Deal, Jennifer A.

Introduction: Accelerated cognitive decline is influenced by vascular aging. Arterial stiffness and pressure amplification, measures of vascular aging, are associated with lower cognitive performance though their association with cognitive domains has been understudied. Hypothesis: Arterial stiffness and pressure amplification are associated with lower global and domain-specific cognition among a sample of Caucasian and African American (AA) older adults. Methods: In a cross-sectional study of 4618 members from visit 5 (2011-2013) of ARIC (mean age: 75 years, 41% men, 20% AA), we measured arterial stiffness (carotid-femoral pulse wave velocity (cfPWV)) and pressure amplification (pulse pressure amplification (PPA), central pulse pressure (cPP) and carotid systolic blood pressure (cSBP)) using the Omron VP-1000 Plus device. Race-specific 25th percentile cut points were estimated for each measure. Domain-specific cognitive function was examined using the Delayed Word Recall Test (memory), Digit Symbol Substitution Test (executive function/processing speed), and Word Fluency Test (language). Test-specific z scores were calculated from sample means and standard deviations. A global cognition z score was generated by averaging the test-specific z scores. Linear regression was used to estimate the associations between race-specific 25th percentile dichotomies for arterial stiffness and pressure amplification measures with test-specific and global cognition z scores, adjusted for age, sex, education, ApoE4, heart rate, smoking and body mass index. Results: Among AAs, there was no significant association between measures of arterial stiffness and pressure amplification with either global or the domain-specific measures of cognition. Among Caucasians, all measures of arterial stiffness and pressure amplification were associated with lower global cognitive z scores (cfPWV: Beta (β) =-0.11, 95% Confidence Interval (CI): -0.19, -0.04; PPA: β=-0.11, 95% CI: -0.19, -0.03; cPP: β=-0.11, 95% CI: -0.18, -0.04; cSBP: β=-0.12, 95% CI: -0.20, -0.05). All measures of arterial stiffness and pressure amplification also were associated with lower executive function/processing speed (cfPWV: β=-0.09, 95% CI: -0.16, -0.03; PPA: β=-0.15, 95% CI: -0.22, -0.08; cPP: β=-0.14, 95% CI: -0.21, -0.07; cSBP: β=-0.13, 95% CI: -0.20, -0.07). High cfPWV was associated with lower memory (β=-0.12, 95% CI: -0.20, -0.04); and high cSBP was associated with lower language (β=-0.12, 95% CI: -0.20, -0.04). Conclusions: Arterial stiffness and measures of pressure amplification are inversely associated with global and domain-specific cognition in Caucasian older adults, but not in a smaller sample of AAs. Further study of the role of modifiable components of arterial aging on the preservation of cognition, particularly executive function/psychomotor speed, in older adulthood is warranted.

Background: As a high-flow, low-impedance organ, the brain is sensitive to excessive pressure and flow pulsatility. Increased pulsatility and arterial stiffness are hypothesized to contribute to cerebral microvascular damage linked to cognitive impairment. The association of arterial stiffness with mild cognitive impairment (MCI) and dementia in a biethnic population is not well characterized, and the association of pressure amplification with MCI and dementia is relatively unexplored. Objectives: To quantify the cross-sectional association of arterial stiffness, measured by aortic pulse wave velocity (PWV), and pressure amplification with MCI and dementia in a biethnic population of older adults. Methods: We included 4,945 adults (2,903 females; 1,069 African Americans; mean age 75 years) from the population-based ARIC-NCS. The Omron VP-1000 plus system was used to measure arterial stiffness (carotid-femoral PWV (cfPWV)) and pressure amplification measures (central systolic blood pressure (cSBP), central pulse pressure (cPP), and pulse pressure amplification (PPA)). A neurologist and neuropsychologist classified MCI and dementia using psychometric assessments, medical history, cerebral magnetic resonance imaging, and physical examinations, with adjudication by a third reviewer. We used multinomial logistic regression to evaluate associations of race-specific 25th percentile cut points of PWV and pressure amplification with normal cognition (reference), MCI and dementia. We stratified by race and adjusted for age, sex, and heart rate, ApoE4, education, smoking status, and study center. Results: There were 760 Caucasians with MCI and 110 with dementia, and 201 African Americans with MCI and 47 with dementia. Among Caucasians, those with lower PPA had a higher prevalence of dementia, odds ratio (OR)=1.84 (95% confidence interval (CI): 1.15, 2.97), comparing participants below the 25th percentile to those above it, and those with higher cSBP had a higher prevalence of MCI, OR=1.33 (95% CI: 1.09, 1.63), comparing participants above the 75th percentile to those below it. Also among Caucasians, those with higher cPP had a higher prevalence of MCI, OR=1.25 (95%CI: 1.01, 1.55), and dementia, OR=1.66 (95% CI: 1.00, 2.73), comparing participants above the 75th percentile to those below it. There were no statistically significant associations with cfPWV, among African Americans, and no evidence for effect modification by hypertension or diabetes. Conclusion: Arterial stiffness and components of pressure amplification were associated with MCI and dementia in Caucasians but not in African Americans, possibly due to the limited sample size. Longitudinal characterization of the observed associations is warranted to determine whether these measures are independent predictors of MCI and dementia among Caucasian and African American older adults.

AbstractBackgroundPrior evidence has suggested associations between hearing loss and smaller brain volumes particularly in the temporal lobe where the primary auditory cortex is located, probably due to changes in cortical organization associated with reduced auditory stimulation. Evidence regarding associations of central auditory processing with brain volumes is relatively limited. The study aims to investigate cross‐sectional associations of central auditory processing with brain volumes in older adults.MethodWe studied 587 cognitively normal (Mini‐Mental State Exam ≥23 if high school degree or less and ≥25 if above high school degree) older adults (mean age: 77±4 years, 56% female, 17% black), including 426 with hearing loss from the Aging and Cognitive Health Evaluation in Elders (ACHIEVE) baseline (2018‐19), which is an ancillary randomized controlled trial of the Atherosclerosis Risk in Communities (ARIC) Study and 161 with normal hearing, comparable age and cognitive status from the ARIC Visit 6/7 (2016‐17/2018‐19). Brain volumes were measured by magnetic resonance imaging (MRI) scans and were transformed to z‐scores. Central auditory processing was measured by the Quick Speech‐in‐Noise (QuickSIN) test. Total scores range from 0 to 30 with lower scores indicating worse speech‐in‐noise performance. Multivariable‐adjusted linear regression was used to estimate cross‐sectional differences in standardized brain volumes associated with differences in QuickSIN score. Models adjusted for age, sex, race, education, cohort, body mass index, smoking, hypertension, diabetes, stroke, intracranial volume, and pure‐tone average.ResultEvery 5‐point decrease in QuickSIN score (worse performance) was associated with smaller volumes of the temporal lobe (‐0.07SD, 95% CI: ‐0.13, ‐0.01). QuickSIN score was also associated with subregions of the temporal lobe related to auditory processing, memory and emotion, including amygdala (‐0.13SD, 95% CI: ‐0.21, ‐0.04), middle (‐0.08SD, 95% CI: ‐0.15, ‐0.00) and superior temporal gyri (‐0.08SD, 95% CI: ‐0.15, ‐0.01).ConclusionPoorer central auditory processing was associated with smaller temporal lobe volumes, including but not limited to subregions important for auditory processing. The ongoing collection of ACHIEVE data with longitudinal MRI data will facilitate understanding of association between hearing loss and brain atrophy as well as the potential promising effects of hearing treatment in mitigating brain aging.

Abstract We investigated the cross-sectional associations of speech-in-noise performance with magnetic resonance imaging brain volumes among 588 cognitively normal participants (77±4 years, 56% female) from the Aging and Cognitive Health Evaluation in Elders Study (randomized trial embedded in the Atherosclerosis Risk in Communities (ARIC) Study) baseline in 2018-19 (N=427, with hearing loss) and ARIC (N=161, normal hearing) Visit 6/7 in 2016-17/2018-19. Central auditory processing was measured by Quick Speech-in-Noise (QuickSIN) test; range: 0 to 30, lower scores=worse performance. In models adjusted for demographic and disease covariates, every 5-point decrease in QuickSIN score was associated with smaller volumes of the temporal lobe overall (-0.07SD, 95% CI:-0.13,-0.01) as well as subregions including but not limited to those important for auditory processing (amygdala:-0.13SD, 95% CI:-0.21,-0.04; middle temporal gyrus:-0.08SD, 95% CI:-0.15,-0.00; superior temporal gyrus:-0.08SD, 95% CI:-0.15,-0.01). Further research is needed to understand the mechanisms underlying these observed associations.

Introduction: Impairment in the sense of smell is associated with plaques and tangles in the olfactory region of the brain, which connects to the hippocampus where neuropathologic changes related to mild cognitive impairment (MCI) and dementia due to Alzheimer’s disease are first sited. Olfactory impairments may thus be a marker for poor cognitive function and MCI. We assessed olfaction and cognitive function in 6055 White and Black men and women aged 60-99 years. Methods: Sense of smell was measured in ARIC-NCS participants (2011-2013) by the 12-item Sniffin’ Sticks screening test (score range: 0-12, median: 10). A clinically validated threshold (smell score <6) defined olfactory impairment (OI). A multidimensional neuropsychological assessment (10 tests) ascertained performance in domains of memory, language, executive function/processing speed, and global cognition. For relative comparisons across the tests, raw cognitive test scores were standardized to z scores and averaged to yield domain scores. Following review of neuropsychological assessments, medical history, cerebral magnetic resonance imaging, and physical examinations, MCI was classified by a neurologist and neuropsychologist, and adjudicated by a third reviewer. Multivariable linear regression estimated the mean difference in domain-specific z scores among participants with and without OI. Logistic regression was used to quantify the prevalence odds of MCI in participants with vs. those without OI. Models were adjusted for age, sex, race, education, ARIC study center, hypertension, diabetes, smoking, and ApoE4. Race and sex were explored as effect modifiers. Results: The participants’ mean age was 76 years; 41% were male and 23% Black. The prevalence of olfactory impairment was 14%. Compared to participants with no OI, those with OI had a statistically significantly lower mean z score across all cognitive domains [memory: Beta= -0.37 (95% confidence interval [CI]: -0.45, -0.30); language: Beta= -0.39 (95% CI: -0.46, -0.33); executive function/processing speed: Beta= -0.24 (95% CI: -0.32, -0.17); global cognition: Beta= -0.34 (95% CI: -0.41, -0.26). Effect modification by race was observed in the domain of language. Blacks with OI had a greater mean difference in language z score compared to Blacks without OI (Beta= -0.57 (95% CI: -0.70, -0.44)). OI was associated with MCI in Whites, but not Blacks: white participants with OI had greater odds of MCI (Odds Ratio [OR] =1.76, 95% CI: 1.40, 2.21). Sex did not modify these associations. Conclusions: Compared to average cognitive aging (annual rate of decline of 0.04-0.05 standard deviation units/year) relatively large differences in standardized cognitive domain scores are observed between those with and without olfactory impairment among older adults. An impaired sense of smell may serve as a readily accessible early marker of neurodegeneration.

Introduction: Small vessel disease is associated with decreased cognitive function, possibly differential by race. Age-related central arterial stiffening increases pulsatility resulting in hypoperfusion, microvascular damage and remodeling in the brain, potentially impairing cognition. We examined if arterial stiffness and pressure amplification are associated with lacunar infarcts and greater volumes of white matter hyperintensities (WMH) in a sample of Caucasian and African American (AA) older adults. Methods: We analyzed a cross-sectional sample of ARIC participants aged 67-90 years (n=1486) from visit 5 (2011-2013), with brain magnetic resonance imaging (MRI). The Omron VP-1000 Plus was used to measure aortic stiffness (carotid-femoral pulse wave velocity [cfPWV]) and pressure amplification measures (pulse pressure amplification [PPA], central pulse pressure [cPP], and estimated central systolic blood pressure [cSBP]). Aortic stiffness and pressure amplification were dichotomized at race-specific 25th percentile cut points. Brain MRI using 3D-1.5T equipment quantified the presence of lacunar infarcts and volumes of WMH following a standardized protocol. Logistic regression, adjusted for age, sex, education, ApoE4, heart rate, smoking and body mass index, was used to quantify the odds of lacunar infarcts in participants with high vs. low cfPWV, cPP, cSBP, and low vs. high PPA. Linear regression models, additionally adjusted for intracranial volume, estimated the difference in log-transformed volumes of WMH among participants with high vs. low cfPWV, cPP, cSBP, and low vs. high PPA. Probability sampling weights for an MRI were included to allow for generalizability to the full visit 5 cohort. Results: Among the 1486 participants with a brain MRI (mean age: 76, 41% male, 26% AA), measures of aortic stiffness and pressure amplification were associated with lacunar infarcts in Caucasians, but not in AAs. Caucasian participants with a high cfPWV had greater odds of lacunar infarcts (Odds Ratio [OR] =2.02, 95% confidence interval [CI]: 1.23, 2.20). Caucasians with high cSBP had higher odds of lacunar infarcts (OR=1.72, 95% CI: 1.10, 2.69). In Caucasians, high cfPWV was associated with a 21% (95% CI: 6, 38) greater volume of WMH as compared to a low cfPWV; high cSBP was associated with a 28% (95% CI: 14, 45) greater volume of WMH compared to a low cSBP. In AAs, high cfPWV was associated with a 32% (95% CI: 7, 62) greater volume of WMH as compared to low cfPWV. Cerebral microvascular imaging markers did not differ quantitatively with measures of PPA and cPP. Conclusions: Central arterial stiffening and pressure amplification are plausible microvascular contributors to cognitive aging, providing new information on modifiable pathways for previously observed associations between cardiovascular disease risk factors and the rates of cognitive decline and dementia among older adults.

Introduction: The microvascular contribution to dementia may be under-recognized because of the inability to visualize the brain microvasculature in vivo. Although the easily-imaged retinal vasculature may be a surrogate measure for that in the brain, large prospective studies of the relationship between retinal vascular signs and dementia are scarce. Hypothesis: Retinal signs are associated with greater subsequent risk of all-cause dementia and etiologic subtype over 20 years in 12482 men and women (mean age of 60 years when retinal signs were measured, 22% African American). Methods: Retinal signs were measured using fundus photography (1993-1995). Presence and etiology of dementia and mild cognitive impairment (MCI) were adjudicated using data collected in 2011-13, including a complete neuropsychological battery and brain magnetic resonance imaging (subset of participants). For participants not attending the 2011-13 visit, dementia cases were identified using the Telephone Interview for Cognitive Status–Modified or informant interview, or by hospitalization or death certificate code. Multivariable-adjusted Cox proportional hazards models and logistic regression were used to quantify the relationship of retinal signs with dementia risk and with etiologic subtype, respectively. Results: During a mean 16 years of follow-up, 1259 (10%) participants developed dementia. Moderate or severe (vs. no) retinopathy (hazard ratio [HR], 1.86; 95% CI: 1.36, 2.55) and generalized arteriolar narrowing, measured as the central retinal arteriolar equivalent (CRAE, narrowest quartile vs. widest three quartiles), (HR, 1.26; 95% CI: 1.09, 1.45) were associated with all-cause dementia. Results did not differ by diabetes, race or APOE ε4 genotype. Retinopathy was associated with cerebrovascular-related dementia and MCI (odds ratio, 2.66; 95% CI: 1.30, 5.42). Conclusions: Retinal photography captures small vascular signs in the eye that are related to increased dementia risk. Emerging techniques, such as optical coherence tomography angiography, may have the sensitivity to provide surrogate indices of microvascular lesions relevant to dementia in older adults.

Background: Vascular risk factors have been associated with risk of cognitive decline, with increasing evidence that midlife exposure to these risk factors may be most important in conferring late-life risk of cognitive impairment. We explored associations between vascular risk factors measured in midlife and the development of dementia over 25 years in the biracial Atherosclerosis Risk in Communities (ARIC) cohort. Methods: Participants in the ARIC study were recruited from four U.S. communities in 1987-1989, at ages 45-64, with four additional in-person visits, surveillance for hospitalizations, annual phone calls, and repeated cognitive evaluations over a 25-year period. In 2011-2013, ARIC participants were seen for the ARIC Neurocognitive Study (ARIC-NCS), and underwent a detailed neurocognitive battery and informant interviews. Through adjudicated review, dementia cases were defined. Additional dementia cases were identified through the telephone interview for cognitive status (TICS) or informant interview for those participants not attending ARIC-NCS; or by a prior dementia ICD-9 code during a hospitalization. Results: Of 15,744 participants in the cohort, 1516 cases of dementia were identified, of whom over one third were among black participants. Risk of dementia was highest in individuals of black race, with less than a high school education, older age, APOE ε4 carriage, and who, at ARIC baseline, had hypertension, diabetes, or were current smokers (table). APOE ε4 and smoking were each stronger risk factors for dementia in whites than in blacks. Discussion: Vascular risk factors measured in midlife are associated with increased risk of dementia in this biracial cohort, in black and white participants. The risk associated with diabetes nears the increased risk associated with having an APOE ε4 allele. Further studies are needed to evaluate the mechanism of and opportunities for prevention of the cognitive sequelae of these risk factors in midlife.

AbstractBackgroundHearing impairment is associated with cognitive decline but whether it is a cause or marker is unknown. We investigated the association of hearing impairment with brain volumes and 8‐year cognitive decline. Because the superior temporal gyrus (STG) is the location of the primary auditory cortex, we stratified results by STG volume to investigate if the association of hearing and cognition differed among participants with and without evidence of possible hearing‐related brain atrophy.MethodWe used data from 1195 community‐dwelling adults (72‐94 years, 61% female, 36% black) from the Atherosclerosis Risk in Communities Study. A composite cognitive score was created from 10 neuropsychological tests administered at 3 study visits spanning 8 years (2011‐13 to 2018‐19). Brain volumes were calculated from structural magnetic resonance imaging scans for 6 regions of interest. Pure tone air conduction hearing thresholds (frequencies 0.5‐4 kHz) were obtained in 2016‐17 and averaged, with better‐ear hearing impairment defined as an average >25 dB. Multivariable‐adjusted linear regression was used to estimate cross‐sectional differences in standardized brain volumes, adjusting for intracranial volume, demographic and clinical covariates. We estimated differences in annual rates of cognitive change by hearing impairment status adjusting for demographic and clinical covariates using linear mixed models; results were stratified by intracranial volume‐adjusted STG volume (below vs. equal to or greater than the median value).ResultThe mean STG volume difference comparing hearing impairment to normal hearing was ‐0.121 standard deviations (SD) (95% CI: ‐0.213, ‐0.028). Overall, the difference in the rate of cognitive decline associated with hearing impairment was ‐0.014 SD (‐0.023, ‐0.005). Hearing was more strongly associated with cognitive decline among participants with smaller STG volumes; rate difference, ‐0.014 SD (‐0.027, ‐0.002) compared to ‐0.008 (‐0.022, 0.006) for participants with larger STG volumes.ConclusionHearing impairment was associated with smaller brain volumes in the primary auditory region, but not with other regions. Our stratified analysis suggests that hearing treatment might be an important possible strategy to delay cognitive decline, even among participants with hearing‐related brain atrophy. Furthermore, the adverse cognitive effects of hearing impairment could potentially be mitigated if early hearing treatment can prevent STG atrophy.

AbstractBackgroundRecently, hearing loss has been identified as a promising modifiable risk factor for dementia. Several hypotheses explaining a potential underlying pathway have been proposed, including the sensory deprivation hypothesis, describing a direct causal relationship in which hearing loss leads to neuroplastic changes in the brain. Indeed, hearing loss has been associated with smaller macrostructural brain volumes, which is believed to at least partly explain the association between hearing loss and neurodegenerative disease. However, microstructural changes precede macrostructural changes. Therefore, we aimed to assess the association between hearing loss and microstructural integrity of the brain.Methods1,086 dementia‐free older adults from the Atherosclerosis Risk in Communities (ARIC) study (mean age = 75.2 [SD: 4.9], 61.4% female) underwent hearing assessment (2016‐2017) and magnetic resonance imaging (MRI) of the brain (2011‐2013). Hearing was assessed with pure‐tone audiometry. Microstructural integrity (fractional anisotropy (FA) and mean diffusivity (MD)) of multiple brain regions was determined with diffusion tensor imaging (DTI). Multivariable linear regression models were used to investigate the association between hearing loss and microstructural integrity of the lobes, temporal lobe gyri, medial temporal lobe structures and white matter (WM) tracts, adjusting for relevant confounders.ResultHearing loss was associated with lower WM microstructural integrity in the temporal lobe (difference in SD FA for moderate/severe hearing loss as compared to normal hearing: ‐0.19 [95% CI: ‐0.35, ‐0.03]; and difference in SD MD for moderate/severe hearing loss as compared to normal hearing: 0.15 [95% CI: 0.01, 0.28]). Hearing loss was associated with lower gray matter (GM) microstructure of the hippocampus, but not the amygdala. Moreover, hearing loss was associated with lower WM microstructural integrity of the limbic tracts and the uncinate fasciculus (Figure 1).ConclusionOur results demonstrate that age‐related hearing loss is associated with lower WM microstructural integrity in the temporal lobe, the limbic tracts and the uncinate fasciculus and lower GM microstructure in the hippocampus. These associations suggest that poorer hearing may affect brain regions that are important for different cognitive processes. However, the results should be interpreted with caution as this study is of a cross‐sectional design.