Loss of intranetwork and internetwork resting state functional connections with Alzheimer\u27s disease progression

Alzheimer\u27s disease (AD) is the most common cause of dementia. Much is known concerning AD pathophysiology but our understanding of the disease at the systems level remains incomplete. Previous AD research has used resting-state functional connectivity magnetic resonance imaging (rs-fcMRI) to assess the integrity of functional networks within the brain. Most studies have focused on the default-mode network (DMN), a primary locus of AD pathology. However, other brain regions are inevitably affected with disease progression. We studied rs-fcMRI in five functionally defined brain networks within a large cohort of human participants of either gender (n = 510) that ranged in AD severity from unaffected [clinical dementia rating (CDR) 0] to very mild (CDR 0.5) to mild (CDR 1). We observed loss of correlations within not only the DMN but other networks at CDR 0.5. Within the salience network (SAL), increases were seen between CDR 0 and CDR 0.5. However, at CDR 1, all networks, including SAL, exhibited reduced correlations. Specific networks were preferentially affected at certain CDR stages. In addition, cross-network relations were consistently lost with increasing AD severity. Our results demonstrate that AD is associated with widespread loss of both intranetwork and internetwork correlations. These results provide insight into AD pathophysiology and reinforce an integrative view of the brain\u27s functional organization

Using the A/T/N framework to examine driving in preclinical Alzheimer’s disease

The A/T/N classification system is the foundation of the 2018 NIA-AA Research Framework and is intended to guide the Alzheimer disease (AD) research agenda for the next 5–10 years. Driving is a widespread functional activity that may be particularly useful in investigation of functional changes in pathological AD before onset of cognitive symptoms. We examined driving in preclinical AD using the A/T/N framework and found that the onset of driving difficulties is most associated with abnormality of both amyloid and tau pathology, rather than amyloid alone. These results have implications for participant selection into clinical trials and for the application time of interventions aimed at prolonging the time of safe driving among older adults with preclinical AD

Major depressive disorder and driving behavior among older adults

IMPORTANCE: Depression and antidepressant use are independently associated with crash risk among older drivers. However, it is unclear what factors impact daily driving that increase safety risk for drivers with depression. OBJECTIVE: To examine differences in naturalistic driving behavior and safety between older adults with and without major depressive disorder (MDD). DESIGN, SETTING, AND PARTICIPANTS: A prospective longitudinal cohort study was conducted among older adults (≥65 years) from the Driving Real-World In-Vehicle Evaluation System Project collected from July 1, 2021, to December 30, 2023. The sample included 85 participants with MDD and 310 participants without. Neurological, clinical, mood, and neuropsychological tests were collected annually. Daily driving behavior was recorded using a commercial data logger. Statistical analysis was performed from January 31 to June 24, 2024. EXPOSURE: MDD and antidepressant usage. MAIN OUTCOMES AND MEASURES: Linear mixed models with propensity score weighting compared slopes of driving behaviors over time (trips taken at night, speeding, hard braking, entropy, and radius of gyration) between groups. RESULTS: In a sample of 395 participants, 85 were classified as individuals with MDD (mean [SD] age, 69.6 [6.1] years; 60 [70.6%] female; 8 [9.4%] non-Hispanic Black and 77 [90.6%] non-Hispanic White) and 310 as individuals in the control group without depression (mean [SD] age, 70.1 [5.1] years; 153 [49.4%] female; 40 [12.9%] non-Hispanic Black and 270 [87.1%] non-Hispanic White). Adults with MDD had greater depressive symptoms (mean [SD], 8.35 [5.35] vs 2.33 [2.72]; difference, 6.02; 95% CI for difference, 5.17 to 6.85; P \u3c .001), comorbidities (mean [SD], 4.08 [2.07] vs 2.79 [1.67]; difference, 1.29; 95% CI for difference, 0.87 to 1.70; P \u3c .001), used more antidepressants (mean [SD], 0.94 [0.81] vs 0.27 [0.54]; χ21 = 65.8; P \u3c .001), and had a higher number of medications (mean [SD], 3.80 [3.27] vs 1.98 [2.21]; χ21 = 21.0; P \u3c .001) compared with controls at baseline. Longitudinal analysis demonstrated an association between adults with MDD and hard braking (mean [SE], 3.17 × 10-4 [7.30 × 10-5] vs 6.70 × 10-5 [4.00 × 10-5]; difference, 2.50 × 10-4; 95% CI for difference, 1.74 × 10-4 to 4.61 × 10-4; P \u3c .001) and hard cornering events per trip (mean [SE], 0.80 [0.64] vs 0.57 [0.25]; difference, 0.23; 95% CI for difference, 0.08 to 1.06; P = .04), greater distances driven from home (mean [SE], 31.19 [7.35] vs 7.76 [3.80] km; difference, 23.43; 95% CI for difference, 0.28 to 15.2; P \u3c .001), more unique destinations visited (mean [SE], 0.34 [0.10] vs -0.27 [0.03]; difference, 0.61; 95% CI for difference, 0.14 to 0.54; P \u3c .001), and higher random entropy (mean [SE], 0.01 [0.01] vs -0.02 [0.00]; difference, 0.03; 95% CI for difference, -0.03 to -0.01; P \u3c .001) over time. CONCLUSIONS AND RELEVANCE: In this longitudinal cohort study of older drivers, adults with MDD demonstrated distinct and riskier driving behaviors than those in the control group without depression, with higher rates of hard braking, cornering, and unpredictability in driving patterns over time. Routine depression screening and tailored interventions are essential for enhancing driving safety and maintaining independence among older adults with MDD. Comprehensive care approaches addressing both mental and physical health are crucial for this vulnerable population

The BIN1 rs744373 SNP is associated with increased tau-PET levels and impaired memory

© 2019, The Author(s). The single nucleotide polymorphism (SNP) rs744373 in the bridging integrator-1 gene (BIN1) is a risk factor for Alzheimer’s disease (AD). In the brain, BIN1 is involved in endocytosis and sustaining cytoskeleton integrity. Post-mortem and in vitro studies suggest that BIN1-associated AD risk is mediated by increased tau pathology but whether rs744373 is associated with increased tau pathology in vivo is unknown. Here we find in 89 older individuals without dementia, that BIN1 rs744373 risk-allele carriers show higher AV1451 tau-PET across brain regions corresponding to Braak stages II–VI. In contrast, the BIN1 rs744373 SNP was not associated with AV45 amyloid-PET uptake. Furthermore, the rs744373 risk-allele was associated with worse memory performance, mediated by increased global tau levels. Together, our findings suggest that the BIN1 rs744373 SNP is associated with increased tau but not beta-amyloid pathology, suggesting that alterations in BIN1 may contribute to memory deficits via increased tau pathology

Pathogenesis of HIV in the Central Nervous System

HIV can infect the brain and impair central nervous system (CNS) function. Combination antiretroviral therapy (cART) has not eradicated CNS complications. HIV-associated neurocognitive disorders (HAND) remain common despite cART, although attenuated in severity. This may result from a combination of factors including inadequate treatment of HIV reservoirs such as circulating monocytes and glia, decreased effectiveness of cART in CNS, concurrent illnesses, stimulant use, and factors associated with prescribed drugs, including antiretrovirals. This review highlights recent investigations of HIV-related CNS injury with emphasis on cART-era neuropathological mechanisms in the context of both US and international settings

Imaging of brain structural and functional effects in people with human immunodeficiency virus

Before the introduction of antiretroviral therapy, human immunodeficiency virus (HIV) infection was often accompanied by central nervous system (CNS) opportunistic infections and HIV encephalopathy marked by profound structural and functional alterations detectable with neuroimaging. Treatment with antiretroviral therapy nearly eliminated CNS opportunistic infections, while neuropsychiatric impairment and peripheral nerve and organ damage have persisted among virally suppressed people with HIV (PWH), suggesting ongoing brain injury. Neuroimaging research must use methods sensitive for detecting subtle HIV-associated brain structural and functional abnormalities, while allowing for adjustments for potential confounders, such as age, sex, substance use, hepatitis C coinfection, cardiovascular risk, and others. Here, we review existing and emerging neuroimaging tools that demonstrated promise in detecting markers of HIV-associated brain pathology and explore strategies to study the impact of potential confounding factors on these brain measures. We emphasize neuroimaging approaches that may be used in parallel to gather complementary information, allowing efficient detection and interpretation of altered brain structure and function associated with suboptimal clinical outcomes among virally suppressed PWH. We examine the advantages of each imaging modality and systematic approaches in study design and analysis. We also consider advantages of combining experimental and statistical control techniques to improve sensitivity and specificity of biotype identification and explore the costs and benefits of aggregating data from multiple studies to achieve larger sample sizes, enabling use of emerging methods for combining and analyzing large, multifaceted data sets. Many of the topics addressed in this article were discussed at the National Institute of Mental Health meeting Biotypes of CNS Complications in People Living with HIV, held in October 2021, and are part of ongoing research initiatives to define the role of neuroimaging in emerging alternative approaches to identifying biotypes of CNS complications in PWH. An outcome of these considerations may be the development of a common neuroimaging protocol available for researchers to use in future studies examining neurological changes in the brains of PWH

Cognitive and brain reserve predict decline in adverse driving behaviors among cognitively normal older adults

Daily driving is a multi-faceted, real-world, behavioral measure of cognitive functioning requiring multiple cognitive domains working synergistically to complete this instrumental activity of daily living. As the global population of older adult continues to grow, motor vehicle crashes become more frequent among this demographic. Cognitive reserve (CR) is the brain\u27s adaptability or functional robustness despite damage, while brain reserve (BR) refers the structural, neuroanatomical resources. This study examined whether CR and BR predicted changes in adverse driving behaviors in cognitively normal older adults. Cognitively normal older adults (Clinical Dementia Rating 0) were enrolled from longitudinal studies at the Knight Alzheimer\u27s Disease Research Center at Washington University. Participants

White Matter Hyperintensity Longitudinal Morphometric Analysis In Association With Alzheimer Disease

INTRODUCTION: Vascular damage in Alzheimer\u27s disease (AD) has shown conflicting findings particularly when analyzing longitudinal data. We introduce white matter hyperintensity (WMH) longitudinal morphometric analysis (WLMA) that quantifies WMH expansion as the distance from lesion voxels to a region of interest boundary. METHODS: WMH segmentation maps were derived from 270 longitudinal fluid-attenuated inversion recovery (FLAIR) ADNI images. WLMA was performed on five data driven WMH patterns with distinct spatial distributions. Amyloid accumulation was evaluated with WMH expansion across the five WMH patterns. RESULTS: The preclinical group had significantly greater expansion in the posterior ventricular WM compared to controls. Amyloid significantly associated with frontal WMH expansion primarily within AD individuals. WLMA outperformed WMH volume changes for classifying AD from controls primarily in periventricular and posterior WMH. DISCUSSION: These data support the concept that localized WMH expansion continues to proliferate with amyloid accumulation throughout the entirety of the disease in distinct spatial locations

Resting-State Functional Connectivity Disruption as a Pathological Biomarker in Autosomal Dominant Alzheimer Disease

AIM: Identify a global resting state functional connectivity (gFC) signature in mutation carriers (MC) from the Dominantly Inherited Alzheimer Network (DIAN). Assess the gFC with regards to amyloid (A), tau (T), and neurodegeneration (N) biomarkers and estimated years to symptom onset (EYO). INTRODUCTION: Cross-sectional measures were assessed in MC (n=171) and mutation non-carriers (NC) (n=70) participants. A FC matrix that encompassed multiple resting state networks (RSNs) was computed for each participant. METHODS: A gFC was compiled as a single index indicating functional connectivity strength. Global FC signature was modeled as a non-linear function of EYO. gFC was linearly associated with other biomarkers used for assessing the AT(N) framework including: cerebrospinal fluid (CSF), positron emission tomography (PET) molecular biomarkers, and structural magnetic resonance imaging. RESULTS: The gFC was reduced in MC compared to NC participants. When MC participants were differentiated by clinical dementia rating (CDR), the gFC was significantly decreased in MC CDR > 0 (demented) compared to either MC CDR 0 (cognitively normal) or NC participants. The gFC varied non-linearly with EYO and initially decreased at EYO = -24 years, followed by a stable period followed by a further decline near EYO =0 years. Irrespective of EYO, a lower gFC associated with values of amyloid PET, CSF Aβ1-42, CSF p-tau, CSF t-tau, FDG and hippocampal volume. CONCLUSIONS: The gFC correlated with biomarkers used for defining the AT(N) framework. A biphasic change in the gFC suggested early changes associated with CSF amyloid and later changes associated with hippocampal volume