Sullivan, Kevin

AbstractBackgroundPhysical frailty is associated with increased risk for dementia and other neurologic sequelae. However, the neurobiological changes underlying frailty and frailty risk remain unknown. We examined the association of cerebral white matter structure with current and future frailty.MethodsAtherosclerosis Risk in Communities Study Neurocognitive Study participants who underwent 3T brain MRI were included. Frailty status was classified according to the Fried criteria. Cerebral white matter integrity was defined using white matter hyperintensity (WMH) volume and microstructure, measured using diffusion tensor imaging fractional anisotropy (FA) and mean diffusivity (MD). Multivariable linear regression was used to relate baseline frailty to white matter structure; multivariable logistic regression was used to relate baseline white matter to frailty risk among participants nonfrail at baseline.ResultsIn the cross-sectional analysis (N = 1 754; mean age: 76 years), frailty was associated with greater WMH volume, lower FA, and greater MD. These associations remained consistent after excluding participants with a history of stroke or dementia. Among participants nonfrail at baseline who completed follow-up frailty assessment (N = 1 379; 6.6-year follow-up period), each standard deviation increase in WMH volume was associated with 1.46 higher odds of frailty at follow-up. Composite FA and MD measures were not associated with future frailty; however, secondary analyses found several significant white matter tract-specific associations with frailty risk.ConclusionThe current study demonstrates a robust association of WMH volume with current and future frailty. Although measures of white matter microstructure were altered in frail individuals, these measures were not generally associated with progression from nonfrail to frail status.

AbstractIntroductionSlower mobility is associated with mild cognitive impairment (MCI) and dementia. We examined the interaction of endurance with gait speed on prevalent MCI and dementia.MethodsCross‐sectional multinomial regression in the ARIC cohort (n = 2844 participants; 71 to 94 years; 44% men; 18% Black persons) with cognitive status (normal/MCI/dementia), 4 m gait speed, and endurance (2 minute walk [2MW]).ResultsFaster gait speed (up to but not above 1 m/s) and better 2MW were separately associated with lower dementia risk. Good performance in both (2MW = 200 m, gait speed = 1.2 m/s) was associated with 99% lower dementia (Relative Prevalence Ratio [RPR] = 0.01 [95% CI: 0.0 to 0.06]) and 73% lower MCI, RPR = 0.27 (0.15 to 0.48) compared to poor performance in both (2MW = 100 m, gait speed = 0.8 m/s). Models incorporating a gait speed‐by‐2MW interaction term outperformed gait speed‐only models (P < .001).DiscussionGait speed relationships with dementia diminish at faster gait speeds. Combining endurance with gait speed may yield more sensitive markers of MCI and dementia than gait speed alone.

AbstractBackgroundImaging‐based markers of cerebrovascular disease are associated with adverse health events, including incident dementia. However, only infarcts ≥3mm are typically considered in clinical and research settings. Recent evidence demonstrates that smaller infarcts in individuals during mid‐life, particularly when co‐occurring with larger infarcts, may be clinically relevant to cognitive decline, incident stroke, and stroke mortality. We aimed to determine if there was a similar compounding of risk for incident dementia among those with both smaller and larger infarcts at midlife.MethodThe ARIC study is a multi‐site longitudinal cohort study which began in 1987. At visit 3 (1993‐95), brain 1.5T MRI scans were completed in 1881 participants with self‐reported Black/White race and no history of stroke (Mean age=62.9±4.9, 40% Male, 50% Black). Infarcts were identified on T2 and proton density weighted images, with smaller infarcts defined as those <3mm and larger infarcts defined as ≥3mm. All participants were followed prospectively for incident dementia using a combination of medical record surveillance, telephone interviews, in‐person assessments, and expert adjudicated dementia status at three in‐person exams (2011‐2013, 2015‐17, 2018‐19). Cox regression was used to determine the association between infarct group [none(referent), smaller only, larger only, both] and incident dementia adjusted for age, sex, education, site‐race, APOE4, and competing risk of mortality.ResultAmong 1881 participants, 539 incident dementia cases were identified over 25 years of follow‐up. 1611 participants were infarct‐free, 50 participants had only smaller infarcts, 185 had only larger infarcts, and 35 participants had both. Compared to those with no infarcts, participants with both smaller and larger infarcts were over 2.5 times more likely to develop dementia [Hazard Ratio(HR)=2.61; 95% Confidence Interval(CI)=1.44, 4.72]. Associations were in similar directions but had wider and indeterminate confidence intervals when comparing the smaller infarcts only (HR=1.22; 95%CI=0.70, 2.13) or larger infarcts only (HR=1.27; 95%CI=0.92, 1.74) to the no infarct group. Of the 35 participants with both smaller and larger infarcts, all but two either died or developed dementia.ConclusionA midlife infarct burden including both smaller and larger lesions may represent a vulnerability to dementia beyond the risk conferred by either smaller or larger infarcts alone.

Abstract Brain imaging-based biomarkers of neuropathology are associated with mobility in older adults, but the relation of regional microstructural integrity to gait speed in the context of a broader neuropathological profile is less understood. We examined cross-sectional associations of microstructural integrity with 4-meter usual-pace gait speed (cm/s) in a subsample of ARIC study participants who completed 3T MRI brain scans with diffusion tensor imaging(2011-13; n=1785; mean age=76.2±5.3, 60% Female, 28% Black). We considered total brain and six regional averages of fractional anisotropy (FA; lower=worse microstructural integrity) and mean diffusivity (MD; higher=worse microstructural integrity): frontal, temporal, parietal, occipital, anterior and posterior corpus callosum. Associations were tested in multivariable linear regression models adjusted for demographics, cardiovascular risk factors, and with and without additional neuropathological indices: total brain volume, white matter hyperintensities, infarcts, and microhemorrhages. When modeled separately, all neuropathology indices were associated with slower gait speed. Every standard deviation(SD) higher total brain FA was associated with +2.56 cm/s gait speed (95%CI: 1.64,3.48) and every SD higher MD was associated with -4.27 cm/s gait speed (-5.34,-3.20). All regional estimates were comparable. When adjusted for all other neuropathology indices, only posterior corpus callosum FA (β=1.72; 0.67,2.77), total MD (β=-1.63; -3.02,-0.25), frontal lobe MD (β=-1.76; -3.03,-0.48), and temporal lobe MD (β=-1.40; -2.78,-0.02) remained significantly associated with gait speed. Microstructural integrity is an informative measure of brain pathology in relation to mobility, with regional measures tied to executive, memory, and somatosensory function being more informative when a broader neuropathological profile is considered.

AbstractIntroductionMotoric cognitive risk (MCR), a clinical syndrome characterized by slow gait speed and subjective cognitive complaints, has been associated with dementia risk. The neuropathological features underlying MCR remain poorly understood.MethodsThe Atherosclerosis Risk in Communities (ARIC) community‐based cohort study classified participants using standardized criteria as MCR+/– and mild cognitive impairment (MCI)+/– at study baseline (2011–2013). We examined the 5‐year dementia risk and baseline brain structural/molecular abnormalities associated with MCR+ and MCI+ status.ResultsOf 5023 nondemented participants included, 204 were MCR+ and 1030 were MCI+. Both MCR+ and MCI+ participants demonstrated increased dementia risk. The pattern of structural brain abnormalities associated with MCR+ differed from that of MCI+. Whereas MCI+ was associated with comparatively smaller volumes in brain regions vulnerable to Alzheimer's disease pathology, MCR+ status was associated with smaller volumes in frontoparietal regions and greater white matter abnormalities.DiscussionMCR may represent a predementia syndrome characterized by prominent white matter abnormalities and frontoparietal atrophy.

Background: Elevated carotid intima-media thickness (cIMT) and presence of carotid plaque are markers of atherosclerosis, which may be linked to structural brain injury. Using data from the ARIC-NCS cohort, we tested the hypotheses that greater cIMT and presence of carotid plaque at late midlife were each associated with presence of infarcts (lacunar and cortical) and cerebral microbleeds (lobar and subcortical), greater white matter hyperintensity (WMH) volume, and smaller regional brain volumes in late life. Methods: We included 1,795 ARIC participants who had carotid ultrasounds in 1990-92 and brain MRI scans in 2011-13. Weighted linear regression was used for continuous (brain volume) outcomes, and weighted logistic regression for dichotomous outcomes (infarcts and cerebral microbleeds). Results: Participants were aged 57±6 years at baseline, 57% were female, and 23% were Black. Mean ± SD follow-up was 21±1 years. After multivariable adjustments, the highest quintile of cIMT in late midlife was associated with smaller deep grey matter volume (β [95% CI]: -0.11 [-0.22, -0.01]) and cortical volume in a temporal-parietal meta region of interest (ROI) (β [95% CI]: -0.10 [-0.20, -0.01]) in late life (Table). At baseline, 473 (26%) participants had carotid plaque present on their carotid ultrasound. Similar to cIMT, those with carotid plaque had smaller regional brain volumes than those without carotid plaque present (βs [95% CIs]: -0.05 [-0.12, 0.03] and -0.06 [-0.13, 0.01] for deep grey matter and temporal-parietal meta ROI volumes, respectively). No significant relations were observed with WMH volume, or the presence of any infarcts or cerebral microbleeds. Conclusion: Greater midlife cIMT and presence of carotid plaque were associated with smaller deep grey matter volume and cortical volume in a temporal-parietal meta ROI in later life. Contrary to our hypothesis, associations between midlife subclinical atherosclerosis and markers of vascular brain injury in later life were null.

Abstract Plasma-based biomarkers of amyloid beta (Aβ), a neuropathological hallmark of Alzheimer’s disease, show promise in predicting cognitive impairment and mapping onto cerebral amyloidosis, but little is known about how midlife plasma Aβ associates with late-life cognitive outcomes. Midlife plasma variants Aβ42 and Aβ40 were measured using a fluorimetric bead-based immunoassay in a subsample of visit 3 ARIC participants (1993-95; n=2585, mean age=59.4±5.2, 57% female, 23% African American). We investigated the relationship between midlife plasma Aβ and late-life mild cognitive impairment (MCI; n=923) and dementia (n=628) diagnosed from 2011-19. Multinomial logistic regressions estimated relative risk ratios (RRR) of MCI, dementia, and death vs normal cognitive status as a function of:(1) Aβ42:Aβ40 ratio, (2) Aβ42 and Aβ40 included as separate terms, and (3) Protected Aβ group (participants with Aβ42≥46 pg/ml and Aβ40 &lt;233 pg/ml). Adjusters included age, sex, education, site-race, and APOE4. Every doubling of midlife plasma Aβ42:Aβ40 up to a threshold of 0.20 was associated with 41% lower risk of developing MCI/dementia in comparison to cognitively normal (RRR=0.59 [95% CI:0.42, 0.82]), with no association for ratio values ≥0.20. Every standard deviation increase in plasma Aβ42 was associated with 17% lower risk of dementia (RRR=0.83 [0.70, 0.99]), whereas every standard deviation increase in plasma Aβ40 was associated with 16% higher risk of MCI (RRR=1.16 [1.02, 1.31]). The protected midlife plasma Aβ group had 86% lower risk of late-life dementia vs all others (RRR=0.14 [0.04, 0.47]). Early measurement of plasma Aβ may prove an accessible and effective population screener for future cognitive impairment.

Objective. The optimal management of pediatric patients with arterial ischemic stroke (AIS) is not known. Despite this, goal-oriented, time-sensitive therapies geared to rapid reestablishment of arterial blood flow are occasionally applied with beneficial effects. The inconsistent approach to AIS is in part due to a lack of knowledge and preparedness.Methods. Case report of a 12-year-old male with right middle cerebral artery (MCA) occlusion resulting in dense left hemiplegia and mutism and review of the literature.Intervention(s). Mechanical thrombectomy, intra-arterial administration of rt-PA, vasodilators, and platelet inhibitors, and systemic anticoagulation and subsequent critical care support.Results. Restoration of right MCA blood flow and complete resolution of neurologic deficits.Conclusion. We report the gratifying outcome of treatment of a case of AIS in a pediatric patient treated with hyperacute therapies geared to arterial recanalization and subsequent neurologic critical care and review the pertinent literature. Guidelines for the emergency room management of pediatric AIS from prospective, randomized trials are needed.