Alzheimer's and neurodegenerative disease biomarkers in blood predict brain atrophy and cognitive decline.

BACKGROUND: Although blood-based biomarkers have been identified as cost-effective and scalable alternatives to PET and CSF markers of neurodegenerative disease, little is known about how these biomarkers predict future brain atrophy and cognitive decline in cognitively unimpaired individuals. Using data from the Baltimore Longitudinal Study of Aging (BLSA), we examined whether plasma biomarkers of Alzheimer's disease (AD) pathology (amyloid-ß [Aß42/40], phosphorylated tau [pTau-181]), astrogliosis (glial fibrillary acidic protein [GFAP]), and neuronal injury (neurofilament light chain [NfL]) were associated with longitudinal brain volume loss and cognitive decline. Additionally, we determined whether sex, APOEε4 status, and plasma amyloid-ß status modified these associations. METHODS: Plasma biomarkers were measured using Quanterix SIMOA assays. Regional brain volumes were measured by 3T MRI, and a battery of neuropsychological tests assessed five cognitive domains. Linear mixed effects models adjusted for demographic factors, kidney function, and intracranial volume (MRI analyses) were completed to relate baseline plasma biomarkers to baseline and longitudinal brain volume and cognitive performance. RESULTS: Brain volume analyses included 622 participants (mean age ± SD: 70.9 ± 10.2) with an average of 3.3 MRI scans over 4.7 years. Cognitive performance analyses included 674 participants (mean age ± SD: 71.2 ± 10.0) with an average of 3.9 cognitive assessments over 5.7 years. Higher baseline pTau-181 was associated with steeper declines in total gray matter volume and steeper regional declines in several medial temporal regions, whereas higher baseline GFAP was associated with greater longitudinal increases in ventricular volume. Baseline Aß42/40 and NfL levels were not associated with changes in brain volume. Lower baseline Aß42/40 (higher Aß burden) was associated with a faster decline in verbal memory and visuospatial performance, whereas higher baseline GFAP was associated with a faster decline in verbal fluency. Results were generally consistent across sex and APOEε4 status. However, the associations of higher pTau-181 with increasing ventricular volume and memory declines were significantly stronger among individuals with higher Aß burden, as was the association of higher GFAP with memory decline. CONCLUSIONS: Among cognitively unimpaired older adults, plasma biomarkers of AD pathology (pTau-181) and astrogliosis (GFAP), but not neuronal injury (NfL), serve as markers of future brain atrophy and cognitive decline.

Plasma biomarkers for Alzheimer's and related dementias: A review and outlook for clinical neuropsychology.

Recent technological advances have improved the sensitivity and specificity of blood-based biomarkers for Alzheimer's disease and related dementias. Accurate quantification of amyloid-ß peptide, phosphorylated tau (pTau) isoforms, as well as markers of neurodegeneration (neurofilament light chain [NfL]) and neuro-immune activation (glial fibrillary acidic protein [GFAP] and chitinase-3-like protein 1 [YKL-40]) in blood has allowed researchers to characterize neurobiological processes at scale in a cost-effective and minimally invasive manner. Although currently used primarily for research purposes, these blood-based biomarkers have the potential to be highly impactful in the clinical setting - aiding in diagnosis, predicting disease risk, and monitoring disease progression. Whereas plasma NfL has shown promise as a non-specific marker of neuronal injury, plasma pTau181, pTau217, pTau231, and GFAP have demonstrated desirable levels of sensitivity and specificity for identification of individuals with Alzheimer's disease pathology and Alzheimer's dementia. In this forward looking review, we (i) provide an overview of the most commonly used blood-based biomarkers for Alzheimer's disease and related dementias, (ii) discuss how comorbid medical conditions, demographic, and genetic factors can inform the interpretation of these biomarkers, (iii) describe ongoing efforts to move blood-based biomarkers into the clinic, and (iv) highlight the central role that clinical neuropsychologists may play in contextualizing and communicating blood-based biomarker results for patients.

Proteomic Indicators of Health Predict Alzheimer's Disease Biomarker Levels and Dementia Risk.

OBJECTIVE: Few studies have comprehensively examined how health and disease risk influence Alzheimer's disease (AD) biomarkers. The present study examined the association of 14 protein-based health indicators with plasma and neuroimaging biomarkers of AD and neurodegeneration. METHODS: In 706 cognitively normal adults, we examined whether 14 protein-based health indices (ie, SomaSignal® tests) were associated with concurrently measured plasma-based biomarkers of AD pathology (amyloid-ß [Aß]42/40 , tau phosphorylated at threonine-181 [pTau-181]), neuronal injury (neurofilament light chain [NfL]), and reactive astrogliosis (glial fibrillary acidic protein [GFAP]), brain volume, and cortical Aß and tau. In a separate cohort (n = 11,285), we examined whether protein-based health indicators associated with neurodegeneration also predict 25-year dementia risk. RESULTS: Greater protein-based risk for cardiovascular disease, heart failure mortality, and kidney disease was associated with lower Aß42/40 and higher pTau-181, NfL, and GFAP levels, even in individuals without cardiovascular or kidney disease. Proteomic indicators of body fat percentage, lean body mass, and visceral fat were associated with pTau-181, NfL, and GFAP, whereas resting energy rate was negatively associated with NfL and GFAP. Together, these health indicators predicted 12, 31, 50, and 33% of plasma Aß42/40 , pTau-181, NfL, and GFAP levels, respectively. Only protein-based measures of cardiovascular risk were associated with reduced regional brain volumes; these measures predicted 25-year dementia risk, even among those without clinically defined cardiovascular disease. INTERPRETATION: Subclinical peripheral health may influence AD and neurodegenerative disease processes and relevant biomarker levels, particularly NfL. Cardiovascular health, even in the absence of clinically defined disease, plays a central role in brain aging and dementia. ANN NEUROL 2024;95:260-273.

Identification of Clinically Relevant Brain Endothelial Cell Biomarkers in Plasma.

BACKGROUND: Proteins expressed by brain endothelial cells (BECs), the primary cell type of the blood-brain barrier, may serve as sensitive plasma biomarkers for neurological and neurovascular conditions, including cerebral small vessel disease. METHODS: Using data from the BLSA (Baltimore Longitudinal Study of Aging; n=886; 2009-2020), BEC-enriched proteins were identified among 7268 plasma proteins (measured with SomaScanv4.1) using an automated annotation algorithm that filtered endothelial cell transcripts followed by cross-referencing with BEC-specific transcripts reported in single-cell RNA-sequencing studies. To identify BEC-enriched proteins in plasma most relevant to the maintenance of neurological and neurovascular health, we selected proteins significantly associated with 3T magnetic resonance imaging-defined white matter lesion volumes. We then examined how these candidate BEC biomarkers related to white matter lesion volumes, cerebral microhemorrhages, and lacunar infarcts in the ARIC study (Atherosclerosis Risk in Communities; US multisite; 1990-2017). Finally, we determined whether these candidate BEC biomarkers, when measured during midlife, were related to dementia risk over a 25-year follow-up period. RESULTS: Of the 28 proteins identified as BEC-enriched, 4 were significantly associated with white matter lesion volumes (CDH5 [cadherin 5], CD93 [cluster of differentiation 93], ICAM2 [intracellular adhesion molecule 2], GP1BB [glycoprotein 1b platelet subunit beta]), while another approached significance (RSPO3 [R-Spondin 3]). A composite score based on 3 of these BEC proteins accounted for 11% of variation in white matter lesion volumes in BLSA participants. We replicated the associations between the BEC composite score, CDH5, and RSPO3 with white matter lesion volumes in ARIC, and further demonstrated that the BEC composite score and RSPO3 were associated with the presence of ≥1 cerebral microhemorrhages. We also showed that the BEC composite score, CDH5, and RSPO3 were associated with 25-year dementia risk. CONCLUSIONS: In addition to identifying BEC proteins in plasma that relate to cerebral small vessel disease and dementia risk, we developed a composite score of plasma BEC proteins that may be used to estimate blood-brain barrier integrity and risk for adverse neurovascular outcomes.

Hippocampal and amygdala volumes vary with residential proximity to toxicants at Birmingham, Alabama's 35th Avenue Superfund site.

Exposure to environmental toxicants have serious implications for the general health and well-being of children, particularly during pivotal neurodevelopmental stages. The Environmental Protection Agency's (EPA) Superfund program has identified several areas (Superfund sites) across the United States with high levels of environmental toxicants, which affect the health of many residents in nearby communities. Exposure to these environmental toxicants has been linked to changes in the structure and function of the brain. However, limited research has investigated the relationship between the proximity of childhood homes to a Superfund site and the development of subcortical structures like the hippocampus and amygdala. The present study investigated the hippocampal and amygdala volumes of young adults in relation to the proximity of their childhood homes to Birmingham, Alabama's 35th Avenue Superfund site. Forty participants who either lived within or adjacent to the Superfund site (Proximal group; n = 20) or who lived elsewhere in the greater Birmingham metropolitan area (Distal group; n = 20) were included in this study. Both groups were matched on age, sex, race, and years of education. Magnetic resonance imaging (MRI) was used to compare the gray matter volume of the hippocampus and amygdala between groups. Differences in bilateral hippocampal and left amygdala volumes were observed. Specifically, hippocampal and amygdala volumes were greater in the Proximal than Distal group. These findings suggest that the proximity of children's homes to environmental toxicants may impact the development of the hippocampus and amygdala. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Stress-induced Changes in Autonomic Reactivity Vary with Adolescent Violence Exposure and Resting-state Functional Connectivity.

Exposure to violence during childhood can lead to functional changes in brain regions that are important for emotion expression and regulation, which may increase susceptibility to internalizing disorders in adulthood. Specifically, childhood violence exposure can disrupt the functional connectivity among brain regions that include the prefrontal cortex (PFC), hippocampus, and amygdala. Together, these regions are important for modulating autonomic responses to stress. However, it is unclear to what extent changes in brain connectivity relate to autonomic stress reactivity and how the relationship between brain connectivity and autonomic responses to stress varies with childhood violence exposure. Thus, the present study examined whether stress-induced changes in autonomic responses (e.g., heart rate, skin conductance level (SCL)) varied with amygdala-, hippocampus-, and ventromedial prefrontal cortex (vmPFC)-whole brain resting-state functional connectivity (rsFC) as a function of violence exposure. Two hundred and ninety-seven participants completed two resting-state functional magnetic resonance imaging scans prior to (pre-stress) and after (post-stress) a psychosocial stress task. Heart rate and SCL were recorded during each scan. Post-stress heart rate varied negatively with post-stress amygdala-inferior parietal lobule rsFC and positively with post-stress hippocampus-anterior cingulate cortex rsFC among those exposed to high, but not low, levels of violence. Results from the present study suggest that post-stress fronto-limbic and parieto-limbic rsFC modulates heart rate and may underlie differences in the stress response among those exposed to high levels of violence.

The association of perceived discrimination with dementia risk in Black older adults.

INTRODUCTION: Non-Hispanic Black, compared to non-Hispanic White, older adults are at increased risk for dementia. This may be due partly to greater exposure to psychosocial stressors, such as discrimination; however, few studies have examined this association. METHODS: We examined the association of perceived discrimination (e.g., everyday, lifetime, and discrimination burden) with dementia risk in 1583 Black adults co-enrolled in the Atherosclerosis Risk in Communities (ARIC) Study and the Jackson Heart Study (JHS). Perceived discrimination (defined continuously and using tertiles) was assessed at JHS Exam 1 (2000-2004; mean age ± SD:66.2 ± 5.5) and related to dementia risk through ARIC visit 6 (2017) using covariate-adjusted Cox proportional hazards models. RESULTS: Associations of perceived everyday, lifetime, and burden of discrimination with dementia risk were not supported in age-adjusted models or demographic- and cardiovascular health-adjusted models. Results were similar across sex, income, and education. DISCUSSION: In this sample, associations between perceived discrimination and dementia risk were not supported. HIGHLIGHTS: In Black older adults perceived discrimination not associated with dementia risk. Younger age and greater education linked to greater perceived discrimination. Older age and less education among factors associated with dementia risk. Factors increasing exposure to discrimination (education) are also neuroprotective.

MRI and fluid biomarkers reveal determinants of myelin and axonal loss with aging.

OBJECTIVE: White matter damage is a feature of Alzheimer's disease, yet little is known about how facets of the Alzheimer's disease process relate to key features of white matter structure. We examined the association of Alzheimer's disease (Aß42/40 ratio; pTau181), neuronal injury (NfL), and reactive astrogliosis (GFAP) biomarkers with MRI measures of myelin content and axonal density. METHODS: Among cognitively normal participants in the BLSA and GESTALT studies who received MRI measures of myelin content (defined by myelin water fraction [MWF]) and axonal density (defined by neurite density index [NDI]), we quantified plasma levels of Aß42 , Aß40 , pTau181, NfL, and GFAP. Linear regression models adjusted for demographic variables were used to relate these plasma biomarker levels to the MRI measures. RESULTS: In total, 119 participants received MWF imaging (age: 56 [SD 21]), of which 43 received NDI imaging (age: 50 [SD 18]). We found no relationship between plasma biomarkers and total brain myelin content. However, secondary analysis found higher GFAP was associated with lower MWF in the temporal lobes (ß = -0.13; P = 0.049). Further, higher levels of NfL (ß = -0.22; P = 0.009) and GFAP (ß = -0.29; P = 0.002) were associated with lower total brain axonal density. Secondary analyses found lower Aß42/40 ratio and higher pTau181 were also associated with lower axonal density, but only in select brain regions. These results remained similar after additionally adjusting for cardiovascular risk factors. INTERPRETATION: Plasma biomarkers of neuronal injury and astrogliosis are associated with reduced axonal density and region-specific myelin content. Axonal loss and demyelination may co-occur with neurodegeneration and astrogliosis ahead of clinically meaningful cognitive decline.

Association of liver disease with brain volume loss, cognitive decline, and plasma neurodegenerative disease biomarkers.

Although liver dysfunction has been implicated in Alzheimer's disease (AD), it remains unknown how liver disease may influence the trajectory of brain and cognitive changes in older adults. We related self-reported liver disease to longitudinal measures of brain structure and cognition, as well as baseline measures of plasma AD/neurodegeneration biomarkers in the Baltimore Longitudinal Study of Aging. Liver disease was identified using ICD-9 classification codes. Brain volume and cognition were assessed serially using 3T-MRI and a cognitive battery. 1008, 2157, and 780 participants were included in the MRI, cognitive, and plasma biomarker analysis, respectively. After adjustment for confounders, liver disease was associated with accelerated decline in total brain and white matter volume, but not total gray matter or AD signature region volume. Although liver disease showed no relationship with domain-specific cognitive decline or plasma biomarkers, participants with a history of hepatitis demonstrated accelerated decline in verbal fluency and elevated neurofilament light. Results suggest all-cause liver disease may accelerate brain volume loss but does not appear to promote AD-specific neurocognitive changes.

Sex-related differences in violence exposure, neural reactivity to threat, and mental health.

The prefrontal cortex (PFC), hippocampus, and amygdala play an important role in emotional health. However, adverse life events (e.g., violence exposure) affect the function of these brain regions, which may lead to disorders such as depression and anxiety. Depression and anxiety disproportionately affect women compared to men, and this disparity may reflect sex differences in the neural processes that underlie emotion expression and regulation. The present study investigated sex differences in the relationship between violence exposure and the neural processes that underlie emotion regulation. In the present study, 200 participants completed a Pavlovian fear conditioning procedure in which cued and non-cued threats (i.e., unconditioned stimuli) were presented during functional magnetic resonance imaging. Violence exposure was previously assessed at four separate time points when participants were 11-19 years of age. Significant threat type (cued versus non-cued) × sex and sex × violence exposure interactions were observed. Specifically, women and men differed in amygdala and parahippocampal gyrus reactivity to cued versus non-cued threat. Further, dorsolateral PFC (dlPFC) and inferior parietal lobule (IPL) reactivity to threat varied positively with violence exposure among women, but not men. Similarly, threat-elicited skin conductance responses varied positively with violence exposure among women. Finally, women reported greater depression and anxiety symptoms than men. These findings suggest that sex differences in threat-related brain and psychophysiological activity may have implications for mental health.

Hippocampal volume varies with acute posttraumatic stress symptoms following medical trauma.

The hippocampus and amygdala play an important role in the pathophysiology of posttraumatic stress disorder (PTSD). In fact, chronic PTSD has been consistently linked to reductions in hippocampal and amygdala volume. However, the acute impact posttraumatic stress has on the volume of these brain regions has received limited attention. Determining the acute impact posttraumatic stress has on brain volume may improve our understanding of the development of PTSD. Therefore, the present study recruited participants acutely (i.e., ∼1-month posttrauma) following trauma exposure and examined the relationship between brain volume (assessed at ∼1-month posttrauma) and posttraumatic stress symptoms (assessed at ∼1 and >3-months posttrauma) to determine whether brain volume was associated with acute posttraumatic stress symptom expression. Twenty-one trauma-exposed (TE) patients and 19 nontrauma-exposed (NTE) controls were recruited for the present study. Brain volume was assessed by structural magnetic resonance imaging completed during the ∼1-month assessment. Left hippocampal volumes were smaller in TE than NTE participants. Among TE participants, bilateral hippocampal volumes decreased as the number of days posttrauma increased. Further, bilateral hippocampal volumes varied negatively with the severity of posttraumatic stress symptoms at ∼1-month posttrauma. The present findings suggest that there is a progressive decrease in hippocampal volume acutely (e.g., within approximately 1 month) following trauma exposure, and demonstrates that acutely assessed hippocampal volumes vary with posttraumatic stress symptom expression. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Violence exposure, affective style, and stress-induced changes in resting state functional connectivity.

Chronic childhood stress is linked to greater susceptibility to internalizing disorders in adulthood. Specifically, chronic stress leads to changes in brain connectivity patterns, and, in turn, affects psychological functioning. Violence exposure, a chronic stressor, increases stress reactivity and disrupts emotion regulation processes. However, it is unclear to what extent violence exposure affects the neural circuitry underlying emotion regulation. Individual differences in affective style also moderate the impact of stress on psychological function and can thus alter the relationship between violence exposure and brain function. Resting-state functional connectivity (rsFC) is an index of intrinsic brain activity. Stress-induced changes in rsFC between the amygdala, hippocampus, and prefrontal cortex (PFC) are associated with emotion dysregulation and may elucidate how affective style modulates the relationship between violence exposure and brain connectivity. Therefore, the present study examined the impact of violence exposure and affective style on stress-induced changes in rsFC. Participants (n = 233) completed two 6-minute resting-state functional magnetic resonance imaging scans, one before (pre-stress) and one after (post-stress) a psychosocial stress task. The bilateral amygdala, hippocampus, and ventromedial prefrontal cortex (vmPFC) were used as seed regions for rsFC analyses. Significant stress-induced changes in the prefrontal, fronto-limbic, and parieto-limbic rsFC were observed. Further, pre-stress to post-stress differences in rsFC varied with violence exposure and affective style. These findings suggest that prefrontal, fronto-limbic, and parieto-limbic connectivity is associated with the emotional response to stress and provide new insight into the neural mechanisms through which affective style moderates the impact violence exposure has on the brain.

Brief Report: Interpersonal and Intrapersonal Factors as Parallel Independent Mediators in the Association Between Internalized HIV Stigma and ART Adherence.

INTRODUCTION: People living with HIV (PLWH) need to adhere to antiretroviral therapy (ART) to achieve optimal health. One reason for ART nonadherence is HIV-related stigma. OBJECTIVES: We aimed to examine whether HIV treatment self-efficacy (an intrapersonal mechanism) mediates the stigma-adherence association. We also examined whether self-efficacy and the concern about being seen while taking HIV medication (an interpersonal mechanism) are parallel mediators independent of each other. METHODS: A total of 180 people living with HIV self-reported internalized HIV stigma, ART adherence, HIV treatment self-efficacy, and concerns about being seen while taking HIV medication. We calculated bias-corrected 95% confidence intervals for indirect effects using bootstrapping to conduct mediation analyses. RESULTS: Adherence self-efficacy mediated the relationship between internalized stigma and ART adherence. Additionally, self-efficacy and concern about being seen while taking HIV medication uniquely mediated and explained almost all the stigma-adherence association in independent paths (parallel mediation). CONCLUSION: These results can inform intervention strategies to promote ART adherence.