognitive decline, with power analyses suggesting the latter group as potential trial enrichment candidates. Furthermore, we demonstrate that individuals with intermediate‐range CSF status have similar rates of Aβ deposition to those in the clearly abnormal group. Discussion The proposed approach can refine clinico‐biological prognostic assessment and potentially enhance trial recruitment, as it captures faster biomarker‐related cognitive decline in comparison to binary cut‐points. Although this approach has implications for trial recruitment and observational studies, further discussion is needed regarding clinical practice applications.