Insulin, insulin-like growth factors (IGF) and their receptors are highly expressed in the adult hippocampus. Thus, disturbances in the insulin-IGF signalling pathway may account for the selective ...vulnerability of the hippocampus to nascent Alzheimer's disease (AD) pathology. In the present study, we examined the predominant IGF-binding protein in the CSF, IGFBP2. CSF was collected from 109 asymptomatic members of the parental history-positive PREVENT-AD cohort. CSF levels of IGFBP2, core AD and synaptic biomarkers were measured using proximity extension assay, ELISA and mass spectrometry. Cortical amyloid-beta (Aβ) and tau deposition were examined using 18F-NAV4694 and flortaucipir. Cognitive assessments were performed during up to 8 years of follow-up, using the Repeatable Battery for the Assessment of Neuropsychological Status. T1-weighted structural MRI scans were acquired, and neuroimaging analyses were performed on pre-specified temporal and parietal brain regions. Next, in an independent cohort, we allocated 241 dementia-free ADNI-1 participants into four stages of AD progression based on the biomarkers CSF Aβ42 and total-tau (t-tau). In this analysis, differences in CSF and plasma IGFBP2 levels were examined across the pathological stages. Finally, IGFBP2 mRNA and protein levels were examined in the frontal cortex of 55 autopsy-confirmed AD and 31 control brains from the Quebec Founder Population (QFP) cohort, a unique population isolated from Eastern Canada. CSF IGFBP2 progressively increased over 5 years in asymptomatic PREVENT-AD participants. Baseline CSF IGFBP2 was positively correlated with CSF AD biomarkers and synaptic biomarkers, and negatively correlated with longitudinal changes in delayed memory (P = 0.024) and visuospatial abilities (P = 0.019). CSF IGFBP2 was negatively correlated at a trend-level with entorhinal cortex volume (P = 0.082) and cortical thickness in the piriform (P = 0.039), inferior temporal (P = 0.008), middle temporal (P = 0.014) and precuneus (P = 0.033) regions. In ADNI-1, CSF (P = 0.009) and plasma (P = 0.001) IGFBP2 were significantly elevated in Stage 2 CSF Aβ(+)/t-tau(+). In survival analyses in ADNI-1, elevated plasma IGFBP2 was associated with a greater rate of AD conversion (hazard ratio = 1.62, P = 0.021). In the QFP cohort, IGFBP2 mRNA was reduced (P = 0.049); however, IGFBP2 protein levels did not differ in the frontal cortex of autopsy-confirmed AD brains (P = 0.462). Nascent AD pathology may induce an upregulation in IGFBP2 in asymptomatic individuals. CSF and plasma IGFBP2 may be valuable markers for identifying CSF Aβ(+)/t-tau(+) individuals and those with a greater risk of AD conversion.
Background
Disentangling the etiology of common, complex diseases is a major challenge in genetic research. For bipolar disorder (BD), several genome-wide association studies (GWAS) have been ...performed. Similar to other complex disorders, major breakthroughs in explaining the high heritability of BD through GWAS have remained elusive. To overcome this dilemma, genetic research into BD, has embraced a variety of strategies such as the formation of large consortia to increase sample size and sequencing approaches. Here we advocate a complementary approach making use of already existing GWAS data: a novel data mining procedure to identify yet undetected genotype–phenotype relationships. We adapted association rule mining, a data mining technique traditionally used in retail market research, to identify frequent and characteristic genotype patterns showing strong associations to phenotype clusters. We applied this strategy to three independent GWAS datasets from 2835 phenotypically characterized patients with BD. In a discovery step, 20,882 candidate association rules were extracted.
Results
Two of these rules—one associated with eating disorder and the other with anxiety—remained significant in an independent dataset after robust correction for multiple testing. Both showed considerable effect sizes (odds ratio ~ 3.4 and 3.0, respectively) and support previously reported molecular biological findings.
Conclusion
Our approach detected novel specific genotype–phenotype relationships in BD that were missed by standard analyses like GWAS. While we developed and applied our method within the context of BD gene discovery, it may facilitate identifying highly specific genotype–phenotype relationships in subsets of genome-wide data sets of other complex phenotype with similar epidemiological properties and challenges to gene discovery efforts.
•Support from close network ties was generally high, with three latent classes of social support identified as moderate, high and very high.•Participants with more close ties (≥4 vs. <4) had a lower ...odds of receiving the ‘very high’ class of support.•The odds of receiving ‘very high’ support increased for each one-unit increase in mean network member age.•Latent classes of social support did not differ for those who currently vs. formerly injected drugs.•Non-injection use of street drugs was associated with lower odds of receiving ‘very high’ support
Social network members influence risk and health behaviors, yet little is known about the support that persons who inject drugs (PWID) receive from their closest ties.
970 participants from the AIDS Linked to the IntraVenous Experience (ALIVE) study completed a social network survey between April 2016 and June 2017 about their five closest ties. Our analysis: 1) identified latent classes of support received by participants; 2) determined whether class membership differed by current (≤12 months) vs. former (>12 months) injection drug use; 3) compared classes of support by individual and network characteristics.
970 participants listed 3,388 network members. We identified three support classes: (1) Moderate (n = 249): probabilities of support <0.40; (2) High (n = 366): probabilities of support 0.58-0.82; (3) Very high (n = 355): probabilities of support 0.91-0.99. In adjusted analysis compared to moderate support, the odds of high and very high support increased as the mean age of network members increased (Adjusted Odds Ratio AOR:1.03; 95 % CI: 1.01, 1.05) and as the number of network members with whom they interacted daily increased (AOR-high: 1.33; 95 % CI:1.14, 1.56 and AOR-very high: 1.54; 95 % CI: 1.30, 1.83). While current injection drug use was associated with lower unadjusted odds of high and very high support, the associations were not statistically significant in adjusted analysis.
Support was higher among networks of older ties and more frequent interaction, but differences did not appear to be driven by injection drug use status. Findings point to the importance of the closest social ties.
Females are disproportionately affected by dementia due to Alzheimer's disease. Despite a similar amyloid-β (Aβ) load, a higher load of neurofibrillary tangles (NFTs) is seen in females than males. ...Previous literature has proposed that Aβ and phosphorylated-tau (p-tau) synergism accelerates tau tangle formation, yet the effect of biological sex in this process has been overlooked. In this observational study, we examined longitudinal neuroimaging data from the TRIAD and ADNI cohorts from Canada and USA, respectively. We assessed 457 participants across the clinical spectrum of Alzheimer's disease. All participants underwent baseline multimodal imaging assessment, including MRI and PET, with radioligands targeting Aβ plaques and tau tangles, respectively. CSF data were also collected. Follow-up imaging assessments were conducted at 1- and 2-year intervals for the TRIAD cohort and 1-, 2- and 4-year intervals for the ADNI cohort. The upstream pathological events contributing to faster tau progression in females were investigated-specifically, whether the contribution of Aβ and p-tau synergism to accelerated tau tangle formation is modulated by biological sex. We hypothesized that cortical Aβ predisposes tau phosphorylation and tangle accumulation in a sex-specific manner. Findings revealed that Aβ-positive females presented higher CSF p-tau181 concentrations compared with Aβ-positive males in both the TRIAD (P = 0.04, Cohen's d = 0.51) and ADNI (P = 0.027, Cohen's d = 0.41) cohorts. In addition, Aβ-positive females presented faster NFT accumulation compared with their male counterparts (TRIAD: P = 0.026, Cohen's d = 0.52; ADNI: P = 0.049, Cohen's d = 1.14). Finally, the triple interaction between female sex, Aβ and CSF p-tau181 was revealed as a significant predictor of accelerated tau accumulation at the 2-year follow-up visit (Braak I: P = 0.0067, t = 2.81; Braak III: P = 0.017, t = 2.45; Braak IV: P = 0.002, t = 3.17; Braak V: P = 0.006, t = 2.88; Braak VI: P = 0.0049, t = 2.93). Overall, we report sex-specific modulation of cortical Aβ in tau phosphorylation, consequently facilitating faster NFT progression in female individuals over time. This presents important clinical implications and suggests that early intervention that targets Aβ plaques and tau phosphorylation may be a promising therapeutic strategy in females to prevent the further accumulation and spread of tau aggregates.
Abstract
The biological age of the brain differs from its chronological age (CA) and can be used as biomarker of neural/cognitive disease processes and as predictor of mortality. Brain age (BA) is ...often estimated from magnetic resonance images (MRIs) using machine learning (ML) that rarely indicates how regional brain features contribute to BA. Leveraging an aggregate training sample of 3 418 healthy controls (HCs), we describe a ridge regression model that quantifies each region’s contribution to BA. After model testing on an independent sample of 651 HCs, we compute the coefficient of partial determination R¯p2 for each regional brain volume to quantify its contribution to BA. Model performance is also evaluated using the correlation r between chronological and biological ages, the mean absolute error (MAE ) and mean squared error (MSE) of BA estimates. On training data, r=0.92, MSE=70.94 years, MAE=6.57 years, and R¯2=0.81; on test data, r=0.90, MSE=81.96 years, MAE=7.00 years, and R¯2=0.79. The regions whose volumes contribute most to BA are the nucleus accumbens (R¯p2=7.27%), inferior temporal gyrus (R¯p2=4.03%), thalamus (R¯p2=3.61%), brainstem (R¯p2=3.29%), posterior lateral sulcus (R¯p2=3.22%), caudate nucleus (R¯p2=3.05%), orbital gyrus (R¯p2=2.96%), and precentral gyrus (R¯p2=2.80%). Our ridge regression, although outperformed by the most sophisticated ML approaches, identifies the importance and relative contribution of each brain structure to overall BA. Aside from its interpretability and quasi-mechanistic insights, our model can be used to validate future ML approaches for BA estimation.
Men who have sex with men (MSM) are at high risk for hepatitis B virus (HBV) infection. Data on the effect of highly active antiretroviral therapy (HAART) on incident HBV infection in HIV-infected ...and HIV-uninfected MSM are limited.
To determine predictors of incident HBV infection in MSM during pre-HAART and HAART periods.
Observational cohort study.
Cohort of MSM who have, or are at risk for, HIV infection.
2375 HBV-uninfected MSM in the Multicenter AIDS Cohort Study.
Poisson regression was used to compare incidence rates of HBV infection in the pre-HAART and HAART eras and to identify factors associated with incidence of HBV infection.
In 25,322 person-years of follow-up, 244 incident HBV infections occurred. The unadjusted incidence rate was higher in HIV-infected MSM than in HIV-uninfected MSM (incidence rate ratio IRR, 1.9 95% CI, 1.5 to 2.4) and was significantly lower in the HAART era than in the pre-HAART era among HIV-infected (IRR, 0.2 CI, 0.1 to 0.4) and HIV-uninfected (IRR, 0.3 CI, 0.2 to 0.4) MSM. Age younger than 40 years (IRR, 2.3 CI, 1.7 to 3.0), more than 1 recent sexual partner (IRR, 3.1 CI, 2.3 to 4.2), and HIV infection (IRR, 2.4 CI, 1.8 to 3.1) were independently associated with higher incidence of HBV infection, whereas HBV vaccination was protective (IRR, 0.3 CI, 0.2 to 0.4). Highly active antiretroviral therapy with HIV RNA levels less than 400 copies/mL was associated with protection (IRR, 0.2 CI, 0.1 to 0.5), but HAART in those with HIV RNA levels of 400 copies/mL or greater was not.
The observational nature limits inferences about causality.
Effective HAART is associated with lower incidence of HBV infection; however, even in the HAART era, incidence of HBV infection remains high among MSM.
National Institute of Allergy and Infectious Diseases.
Abstract We introduce a novel framework for the classification of functional data supported on nonlinear, and possibly random, manifold domains. The motivating application is the identification of ...subjects with Alzheimer’s disease from their cortical surface geometry and associated cortical thickness map. The proposed model is based upon a reformulation of the classification problem as a regularized multivariate functional linear regression model. This allows us to adopt a direct approach to the estimation of the most discriminant direction while controlling for its complexity with appropriate differential regularization. Our approach does not require prior estimation of the covariance structure of the functional predictors, which is computationally prohibitive in our application setting. We provide a theoretical analysis of the out-of-sample prediction error of the proposed model and explore the finite sample performance in a simulation setting. We apply the proposed method to a pooled dataset from Alzheimer’s Disease Neuroimaging Initiative and Parkinson’s Progression Markers Initiative. Through this application, we identify discriminant directions that capture both cortical geometric and thickness predictive features of Alzheimer’s disease that are consistent with the existing neuroscience literature.
Understanding the mechanisms of delusion formation in Alzheimer disease (AD) could inform the development of therapeutic interventions. It has been suggested that delusions arise as a consequence of ...false memories.
To investigate whether delusions in AD are associated with false recognition, and whether higher rates of false recognition and the presence of delusions are associated with lower regional brain volumes in the same brain regions.
Since the Alzheimer's Disease Neuroimaging Initiative (ADNI) launched in 2004, it has amassed an archive of longitudinal behavioral and biomarker data. This cross-sectional study used data downloaded in 2020 from ADNI participants with an AD diagnosis at baseline or follow-up. Data analysis was performed between June 24, 2020, and September 21, 2021.
Enrollment in the ADNI.
The main outcomes included false recognition, measured with the 13-item Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 13) and the Rey Auditory Verbal Learning Test (RAVLT) and volume of brain regions corrected for total intracranial volume. Behavioral data were compared for individuals with delusions in AD and those without using independent-samples t tests or Mann-Whitney nonparametric tests. Significant findings were further explored using binary logistic regression modeling. For neuroimaging data region of interest analyses using t tests, Poisson regression modeling or binary logistic regression modeling and further exploratory, whole-brain voxel-based morphometry analyses were carried out to explore the association between regional brain volume and false recognition or presence of delusions.
Of the 2248 individuals in the ADNI database, 728 met the inclusion criteria and were included in this study. There were 317 (43.5%) women and 411 (56.5%) men. Their mean (SD) age was 74.8 (7.4) years. The 42 participants with delusions at baseline had higher rates of false recognition on the ADAS-Cog 13 (median score, 3; IQR, 1 to 6) compared with the 549 control participants (median score, 2; IQR, 0 to 4; U = 9398.5; P = .04). False recognition was not associated with the presence of delusions when confounding variables were included in binary logistic regression models. An ADAS-Cog 13 false recognition score was inversely associated with left hippocampal volume (odds ratio OR, 0.91 95% CI, 0.88-0.94, P < .001), right hippocampal volume (0.94 0.92-0.97, P < .001), left entorhinal cortex volume (0.94 0.91-0.97, P < .001), left parahippocampal gyrus volume (0.93 0.91-0.96, P < .001), and left fusiform gyrus volume (0.97 0.96-0.99, P < .001). There was no overlap between locations associated with false recognition and those associated with delusions.
In this cross-sectional study, false memories were not associated with the presence of delusions after accounting for confounding variables, and no indication for overlap of neural networks for false memories and delusions was observed on volumetric neuroimaging. These findings suggest that delusions in AD do not arise as a direct consequence of misremembering, lending weight to ongoing attempts to delineate specific therapeutic targets for treatment of psychosis.
Plasma phosphorylated-tau181 (p-tau181) showed the potential for Alzheimer's diagnosis and prognosis, but its role in detecting cerebral pathologies is unclear. We aimed to evaluate whether it could ...serve as a marker for Alzheimer's pathology in the brain. A total of 1189 participants with plasma p-tau181 and PET data of amyloid, tau or FDG PET were included from ADNI. Cross-sectional relationships of plasma p-tau181 with PET biomarkers were tested. Longitudinally, we further investigated whether different p-tau181 levels at baseline predicted different progression of Alzheimer's pathological changes in the brain. We found plasma p-tau181 significantly correlated with brain amyloid (Spearman ρ = 0.45, P < 0.0001), tau (0.25, P = 0.0003), and FDG PET uptakes (-0.37, P < 0.0001), and increased along the Alzheimer's continuum. Individually, plasma p-tau181 could detect abnormal amyloid, tau pathologies and hypometabolism in the brain, similar with or even better than clinical indicators. The diagnostic accuracy of plasma p-tau181 elevated significantly when combined with clinical information (AUC = 0.814 for amyloid PET, 0.773 for tau PET, and 0.708 for FDG PET). Relationships of plasma p-tau181 with brain pathologies were partly or entirely mediated by the corresponding CSF biomarkers. Besides, individuals with abnormal plasma p-tau181 level (>18.85 pg/ml) at baseline had a higher risk of pathological progression in brain amyloid (HR: 2.32, 95%CI 1.32-4.08) and FDG PET (3.21, 95%CI 2.06-5.01) status. Plasma p-tau181 may be a sensitive screening test for detecting brain pathologies, and serve as a predictive biomarker for Alzheimer's pathophysiology.
A biological research framework to define Alzheimer' disease with dichotomized biomarker measurement was proposed by National Institute on Aging-Alzheimer's Association (NIA-AA). However, it cannot ...characterize the hierarchy spreading pattern of tau pathology. To reflect in vivo tau progression using biomarker, we constructed a refined topographic
F-AV-1451 tau PET staging scheme with longitudinal clinical validation. Seven hundred and thirty-four participants with baseline
F-AV-1451 tau PET (baseline age 73.9 ± 7.7 years, 375 female) were stratified into five stages by a topographic PET staging scheme. Cognitive trajectories and clinical progression were compared across stages with or without further dichotomy of amyloid status, using linear mixed-effect models and Cox proportional hazard models. Significant cognitive decline was first observed in stage 1 when tau levels only increased in transentorhinal regions. Rates of cognitive decline and clinical progression accelerated from stage 2 to stage 3 and stage 4. Higher stages were also associated with greater CSF phosphorylated tau and total tau concentrations from stage 1. Abnormal tau accumulation did not appear with normal β-amyloid in neocortical regions but prompt cognitive decline by interacting with β-amyloid in temporal regions. Highly accumulated tau in temporal regions independently led to cognitive deterioration. Topographic PET staging scheme have potentials in early diagnosis, predicting disease progression, and studying disease mechanism. Characteristic tau spreading pattern in Alzheimer's disease could be illustrated with biomarker measurement under NIA-AA framework. Clinical-neuroimaging-neuropathological studies in other cohorts are needed to validate these findings.
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