Nondemented Adults Research Articles

Motor control complexity can be dynamically simplified during gait pattern exploration using motor control-based biofeedback.

Understanding how the central nervous system coordinates diverse motor outputs has been a topic of extensive investigation. Although it is generally accepted that a small set of synergies underlies many common activities, such as walking, whether synergies are equally robust across a broader array of gait patterns or can be flexibly modified remains unclear. Here, we evaluated the extent to which synergies changed as nondisabled adults (n = 14) explored gait patterns using custom biofeedback. Secondarily, we used Bayesian additive regression trees to identify factors that were associated with synergy modulation. Participants explored 41.1 ± 8.0 gait patterns using biofeedback, during which synergy recruitment changed depending on the type and magnitude of gait pattern modification. Specifically, a consistent set of synergies was recruited to accommodate small deviations from baseline, but additional synergies emerged for larger gait changes. Synergy complexity was similarly modulated; complexity decreased for 82.6% of the attempted gait patterns, but distal gait mechanics were strongly associated with these changes. In particular, greater ankle dorsiflexion moments and knee flexion through stance, as well as greater knee extension moments at initial contact, corresponded to a reduction in synergy complexity. Taken together, these results suggest that the central nervous system preferentially adopts a low-dimensional, largely invariant control strategy but can modify that strategy to produce diverse gait patterns. Beyond improving understanding of how synergies are recruited during gait, study outcomes may also help identify parameters that can be targeted with interventions to alter synergies and improve motor control after neurological injury.NEW & NOTEWORTHY We used a motor control-based biofeedback system and machine learning to characterize the extent to which nondisabled adults can modulate synergies during gait pattern exploration. Results revealed that a small library of synergies underlies an array of gait patterns but that recruitment from this library changes as a function of the imposed biomechanical constraints. Our findings enhance understanding of the neural control of gait and may inform biofeedback strategies to improve synergy recruitment after neurological injury.

Neuronal Hyperactivation in EEG Data during Cognitive Tasks Is Related to the Apolipoprotein J/Clusterin Genotype in Nondemented Adults.

The clusterin (CLU) rs11136000 CC genotype is a probable risk factor for Alzheimer's disease (AD). CLU, also known as the apolipoprotein J gene, shares certain properties with the apolipoprotein E (APOE) gene with a well-established relationship with AD. This study aimed to determine whether the electrophysiological patterns of brain activation during the letter fluency task (LFT) depend on CLU genotypes in adults without dementia. Previous studies have shown that LFT performance involves activation of the frontal cortex. We examined EEG alpha1 and alpha2 band desynchronization in the frontal regions during the LFT in 94 nondemented individuals stratified by CLU (rs11136000) genotype. Starting at 30 years of age, CLU CC carriers exhibited more pronounced task-related alpha2 desynchronization than CLU CT&TT carriers in the absence of any differences in LFT performance. In CLU CC carriers, alpha2 desynchronization was significantly correlated with age. Increased task-related activation in individuals at genetic risk for AD may reflect greater "effort" to perform the task and/or neuronal hyperexcitability. The results show that the CLU genotype is associated with neuronal hyperactivation in the frontal cortex during cognitive tasks performances in nondemented individuals, suggesting systematic vulnerability of LFT related cognitive networks in people carrying unfavorable CLU alleles.

Differential involvement of hippocampal subfields in the relationship between Alzheimer's pathology and memory interference in older adults.

We tested whether Alzheimer's disease (AD) pathology predicts memory deficits in non-demented older adults through its effects on medial temporal lobe (MTL) subregional volume. Thirty-two, non-demented older adults with cerebrospinal fluid (CSF) (amyloid-beta [Aβ]42/Aβ40, phosphorylated tau [p-tau]181, total tau [t-tau]), positron emission tomography (PET; 18F-florbetapir), high-resolution structural magnetic resonance imaging (MRI), and neuropsychological assessment were analyzed. We examined relationships between biomarkers and a highly granular measure of memory consolidation, retroactive interference (RI). Biomarkers of AD pathology were related to RI. Dentate gyrus (DG) and CA3 volume were uniquely associated with RI, whereas CA1 and BA35 volume were related to both RI and overall memory recall. AD pathology was associated with reduced BA35, CA1, and subiculum volume. DG volume and Aβ were independently associated with RI, whereas CA1 volume mediated the relationship between AD pathology and RI. Integrity of distinct hippocampal subfields demonstrate differential relationships with pathology and memory function, indicating specificity in vulnerability and contribution to different memory processes.

Plasma TDP-43 levels are associated with neuroimaging measures of brain structure in limbic regions.

We evaluated the relationship between plasma levels of transactive response DNA binding protein of 43kDa (TDP-43) and neuroimaging (magnetic resonance imaging [MRI]) measures of brain structure in aging. Plasma samples were collected from 72 non-demented older adults (age range 60-94 years) in the University of Kentucky Alzheimer's Disease Research Center cohort. Multivariate linear regression models were run with plasma TDP-43 level as the predictor variable and brain structure (volumetric or cortical thickness) measurements as the dependent variable. Covariates included age, sex, intracranial volume, and plasma markers of Alzheimer's disease neuropathological change (ADNC). Negative associations were observed between plasma TDP-43 level and both the volume of the entorhinal cortex, and cortical thickness in the cingulate/parahippocampal gyrus, after controlling for ADNC plasma markers. Plasma TDP-43 levels may be directly associated with structural MRI measures. Plasma TDP-43 assays may prove useful in clinical trial stratification. Plasma transactive response DNA binding protein of 43kDa (TDP-43) levels were associated with entorhinal cortex volume.Biomarkers of TDP-43 and Alzheimer's disease neuropathologic change (ADNC) may help distinguish limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) from ADNC.A comprehensive biomarker kit could aid enrollment in LATE-NC clinical trials.

Accuracy and Precision of Actigraphy and SMARTwheels for Measuring Push Counts Across a Series of Wheelchair Propulsion Trials in Non-disabled Young Adults

Background: There has been a growing interest in “Lifestyle Physical Activity” (LPA) among wheelchair users. LPA can be quantified via “pushes” as an outcome metric. This study examined the accuracy and precision of research-grade devices for counting pushes across a series of wheelchair propulsion trials. Methods: Eleven non-disabled, young adults completed 19, 1-minute wheelchair propulsion trials at self-selected speeds with a wheelchair equipped with a SMARTwheel (SW) device while being video recorded. Participants also wore 2 ActiGraph accelerometers, one on the wrist and one on the upper arm. Video footage enabled manual counting of the number of pushes (gold standard). Total pushes were averaged across 16 workloads (3 trials of repeated workloads were excluded) for each device and compared to manually counted pushes. Results: Compared to manually counted pushes, SW demonstrated the greatest accuracy (mean difference [MD] compared to video of 2.3 pushes [4.5% error]) and precision (standard deviation of the mean difference [SDMD]) compared to video of 4 pushes, (Coefficient of Variation [CV] =.04), followed by the upper arm-worn accelerometer (MD of 4.4 pushes [10.4% error] and SDMD of 10, [CV= .06]) and the wrist-worn accelerometer (MD of 12.6 pushes [27.8% error] and SDMD of 13 [CV=.15]). Conclusions: SW demonstrated greater accuracy and precision than ActiGraph accelerometers placed on the upper arm and wrist. The accelerometer placed on the upper arm was more accurate and precise than the accelerometer placed on the wrist. Future investigations should be conducted to identify the source(s) of inaccuracy among wearable push counters.

Associations of ApoE4 status and DHA supplementation on plasma and CSF lipid profiles and entorhinal cortex thickness

Apolipoprotein ε allele 4 (APOE4) influences the metabolism of polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA). The entorhinal cortex (EC) in the brain is affected early in Alzheimer's disease and is rich in DHA. The purpose of this study is to identify the effect of APOE4 and DHA lipid species on the EC. Plasma and cerebrospinal fluid (CSF) lipidomic measurements were obtained from the DHA Brain Delivery Pilot, a randomized clinical trial of DHA supplementation (n = 10) versus placebo (n = 12) for six months in nondemented older adults stratified by APOE4 status. Wild-type C57B6/J mice were fed a high or low DHA diet for 6 months followed by plasma and brain lipidomic analysis. Levels of phosphatidylcholine DHA (PC 38:6) and cholesterol ester DHA (CE 22:6) had the largest increases in CSF following supplementation (P < 0.001). DHA within triglyceride (TG) lipids in CSF strongly correlated with corresponding plasma TG lipids, and differed by APOE4, with carriers having a lower increase than noncarriers. Changes in plasma PC DHA had the strongest association with changes in EC thickness in millimeters, independent of APOE4 status (P = 0.007). In mice, a high DHA diet increased PUFAs within brain lipids. Our findings demonstrate an exchange of DHA at the CSF-blood barrier and into the brain within all lipid species with APOE having the strongest effect on DHA-containing TGs. The correlation of PC DHA with EC suggests a functional consequence of DHA accretion in high density lipoprotein for the brain.

Co-Expression Network Analysis Identifies Molecular Determinants of Loneliness Associated with Neuropsychiatric and Neurodegenerative Diseases.

Loneliness and social isolation are detrimental to mental health and may lead to cognitive impairment and neurodegeneration. Although several molecular signatures of loneliness have been identified, the molecular mechanisms by which loneliness impacts the brain remain elusive. Here, we performed a bioinformatics approach to untangle the molecular underpinnings associated with loneliness. Co-expression network analysis identified molecular 'switches' responsible for dramatic transcriptional changes in the nucleus accumbens of individuals with known loneliness. Loneliness-related switch genes were enriched in cell cycle, cancer, TGF-β, FOXO, and PI3K-AKT signaling pathways. Analysis stratified by sex identified switch genes in males with chronic loneliness. Male-specific switch genes were enriched in infection, innate immunity, and cancer-related pathways. Correlation analysis revealed that loneliness-related switch genes significantly overlapped with 82% and 68% of human studies on Alzheimer's (AD) and Parkinson's diseases (PD), respectively, in gene expression databases. Loneliness-related switch genes, BCAM, NECTIN2, NPAS3, RBM38, PELI1, DPP10, and ASGR2, have been identified as genetic risk factors for AD. Likewise, switch genes HLA-DRB5, ALDOA, and GPNMB are known genetic loci in PD. Similarly, loneliness-related switch genes overlapped in 70% and 64% of human studies on major depressive disorder and schizophrenia, respectively. Nine switch genes, HLA-DRB5, ARHGAP15, COL4A1, RBM38, DMD, LGALS3BP, WSCD2, CYTH4, and CNTRL, overlapped with known genetic variants in depression. Seven switch genes, NPAS3, ARHGAP15, LGALS3BP, DPP10, SMYD3, CPXCR1, and HLA-DRB5 were associated with known risk factors for schizophrenia. Collectively, we identified molecular determinants of loneliness and dysregulated pathways in the brain of non-demented adults. The association of switch genes with known risk factors for neuropsychiatric and neurodegenerative diseases provides a molecular explanation for the observed prevalence of these diseases among lonely individuals.

Association of plasma phosphor-tau181 with Aβ levels may vary by APOE ε4 status and sex among non-demented old adults

BackgroundTo evaluate the relationship between blood tau phosphorylated at threonine 181 (p-tau181) levels and β-amyloid (Aβ) levels, this study took the potential role of sex differences and apolipoprotein E (APOE)-ε4 status into account. MethodsWe examined 620 participants with normal cognition (n = 178) and mild cognitive impairment (n = 442). Three-way interactions between sex, APOE ε4 status, and the levels of plasma p-tau181 were examined with linear regression models for Aβ levels adjusting for age, education, and diagnosis. The correlation analysis was performed to detect the association of the levels of plasma p-tau181 with brain Aβ stratified for APOE status and sex. ResultsBlood p-tau181 levels were higher in APOE ε4+ participants as compared to APOE ε4 – participants (p < 0.001). A comparison of APOE ε4 status within each gender showed that APOE ε4 carriers had higher levels of plasma p-tau181 and amyloid-β than APOE ε4 noncarriers in both men and women (p < 0.001). In sex/APOE-stratified analyses, individuals with the APOE ε4 allele showed stronger correlations between plasma p-tau181 and brain Aβ levels in both females (r = 0.49, p < 0.001 for APOE ε4 carriers vs r = 0.28, p < 0.001 for APOE ε4 noncarrier.) and males (r = 0.34, p < 0.001 for APOE ε4 carriers vs r = 0.21, p = 0.04 for APOE ε4 noncarriers.). In interactive analysis, the association of plasma p-tau181 and Aβ levels was significant in the female APOE ε4 carriers (p < 0.003). DiscussionAPOE ε4 status and female sex interact to impact the correlation between plasma p-tau181 and Aβ levels. Although the APOE ε4 genotype is one of the most important risky genes for AD, sex differences may also modify the degree of risk at critical times among non-demented older adults.

Is late-life depression associated with Alzheimer's disease? Evidence from epidemiological, neuropsychological, and neuroimaging perspectives

In 2021, the FDA approved Aducanumab (Aduhelm™), an anti-amyloid antibody intravenous (IV) infusion therapy approved for Alzheimer's disease (AD) that is the first treatment shown to ameliorate neuropathological changes due to AD in the brain. It is well-established that depression increases the risk of future cognitive decline and dementia, but whether depression is specifically associated with AD is unclear, because many of the earlier epidemiological studies employed a relatively short interval (< 5 years) between observation of depression and AD diagnosis. Since neuropathological changes in the brain due to AD may occur years prior to onset of clinical memory symptoms and AD diagnosis, depression that begins late in life may thus represent a non-cognitive prodromal feature of AD. Moreover, the association between depression in older adults and AD biomarkers is also unclear, with some studies suggesting that amyloid-beta, one of the main neuropathological hallmarks of AD, may be reduced in older adults with depression. With the availability of a disease-altering treatment for AD and knowledge that the neuropathological process for AD begins years before onset of clinical memory symptoms, a logical next step in the near future will be to examine whether anti-amyloid therapies can prevent development of AD in high-risk populations. Thus, it is timely to clarify the relationship between depression and dementia. Specifically, is depression an independent risk factor for AD, or is depression associated with dementia more generally? What is the evidence for a distinct form of dementia subtype due to depression?This symposium will address the question of whether major depressive disorder is an independent risk factor for dementia due to AD or other dementia subtypes by presenting evidence from the epidemiological, neuropsychological, and neuroimaging literature. Dr. Linda Mah will begin by presenting an overview of the epidemiological data on the association between depression and AD or dementia subtypes, focusing on differences in the strength of the association as a function of measurement of exposure, follow-up interval, and dementia subtype outcome. Dr. Scott Mackin will present recent work comparing neuropsychological and neuroimaging data including cortico-limbic volume and amyloid-beta burden in older adults with depression versus non-depressed older adults, which provides evidence for late-life depression as having distinct neurodegenerative features independent of AD. Dr. Jennifer Gatchel will present results from a multi-modal neuroimaging study in non-demented older adults with major depressive disorder, which demonstrates a relationship between tau pathology and depression symptoms and decreased interest-motivation-drive, while in contrast, mood symptoms were not associated with either amyloid-beta or medial temporal lobe atrophy. Dr. Benoit Mulsant will serve as discussant for the symposium. Drawing upon the PACt-MD study (“Preventing Alzheimer's dementia with cognitive remediation plus transcranial direct current stimulation in mild cognitive impairment and depression”), Dr. Mulsant will highlight some of the baseline AD biomarker data in the remitted major depressive disorder + mild cognitive impairment group, which suggest that this phenotype may be associated with a distinct dementia subtype. Implications for the clinical management of late-life depression and future research priorities will be discussed.

Effect of indoor air quality on the association of long-term exposure to low-level air pollutants with cognition in older adults

BackgroundHow indoor air quality affects the temporal associations of long-term exposure to low-level air pollutants with cognition remains unclear. MethodsThis cohort study (2011–2019) included 517 non-demented older adults at baseline with four repeated cognitive assessments. The time-varying exposure to PM2.5, PM10, NO2, SO2, CO, and O3 was estimated for each participant from 1994 to 2019. Indoor air quality was determined by ventilation status and daily indoor time. Generalized linear mixed models were used to analyze the association of air pollutants, indoor air quality, and cognition adjusting for important covariates. ResultsOver time, per 2.97 μg/m3 (i.e., an interquartile range) increment of PM2.5 was associated with the poor performance of memory (Z score of a cognitive test, βˆ:-0.14), attention (βˆ:-0.13), and executive function (βˆ:-0.20). Similarly, per 2.05 μg/m3 increase in PM2.5-10 was associated with poor global cognition [adjusted odds ratio (aOR): 1.48, βˆ:-0.28], attention (βˆ:-0.07), and verbal fluency (βˆ:-0.09); per 4.94 μg/m3 increase in PM10 was associated with poor global cognition (aOR: 1.78; βˆ:-0.37). In contrast, per 2.74 ppb increase in O3 was associated with better global cognition (βˆ:0.36 to 0.47). These associations became more evident in participants with poor ventilation or short daily indoor time (<12.5 h/day). For global cognition, the exposure to a 10-μg/m3 increment in PM2.5, PM2.5-10, and PM10 corresponded to 1.4, 5.8, and 2.8 years of aging, respectively. ConclusionThis study demonstrated how indoor air quality in areas using clean fuels differentially affected the associations of long-term exposure to low-level air pollutants with cognition. Tightening air quality standards may help prevent dementia.

Accuracy and feasibility of a novel fine hand motor skill assessment using computer vision object tracking

We developed a computer vision-based three-dimension (3D) motion capture system employing two action cameras to examine fine hand motor skill by tracking an object manipulated by a hand. This study aimed to examine the accuracy and feasibility of this approach for detecting changes in a fine hand motor skill. We conducted three distinct experiments to assess the system's accuracy and feasibility. We employed two high-resolution, high-frame-rate action cameras. We evaluated the accuracy of our system in calculating the 3D locations of moving object in various directions. We also examined the system's feasibility in identifying improvement in fine hand motor skill after practice in eleven non-disabled young adults. We utilized color-based object detection and tracking to estimate the object's 3D location, and then we computed the object's kinematics, representing the endpoint goal-directed arm reaching movement. Compared to ground truth measurements, the findings demonstrated that our system can adequately estimate the 3D locations of a moving object. We also showed that the system can be used to measure the endpoint kinematics of goal-directed arm reaching movements to detect changes in fine hand motor skill after practice. Future research is needed to confirm the system's reliability and validity in assessing fine hand motor skills in patient populations.

Know thyself: Executive functioning and sex predict self-appraisal of functional abilities in community-dwelling older adults

Objective: The capacity for accurate self-appraisals of age-related changes in cognitive and functional abilities is integral to the maintenance of independence in later life, yet there is little understanding of the factors that place nondemented older adults at risk for poor self-awareness. This study examined the potential contributions of executive functioning (EF), crystallized intelligence (IQ-Cr), and sex in predicting congruence between performance and self-appraisals of instrumental activities of daily living (IADL) in a group of community-dwelling older adults. Method: A group of 150 nondemented, community-dwelling older adults (White and majority highly educated) completed measures of EF and IQ-Cr. Participants also completed five timed IADL tasks and self-appraised their performance relative to others of similar age. Results: Sex [F(1,148) = 7.75, p = .006, ηp 2 = .05] and EF [(F(1,147) = 5.30, p = .02, ηp 2 = .04)], but not IQ-Cr, predicted the relationship between performance and self-appraisals, such that those with lower EF and those of male sex overestimated their performance more than those with higher EF and females. Conclusions: Findings indicate that having average to below average EF abilities and being of male sex are risk factors for less accurate self-report of IADL abilities and as such might represent important considerations when assessing IADL abilities via self-report among largely independent, community-dwelling older adults.

APOE ε4 status and plasma p-tau181 interact to influence cognitive performance among non-demented older adults

ObjectiveIn this study, we aimed to investigate the relationships among plasma p-tau181, APOE ε4, and cognitive performance in non-demented elderly individuals. MethodsWe used individuals (n = 630) with cognitive normal (CN, n = 182) and mild cognitive impairment (MCI, n = 448). Multiple linear regression models were performed to test the effects of APOE ε4 × plasma p-tau181 interaction on MMSE, CDR-SOB, ADAS-cog13, and RAVLT immediate recall. All models adjusted for age, sex, and education. ResultsIn total, our study comprised 630 samples including 364 APOE ε4 non-carriers and 266 APOE ε4 carriers. In APOE ε4 carriers, plasma p-tau181 was significantly associated with MMSE (B = −0.04, p = 0.003), ADAS-Cog13 (B [unstandardized coefficient] = 0.21, p < 0.001), CDR-SB (B = 0.02, p = 0.003) and RAVLT immediate recall ((B = −0.17, p = 0.035). After correcting for Aβ status and diagnosis, the interaction between APOE ε4 and plasma p-tau181 was significant or marginally significant associations for RAVLT immediate recall (p = 0.076), MMSE (p = 0.011), CDR (p = 0.008), and ADAS-Cog13 (p < 0.001). ConclusionsOur findings suggested that plasma p-tau181 levels predicted cognitive performance among non-demented older adults, but only in the APOE ε4 carriers.

Influences of Aerobic Exercise on Motor Sequence Learning and Corticomotor Excitability in People With Parkinson’s Disease

Background People with Parkinson’s disease (PD) are known to have motor learning difficulties. Although numerous studies have demonstrated that a single bout of aerobic exercise (AEX) can facilitate motor learning in non-disabled adults, the same beneficial effect in PD is unknown. Furthermore, associated neuroplastic changes have not been investigated. Objectives This study aimed to determine whether a single bout of aerobic exercise (AEX) can facilitate motor sequence learning in people with PD and to investigate the associated neurophysiological changes. Methods Thirty individuals with PD were recruited and randomized into the exercise group (PD + AEX) and non-exercise group (PD − AEX). At the first visit, corticomotor excitability was assessed using transcranial magnetic stimulation (TMS). All participants then performed a serial reaction time task (SRTT) followed by 20 minutes of moderately-high intensity aerobic exercise (AEX) for the PD + AEX group or rest for the PD − AEX group. The SRTT and TMS were reevaluated at 3 time points: immediately after aerobic exercise (AEX) or rest, on the second day after practice (D2), and a week after practice (D7). Results Both groups showed improvement throughout practice. At retention, the PD + AEX group showed improved SRTT performance on D7 compared to D2 (P = .001), while the PD − AEX group showed no change in performance. TMS results showed that the PD + AEX group had significantly higher corticomotor excitability than the PD − AEX group on D7. Conclusion A single session of aerobic exercise (AEX) could enhance motor sequence learning and induce neuroplastic changes. Clinicians can consider providing aerobic exercise (AEX) after motor task training for people with PD. Clinical registration: NCT04189887 (ClinicalTrials.gov).

Adult Renal Dysfunction and Risk of Dementia or Cognitive Decline: Brain-Kidney Axis Hypothesis Based on a Systematic Review and Meta-Analysis.

The brain-kidney axis was proposed to emphasize roles of kidney functioning in modulating neurodegeneration. We aimed to evaluate the associations of renal diseases and blood markers with risk of dementia or cognitive decline among non-demented adults. The PubMed, EMBASE, and Cochrane library were searched until February 1st, 2022, to include longitudinal studies. Multivariate adjusted effects were pooled by random-effects models. The robust error meta-regression models were used for dose-response analyses. The credibility of meta-analyses was graded and an innovative index (Sdifference) was developed to evaluate the evidence tendency. A total of 41 longitudinal studies (6,480,136 participants, mean age range: 58.5-83.5 years) were included, of which 33 were for meta-analyses. Though with low level of evidence, five indicators of kidney were associated with increased risk of dementia or cognitive decline, including acute kidney injury (hazard ratio [HR] = 2.24, p = 0.0001), chronic kidney disease (HR = 1.29, p = 0.0001), higher serum creatinine (HR = 1.35, p = 0.0001), higher urine albumin creatine ratio (UACR, HR = 1.23, p = 0.0001), and lower estimated glomerular filtration rate (eGFR, HR = 1.18, p = 0.0001). A linear relationship was revealed for eGFR (p = 0.0217) or UACR (p = 0.0006). Heterogeneity is a main concern to jeopardize the evidence robustness, especially for eGFR (Sdifference = 0.05). Some renal indicators were associated with a higher risk of dementia, though the evidence base warrants further strengthening. Renal function management might serve as a promising target for dementia prediction and prevention.

Neighborhood greenspace and cognition: The cardiovascular health study.

We examined whether greenspace measures (overall percent greenspace and forest, and number of greenspace types) were associated with clinically adjudicated dementia status. In a sample of non-demented older adults (n=2141, average age=75.3 years) from the Cardiovascular Health and Cognition Study, Cox proportional hazard and logistic regression analyses were used to estimate associations of baseline greenspace with risks of incident dementia and MCI, respectively, while adjusting for demographics, co-morbidities, and other neighborhood factors. We derived quartiles of percent greenness (greenspace), forest (percent tree canopy cover), and tertiles of greenspace diversity (number of greenspace types) for 5-km radial buffers around participant's residences at study entry (1989-1990) from the 1992 National Land Cover Dataset. Dementia status and mild cognitive impairment (MCI) over 10 years was clinically adjudicated. We observed no significant association between overall percent greenspace and risk of mild cognitive impairment or dementia and mostly null results for forest and greenspace diversity. Forest greenspace was associated with lower odds of MCI (OR quartile 4 versus 1: 0.54, 95% CI: 0.29-0.98) and greenspace diversity was associated with lower hazard of incident dementia (HR tertile 2 versus 1: 0.70, 95% CI=0.50-0.99). We found divergent results for different types of greenspace and mild cognitive impairment or dementia. Improved greenspace type and diversity measurement could better characterize the association between greenspace and cognition.

Duration and Continuity of Medicaid Enrollment Before the COVID-19 Pandemic

COVID-19 relief legislation created a temporary moratorium on Medicaid disenrollment, but when the public health emergency ends, states will begin to "unwind" Medicaid enrollment. Prepandemic data shed light on factors that can affect Medicaid coverage stability. To assess factors associated with the duration and continuity of Medicaid enrollment. In this cross-sectional analyses of a Medicaid data set for 2016 that was released by the Agency for Healthcare Research and Quality in June of 2022, we analyze a nationally representative data set of 5.7 million persons, weighted to represent 70 million Medicaid beneficiaries in 2016. We focus on 22 million nondisabled, nonelderly adults for this analysis. The data were analyzed between July and September of 2022. The main outcomes were the average months of Medicaid enrollment in 2016 and the probability of churning, defined as a break in coverage between 2 periods of enrollment during the calendar year. We compared these outcomes by eligibility category, state, demographic characteristics, and key Medicaid policies, including whether the state expanded Medicaid and whether it used ex parte reviews (automated reviews of other administrative data to reduce renewal paperwork burdens). In this cross-sectional analysis, we analyze a nationally representative Medicaid data set of 5.7 million persons, weighted to represent 70 million Medicaid beneficiaries in 2016, released by the Agency for Healthcare Research and Quality in June of 2022. The analysis focused on nonelderly, nondisabled adults (aged 18-64 years) with a weighted population size of 22.7 million, of which 18.4% were Black, 19.2% were Latino, 39.5% were White, 7.3% were other/Asian/Native American, and 15.5% had unknown race. Multivariable regression analysis indicated that those living in states that expanded Medicaid but did not use ex parte reviews had longer average duration (0.31 months longer; 95% CI, 0.03-0.59) and lower risk of churning(odds ratio [OR], .40; 95% CI, 0.39-0.40), whereas those living in nonexpansion states that used ex parte reviews had lower odds of churning (OR, .68; 95% CI, 0.66-0.70) but also had shorter average duration (3.1 months shorter; 95% CI, -3.4 to -2.8). Those living in expansion states that used ex parte reviews also had reduced churning (OR, .83; 95% CI, 0.82-0.85). The average duration varied widely by state, even after adjustments for demographic and state policy factors. If state Medicaid programs revert to prepandemic policies after the temporary moratorium ends, Medicaid coverage, particularly for nondisabled, nonelderly adults, is likely to become less stable again. Medicaid expansions are associated with improved continuity, but ex parte review may have a more complex role.

Association of apolipoprotein E in peripheral blood and in vivo Alzheimer’s disease pathologies in nondemented older adults

AbstractBackgroundPrevious studies reported the link between apolipoprotein E (apoE) in peripheral blood and risk of Alzheimer’s disease (AD) dementia. However, underlying mechanism for this link remains unclear. We investigated whether serum apoE concentration is associated with in vivo AD pathologies in nondemented older adults.MethodA total 437 nondemented older adults were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) cohort. All participants underwent comprehensive evaluation including clinical assessment, blood sampling, as well as 11C‐PiB PET and MRI. A subset of participants (N=130) also underwent 18F‐AV1451 PET for measurement of brain tau pathologies. All participants were divided into low, middle, and high apoE concentration tertile groups (i.e., T1, T2, and T3).ResultThere were no significant differences in demographic and clinical variables except the frequency of female and rate of apoE ε4 allele (APOE4) positivity; the lower serum apoE was associated with fewer female (40.1%, 61.6%, and 67.8% for T1, T2, and T3, respectively) and higher APOE4 positivity rate (34.3%, 25.2%, and 16.8%). In terms of AD biomarker, Aβ positivity rate showed significant negative association with serum apoE (40.1%, 31.8%, and 24.8%), which remained significant after adjustment of covariates including age, sex, and diagnosis. In addition, reduced AD‐signature region volume, a neurodegeneration biomarker of AD, was significantly associated with lower serum apoE after controlling the same covariates. With regard to tau biomarker, positivity rate of global tau deposition showed significant negative association with serum apoE level (56.8%, 50%, and 20%) after adjustment of covariates. When we additively controlled the effect of APOE4 positivity, the associations between low serum apoE and greater neurodegeneration and tau positivity remained significant, whereas the association between apoE and Aβ positivity did not reach statistical significance.ConclusionIn the present study, low serum apoE was associated with greater burden of in vivo AD pathologies and such association appears even independent of APOE4 carrier status in regard of tau deposition and neurodegeneration. The finding suggests a potential role of serum apoE as a surrogate marker for in vivo AD pathologies in nondemented older adults.

Constructional Impairments and Their Neural Correlates in Nondemented Adults With Cerebral Autosomal-dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy.

Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic small-vessel disease that is characterized by a wide range of neurologic and neuropsychological impairments. Constructional impairments have been reported in some cases but have never been assessed systematically. To evaluate constructional abilities and their cognitive and neural correlates in nondemented individuals with CADASIL. Thirty individuals with CADASIL who were not affected by clinically relevant cognitive deterioration and 30 healthy controls (HC) underwent an extensive cognitive assessment and paper-and-pencil visuoconstructional tasks in order to detect constructional impairments. Performance on the visuoconstructional tasks was correlated with the cognitive assessment scores and with quantitative indices of regional gray matter atrophy (obtained via FreeSurfer image analysis) and white matter involvement. The individuals with CADASIL achieved significantly lower scores on the cognitive assessment compared with the HC. Poor visuoconstructional abilities were observed in seven (23.3%) of the individuals with CADASIL when performing the copy drawing task and in nine (30%) when performing the Rey Complex Figure Test. Logistic regression revealed that visuoconstructional impairments were significantly associated with scores on the Frontal Assessment Battery and the Attentional Matrices Test. Morphometric results revealed that scores on the visuoconstructional tasks were related to gray matter atrophy of the left frontal lobe and right parietal lobe. Impairments on visuoconstructional tasks are quite common in individuals with CADASIL, even in the lack of clinically relevant cognitive deterioration, and are critically related to frontal and parietal atrophy.

Brain insulin signaling and neurodegeneration: IRS‐1 isolated from neuronal enriched extracellular vesicles associates with frontal lobe gray matter volume in cognitively unimpaired adults

AbstractBackgroundBrain insulin signaling, as measured by insulin signaling proteins in neuronal enriched extracellular vesicles (nEVs), has previously been associated with gray matter (GM) volume in the temporal lobe of nondemented older adults and in multiple brain regions in those with Alzheimer’s clinical syndrome (Walker et al, 2021; Mullins et al, 2017). We sought to extend these findings by performing a voxel‐wise analysis to test the relationship between whole‐brain GM volume and nEV tyrosine phosphorylated IRS‐1 (pY‐IRS‐1) in a cognitively unimpaired sample enriched for AD risk.MethodCognitively‐unimpaired adults (n=47) from the Wisconsin Registry for Alzheimer’s Prevention underwent MRI and blood collection (Table 1). nEVs were isolated from plasma samples by immunoprecipitation targeting neuronal marker L1CAM. pY‐IRS‐1 was measured in nEVs using an electrochemiluminescence assay (Meso Scale Discovery, Rockville, Maryland) (Mustapic et al, 2017). T1‐weighted images were analyzed using the FMRIB Software Library (FSL), where images were first normalized to MNI space and segmented into WM, GM, and CSF using FSL’s FLIRT, FNIRT, and FAST tools and resulting GM maps were smoothed with a Gaussian kernel (sigma = 3.5mm). General linear models and non‐parametric testing (FSL randomise) were used to assess voxelwise associations between nEV pY‐IRS‐1 concentration and GM volume, while controlling for sex and age effects. Significant associations between GM volume and nEV pY‐IRS‐1 were defined as p &lt; 0.01, uncorrected.ResultWe observed lateralized positive associations between nEV pY‐IRS‐1 and GM volume in the right frontal lobe (Figures 1 and 2). After correcting for multiple comparisons, we observed no significant relationships between nEV pY‐IRS‐1 concentration and GM volume.ConclusionPrevious studies indicate that lower nEV pY‐IRS‐1 is associated with lower GM volume in regions such as the temporal and parietal lobes. Here, we determined that lower nEV pIRS‐1 concentrations were associated with lower GM volume laterally in the right frontal lobe of healthy middle‐aged and older adults. Future studies are needed to determine the mechanism by which disrupted insulin signaling in the brain may cause GM loss in these regions.