Age-related brain atrophy is not a homogenous process: Different functional brain networks associate differentially with aging and blood factors.

Aging is characterized by a progressive loss of brain volume at an estimated rate of 5% per decade after age 40. While these morphometric changes, especially those affecting gray matter and atrophy of the temporal lobe, are predictors of cognitive performance, the strong association with aging obscures the potential parallel, but more specific role, of individual subject physiology. Here, we studied a cohort of 554 human subjects who were monitored using structural MRI scans and blood immune protein concentrations. Using machine learning, we derived a cytokine clock (CyClo), which predicted age with good accuracy (Mean Absolute Error = 6 y) based on the expression of a subset of immune proteins. These proteins included, among others, Placenta Growth Factor (PLGF) and Vascular Endothelial Growth Factor (VEGF), both involved in angiogenesis, the chemoattractant vascular cell adhesion molecule 1 (VCAM-1), the canonical inflammatory proteins interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα), the chemoattractant IP-10 (CXCL10), and eotaxin-1 (CCL11), previously involved in brain disorders. Age, sex, and the CyClo were independently associated with different functionally defined cortical networks in the brain. While age was mostly correlated with changes in the somatomotor system, sex was associated with variability in the frontoparietal, ventral attention, and visual networks. Significant canonical correlation was observed for the CyClo and the default mode, limbic, and dorsal attention networks, indicating that immune circulating proteins preferentially affect brain processes such as focused attention, emotion, memory, response to social stress, internal evaluation, and access to consciousness. Thus, we identified immune biomarkers of brain aging which could be potential therapeutic targets for the prevention of age-related cognitive decline.

Microglial Correlates of Late Life Physical Activity: Relationship with Synaptic and Cognitive Aging in Older Adults.

Physical activity relates to reduced dementia risk, but the cellular and molecular mechanisms are unknown. We translated animal and in vitro studies demonstrating a causal link between physical activity and microglial homeostasis into humans. Decedents from Rush Memory and Aging Project completed actigraphy monitoring (average daily activity) and cognitive evaluation in life, and neuropathological examination at autopsy. Brain tissue was analyzed for microglial activation via immunohistochemistry (anti-human HLA-DP-DQ-DR) and morphology (% Stage I, II, or III), and synaptic protein levels (SNAP-25, synaptophysin, complexin-I, VAMP, syntaxin, synaptotagmin-1). Proportion of morphologically activated microglia (PAM) was estimated in ventromedial caudate, posterior putamen, inferior temporal (IT), and middle frontal gyrus. The 167 decedents averaged 90 years at death, two-thirds were nondemented, and 60% evidenced pathologic Alzheimer's disease (AD). Adjusting for age, sex, education, and motor performances, greater physical activity associated with lower PAM in the ventromedial caudate and IT. Relationships between physical activity and PAM in the ventromedial caudate or IT were particularly prominent in adults evidencing microinfarcts or AD pathology, respectively. Mediational analyses indicated that PAM IT mediated ∼30% of the relationships between (1) physical activity and synaptic protein in IT, and (2) physical activity and global cognition, in separate models. However, the size of the mediation depended on AD pathology ranging from >40% in adults with high AD burden, but <10% in adults with low AD burden. Lower microglial activation may be a pathway linking physical activity to age-related brain health in humans. Physical activity may promote AD-related synaptic and cognitive resilience through reduction of pro-inflammatory microglial states.SIGNIFICANCE STATEMENT Physical activity relates to better cognitive aging and reduced risk of neurodegenerative disease, yet the cellular and molecular pathways linking behavior-to-brain in humans are unknown. Animal studies indicate that increasing physical activity leads to decreased microglial activation and corresponding increases in synaptogenesis and neurogenesis. We objectively monitored physical activity (accelerometer-based actigraphy) and cognitive performances in life, and quantified microglial activation and synaptic markers in brain tissue at death in older adults. These are the first data supporting microglial activation as a physiological pathway by which physical activity relates to brain heath in humans. Although more interventional work is needed, we suggest that physical activity may be a modifiable behavior leveraged to reduce pro-inflammatory microglial states in humans.

Immune cell counts in cerebrospinal fluid predict cognitive function in aging and neurodegenerative disease.

INTRODUCTION: Immune dysfunction is important in aging and neurodegeneration; lacking clinically available tools limits research translation. We tested associations of cerebral spinal fluid (CSF) monocyte-to-lymphocyte ratio (MLR)-innate immune activation surrogate-with cognition in an aging and dementia cohort, hypothesizing that elevated MLR is associated with poorer executive functioning. METHODS: CSF MLR was calculated in well-characterized, genotyped participants enrolled in studies of aging and dementia at University of California, San Francisco Memory and Aging Center (n = 199, mean age 57.5 years, SD 11.9). Linear models tested associations with episodic memory and executive function (verbal fluency, speeded set-shifting). RESULTS: Aging was associated with higher CSF monocyte, lower lymphocyte counts, and higher MLRs (p < 0.001). MLR was associated with verbal fluency (p < 0.05) only. DISCUSSION: Using clinical labs, we show an inverse association between CSF MLR and executive function in aging and dementia, supporting the utility of clinical labs in capturing associations between innate immune dysfunction and neurodegeneration.

Lower White Matter Volume and Worse Executive Functioning Reflected in Higher Levels of Plasma GFAP among Older Adults with and Without Cognitive Impairment.

OBJECTIVE: There are minimal data directly comparing plasma neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) in aging and neurodegenerative disease research. We evaluated associations of plasma NfL and plasma GFAP with brain volume and cognition in two independent cohorts of older adults diagnosed as clinically normal (CN), mild cognitive impairment (MCI), or Alzheimer's dementia. METHODS: We studied 121 total participants (Cohort 1: n = 50, age 71.6 ± 6.9 years, 78% CN, 22% MCI; Cohort 2: n = 71, age 72.2 ± 9.2 years, 45% CN, 25% MCI, 30% dementia). Gray and white matter volumes were obtained for total brain and broad subregions of interest (ROIs). Neuropsychological testing evaluated memory, executive functioning, language, and visuospatial abilities. Plasma samples were analyzed in duplicate for NfL and GFAP using single molecule array assays (Quanterix Simoa). Linear regression models with structural MRI and cognitive outcomes included plasma NfL and GFAP simultaneously along with relevant covariates. RESULTS: Higher plasma GFAP was associated with lower white matter volume in both cohorts for temporal (Cohort 1: ß = -0.33, p = .002; Cohort 2: ß = -0.36, p = .03) and parietal ROIs (Cohort 1: ß = -0.31, p = .01; Cohort 2: ß = -0.35, p = .04). No consistent findings emerged for gray matter volumes. Higher plasma GFAP was associated with lower executive function scores (Cohort 1: ß = -0.38, p = .01; Cohort 2: ß = -0.36, p = .007). Plasma NfL was not associated with gray or white matter volumes, or cognition after adjusting for plasma GFAP. CONCLUSIONS: Plasma GFAP may be more sensitive to white matter and cognitive changes than plasma NfL. Biomarkers reflecting astroglial pathophysiology may capture complex dynamics of aging and neurodegenerative disease.

Wisdom and fluid intelligence are dissociable in healthy older adults.

OBJECTIVES: The relationship between wisdom and fluid intelligence (Gf) is poorly understood, particularly in older adults. We empirically tested the magnitude of the correlation between wisdom and Gf to help determine the extent of overlap between these two constructs. DESIGN: Cross-sectional study with preregistered hypotheses and well-powered analytic plan (https://osf.io/h3pjx). SETTING: Memory and Aging Center at the University of California San Francisco, located in the USA. PARTICIPANTS: 141 healthy older adults (mean age = 76 years; 56% female). MEASUREMENTS: Wisdom was quantified using a well-validated self-report-based scale (San Diego Wisdom Scale or SD-WISE). Gf was assessed via composite measures of processing speed (Gf-PS) and executive functioning (Gf-EF). The relationships of SD-WISE scores to Gf-PS and Gf-EF were tested in bivariate correlational analyses and multiple regression models adjusted for demographics (age, sex, and education). Exploratory analyses evaluated the relationships between SD-WISE and age, episodic memory performance, and dorsolateral and ventromedial prefrontal cortical volumes on magnetic resonance imaging. RESULTS: Wisdom showed a small, positive association with Gf-EF (r = 0.181 [95% CI 0.016, 0.336], p = .031), which was reduced to nonsignificance upon controlling for demographics, and no association with Gf-PS (r = 0.019 [95% CI -0.179, 0.216], p = .854). Wisdom demonstrated a small, negative correlation with age (r = -0.197 [95% CI -0.351, -0.033], p = .019), but was not significantly related to episodic memory or prefrontal volumes. CONCLUSIONS: Our findings indicate that most of the variance in wisdom (>95%) is unaccounted for by Gf. The independence of wisdom from cognitive functions that reliably show age-associated declines suggests that it may hold unique potential to bolster decision-making, interpersonal functioning, and other everyday activities in older adults.

Worth the Wait: Delayed Recall after 1 Week Predicts Cognitive and Medial Temporal Lobe Trajectories in Older Adults.

METHOD: Clinically normal older adults (52-92 years old) were followed longitudinally for up to 8 years after completing a memory paradigm at baseline [Story Recall Test (SRT)] that assessed delayed recall at 30 min and 1 week. Subsets of the cohort underwent neuroimaging (N = 134, mean age = 75) and neuropsychological testing (N = 178-207, mean ages = 74-76) at annual study visits occurring approximately 15-18 months apart. Mixed-effects regression models evaluated if baseline SRT performance predicted longitudinal changes in gray matter volumes and cognitive composite scores, controlling for demographics. RESULTS: Worse SRT 1-week recall was associated with more precipitous rates of longitudinal decline in medial temporal lobe volumes (p = .037), episodic memory (p = .003), and executive functioning (p = .011), but not occipital lobe or total gray matter volumes (demonstrating neuroanatomical specificity; p > .58). By contrast, SRT 30-min recall was only associated with longitudinal decline in executive functioning (p = .044). CONCLUSIONS: Memory paradigms that capture longer-term recall may be particularly sensitive to age-related medial temporal lobe changes and neurodegenerative disease trajectories. (JINS, 2020, xx, xx-xx).

A longitudinal characterization of perfusion in the aging brain and associations with cognition and neural structure.

Cerebral perfusion declines across the lifespan and is altered in the early stages of several age-related neuropathologies. Little is known, however, about the longitudinal evolution of perfusion in healthy older adults, particularly when perfusion is quantified using magnetic resonance imaging with arterial spin labeling (ASL). The objective was to characterize longitudinal perfusion in typically aging adults and elucidate associations with cognition and brain structure. Adults who were functionally intact at baseline (n = 161, ages 47-89) underwent ASL imaging to quantify whole-brain gray matter perfusion; a subset (n = 136) had repeated imaging (average follow-up: 2.3 years). Neuropsychological testing at each visit was summarized into executive function, memory, and processing speed composites. Global gray matter volume, white matter microstructure (mean diffusivity), and white matter hyperintensities were also quantified. We assessed baseline associations among perfusion, cognition, and brain structure using linear regression, and longitudinal relationships using linear mixed effects models. Greater baseline perfusion, particularly in the left dorsolateral prefrontal cortex and right thalamus, was associated with better executive functions. Greater whole-brain perfusion loss was associated with worsening brain structure and declining processing speed. This study helps validate noninvasive MRI-based perfusion imaging and underscores the importance of cerebral blood flow in cognitive aging.

Lutein and Zeaxanthin Influence Brain Function in Older Adults: A Randomized Controlled Trial.

OBJECTIVES: The present study constitutes the first randomized controlled trial to investigate the relation of lutein (L) and zeaxanthin (Z) to brain function using functional magnetic resonance imaging (fMRI). It was hypothesized that L and Z supplementation in older adults would enhance neural efficiency (i.e., reduce activation) and cognitive performance on a verbal learning task relative to placebo. METHODS: A total of 44 community-dwelling older adults (mean age=72 years) were randomly assigned to receive either placebo or L+Z supplementation (12 mg/daily) for 1 year. Neurocognitive performance was assessed at baseline and post-intervention on an fMRI-adapted task involving learning and recalling word pairs. Imaging contrasts of blood-oxygen-level-dependent (BOLD) signal were created by subtracting active control trials from learning and recall trials. A flexible factorial model was employed to investigate the expected group (placebo vs. supplement) by time (baseline vs. post-intervention) interaction in pre-specified regions-of-interest. RESULTS: L and Z appeared to buffer cognitive decline on the verbal learning task (Cohen's d=.84). Significant interactions during learning were observed in left dorsolateral prefrontal cortex and anterior cingulate cortex (p < .05, family-wise-error corrected). However, these effects were in the direction of increased rather than decreased BOLD signal. Although the omnibus interaction was not significant during recall, within-group contrasts revealed significant increases in left prefrontal activation in the supplement group only. CONCLUSIONS: L and Z supplementation appears to benefit neurocognitive function by enhancing cerebral perfusion, even if consumed for a discrete period of time in late life. (JINS, 2018, 24, 77-90).

Cognitive Interventions for Cognitively Healthy, Mildly Impaired, and Mixed Samples of Older Adults: A Systematic Review and Meta-Analysis of Randomized-Controlled Trials.

Cognitive interventions may improve cognition, delay age-related cognitive declines, and improve quality of life for older adults. The current meta-analysis was conducted to update and expand previous work on the efficacy of cognitive interventions for older adults and to examine the impact of key demographic and methodological variables. EBSCOhost and Embase online databases and reference lists were searched to identify relevant randomized-controlled trials (RCTs) of cognitive interventions for cognitively healthy or mildly impaired (MCI) older adults (60+ years). Interventions trained a single cognitive domain (e.g., memory) or were multi-domain training, and outcomes were assessed immediately post-intervention using standard neuropsychological tests. In total, 279 effects from 97 studies were pooled based on a random-effects model and expressed as Hedges' g (unbiased). Overall, results indicated that cognitive interventions produce a small, but significant, improvement in the cognitive functioning of older adults, relative to active and passive control groups (g = 0.298, p < .001, 95% CI = 0.248-0.347). These results were confirmed using multi-level analyses adjusting for nesting of effect sizes within studies (g = 0.362, p < .001, 95% CI = 0.275, 0.449). Age, education, and cognitive status (healthy vs. MCI) were not significant moderators. Working memory interventions proved most effective (g = 0.479), though memory, processing speed, and multi-domain interventions also significantly improved cognition. Effects were larger for directly trained outcomes but were also significant for non-trained outcomes (i.e., "transfer effects"). Implications for future research and clinical practice are discussed. This project was pre-registered with PROSPERO (#42016038386).

Relationship of Lutein and Zeaxanthin Levels to Neurocognitive Functioning: An fMRI Study of Older Adults.

OBJECTIVES: It is well known that the carotenoids lutein (L) and zeaxanthin (Z) improve eye health and an accumulating evidence base suggests cognitive benefits as well. The present study investigated underlying neural mechanisms using functional magnetic resonance imaging (fMRI). It was hypothesized that lower L and Z concentrations would be associated with neurobiological inefficiency (i.e., increased activation) during cognitive performance. METHODS: Forty-three community-dwelling older adults (mean age=72 years; 58% female; 100% Caucasian) were asked to learn and recall pairs of unrelated words in an fMRI-adapted paradigm. L and Z levels were measured in retina (macular pigment optical density) and serum using validated procedures. RESULTS: Following first-level contrasts of encoding and retrieval trials minus control trials (p<.05, family-wise error corrected, minimum voxel cluster=8), L and Z were found to significantly and negatively relate to blood-oxygen-level-dependent signal in central and parietal operculum cortex, inferior frontal gyrus, supramarginal gyrus, planum polare, frontal and middle temporal gyrus, superior parietal lobule, postcentral gyrus, precentral gyrus, occipital cortex bilaterally, and cerebellar regions. CONCLUSIONS: To the authors' knowledge, the present study represents the first attempt to investigate neural mechanisms underlying the relation of L and Z to cognition using fMRI. The observed results suggest that L and Z promote cognitive functioning in old age by enhancing neural efficiency. (JINS, 2017, 23, 11-22).

Functional Disability in Mild Cognitive Impairment: A Systematic Review and Meta-Analysis.

Accumulating evidence suggests that the pre-dementia syndrome mild cognitive impairment (MCI) is characterized by decrements in instrumental activities of daily living (IADL). The current review was a quantitative synthesis of the available literature to objectively characterize IADL disability in MCI while clarifying inconsistencies in findings across studies. It was hypothesized that individuals with MCI would display significantly greater functional impairment relative to cognitively intact controls. Candidate moderators specified a priori included functional assessment approach, MCI subtype, depressive symptoms, and language conducted. Online databases (PubMed/MEDLINE and PsycINFO) and reference lists were searched to identify peer-reviewed publications assessing IADL in MCI compared to normal aging. A total of 151 effect sizes derived from 106 studies met inclusionary criteria (N = 62,260). Random effects models yielded a large overall summary effect size (Hedges' g = 0.76, 95 % confidence interval: 0.68 - 0.83, p < .001) confirmed in multi-level analyses adjusted for nesting of effect sizes within studies (g = 0.78, 95 % confidence interval: 0.69 - 0.87). Functional assessment strategy and MCI subtype were significant moderators of effect size, whereas depressive symptoms and language were not. Results convincingly demonstrate that MCI is associated with significant difficulties in the performance of complex everyday tasks. It appears that functional decline, like cognitive decline, exists on a continuum from healthy aging to dementia onset. Implications for clinical practice and research priorities are discussed.

Personality's association with IADLs in community dwelling older adults.

OBJECTIVES: Extant research has established several predictors of functional ability (FA) in older adults (OAs); however, one factor that has been relatively ignored is personality. Preliminary evidence suggests that openness and agreeableness are associated with instrumental activities of daily living (IADLs). However, how personality is related to IADLs remains unclear. We aimed to determine how personality factors predict performance of IADLs, which we hypothesized, was because of executive functioning (EF). METHODS: To best understand the relationship between personality and IADLs, we recruited and ran 65 independent community dwelling OAs. Bivariate correlations and hierarchical regressions were completed to determine the associations between openness and agreeableness with IADLs. Lastly, mediation analyses were completed to examine our hypothesis that EF would mediate this relationship RESULTS: Correlation and regression findings support the relationship between openness and IADLs but not agreeableness and IADLs. As hypothesized, the relationship between openness and IADLs was mediated by EF. CONCLUSIONS: We replicated the relationship between openness and IADLs and extend the literature by showing the mechanism of action for this relationship is EF. While our mediation results support this perspective, future research should determine if interventions that increase OAs' EF, in turn, increase or attenuate decline in IADLs over time.

Longitudinal Trajectories of Memory Performance in Patients with Early-Stage Breast Cancer.

Background: While breast cancer and its treatments may affect cognition, the longitudinal trajectories of cognition among those receiving differing cancer treatment types remain poorly understood. Prior research suggests hippocampal-prefrontal cortex network integrity may influence cognition, although how this network predicts performance over time remains unclear. Methods: We conducted a prospective trial including 69 patients with early-stage breast cancer receiving adjuvant therapy and 12 controls. Longitudinal cognitive testing was conducted at four visits: pretreatment-baseline, 6-7 months, 14-15 months, and 23-24 months. Cognitive composite scores of episodic memory, executive functioning, and processing speed were assessed at each timepoint. Baseline structural MRI was obtained in a subset of these participants, and hippocampal and prefrontal cortex regional volumes were extracted. Results: Longitudinal linear mixed modeling revealed significant group by time interactions on memory performance, controlling for age and education. Post hoc analyses revealed this effect was driven by patients treated with chemotherapy or chemotherapy plus hormone therapy, who demonstrated the least improvement in memory scores over time. Treatment group did not significantly influence the relationship between time and processing speed or executive functioning. Neither pretreatment hippocampal nor prefrontal volume differed between groups, and there were no significant group by time by baseline regional volume effects on cognition. Conclusion: Patients with early-stage breast cancer treated with chemotherapy or chemotherapy plus hormone therapy benefit less from practice effects seen in healthy controls on memory tests. Loss of longitudinal practice effect may be a new and clinically relevant measure for capturing patients' experience of cognitive difficulties after treatment.

Interbatch Reliability of Blood-Based Cytokine and Chemokine Measurements in Community-Dwelling Older Adults: A Cross-Sectional Study.

Blood-based inflammatory markers hold considerable promise for diagnosis and prognostication of age-related neurodegenerative disease, though a paucity of research has empirically tested how reliably they can be measured across different experimental runs ("batches"). We quantified the interbatch reliability of 13 cytokines and chemokines in a cross-sectional study of 92 community-dwelling older adults (mean age = 74; 48% female). Plasma aliquots from the same blood draw were parallelly processed in 2 separate batches using the same analytic platform and procedures (high-performance electrochemiluminescence by Meso Scale Discovery). Interbatch correlations (Pearson's r) ranged from small and nonsignificant (r = .13 for macrophage inflammatory protein-1 alpha [MIP-1α]) to very large (r > .90 for interferon gamma [IFNγ], interleukin-10 [IL-10], interferon gamma-induced protein 10 [IP-10], MIP-1ß, thymus and activation-regulated chemokine [TARC]) with most markers falling somewhere in between (.67 ≤ r ≤ .90 for IL-6, tumor necrosis factor alpha [TNF-α], Eotaxin, Eotaxin-3, monocyte chemoattractant protein-1 [MCP-1], MCP-4, macrophage-derived chemokine [MDC]). All markers, except for IL-6 and MCP-4, showed significant differences in absolute values between batches, with discrepancies ranging in effect size (Cohen's d) from small to moderate (0.2 ≤ |d| ≤ 0.5 for IL-10, IP-10, MDC) to large or very large (0.68 ≤ |d| ≤ 1.5 for IFNγ, TNF-α, Eotaxin, Eotaxin-3, MCP-1, MIP-1α, MIP-1ß, TARC). Relatively consistent associations with external variables of interest (age, sex, systolic blood pressure, body mass index, cognition) were observed across batches. Taken together, our results suggest heterogeneity in measurement reliability of blood-based cytokines and chemokines, with some analytes outperforming others. Future work is needed to evaluate the generalizability of these findings while identifying potential sources of batch effect measurement error.

Association of remote mild traumatic brain injury with cortical amyloid burden in clinically normal older adults.

We investigated whether clinically normal older adults with remote, mild traumatic brain injury (mTBI) show evidence of higher cortical Aß burden. Our study included 134 clinically normal older adults (age 74.1 ± 6.8 years, 59.7% female, 85.8% white) who underwent Aß positron emission tomography (Aß-PET) and who completed the Ohio State University Traumatic Brain Injury Identification questionnaire. We limited participants to those reporting injuries classified as mTBI. A subset (N = 30) underwent a second Aß-PET scan (mean 2.7 years later). We examined the effect of remote mTBI on Aß-PET burden, interactions between remote mTBI and age, sex, and APOE status, longitudinal Aß accumulation, and the interaction between remote mTBI and Aß burden on memory and executive functioning. Of 134 participants, 48 (36%) reported remote mTBI (0, N = 86; 1, N = 31, 2+, N = 17; mean 37 ± 23 years since last mTBI). Effect size estimates were small to negligible for the association of remote mTBI with Aß burden (p = .94, η2 < 0.01), and for all interaction analyses. Longitudinally, we found a non-statistically significant association of those with remote mTBI (N = 11) having a faster rate of Aß accumulation (B = 0.01, p = .08) than those without (N = 19). There was no significant interaction between remote mTBI and Aß burden on cognition. In clinically normal older adults, history of mTBI is not associated with greater cortical Aß burden and does not interact with Aß burden to impact cognition. Longitudinal analyses suggest remote mTBI may be associated with more rapid cortical Aß accumulation. This finding warrants further study in larger and more diverse samples with well-characterized lifelong head trauma exposure.

The effects of lutein and zeaxanthin on resting state functional connectivity in older Caucasian adults: a randomized controlled trial.

The carotenoids lutein (L) and zeaxanthin (Z) accumulate in retinal regions of the eye and have long been shown to benefit visual health. A growing literature suggests cognitive benefits as well, particularly in older adults. The present randomized controlled trial sought to investigate the effects of L and Z on brain function using resting state functional magnetic resonance imaging (fMRI). It was hypothesized that L and Z supplementation would (1) improve intra-network integrity of default mode network (DMN) and (2) reduce inter-network connectivity between DMN and other resting state networks. 48 community-dwelling older adults (mean age = 72 years) were randomly assigned to receive a daily L (10 mg) and Z (2 mg) supplement or a placebo for 1 year. Resting state fMRI data were acquired at baseline and post-intervention. A dictionary learning and sparse coding computational framework, based on machine learning principles, was used to investigate intervention-related changes in functional connectivity. DMN integrity was evaluated by calculating spatial overlap rate with a well-established DMN template provided in the neuroscience literature. Inter-network connectivity was evaluated via time series correlations between DMN and nine other resting state networks. Contrary to expectation, results indicated that L and Z significantly increased rather than decreased inter-network connectivity (Cohen's d = 0.89). A significant intra-network effect on DMN integrity was not observed. Rather than restoring what has been described in the available literature as a "youth-like" pattern of intrinsic brain activity, L and Z may facilitate the aging brain's capacity for compensation by enhancing integration between networks that tend to be functionally segregated earlier in the lifespan.

BHA-CS: A novel cognitive composite for Alzheimer's disease and related disorders.

INTRODUCTION: Composite scores based on psychometrically rigorous cognitive assessments are well suited for early diagnosis and disease monitoring. METHODS: We developed and cross-validated the Brain Health Assessment-Cognitive Score (BHA-CS), based on a brief computerized battery, in 451 cognitively normal (CN) and 399 cognitively impaired (mild cognitive impairment [MCI] or dementia) older adults. We investigated its long-term reliability and reliable change indices at longitudinal follow-up (N = 340), and the association with amyloid beta (Aß) burden in the CN subgroup with Aß positron emission tomography (N = 119). RESULTS: The BHA-CS was accurate at detecting cognitive impairment and exhibited excellent long-term stability. Reliable decline over one year was detected in 75% of participants with dementia, 44% with MCI, and 3% of CN. Among CN, the Aß-positive group showed worse longitudinal performance on the BHA-CS compared to the Aß-negative group. DISCUSSION: The BHA-CS is sensitive to cognitive decline in preclinical and prodromal neurodegenerative disease.

Systemic Tumor Necrosis Factor-Alpha Trajectories Relate to Brain Health in Typically Aging Older Adults.

BACKGROUND: Central nervous system levels of tumor necrosis factor-alpha (TNF-α), a pro-inflammatory cytokine, regulate the neuroinflammatory response and may play a role in age-related neurodegenerative diseases. The longitudinal relation between peripheral levels of TNF-α and typical brain aging is understudied. We hypothesized that within-person increases in systemic TNF-α would track with poorer brain health outcomes in functionally normal adults. METHODS: Plasma-based TNF-α concentrations (pg/mL; fasting morning draws) and magnetic resonance imaging were acquired in 424 functionally intact adults (mean age = 71) followed annually for up to 8.4 years (mean follow-up = 2.2 years). Brain outcomes included total gray matter volume and white matter hyperintensities. Cognitive outcomes included composites of memory, executive functioning, and processing speed, as well as Mini-Mental State Examination total scores. Longitudinal mixed-effects models were used, controlling for age, sex, education, and total intracranial volume, as appropriate. RESULTS: TNF-α concentrations significantly increased over time (p < .001). Linear increases in within-person TNF-α were longitudinally associated with declines in gray matter volume (p < .001) and increases in white matter hyperintensities (p = .003). Exploratory analyses suggested that the relation between TNF-α and gray matter volume was curvilinear (TNF-α 2p = .002), such that initial increases in inflammation were associated with more precipitous atrophy. There was a negative linear relationship of within-person changes in TNF-α to Mini-Mental State Examination scores over time (p = .036) but not the cognitive composites (all ps >.05). CONCLUSION: Systemic inflammation, as indexed by plasma TNF-α, holds potential as a biomarker for age-related declines in brain health.

Plasma Glial Fibrillary Acidic Protein Levels Differ Along the Spectra of Amyloid Burden and Clinical Disease Stage.

BACKGROUND: Measuring plasma glial fibrillary acidic protein (GFAP) alongside cortical amyloid-ß (Aß) may shed light on astrocytic changes in aging and Alzheimer's disease (AD). OBJECTIVE: To examine associations between plasma GFAP and cortical Aß deposition in older adults across the typical aging-to-AD dementia spectrum. METHODS: We studied two independent samples from UCSF (Cohort 1, N = 50; Cohort 2, N = 37) covering the spectra of clinical severity (CDR Sum of Boxes; CDR-SB) and Aß-PET burden. Aß-PET was completed with either florbetapir or Pittsburgh Compound B and standardized uptake value ratios were converted to the Centiloid (CL) scale for analyses. All participants with CDR-SB > 0 were Aß-PET positive, while clinically normal participants (CDR-SB = 0) were a mix of Aß-PET positive and negative. Regression analyses evaluated main effect and interaction associations between plasma GFAP, Aß-PET, and clinical severity. RESULTS: In both cohorts, plasma GFAP increased linearly with Aß-PET CLs in clinically normal older adults. In Cohort 2, which included participants with more severe clinical dysfunction and Aß-PET burden, the association between Aß and GFAP became curvilinear (inverted U-shape; quadratic model R2 change = 0.165, p = 0.009), and Aß-PET interacted with CDR-SB (R2 change = 0.164, p = 0.007): older adults with intermediate functional impairment (CDR-SB = 0.5-4.0) showed a weak (negative) association between Aß-PET CLs and plasma GFAP, while older adults with dementia (CDR-SB > 4.0) showed a strong, negative association of higher Aß-PET CLs with lower plasma GFAP. CONCLUSION: The relationship between astrocytic integrity and cortical Aß may be highly dynamic, with linear, positive associations early in disease that diverge in more severe disease stages.