Sexually dimorphic differences in angiogenesis markers predict brain aging trajectories.

Aberrant angiogenesis could contribute to cognitive impairment, representing a therapeutic target for preventing dementia. However, most angiogenesis studies focus on model organisms. To test the relevance of angiogenesis to human cognitive aging, we evaluated associations of circulating blood markers of angiogenesis with brain aging trajectories in two deeply phenotyped human cohorts (n=435, age 74 + 9) with longitudinal cognitive assessments, biospecimens, structural brain imaging, and clinical data. Machine learning and traditional statistics revealed sex dimorphic associations of plasma angiogenic growth factors with brain aging outcomes. Specifically, angiogenesis is associated with higher executive function and less brain atrophy in younger women (not men), a directionality of association that reverses around age 75. Higher levels of basic fibroblast growth factor, known for pleiotropic effects on multiple cell types, predicted favorable cognitive trajectories. This work demonstrates the relevance of angiogenesis to brain aging with important therapeutic implications for vascular cognitive impairment and dementia.

Sexual dimorphism of physical activity on cognitive aging: Role of immune functioning.

OBJECTIVE: Exercise is one of the most potent strategies available to support cognitive health with age, yet substantial variability exists. Sexual dimorphism is evident for brain and immune functioning, the latter being implicated as important pathway for exercise. We examined the moderating role of sex on the relationship between physical activity and systemic inflammatory and brain health outcomes in support of more personalized approaches to behavioral interventions. METHODS: Our discovery cohort included 45 typically aging women matched on age (±5y) and education (±2y) to 45 men (mean age = 72.5; Clinical Dementia Rating = 0) who completed self-reported current physical activity (Physical Activity Scale for Elderly), blood draw, neuropsychological evaluation, and brain MRI. An independent sample of 45 typically aging women and 36 men who completed the same measures comprised a replication cohort. Plasma was analyzed for 11 proinflammatory cytokine and chemokine markers via MesoScale Discovery. RESULTS: Discovery cohort: Reported physical activity did not differ between sexes (150 vs. 157, p = 0.72). There was a significant interaction between sex and physical activity on chemokine markers MDC, MIP-1b, MCP-4, and eotaxin-3 (ps < 0.03), with a similar trend for MCP-1 and INFγ (ps < 0.09). Men who reported greater activity demonstrated lower inflammatory markers, an effect attenuated-to-absent in women. An interaction between sex and physical activity was also observed for parahippocampal volumes (p = 0.02) and cognition (processing speed and visual memory; ps < 0.04). Again, the beneficial effect of physical activity on outcomes was present in men, but not women. Replication cohort analyses conferred a consistent effect of sex on the relationship between physical activity and immune markers; models examining neurobehavioral outcomes did not strongly replicate. Across cohorts, post-hoc models demonstrated an interaction between sex and activity-related inflammatory markers on total gray matter volume and visual memory. Men with higher inflammatory markers demonstrated poorer brain structure and function, whereas inflammatory markers did not strongly relate to neurobehavioral outcomes in women. CONCLUSIONS: Greater physical activity was associated with lower markers of inflammation in clinically normal older men, but not women - an effect consistently replicated across cohorts. Additionally, men appeared disproportionately vulnerable to the adverse effects of peripheral inflammatory markers on brain structure and function compared to women. Immune activation may be a male-specific pathway through which exercise confers neurobehavioral benefit.

Active lifestyles moderate clinical outcomes in autosomal dominant frontotemporal degeneration.

INTRODUCTION: Leisure activities impact brain aging and may be prevention targets. We characterized how physical and cognitive activities relate to brain health for the first time in autosomal dominant frontotemporal lobar degeneration (FTLD). METHODS: A total of 105 mutation carriers (C9orf72/MAPT/GRN) and 69 non-carriers reported current physical and cognitive activities at baseline, and completed longitudinal neurobehavioral assessments and brain magnetic resonance imaging (MRI) scans. RESULTS: Greater physical and cognitive activities were each associated with an estimated >55% slower clinical decline per year among dominant gene carriers. There was also an interaction between leisure activities and frontotemporal atrophy on cognition in mutation carriers. High-activity carriers with frontotemporal atrophy (-1 standard deviation/year) demonstrated >two-fold better cognitive performances per year compared to their less active peers with comparable atrophy rates. DISCUSSION: Active lifestyles were associated with less functional decline and moderated brain-to-behavior relationships longitudinally. More active carriers "outperformed" brain volume, commensurate with a cognitive reserve hypothesis. Lifestyle may confer clinical resilience, even in autosomal dominant FTLD.

A comparison of biofluid cytokine markers across platform technologies: Correspondence or divergence?

BACKGROUND: Quantification of biofluid cytokines is a rapidly growing area of translational research. However, comparability across the expanding number of available assay platforms for detection of the same proteins remains to be determined. We aimed to directly compare a panel of commonly measured cytokines in plasma of typically aging adults across two high sensitivity quantification platforms, Meso Scale Discovery high performance electrochemiluminiscence (HPE) and single-molecule immunosorbent assays (Simoa) by Quanterix. METHODS: 57 community-dwelling older adults completed a blood draw, neuropsychological assessment, and brain MRI as part of a healthy brain aging study. Plasma samples from the same draw dates were analyzed for IL-10, IP-10, IL-6, TNFα, and IL-1ß on HPE and Simoa, separately. Reliable detectability (coefficient of variance (CV) < 20% and outliers 3 interquartiles above the median removed), intra-assay precision, absolute concentrations, reproducibility across platforms, and concurrent associations with external variables of interest (e.g., demographics, peripheral markers of vascular health, and brain health) were examined. RESULTS: The proportion of cytokines reliably measured on HPE (87.7-93.0%) and Simoa (75.4-93.0%) did not differ (ps > 0.32), with the exception of IL-1ß which was only reliably measured using Simoa (68.4%). On average, CVs were acceptable at <8% across both platforms. Absolute measured concentrations were higher using Simoa for IL-10, IL-6, and TNFα (ps < 0.05). HPE and Simoa shared only small-to-moderate proportions of variance with one another on the same cytokine proteins (range: r = 0.26 for IL-10 to r = 0.64 for IL-6), though platform agreement did not dependent on cytokine concentrations. Cytokine ratios within each platform demonstrated similar relative patterns of up- and down-regulation across HPE and Simoa, though still significantly differed (ps < 0.001). Supporting concurrent validity, all 95% confidence intervals of the correlations between cytokines and external variables overlapped between the two platforms. Moreover, most associations were in expected directions and consistently so across platforms (e.g., IL-6 and TNFα), though with several notable exceptions for IP-10 and IL-10. CONCLUSIONS: HPE and Simoa showed comparable detectability and intra-assay precision measuring a panel of commonly examined cytokine proteins, with the exception of IL-1ß which was not reliably detected on HPE. However, Simoa demonstrated overall higher concentrations and the two platforms did not show agreement when directly compared against one another. Relative cytokine ratios and associations demonstrated similar patterns across platforms. Absolute cytokine concentrations may not be directly comparable across platforms, may be analyte dependent, and interpretation may be best limited to discussion of relative associations.

Performance on a 1-week delayed recall task is associated with medial temporal lobe structures in neurologically normal older adults.

OBJECTIVE: Traditional episodic memory tests employ a delayed recall length ranging from 10 to 30 min. The neurobiological process of memory consolidation extends well beyond these time intervals, however, raising the possibility that these tests might not be fully sensitive to the subtle neurocognitive changes found in early disease or age-related decline. We aimed to determine the sensitivity of a 1-week delayed recall paradigm to medial temporal lobe (MTL) structure among neurologically normal older adults. METHODS: One hundred and forty functionally intact, older adults (mean age = 75.8) completed a story recall test in which participants learned to 90% criterion. Recall was tested after 30-min and 1-week. Participants also completed a standardized list learning task with a 20-min delay (n = 129) and a structural brain MRI. The MTL, including the parahippocampal gyrus, hippocampus, and entorhinal, was our primary region of interest. RESULTS: Controlling for age, education, gender and total intracranial volume, the standard 20- and 30-min recalls showed no significant relationship with MTL. In contrast, 1-week recall was uniquely associated with MTL structure (partial r = .24, p = .006), specifically entorhinal (partial r = .27; p = .001) and hippocampal (partial r = .21, p = .02) volumes. CONCLUSION: Memory paradigms that utilize 1-week delays are more sensitive than standard paradigms to MTL volumes in neurologically normal older adults. Longer delay periods may improve detection of memory consolidation abilities associated with age-related, and potentially pathological, neurobehavioral change.

Everyday Multitasking Abilities in Older HIV+ Adults: Neurobehavioral Correlates and the Mediating Role of Metacognition.

OBJECTIVE: The prevalence of older adults living with HIV is rising, as is their risk for everyday functioning problems associated with neurocognitive dysfunction. Multitasking, the ability to maintain and carry out subgoals in support of a larger goal, is a multidimensional skill ubiquitous during most real-life tasks and associated with prefrontal networks that are vulnerable in HIV. Understanding factors associated with multitasking will improve characterization of HIV-associated neurocognitive disorders. Metacognition is also associated with frontal systems, is impaired among individuals with HIV, and may contribute to multitasking. METHOD: Ninety-nine older (≥50 years) adults with HIV completed: the Everyday Multitasking Test (MT), a performance-based measure during which participants concurrently attempt four everyday tasks (e.g., medication management) within a time limit; a comprehensive neuropsychological battery; measures of metacognition regarding their MT performance (e.g., metacognitive knowledge and online awareness). RESULTS: Better global neuropsychological performance (i.e., average T-score across all domains) was associated with better Everyday MT total scores (rho = 0.34; p < .001), as was global metacognition (rho = 0.37, p < .01). Bootstrapping mediation analysis revealed global metacognition was a significant partial mediator between neurocognition and Everyday MT (b = 0.09, 95% confidence interval [CI] = 0.01, 0.25). Specifically, metacognitive knowledge (but not online awareness) drove this mediation (b = 0.13, 95% CI = 0.03, 0.27). CONCLUSIONS: Consistent with findings among younger persons with HIV, neuropsychological performance is strongly associated with a complex, laboratory-based test of everyday multitasking, and metacognition of task performance was a pathway through which successful multitasking occurred. Interventions aimed at modifying metacognition to improve daily functioning may be warranted among older adults with HIV.

Is "Learning" episodic memory? Distinct cognitive and neuroanatomic correlates of immediate recall during learning trials in neurologically normal aging and neurodegenerative cohorts.

Although commonly interpreted as a marker of episodic memory during neuropsychological exams, relatively little is known regarding the neurobehavior of "total learning" immediate recall scores. Medial temporal lobes are clearly associated with delayed recall performances, yet immediate recall may necessitate networks beyond traditional episodic memory. We aimed to operationalize cognitive and neuroanatomic correlates of total immediate recall in several aging syndromes. Demographically-matched neurologically normal adults (n=91), individuals with Alzheimer's disease (n=566), logopenic variant primary progressive aphasia (PPA) (n=34), behavioral variant frontotemporal dementia (n=97), semantic variant PPA (n=71), or nonfluent/agrammatic variant PPA (n=39) completed a neurocognitive battery, including the CVLT-Short Form trials 1-4 Total Immediate Recall; a majority subset also completed a brain MRI. Regressions covaried for age and sex, and MMSE in cognitive and total intracranial volume in neuroanatomic models. Neurologically normal adults demonstrated a heterogeneous pattern of cognitive associations with total immediate recall (executive, speed, delayed recall), such that no singular cognitive or neuroanatomic correlate uniquely predicted performance. Within the clinical cohorts, there were syndrome-specific cognitive and neural associations with total immediate recall; e.g., semantic processing was the strongest cognitive correlate in svPPA (partial r=0.41), while frontal volumes was the only meaningful neural correlate in bvFTD (partial r=0.20). Medial temporal lobes were not independently associated with total immediate recall in any group (ps>0.05). Multiple neurobehavioral systems are associated with "total learning" immediate recall scores that importantly differ across distinct clinical syndromes. Conventional memory networks may not be sufficient or even importantly contribute to total immediate recall in many syndromes. Interpreting learning scores as equivalent to episodic memory may be erroneous.

Validation of the NIH Toolbox in Individuals with Neurologic Disorders.

OBJECTIVE: Individuals with spinal cord injury (SCI), traumatic brain injury (TBI), and stroke experience a variety of neurologically related deficits across multiple domains of function. The NIH Toolbox for the Assessment of Neurological and Behavioral Function (NIHTB) examines motor, sensation, cognition, and emotional functioning. The purpose of this paper is to establish the validity of the NIHTB in individuals with neurologic conditions. METHODS: Community-dwelling individuals with SCI (n = 209), TBI (n = 184), or stroke (n = 211) completed the NIHTB. Relative risks for impaired performance were examined relative to a matched control groups. RESULTS: The largest group differences were observed on the Motor domain and for the Fluid Cognition measures. All groups were at increased risk for motor impairment relative to normative standards and matched controls. Fluid cognitive abilities varied across groups such that individuals with stroke and TBI performed more poorly than individuals with SCI; increased relative risks for impaired fluid cognition were seen for individuals in the stroke and TBI groups, but not for those in the SCI group. All three neurologic groups performed normally on most measures in the Sensation Battery, although TBI participants evidenced increased risk for impaired odor identification and the stroke group showed more vision difficulties. On the Emotion Battery, participants in all three groups showed comparably poor psychological well-being, social satisfaction, and self-efficacy, whereas the TBI group also evidenced slightly increased negative affect. CONCLUSIONS: Data provide support for the validity of the NIHTB in individuals with neurologic conditions.

Screening for neurocognitive impairment in HIV-positive adults aged 50 years and older: Montreal Cognitive Assessment relates to self-reported and clinician-rated everyday functioning.

As the HIV+ population ages, the risk for and need to screen for HIV-associated neurocognitive disorders (HAND) increases. The aim of this study is to determine the utility and ecological validity of the Montreal Cognitive Assessment (MoCA) among older HIV+ adults. A total of 100 HIV+ older adults aged 50 years or over completed a comprehensive neuromedical and neurocognitive battery, including the MoCA and several everyday functioning measures. The receiver operating characteristic curve indicates ≤26 as the optimal cut-off balancing sensitivity (84.2%) and specificity (55.8%) compared to "gold standard" impairment as measured on a comprehensive neuropsychological battery. Higher MoCA total scores are significantly (p < .01) associated with better performance in all individual cognitive domains except motor abilities, with the strongest association with executive functions (r = -0.49, p < .01). Higher MoCA total scores are also significantly (p <.01) associated with fewer instrumental activities of daily living declines (r = -0.28), fewer everyday cognitive symptoms (r = -0.25), and better clinician-rated functional status (i.e., Karnofsky scores; r = 0.28); these associations remain when controlling for depressive symptoms. HIV+ individuals who are neurocognitively normal demonstrate medium-to-large effect size differences in their MoCA performance compared to those with asymptomatic neurocognitive impairment (d = 0.85) or syndromic HAND (mild neurocognitive disorder or HIV-associated dementia; d = 0.78), while the latter two categories do not differ. Although limited by less than optimal specificity, the MoCA demonstrates good sensitivity and ecological validity, which lends support to its psychometric integrity as a brief cognitive screening tool among older HIV+ adults.

Depression and executive dysfunction contribute to a metamemory deficit among individuals with methamphetamine use disorders.

OBJECTIVE: Chronic methamphetamine (MA) use is associated with moderate deficits in learning and memory, but the extend to which MA users are aware of such memory deficits (i.e., metamemory) is not known. METHODS: In the current study, 195 participants with lifetime MA use diagnoses (MA +) and 195 non-MA-using comparison subjects (MA -) underwent comprehensive neuropsychiatry research assessments, including performance-based and self-report measures of episodic memory. RESULTS: MA use disorders, major depressive disorder (MDD), and their interaction were uniquely associated with metamemory functioning, such that MDD increased the likelihood of a metamemory deficit among MA + participants. Within the MA group, individuals who over-estimated their memory abilities demonstrated greater executive dysfunction and lower cognitive reserve. CONCLUSIONS: Chronic MA use is associated with reduced awareness of objective deficits in memory acquisition and recall, which is particularly exacerbated by the presence of major depression. Efforts to enhance metamemory accuracy and deployment of compensatory mnemonic strategies may benefit substance abuse treatment outcomes.