Regional Vulnerability of the Corpus Callosum in the Context of Cardiovascular Risk.

Many factors outside of cardiovascular health can impact the structure of white matter. Identification of reliable and clinically meaningful biomarkers of the neural effects of systemic and cardiovascular health are needed to refine etiologic predictions. We examined whether the corpus callosum demonstrates regional vulnerability to systemic cardiovascular risk factors. Three hundred and ninety-four older adults without dementia completed brain MRI, neurobehavioral evaluations, and blood draws. A subset (n = 126, n = 128) of individuals had blood plasma analyzed for inflammatory markers of interest (IL-6 and TNF-alpha). Considering diffusion tensor imaging (DTI) is a particularly reliable measure of white matter integrity, we utilized DTI to examine fractional anisotropy (FA) of anterior and posterior regions of the corpus callosum. Using multiple linear regression models, we simultaneously examined FA of the genu and the splenium to compare their associations with systemic and cardiovascular risk factors. Lower FA of the genu but not splenium was associated with greater systemic and cardiovascular risk, including higher systolic blood pressure (β = -0.17, p = .020), hemoglobin A1C (β = -0.21, p = .016) and IL-6 (β = -0.34, p = .005). FA of the genu was uniquely associated with cognitive processing speed (β = 0.20, p = .0015) and executive functioning (β = 0.15, p = .012), but not memory performances (β = 0.05, p = .357). Our results demonstrated differential vulnerability of the corpus callosum, such that frontal regions showed stronger, independent associations with biomarkers of systemic and cardiovascular health in comparison to posterior regions. Posterior white matter integrity may not reflect cardiovascular health. Clinically, these findings support the utility of examining the anterior corpus callosum as an indicator of cerebrovascular health

Wearable Use in an Observational Study Among Older Adults: Adherence, Feasibility, and Effects of Clinicodemographic Factors.

IntroductionWearables have great potential to improve monitoring and delivery of physical activity interventions to older adults with downstream benefits to multisystem health and longevity; however, benefits obtained from wearables depend on their uptake and usage. Few studies have examined person-specific factors that relate to wearable adherence. We characterized adherence to using a wearable activity tracker for 30 days and examined associations between adherence and demographics, cognitive functioning, brain volumes, and technology familiarity among community-dwelling older adults.MethodsParticipants were 175 older adults enrolled in the UCSF Longitudinal Brain Aging Study who were asked to wear a FitbitTM Flex 2 during waking hours for 30 days. Sixty two of these participants were also asked to sync their devices to the Fitbit smartphone app daily to collect minute-level data. We calculated adherence to wearing the Fitbit daily (i.e., proportion of days with valid activity data) and adherence to daily device syncing (i.e., proportion of days with minute-level activity data). Participants also completed a brain MRI and in-person cognitive testing measuring memory, executive functioning, and processing speed. Spearman correlations, Wilcoxon rank sum tests, and logistic regression tested relationships between wearable adherence and clinicodemographic factors.ResultsParticipants wore the Fitbits for an average of 95% of study days and were 85% adherent to the daily syncing protocol. Greater adherence to wearing the device was related to female sex. Greater adherence to daily device syncing was related to better memory, independent of demographic factors. Wearable adherence was not significantly related to age, education, executive functioning, processing speed, brain gray matter volumes, or self-reported familiarity with technology. Participants reported little-to-no difficulty using the wearable and all reported willingness to participate in another wearable study in the future.ConclusionsOlder adults have overall high adherence to wearable use in the current study protocol. Person-specific factors, however, may represent potential barriers to equitable uptake of wearables for physical activity among older adults, including demographics and cognitive functioning. Future studies and clinical providers utilizing wearable activity trackers with older adults may benefit from implementation of reminders (e.g., texts, calls) for device use, particularly among men and individuals with memory impairment

Sex-specific effects of SNAP-25 genotype on verbal memory and Alzheimers disease biomarkers in clinically normal older adults.

INTRODUCTION: We tested sex-dependent associations of variation in the SNAP-25 gene, which encodes a presynaptic protein involved in hippocampal plasticity and memory, on cognitive and Alzheimers disease (AD) neuroimaging outcomes in clinically normal adults. METHODS: Participants were genotyped for SNAP-25 rs1051312 (T > C; SNAP-25 expression: C-allele > T/T). In a discovery cohort (N = 311), we tested the sex by SNAP-25 variant interaction on cognition, Aβ-PET positivity, and temporal lobe volumes. Cognitive models were replicated in an independent cohort (N = 82). RESULTS: In the discovery cohort, C-allele carriers exhibited better verbal memory and language, lower Aβ-PET positivity rates, and larger temporal volumes than T/T homozygotes among females, but not males. Larger temporal volumes related to better verbal memory only in C-carrier females. The female-specific C-allele verbal memory advantage was evidenced in the replication cohort. CONCLUSIONS: In females, genetic variation in SNAP-25 is associated with resistance to amyloid plaque formation and may support verbal memory through fortification of temporal lobe architecture. HIGHLIGHTS: The SNAP-25 rs1051312 (T > C) C-allele results in higher basal SNAP-25 expression. C-allele carriers had better verbal memory in clinically normal women, but not men. Female C-carriers had higher temporal lobe volumes, which predicted verbal memory. Female C-carriers also exhibited the lowest rates of amyloid-beta PET positivity. The SNAP-25 gene may influence female-specific resistance to Alzheimers disease (AD)

Supplemental Material - Regional Vulnerability of the Corpus Callosum in the Context of Cardiovascular Risk

Supplemental Material for Regional Vulnerability of the Corpus Callosum in the Context of Cardiovascular Risk by Anna M. VandeBunte, Corrina Fonseca, Emily W. Paolillo, Eva Gontrum, Shannon Y. Lee, Joel H. Kramer, and Kaitlin B. Casaletto in Journal of Geriatric Psychiatry and Neurology</p

Development and validation of the Uniform Data Set (v3.0) executive function composite score (UDS3-EF).

IntroductionCognitive composite scores offer a means of precisely measuring executive functioning (EF).MethodsWe developed the Uniform Data Set v3.0 EF composite score (UDS3-EF) in 3507 controls from the National Alzheimer's Coordinating Center dataset using item-response theory and applied nonlinear and linear demographic adjustments. The UDS3-EF was validated with other neuropsychological tests and brain magnetic resonance imaging from independent research cohorts using linear models.ResultsFinal model fit was good-to-excellent: comparative fit index&nbsp;=&nbsp;0.99; root mean squared error of approximation&nbsp;=&nbsp;0.057. UDS3-EF scores differed across validation cohorts (controls&nbsp;&gt;&nbsp;mild cognitive impairment&nbsp;&gt;&nbsp;Alzheimer's disease-dementia ≈ behavioral variant frontotemporal dementia; P&nbsp;&lt;&nbsp;0.001). The UDS3-EF correlated most strongly with other EF tests (βs&nbsp;=&nbsp;0.50 to 0.85, Ps&nbsp;&lt;&nbsp;0.001) and more with frontal, parietal, and temporal lobe gray matter volumes (βs&nbsp;=&nbsp;0.18 to 0.33, Ps&nbsp;≤&nbsp;0.004) than occipital gray matter (β&nbsp;=&nbsp;0.12, P&nbsp;=&nbsp;0.04). The total sample needed to detect a 40% reduction in UDS3-EF change (n&nbsp;=&nbsp;286) was ≈40% of the next best measure (F-words; n&nbsp;=&nbsp;714).ConclusionsThe UDS3-EF is well suited to quantify EF in research and clinical trials and offers psychometric and practical advantages over its component tests

APOE moderates the effect of hippocampal blood flow on memory pattern separation in clinically normal older adults.

Pattern separation, the ability to differentiate new information from previously experienced similar information, is highly sensitive to hippocampal structure and function and declines with age. Functional MRI studies have demonstrated hippocampal hyperactivation in older adults compared to young, with greater task-related activation associated with worse pattern separation performance. The current study was designed to determine whether pattern separation was sensitive to differences in task-free hippocampal cerebral blood flow (CBF) in 130 functionally intact older adults. Given prior evidence that apolipoprotein E e4 (APOE e4) status moderates the relationship between CBF and episodic memory, we predicted a stronger negative relationship between hippocampal CBF and pattern separation in APOE e4 carriers. An interaction between APOE group and right hippocampal CBF was present, such that greater right hippocampal CBF was related to better lure discrimination in noncarriers, whereas the effect reversed directionality in e4 carriers. These findings suggest that neurovascular changes in the medial temporal lobe may underlie memory deficits in cognitively normal older adults who are APOE e4 carriers

Combined Effects of Synaptic and Axonal Integrity on Longitudinal Gray Matter Atrophy in Cognitively Unimpaired Adults

BACKGROUND AND OBJECTIVES: Synaptic dysfunction and degeneration is a predominant feature of brain aging and synaptic preservation buffers against Alzheimer's disease (AD) protein-related brain atrophy. We tested whether cerebrospinal fluid (CSF) synaptic protein concentrations similarly moderate the effects of axonal injury, indexed via CSF neurofilament light [NfL], on brain atrophy in clinically normal adults. METHODS: Clinically normal older adults enrolled in the observational Hillblom Aging Network study at the UCSF Memory and Aging Center completed baseline lumbar puncture and longitudinal brain MRI (Mean scan [follow-up]=2.6 [3.7 years]). CSF was assayed for synaptic proteins (synaptotagmin-1, synaptosomal-associated protein 2 [SNAP-25], neurogranin, growth associated protein 43 [GAP-43]), axonal injury (NfL), and core AD biomarkers (ptau181/Aβ42 ratio; reflecting AD proteinopathy). Ten bilateral temporo-parietal gray matter ROIs shown to be sensitive to clinical AD were summed to generate a composite temporo-parietal ROI. Linear mixed-effects models tested statistical moderation of baseline synaptic proteins on baseline NfL-related temporo-parietal trajectories, controlling for ptau181/Aβ42 ratios. RESULTS: Forty-six clinically normal older adults (Mean age=70; 43% female) were included. Synaptic proteins exhibited small to medium correlations with NfL (r range: .10 to .36). Higher baseline NfL, but not ptau181/Aβ42 ratios, predicted steeper temporo-parietal atrophy (NfL x time: β=-0.08, p<.001; ptau181/Aβ42 x time: β=-0.02, p=.31). SNAP-25, neurogranin, and GAP-43 significantly moderated NfL-related atrophy trajectories (-0.07≤βs≥-0.06, ps<.05) such that NfL was associated with temporo-parietal atrophy at high (more abnormal) but not low (more normal) synaptic protein concentrations. At high NfL concentrations, atrophy trajectories were 1.5 to 4.5 times weaker when synaptic protein concentrations were low (β range: -0.21 to -0.07) than high (β range: -0.33 to -0.30). CONCLUSIONS: The association between baseline CSF NfL and longitudinal temporo-parietal atrophy is accelerated by synaptic dysfunction and buffered by synaptic integrity. Beyond AD proteins, concurrent examination of in vivo axonal and synaptic biomarkers may improve detection of neural alterations that precede overt structural changes in AD-sensitive brain regions

Tripartite Relationship Among Synaptic, Amyloid, and Tau Proteins: An In Vivo and Postmortem Study.

ObjectiveTo test the hypothesis that fundamental relationships along the amyloid, tau, and neurodegeneration (A/T/N) cascade depend on synaptic integrity in older adults in-vivo and postmortem.MethodsTwo independent observational, cross-sectional cohorts: 1) in-vivo community-dwelling, clinically normal adults from the UCSF Memory and Aging Center completed lumbar puncture and MRI (exclusion criteria, CDR&gt;0), and 2) postmortem decedents from the Rush Memory and Aging Project (exclusion criteria, inability to sign informed consent). In-vivo measures included cerebrospinal fluid (CSF) synaptic proteins (synaptotagmin-1, SNAP-25, neurogranin, and GAP-43), Aβ42/40, ptau181, and MRI gray matter volume (GMV). Postmortem measures captured brain tissue levels of presynaptic proteins (complexin-I, complexin-II, VAMP, and SNARE complex), and neuritic plaque and neurofibrillary tangle (NFT) counts. Regression models tested statistical moderation of synaptic protein levels along the A/T/N cascade (synaptic proteins*amyloid on tau, and synaptic proteins*tau on GMV).Results68 in-vivo older adults (age=71y, 43%F) and 633 decedents (age=90y, 68%F, 34% clinically normal) were included. Each in-vivo CSF synaptic protein moderated the relationship between Aβ42/40 and ptau181 (-0.23&lt;?s&lt;-0.12, ps&lt;0.05) and the relationship between ptau and GMV (-0.49&lt;?s&lt;-0.32, ps&lt;0.05). Individuals with more abnormal CSF synaptic protein demonstrated expected relationships between Aβ-ptau and ptau-brain volume, effects that were absent or reversed in those with more normal CSF synaptic protein. Postmortem analyses recapitulated CSF models. More normal brain tissue levels of complexin-I, VAMP, and SNARE moderated the adverse relationship between neuritic plaque and NFT counts (-0.10&lt;?s&lt;-0.08, ps&lt;0.05).ConclusionsPathogenic relationships of Aβ and tau may depend on synaptic state. Synaptic markers may help identify risk and/or resilience to AD proteinopathy

Wisdom and fluid intelligence are dissociable in healthy older adults.

ObjectivesThe 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.DesignCross-sectional study with preregistered hypotheses and well-powered analytic plan (https://osf.io/h3pjx).SettingMemory and Aging Center at the University of California San Francisco, located in the USA.Participants141 healthy older adults (mean age = 76 years; 56% female).MeasurementsWisdom 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.ResultsWisdom 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.ConclusionsOur findings indicate that most of the variance in wisdom (&gt;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

Wisdom and fluid intelligence are dissociable in healthy older adults.

ObjectivesThe 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.DesignCross-sectional study with preregistered hypotheses and well-powered analytic plan (https://osf.io/h3pjx).SettingMemory and Aging Center at the University of California San Francisco, located in the USA.Participants141 healthy older adults (mean age = 76 years; 56% female).MeasurementsWisdom 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.ResultsWisdom 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.ConclusionsOur findings indicate that most of the variance in wisdom (&gt;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