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Open Access Publications from the University of California

Scholarly Works (75 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2023)

Background: Traumatic brain injury (TBI), multimorbidity, and lower social contact are associated with worse cognitive health outcomes among older adults. While greater social contact is associated with lower risk of dementia, it is unknown if aspects of social connection buffer the relationships of TBI or multimorbidity with cognitive and brain health in aging. Methods: This dissertation includes three studies. Using Vietnam Era Twin Study of Aging data, we tested prospective associations of TBI with cognitive performance trajectories in Study 1, and cross-sectional associations between TBI and markers of brain health in Study 2. In Study 3, we tested prospective associations of multimorbidity with cognitive performance trajectories in the Rancho Bernardo Study of Healthy Aging. In all studies, we tested for effect measure modification (EMM) by measures of social connectedness. Results: In Study 1, TBI was associated with greater decline in executive function, primarily among APOE ε4 carriers (β=-0.017; 95% CI=-0.033,-0.0019) compared to non-carriers (β=-0.0036; 95% CI=-0.013,0.0063; PInteraction=0.03). Relative to no TBI, TBI prior to military induction was associated with greater executive function decline (β=-0.011; 95% CI=-0.021,-7e-04). In Study 2, TBI was associated with microstructural differences in a white matter tract connecting occipital and temporal lobes, compared to no TBI (β=-0.017; SE=0.005; FDR-corrected p-value<0.01). There was no evidence of EMM by social connectedness (defined as loneliness) in Studies 1 or 2. In Study 3, multimorbidity was associated with faster declines in scores on the Mini-Mental State Examination (MMSE; β=-0.20; 95% CI=-0.35,-0.04), Trail-Making Test Part B (β=10.02; 95% CI=5.77,14.27), and Category Fluency (β=-0.42; 95% CI=-0.72,-0.13). There was EMM by social engagement; multimorbidity was associated with faster MMSE declines among those with low compared to medium or high social engagement (PInteraction<0.01). Conclusion: These results highlight the role of multimorbidity and remote TBI on cognitive health in aging. While our results do not support a buffering role of loneliness on effects of remote TBI on cognitive or brain health, they suggest that social engagement may support reducing adverse cognitive consequences of multimorbidity. These findings can inform efforts focused on increasing social contact to reduce cognitive decline and improve wellbeing, particularly among those with multimorbidity.

    • Article
    • Peer Reviewed
    UC San Diego Previously Published Works (2023)

    Purpose

    Cerebrospinal fluid (CSF) clearance is essential for maintaining a healthy brain and cognition by removal of metabolic waste from the central nervous system. Physical exercise has been shown to improve human health; however, the effect of physical exercise on intrinsic CSF outflow in humans remains unexplored. The purpose of this study was to investigate intrinsic CSF outflow pathways and quantitative metrics of healthy individuals with active and sedentary lifestyles. In addition, the effect of exercise was investigated among the sedentary subjects before and after 3 weeks of physical activity.

    Methods

    This study was performed on 18 healthy adults with informed consent, using a clinical 3-Tesla MRI scanner. We classified participants into two groups based on reported time spent sitting per day (active group: < 7 hours sitting per day and sedentary group: ≥ 7 hours sitting per day). To elucidate the effect of exercise, sedentary individuals increased their activity to 3.5 hours for 3 weeks.

    Results

    We show that there are two intrinsic CSF egress pathways of the dura mater and lower parasagittal dura (PSD). The adults with an active lifestyle had greater intrinsic CSF outflow metrics than adults with a more sedentary lifestyle. However, after increased physical activity, the sedentary group showed improved CSF outflow metrics. This improvement was particularly notable at the lower PSD, where outflow metrics were highest among the active group.

    Conclusion

    Our findings describe the relationship between physical activity and intrinsic CSF outflow and show a potential selective outflow pathway with increasing physical activity in the lower PSD pathway, potentially from the perivascular space or cortical venous subpial space.
      Cover page: Physical Exercise Alters Egress Pathways for Intrinsic CSF Outflow: An Investigation Performed with Spin-labeling MR ImagingCreative Commons 'BY-ND' version 4.0 license
      • Article
      • Peer Reviewed
      UC San Diego Previously Published Works (2022)

      Purpose

      Clearance of cerebrospinal fluid (CSF) is important for the removal of toxins from the brain, with implications for neurodegenerative diseases. Imaging evaluation of CSF outflow in humans has been limited, relying on venous or invasive intrathecal injections of contrast agents. The objective of this study was to introduce a novel spin-labeling MRI technique to detect and quantify the movement of endogenously tagged CSF, and then apply it to evaluate CSF outflow in normal humans of varying ages.

      Methods

      This study was performed on a clinical 3-Tesla MRI scanner in 16 healthy subjects with an age range of 19-71 years with informed consent. Our spin-labeling MRI technique applies a tag pulse on the brain hemisphere, and images the outflow of the tagged CSF into the superior sagittal sinus (SSS). We obtained 3D images in real time, which was analyzed to determine tagged-signal changes in different regions of the meninges involved in CSF outflow. Additionally, the signal changes over time were fit to a signal curve to determine quantitative flow metrics. These were correlated against subject age to determine aging effects.

      Results

      We observed the signal of the tagged CSF moving from the dura mater and parasagittal dura, and finally draining into the SSS. In addition, we observed a possibility of another pathway which is seen in some young subjects. Furthermore, quantitative CSF outflow metrics were shown to decrease significantly with age.

      Conclusion

      We demonstrate a novel non-invasive MRI technique identifying two intrinsic CSF clearance pathways, and observe an age-related decline of CSF flow metrics in healthy subjects. Our work provides a new opportunity to better understand the relationships of these CSF clearance pathways during the aging process, which may ultimately provide insight into the age-related prevalence of neurodegenerative diseases.
        Cover page: Age-related Decline of Intrinsic Cerebrospinal Fluid Outflow in Healthy Humans Detected with Non-contrast Spin-labeling MR Imaging.Creative Commons 'BY-ND' version 4.0 license
        • Article
        • Peer Reviewed
        UC San Diego Previously Published Works (2012)
        The tau and amyloid pathobiological processes underlying Alzheimer disease (AD) progresses slowly over periods of decades before clinical manifestation as mild cognitive impairment (MCI), then more rapidly to dementia, and eventually to end-stage organ failure. The failure of clinical trials of candidate disease modifying therapies to slow disease progression in patients already diagnosed with early AD has led to increased interest in exploring the possibility of early intervention and prevention trials, targeting MCI and cognitively healthy (HC) populations. Here, we stratify MCI individuals based on cerebrospinal fluid (CSF) biomarkers and structural atrophy risk factors for the disease. We also stratify HC individuals into risk groups on the basis of CSF biomarkers for the two hallmark AD pathologies. Results show that the broad category of MCI can be decomposed into subsets of individuals with significantly different average regional atrophy rates. By thus selectively identifying individuals, combinations of these biomarkers and risk factors could enable significant reductions in sample size requirements for clinical trials of investigational AD-modifying therapies, and provide stratification mechanisms to more finely assess response to therapy. Power is sufficiently high that detecting efficacy in MCI cohorts should not be a limiting factor in AD therapeutics research. In contrast, we show that sample size estimates for clinical trials aimed at the preclinical stage of the disorder (HCs with evidence of AD pathology) are prohibitively large. Longer natural history studies are needed to inform design of trials aimed at the presymptomatic stage.
          Cover page: Enrichment and Stratification for Predementia Alzheimer Disease Clinical Trials
          • Article
          • Peer Reviewed
          ICTS Publications (2012)

          Age is the strongest risk factor for sporadic Alzheimer disease (AD), yet the effects of age on rates of clinical decline and brain atrophy in AD have been largely unexplored. Here, we examined longitudinal rates of change as a function of baseline age for measures of clinical decline and structural MRI-based regional brain atrophy, in cohorts of AD, mild cognitive impairment (MCI), and cognitively healthy (HC) individuals aged 65 to 90 years (total n = 723). The effect of age was modeled using mixed effects linear regression. There was pronounced reduction in rates of clinical decline and atrophy with age for AD and MCI individuals, whereas HCs showed increased rates of clinical decline and atrophy with age. This resulted in convergence in rates of change for HCs and patients with advancing age for several measures. Baseline cerebrospinal fluid densities of AD-relevant proteins, Aβ1–42, tau, and phospho-tau181p (ptau), showed a similar pattern of convergence with advanced age across cohorts, particularly for ptau. In contrast, baseline clinical measures did not differ by age, indicating uniformity of clinical severity at baseline. These results imply that the phenotypic expression of AD is relatively mild in individuals older than approximately 85 years, and this may affect the ability to distinguish AD from normal aging in the very old. Our findings show that inclusion of older individuals in clinical trials will substantially reduce the power to detect disease-modifying therapeutic effects, leading to dramatic increases in required clinical trial sample sizes with age of study sample.

            Cover page: Rates of Decline in Alzheimer Disease Decrease with Age
            • Article
            • Peer Reviewed
            UC San Diego Previously Published Works (2019)

            Objective

            The apolipoprotein E (APOE) gene is an established risk factor for sporadic Alzheimer's disease, with elevated risk for ε4-carriers and reduced risk for ε2-carriers. However, it is unclear whether APOE modifies risk for cognitive decline in normal aging. The objective of this study was to determine whether ε2 and ε4 are associated with rates of normal cognitive aging, and whether associations of ε4 with cognitive decline are modified by sex, education or health behaviors (exercise, alcohol consumption, smoking).

            Method

            A community-based sample of 1,393 older adults were genotyped for APOE and underwent cognitive assessment up to seven times over a maximum of period of 27 years.

            Results

            ε2-carriers showed slower executive function decline with age relative to ε3 homozygotes or ε4-carriers, whereas ε4-carriers demonstrated more rapid executive function and verbal fluency decline. Accelerated executive function decline was particularly pronounced in ε4-carriers with lower education. After excluding individuals with cognitive impairment, faster executive function decline was still apparent in ε4-carriers, and the effect of ε4 on episodic memory interacted with alcohol consumption, such that only ε4-carriers who did not drink showed more rapid memory decline than ε4 noncarriers. The influence of ε4 on cognitive aging did not differ by sex, nor was it modified by smoking or exercise.

            Conclusions

            These findings indicate that the ε2 and ε4 alleles have differential effects on cognitive aging, and that negative effects of ε4 may be partly mitigated by behavioral choices. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
              • Article
              • Peer Reviewed
              UC San Diego Previously Published Works (2016)
                Cover page: Moderate, regular alcohol consumption is associated with higher cognitive function in older, community-dwelling adults
                • Article
                • Peer Reviewed
                UC San Diego Previously Published Works (2024)

                Background

                APOE4 is the strongest genetic risk factor for sporadic Alzheimer's disease (AD), whereas APOE2 confers protection. However, effects of APOE on neurodegeneration in cognitively intact individuals, and how these associations evolve with cognitive decline, are unclear. Furthermore, few studies have evaluated whether effects of APOE on neurodegenerative changes are modified by other AD key risk factors including age and sex.

                Methods

                Participants included older adults (57% women; 77 ± 7 years) from the Rancho Bernardo Study of Health Aging and the University of California San Diego Alzheimer's Disease Research Center, including 192 cognitively normal (CN) individuals and 33 with mild cognitive impairment. Participants underwent diffusion MRI, and multicompartment restriction spectrum imaging (RSI) metrics were computed in white matter, gray matter, and subcortical regions of interest. Participants were classified as APOE4 carriers, APOE2 carriers, and APOE3 homozygotes. Analysis of covariance among CN (adjusting for age, sex, and scanner) assessed differences in brain microstructure by APOE, as well as interactions between APOE and sex. Analyses across all participants examined interactions between APOE4 and cognitive status. Linear regressions assessed APOE by age interactions.

                Results

                Among CN, APOE4 carriers showed lower entorhinal cortex neurite density than non-carriers, whereas APOE2 carriers showed lower cingulum neurite density than non-carriers. Differences in entorhinal microstructure by APOE4 and in entorhinal and cingulum microstructure by APOE2 were present for women only. Age correlated with lower entorhinal restricted isotropic diffusion among APOE4 non-carriers, whereas age correlated with lower putamen restricted isotropic diffusion among APOE4 carriers. Differences in microstructure between cognitively normal and impaired participants were stronger for APOE4-carriers in medial temporal regions, thalamus, and global gray matter, but stronger for non-carriers in caudate.

                Conclusions

                The entorhinal cortex may be an early target of neurodegenerative changes associated with APOE4 in presymptomatic individuals, whereas APOE2 may support beneficial white matter and entorhinal microstructure, with potential sex differences that warrant further investigation. APOE modifies microstructural patterns associated with aging and cognitive impairment, which may advance the development of biomarkers to distinguish microstructural changes characteristic of normal brain aging, APOE-dependent pathways, and non-AD etiologies.
                  Cover page: Effects of APOE2 and APOE4 on brain microstructure in older adults: modification by age, sex, and cognitive status
                  • Article
                  • Peer Reviewed
                  UC San Diego Previously Published Works (2019)

                  Background

                  Although physical activity has been associated with better cognitive function and reduced dementia risk, its association with cognitive decline in normal aging remains uncertain.

                  Objective

                  To determine whether physical activity in youth and older age are associated with age-related cognitive change.

                  Methods

                  Over a period of 27 years, 2,027 community-dwelling adults (mean age 73.5; 60% women) of the Rancho Bernardo Study of Healthy Aging completed up to seven cognitive assessments, including tests of global cognitive function, executive function, verbal fluency, and episodic memory. At each visit, participants reported concurrent physical activity. At baseline (1988- 1992), participants additionally reported physical activity as a teenager and at age 30. For each age period, participants were classified as regularly active (3+ times/week) or inactive.

                  Results

                  Associations between concurrent physical activity and better cognitive function were stronger with advancing age on all tests, even after accounting for education, health, and lifestyle factors, as well as survival differences (ps < 0.05). Baseline physical activity did not predict rates of cognitive decline (ps > 0.40). Individuals who were physically active at age 30 and older age maintained the highest global cognitive function with advancing age (p = 0.002).

                  Conclusion

                  Regular physical activity is associated with better cognitive function with advancing age. Physical activity in young adulthood may contribute to cognitive reserve, which together with physical activity in later years, may act to preserve cognitive function with age.
                    • Article
                    • Peer Reviewed
                    UC San Diego Previously Published Works (2021)
                    Normal brain aging is characterized by declining neuronal integrity, yet it remains unclear how microstructural injury influences cognitive aging and whether such mechanisms differ between sexes. Using restriction spectrum imaging (RSI), we examined sex differences in associations between brain microstructure and cognitive function in 147 community-dwelling older men and women (56-99 years). Gray and white matter microstructure correlated with global cognition, executive function, visuospatial memory, episodic memory, and logical memory, with the strongest associations for restricted, hindered and free isotropic diffusion. Associations were stronger for women than for men, a difference likely due to greater age-related variability in cognitive scores and microstructure in women. Isotropic diffusion mediated effects of age on cognition for both sexes, though distinct mediation patterns were present for women and men. For women, hippocampal and corpus callosum microstructure mediated age effects on verbal and visuospatial memory, respectively, whereas for men fiber microstructure (mainly fornix and corpus callosum) mediated age effects on executive function and visuospatial memory. These findings implicate sex-specific pathways by which changing brain cytoarchitecture contributes to cognitive aging, and suggest that RSI may be useful for evaluating risk for cognitive decline or monitoring efficacy of interventions to preserve brain health in later life.
                      Cover page: Brain microstructure mediates sex-specific patterns of cognitive aging
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