Communities Neurocognitive Study Research Articles

Lung Function and Brain MRI Outcomes in the Atherosclerosis Risk in Communities Neurocognitive Study

Background: Brain imaging studies may provide etiologic insight into observed links between lung function and dementia and stroke. Objective: We evaluated associations of lung function measures with brain MRI markers of vascular and neurodegenerative disease in the ARIC Neurocognitive Study, as few studies have examined the associations. Methods: Lung function was measured at participants’ midlife in 1990–1992 (mean age = 56±5 years) and later-life in 2011–2013 (mean age = 76±5 years), and brain MRI was performed in 2011–2013. Linear regression models were used to examine the associations of lung function with brain and white matter hyperintensity (WMH) volumes, and logistic regression models were used for cerebral infarcts and microbleeds, adjusting for potential confounders. Results: In cross-sectional analysis (i.e., examining later-life lung function and MRI markers, n = 1,223), higher forced-expiratory volume in one second (FEV1) and forced vital capacity (FVC) were associated with larger brain and lower WMH volumes [e.g., 8.62 (95% CI:2.54–14.71) cm3 greater total brain volume per one-liter higher FEV1]. No association was seen with microbleeds in the overall sample, but higher FVC was associated with lower odds of microbleeds in never-smokers and higher odds in ever-smokers. In the cross-temporal analysis (i.e., associations with midlife lung function, n = 1,787), higher FVC levels were significantly associated with lower later-life brain volumes. Conclusions: Our results support modest associations of better lung function with less neurodegenerative and cerebrovascular pathology, although findings for microbleeds were unexpected in ever-smokers.

Cross-Sectional Associations of Peripheral Hearing, Brain Imaging, and Cognitive Performance With Speech-in-Noise Performance: The Aging and Cognitive Health Evaluation in Elders Brain Magnetic Resonance Imaging Ancillary Study.

Population-based evidence in the interrelationships among hearing, brain structure, and cognition is limited. This study aims to investigate the cross-sectional associations of peripheral hearing, brain imaging measures, and cognitive function with speech-in-noise performance among older adults. We studied 602 participants in the Aging and Cognitive Health Evaluation in Elders (ACHIEVE) brain magnetic resonance imaging (MRI) ancillary study, including 427 ACHIEVE baseline (2018-2020) participants with hearing loss and 175 Atherosclerosis Risk in Communities Neurocognitive Study Visit 6/7 (2016-2017/2018-2019) participants with normal hearing. Speech-in-noise performance, as outcome of interest, was assessed by the Quick Speech-in-Noise (QuickSIN) test (range: 0-30; higher = better). Predictors of interest included (a) peripheral hearing assessed by pure-tone audiometry; (b) brain imaging measures: structural MRI measures, white matter hyperintensities, and diffusion tensor imaging measures; and (c) cognitive performance assessed by a battery of 10 cognitive tests. All predictors were standardized to z scores. We estimated the differences in QuickSIN associated with every standard deviation (SD) worse in each predictor (peripheral hearing, brain imaging, and cognition) using multivariable-adjusted linear regression, adjusting for demographic variables, lifestyle, and disease factors (Model 1), and, additionally, for other predictors to assess independent associations (Model 2). Participants were aged 70-84 years, 56% female, and 17% Black. Every SD worse in better-ear 4-frequency pure-tone average was associated with worse QuickSIN (-4.89, 95% confidence interval, CI [-5.57, -4.21]) when participants had peripheral hearing loss, independent of other predictors. Smaller temporal lobe volume was associated with worse QuickSIN, but the association was not independent of other predictors (-0.30, 95% CI [-0.86, 0.26]). Every SD worse in global cognitive performance was independently associated with worse QuickSIN (-0.90, 95% CI [-1.30, -0.50]). Peripheral hearing and cognitive performance are independently associated with speech-in-noise performance among dementia-free older adults. The ongoing ACHIEVE trial will elucidate the effect of a hearing intervention that includes amplification and auditory rehabilitation on speech-in-noise understanding in older adults. https://doi.org/10.23641/asha.25733679.

Occupation, Retirement Age, and 20-Year Cognitive Decline: The Atherosclerosis Risk in Communities Neurocognitive Study

Introduction: We examined the association of both midlife occupation and age at retirement with cognitive decline in the Atherosclerosis Risk in Communities (ARIC) biracial community-based cohort. Methods: Current or most recent occupation at ARIC baseline (1987–1989; aged 45–64 years) was categorized based on 1980 US Census major occupation groups and tertiles of the Nam-Powers-Boyd occupational status score (n = 14,090). Retirement status via annual follow-up questionnaires administered ascertained in 1999–2007 was classified as occurring before or after age 70 (n = 7,503). Generalized estimating equation models were used to examine associations of occupation and age at retirement with trajectories of global cognitive factor scores, assessed from visit 2 (1990–1992) to visit 5 (2011–2013). Models were a priori stratified by race and sex and adjusted for demographics and comorbidities. Results: Low occupational status and blue-collar occupations were associated with low baseline cognitive scores in all race-sex strata. Low occupational status and homemaker status were associated with faster decline in white women but slower decline in black women compared to high occupational status. Retirement before age 70 was associated with slower cognitive decline in white men and women and in black men. Results did not change substantially after accounting for attrition. Conclusion: Low occupational status was associated with cognitive decline in women but not in men. Earlier retirement was associated with a slower cognitive decline in white participants and in black men. Further research should explore reasons for the observed associations and race-sex differences.

Abstract TP35: A 2-Stage Recruitment Design to Reduce MRI Screening Costs for a Theoretical Clinical Trial of WMH Progression

Background: White matter hyperintensities (WMH) are associated with risk of dementia and stroke, so are an important therapeutic target for clinical trials. The cost of broad MRI screening to identify those individuals with significant WMH, however, limits the feasibility of designing clinical trials which target WMH presence and which test treatments that slow progression. Hypothesis: A low-cost retinal or clinical screening measure prior to an MRI screening stage reduces the cost of recruiting persons with significant WMH burden in a hypothetical clinical trial vs an MRI-only screening design. Method: Data were from participants in the Atherosclerosis Risk in Communities-Neurocognitive study with clinical, retinal and WMH measurements ( N = 1311) at ages 53-70 years. Significant WMH burden was defined as a Cardiovascular Health Study score >2. Three low-cost pre-screening measures were assessed: (1) retinal: a score incorporating multiple markers of abnormal retinal vasculature, (2) clinical: a score incorporating hypertension, diabetes, and age, (3) combined retinal-clinical: a score incorporating retinal and clinical factors. Given a prior published target sample for a WMH clinical trial (N= 646), we calculated a theoretical screening sample size based on the proportion of each pre-screening measure in the population multiplied by the proportion of significant WMH burden among those with a prevalent pre-screening feature. Total recruitment cost was calculated using standard retinal ($32.50) and MRI ($650) cost estimates. Results: Compared to the estimated cost of MRI-only screening (>$4.24M, requiring MRI screening 6,526 participants), pre-screening for a high clinical score reduced total cost to $2.47M, but increased the initial screening group to 52,778 participants, of whom 3,801 would be screened by MRI). A high retinal-clinical score cutoff reduced costs to $2.9M while only requiring 13,572 screened participants (of these only 3,801 would require MRI). Conclusion: A 2-stage recruitment design with a low-cost pre-screening retinal and clinical measure is a promising approach, resulting in a reduction of theoretical recruitment costs for recruiting persons with significant WMH burden compared to an MRI-only design.

Association of birth weight with incident dementia: The Atherosclerosis Risk in Communities (ARIC) Neurocognitive Study

AbstractBackgroundEarly life factors, such as birth weight (BW), may have long‐term health consequences, but the importance of these factors in dementia risk is poorly understood. Our objective was to prospectively examine the association of BW with dementia incidence over mid‐ to late‐adulthood in the ARIC study. We hypothesized that participants who report lower BW experience more incident dementia than participants who report normal BW, and this association may differ by race.Method10,789 participants who were dementia‐free at ARIC baseline (Visit 1: 1987‐1989; ages 45‐64) and followed through 2019 were included. Participants were asked their BW through standard interviews at Visit 4 (1996‐1998), but if unable to recall, they selected their BW category: low (<5.5 lbs.), medium (normal) (5.5‐9.0 lbs.), or high (>9.0 lbs.), and to identify if they were premature (yes/no). Adjudicated dementia cases from baseline through 2019 were classified using in‐person cognitive evaluations, informant interviews, and phone assessments as well as hospitalization codes and death certificate codes. The associations between having high or low (vs medium) BW and dementia, or premature birth status and dementia were investigated using Cox proportional hazards models, with testing for interaction by race.ResultOur overall population was 54 yo at baseline, 56% female, and 20% Black; 2,255 dementia cases were identified over a median of 28.2 years. Participants who reported a low BW had 1.2 times (95% CI 1.02, 1.41) increased risk of incident dementia compared to those with medium BW in demographic‐ and APOE‐adjusted models (Table 1). This association was no longer significant when the model additionally adjusted for vascular risk factors. The risk for dementia was not increased among participants who reported having been born premature (vs not premature). When stratified by race, the risk of incident dementia was elevated in Black participants reporting high (vs medium) BW, but not in White participants reporting high BW (p‐interaction = 0.006) (Table 2).ConclusionIn this cohort, low BW was associated with risk of dementia in minimally adjusted models. The association was attenuated after accounting for vascular risk factors. High BW was associated with risk of dementia in Black participants only.

Timing of Cognitive Test Score Decline Prior to Incident Dementia Diagnosis in Blacks and Whites: The Atherosclerosis Risk in Communities Neurocognitive Study

Introduction: Commonly occurring dementias include those of Alzheimer’s, vascular, and mixtures of these and other pathologies. They are believed to evolve over many years, but that time interval has been difficult to establish. Our objective was to determine how many years in advance of a dementia diagnosis cognitive scores begin to change. Methods: 14,086 dementia-free ARIC participants underwent a cognitive exam at baseline visit 2 (1990–1992, mean age 57 ± 5.72), and 11,244 at visit 4 (1996–1998), 5,640 at visit 5 (2011–2013), and 3,574 at visit 6 (2016–2017) with surveillance for dementias of all-causes combined. Within 5-year intervals after each visit, we compared performance on the Delayed Word Recall Test (DWRT), the Digit Symbol Substitution Test (DSST), the Word Fluency Test (WFT), and the combined mean of three cognitive tests at baseline in participants who were diagnosed with dementia within each interval versus those who survived the interval without a dementia diagnosis. Z-scores were adjusted for demographics and education in separate regression models for each visit. We plotted adjusted z-score means by time interval following each visit. Results: During follow-up 3,334, 2,821, 1,218, and 329 dementia cases were ascertained after visits 2, 4, 5, and 6, respectively. Adjusted DWRT z-scores were significantly lower 20–25 years before dementia than those who did not experience dementia within 25 years. DSST z-scores were significantly lower at 25–30 years and 3-test combination z-scores were significantly lower as early as 30–31 years before onset. The difference between dementia and non-dementia group in the visit 2 3-test combination z-score was −0.20 at 30–31 years prior to dementia diagnosis. As expected, differences between the dementia and non-dementia groups increased closer to the time of dementia occurrence, up to their widest point at 0–5 years prior to dementia diagnosis. The difference between dementia and non-dementia groups in the visit 2 3-test combination z-score at 0–5 years was −0.90. WFT z-score differences were smaller than for the DSST or DWRT and began later. Patterns were similar in Black and White participants. Conclusion: DWRT, DSST, and combined 3-test z-scores were significantly lower more than 20 years prior to diagnosis in the dementia group versus the non-dementia group. Findings contribute to our knowledge of the long prodromal period in Blacks and Whites.

Association of Olfaction and Microstructural Integrity of Brain Tissue in Community-Dwelling Adults: Atherosclerosis Risk in Communities Neurocognitive Study.

Research on olfaction and brain neuropathology may help understand brain regions associated with normal olfaction and dementia pathophysiology. To identify early regional brain structures affected in poor olfaction, we examined cross-sectional associations of microstructural integrity of the brain with olfaction in the Atherosclerosis Risk in Communities Neurocognitive Study. Participants were selected from a prospective cohort study of community-dwelling adults; selection criteria included: evidence of cognitive impairment, participation in a previous MRI study, and a random sample of cognitively normal participants. Microstructural integrity was measured by two diffusion tensor imaging (DTI) measures, fractional anisotropy (FA) and mean diffusivity (MD), and olfaction by a 12-item odor-identification test at the same visit. Higher FA and MD values indicate better and worse microstructural integrity, respectively, and higher odor-identification scores indicate better olfaction. We used brain region-specific linear regression models to examine associations between DTI measures and olfaction, adjusting for potential confounders. Among 1,418 participants (mean age: 76±5years, 41% male, 21% Black race, 59% with normal cognition), the mean olfaction score was 9±2.3. Relevant to olfaction, higher MD in the medial temporal lobe (MTL) regions, namely, the hippocampus (β: -0.79 (95%CI: -0.94, -0.65) units lower olfaction score per SD higher MD), amygdala, entorhinal area, and some white matter (WM) tracts connecting to these regions, was associated with olfaction. We also observed associations with MD and WM FA in multiple atlas regions that were not previously implicated in olfaction. The associations between MD and olfaction were particularly stronger in the MTL regions among individuals with mild cognitive impairment (MCI) compared to those with normal cognition (e.g., βhippocampus: -0.75 (95%CI: -1.02, -0.49) and -0.44 (95%CI: -0.63, -0.26) for MCI and normal cognition, respectively, p-interaction=0.004). Neuronal microstructural integrity in multiple brain regions, in particular the MTL (the regions known to be affected in early Alzheimer's), is associated with odor-identification ability. Differential associations in the MTL regions among cognitively normal individuals compared to those with MCI may reflect the earlier vs. later effects of the dementia pathogenesis. It is likely that some of the associated regions may not have any functional relevance to olfaction.

Association of remnant cholesterol with intracranial atherosclerosis in community-based population: The ARIC study

ObjectiveTo evaluate the association between remnant cholesterol (remnant-C) and intracranial atherosclerotic disease (ICAD) in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). MethodsWe studied 1,564 participants with data on lipid profiles and high-resolution vessel wall MRI (VWMRI) from the ARIC-NCS. Remnant-C was computed as total cholesterol minus high-density lipoprotein cholesterol minus low-density lipoprotein cholesterol (LDL-C). The primary outcomes were the presence of intracranial plaques and luminal stenosis. Contributors were separated into four different groups based on remnant-C (22 mg/dL) and LDL-C (100 mg/dL) levels to investigate the function of remnant-C vs. LDL-C on ICAD. Multivariable logistic regression models were utilized to estimate the correlation among the discordant/concordant remnant-C and LDL-C, and ICAD. ResultsA total of 1,564 participants were included (age 76.2 ± 5.3). After multivariable adjustment, log remnant-C was correlated with greater ICAD risk [odds ratio (OR) 1.36, 95% confidence interval (CI) 1.01 to 1.83]. The lower remnant-C/higher LDL-C group and the higher remnant-C/lower LDL-C group manifested a 1.53-fold (95% CI 1.06 to 2.20) and 1.52-fold (95% CI 1.08 to 2.14) greater risk of ICAD, relative to those having lower remnant-C/low LDL-C. Additionally, remnant-C ≥ 22 mg/dL distinguished participants at a greater risk of the presence of any stenosis compared to those at lower levels, even in participants with optimal levels of LDL-C. ConclusionsElevated levels of remnant-C were connected to ICAD independent of LDL-C and traditional risk factors. The mechanisms of remnant-C association with ICAD probably offer insight into preventive risk-factor of ischemic stroke.

Factors Associated with Poor Olfaction and Olfactory Decline in Older Adults in the ARIC Neurocognitive Study.

Olfactory function has significant implications for human health, but few risk factors for olfactory decline have been identified. We examined the factors associated with olfactory status and decline over five years in the Atherosclerosis Risk in Communities (ARIC) Neurocognitive Study. A 12-item odor identification test was used to assess olfaction in 6053 participants in 2011-2013 (ARIC visit 5, mean age: 75.6, 41% male, 23% Black race) and in 3235 participants in 2016-2017 (visit 6). We used Poisson regression models to examine cross-sectional associations of a range of potential factors with the total odor identification errors (mean errors: 2.8 ± 2.4) in visit 5 participants. We used mixed-effect Poisson regression to examine associations with olfactory decline between visits 5 and 6. We also examined associations with visit 5 anosmia prevalence (847 cases, 14%) and incident anosmia between the two visits (510 cases, 16%) using Poisson models. Older age, male sex, lower education, Black race, APOE ε4 alleles, and diabetes were associated with higher odor identification errors and higher anosmia prevalence, and greater physical activity and hypertension with better olfaction. Age, male sex, lower education, Black race, APOE ε4 allele, and vitamin B12 levels were associated with incident anosmia over 5 years. Older age was associated with faster olfactory decline. Future studies with longer follow-ups are warranted.

Association of abnormal p-wave parameters with brain MRI morphology: The atherosclerosis risk in communities neurocognitive study (ARIC-NCS).

Recent evidence indicates that abnormal P-wave parameters (PWPs)-ECG markers of atrial myopathy-are associated with incident dementia, independent of atrial fibrillation (AF) and clinical ischemic stroke. However, the mechanisms remain unclear and may include subclinical vascular brain injury. Hence, we evaluated the association of abnormal PWPs with brain MRI correlates of vascular brain injury in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). ARIC-NCS participants who underwent 3T brain MRI scans in 2011-2013 were included. PWPs were measured from standard 12-lead ECGs. Brain MRI outcomes included cortical infarcts, lacunar infarcts, cerebral microhemorrhages, brain volumes, and white matter disease (WMD) volume. We used weighted multivariable logistic and linear regression to evaluate the associations of abnormal PWPs with brain MRI outcomes. Among 1715 participants (mean age, 76.1 years; 61% women; 29% Black), 797 (46%) had ≥1 abnormal PWP. After multivariable adjustment, including adjusting for prevalent AF, abnormal P-wave terminal force in lead V1 (aPTFV1) and prolonged P-wave duration (PPWD) were associated with increased odds of both cortical (OR 1.41; 95% CI, 1.14 to 1.74 and OR 1.30; 95% CI, 1.04 to 1.63, respectively) and lacunar infarcts (OR 1.36; 95% CI, 1.15 to 1.63 and OR 1.37; 95% CI, 1.15 to 1.65, respectively). Advanced interatrial block (aIAB) was associated with higher odds of subcortical microhemorrhage (OR 2.04; 95% CI, 1.36 to 3.06). Other than a significant association between aPTFV1 with lower parietal lobe volume, there were no other significant associations with brain or WMD volume. In this exploratory analysis of a US community-based cohort, ECG surrogates of atrial myopathy are associated with a higher prevalence of brain infarcts and microhemorrhage, suggesting subclinical vascular brain injury as a possible mechanism underlying the association of atrial myopathy with dementia.

HEARING LOSS AND SUBJECTIVE COGNITIVE DECLINE IN THE ARIC-NEUROCOGNITIVE STUDY

Abstract Subjective cognitive decline (SCD) impacts quality-of-life, healthcare utilization and predicts dementia. If hearing loss is associated with SCD is unknown. We estimated the cross-sectional association between hearing loss and SCD in 2,536 participants (79.3±4.4 years, 60% female, 20% Black) in the Atherosclerosis Risk in Communities Neurocognitive Study. SCD was defined as self-reported persistent decline in memory (yes/no) among adults with normal cognition. Hearing was measured using pure tone better-ear thresholds (0.5-4 kHz), speech-in-noise, and self-report. Using Poisson models with robust standard errors, after adjustment for demographic and clinical covariates, self-reported moderate or greater trouble hearing (vs. excellent/good) was associated with a 30% increase in the prevalence of SCD (95%CI:1.12,1.51). Audiometric hearing and speech-in-noise performance were not associated. Use of self-report to approximate audiometric hearing warrants caution, particularly when the outcome is also self-reported; our findings suggest the association between self-reported hearing and SCD may be due to correlated measurement error.

Association of Spousal Separation and Widowhood with Incident Dementia: The Atherosclerosis Risk in Communities (ARIC) Neurocognitive Study (NCS)

AbstractBackgroundCommunity‐based investigations suggest that being unmarried in mid‐ to late‐life increases dementia risk. However, these studies rarely distinguish the cause of unmarried status (i.e., whether divorced, widowed, or never married). We prospectively examined spousal separation/loss and dementia incidence in the ARIC study.Method14,922 participants reported marital status and were dementia‐free at baseline (Visit 3, 1993‐95; mean age 59.6, SD 5.8). They were followed through 2019 with annual follow‐up surveys of marital status (never married [n = 390], married [n = 7,314], divorced/separated [n = 1,512], widowed [n = 5,706]). Widowed or divorced/separated participants were asked when this event occurred. Dementia cases were adjudicated through in‐person evaluations, informant interviews, and phone assessments from Visit 5 onward, and pre‐ and post‐Visit 5 hospitalization codes and death certificates. We investigated the association between being widowed and being divorced/separated (both as time‐varying variables) with dementia (excluding dementia in the first year after widowhood event) using Cox proportional hazards models, adjusted for demographics, APOEε4, and vascular risk factors.Results2,931 dementia cases were identified. Demographic‐ and APOEε4‐adjusted hazard ratio (HR) (95% CI) for dementia was 1.11 (1.02‐1.21) in participants who were widowed compared to those who were not widowed, when time‐varying widowhood status was considered. (Table 1). This association was no longer significant when the model was further adjusted for time‐variant covariates (e.g., vascular risk factors, occupation, health insurance status). A similar pattern was seen for number of times widowed, where results were suggestive of elevated dementia risk in minimally adjusted but not more fully adjusted models. Compared to participants who were neither widowed nor separated, participants who were widowed had a higher unadjusted HR (95% CI) for dementia, HR = 1.78 (1.65‐1.93) vs HR = 0.94 for those who were separated or divorced (0.81‐1.09) (Table 2).ConclusionWidowhood is associated with dementia incidence in minimally adjusted models, with limited evidence that the association is stronger than that which is seen from divorce/separation alone. However, this association was not statistically significant in the adjusted model, indicating that other factors may contribute to the observed relationship.

Abstract 100: Effects Of Upregulation Of Cyp4a In Dahl Salt-sensitive Rats And Ko Of Cyp4a2 And 4a3 In Ss.5 Bn Rats On The Development Of Hypertension And Renal Injury

Mutations in CYP4F2 (rs2108622) and CYP4A11 (rs1126742) that inhibit the production of 20-HETE have been linked to hypertension in human genetic studies. We confirmed that these same variants are associated with hypertension and cognitive dysfunction in 4,286 elderly subjects in the Atherosclerosis Risk in Communities Neurocognitive Study . These studies establish that mutations in CYP enzymes that reduce 20-HETE promote hypertension, but the mechanisms remain controversial since 20-HETE has both pro- and antihypertensive actions. To address this question, we identified a homologous genetic deficiency in the formation of 20-HETE in Dahl S (SS) rats and created SS.5 BN consomic and CYP4A transgenic SS rats to restore CYP4A expression and 20-HETE production, and CYP4A2 and CYP4A3 KO rats on the rescued SS.5 BN background. Mean arterial pressure (MAP), renal and cerebral blood flow, proteinuria, and renal injury were compared in SS versus SS.5 BN and CYP4A transgenic SS rats and in SS.5 BN versus CYP4A2 and CYP4A3 KO rats. MAP increased from 117±2 to 158±5 mmHg (n=34) in SS rats fed a high salt (HS) diet for 3 weeks. Proteinuria rose from 50±4 to 403±30 mg/day. MAP increased less, from 108 + 5 to 133 + 5 mmHg (n=7) in CYP4A1 transgenic SS rats and from 109 + 2 to 132 + 2 mmHg (n=23) in SS.5 BN rats. Proteinuria (141±15 and 169±11 mg/day), glomerular injury, and renal fibrosis were all significantly reduced in the CYP4A transgenic and SS.5 BN rats compared to SS rats. KO of CYP4A2 had no effect on MAP (134 + 2 mmHg, n=23) or proteinuria (248 + 23 mg/day) relative to SS.5 BN rats fed an HS diet for 3 weeks. In contrast, MAP and proteinuria were elevated to 148 + 3 mmHg and 350 + 23 mg/day in CYP4A3 KO rats (n=23). The myogenic response of renal and cerebral arteries and autoregulation of RBF and CBF were impaired in SS and CYP4A3 KO rats but were intact in CYP4A transgenic SS rats, SS.5 BN and CYP4A2 KO rats. These findings indicate that a deficiency in the formation of 20-HETE that impairs the myogenic response of renal and cerebral arteries, autoregulation of RBF and CBF, and increases glomerular capillary pressure, promotes the development of hypertension, proteinuria, and renal injury in genetically susceptible individuals and SS rats.

The Neuroanatomic Correlates of Olfactory Identification Impairment in Healthy Older Adults and in Persons with Mild Cognitive Impairment.

Olfactory identification (OI) impairment appears early in the course of Alzheimer's disease dementia (AD), prior to detectable cognitive impairment. However, the neuroanatomical correlates of impaired OI in cognitively normal older adults (CN) and persons with mild cognitive impairment (MCI) are not fully understood. We examined the neuroanatomic correlates of OI impairment in older adults from the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). Our sample included 1,600 older adults without dementia who completed clinical assessment and structural brain imaging from 2011 to 2013. We characterized OI impairment using the 12-item Sniffin' Sticks odor identification test (score ≤6). We used voxel-based morphometry (VBM) and region of interest (ROI) analyses to examine the neuroanatomic correlates of impaired OI in CN and MCI, after adjusting for potential confounders. Analyses were also separately stratified by race and sex. In CN, OI impairment was associated with smaller amygdala gray matter (GM) volume (p < 0.05). In MCI, OI impairment was associated with smaller GM volumes of the olfactory cortex, amygdala, entorhinal cortex, hippocampus, and insula (ps < 0.05). Differential associations were observed by sex in MCI; OI impairment was associated with lower insular GM volumes among men but not among women (p-interaction = 0.04). There were no meaningful interactions by race. The brain regions associated with OI impairment in individuals without dementia are specifically those regions known to be the primary targets of AD pathogenic processes. These findings highlight the potential utility of olfactory assessment in the identification and stratification of older adults at risk for AD.

Left Atrial Remodeling and Stroke in Patients With Sinus Rhythm and Normal Ejection Fraction: ARIC-NCS.

BackgroundAge‐related left atrial (LA) structural and functional abnormalities may be related to subclinical cerebral infarcts (SCIs) and stroke. We evaluated the association of 3‐dimensional echocardiographic LA contractility parameters with SCIs and stroke across the spectrum of tertiles of age increment in elderly patients with sinus rhythm, normal ejection fraction, and no history of atrial fibrillation.Methods and ResultsWe enrolled 407 participants (mean age, 76±8 years; 40% men) from ARIC‐NCS (Atherosclerosis Risk in Communities Neurocognitive Study) undergoing a brain magnetic resonance imaging and 3‐dimensional echocardiographic examinations in 2011 to 2013. The sample was analyzed among age tertiles and subgroups: no cerebral magnetic resonance imaging–detectable infarcts (n=315), magnetic resonance imaging–diagnosed SCIs (n=58), and clinically diagnosed stroke (n=34). The frequency of SCIs significantly increased over age tertiles (P trend 0.023). LA global longitudinal strain—a 3‐dimensional echocardiographic index of LA reservoir function—and E/e’ divided by LA global longitudinal strain—an index of LA stiffness—worsened across age tertiles (P trend 0.014 and 0.001, respectively), and only in the categories of SCIs (P trend <0.001 and 0.045, respectively) and stroke (P trend 0.001 and 0.011, respectively). LA global longitudinal strain was negatively associated with increased odds of SCIs (P=0.036, P=0.008, and P=0.001, respectively) and strokes (P=0.043, P=0.015, and P=0.001, respectively) over age tertiles, with a significant interaction between age tertiles (interaction P=0.043 and P=0.010, respectively). E/e’ divided by LA global longitudinal strain was positively associated with the presence of SCIs (P=0.037, P=0.007, and P=0.001, respectively) and strokes (P=0.045, P=0.007, and P=0.003, respectively) over age tertiles, with a significant interaction only for SCIs (interaction P=0.040) and not for clinical stroke.ConclusionsIn a large cohort study of elderly patients, among participants with sinus rhythm, normal ejection fraction, and no history of atrial fibrillation, measures of worse age‐related LA reservoir function and stiffness are associated with higher odds of SCIs and stroke.

Associations of Peripheral Neuropathy Defined by Monofilament Insensitivity with Mild Cognitive Impairment and Dementia in Older Adults

Introduction: The aim of this study was to assess the association of peripheral neuropathy (PN) as defined by monofilament insensitivity with mild cognitive impairment (MCI) and dementia in older adults with and without diabetes. Methods: We conducted a cross-sectional analysis of 3,362 Black and White participants in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS) who underwent monofilament testing at visit 6 (2016–2017, age 71–94 years). Participants’ cognitive status was classified by an adjudication committee as cognitively normal, MCI, or dementia after completing a comprehensive battery of neurocognitive assessments. We used logistic regression to evaluate the association of PN with MCI or dementia overall and stratified by diabetes status after adjusting for traditional dementia risk factors. We also compared age-adjusted brain MRI measures among a subset (N = 1,095) of participants with versus without PN. Results: Overall, the prevalence of MCI (21.9% vs. 16.7%) and dementia (7.8% vs. 3.9%) were higher among participants with versus without PN (both p < 0.05). After adjustment, PN was positively associated with MCI or dementia in the overall study population (OR 1.45, 95% CI 1.23, 1.73). Results were similar by diabetes status (diabetes: OR 1.38, 95% CI 1.03–1.87; no diabetes: OR 1.48, 95% CI 1.20–1.83; p-for-interaction = 0.46). Age-adjusted total and lobar brain volumes were significantly lower in participants with versus without PN (both, p < 0.05). Discussion/Conclusions: PN as defined by monofilament insensitivity was associated with cognitive status independent of vascular risk factors and regardless of diabetes status. Our findings support a connection between PN and cognitive impairment, even in the absence of diabetes.

The effect of missing data and imputation on the detection of bias in cognitive testing using differential item functioning methods

BackgroundItem response theory (IRT) methods for addressing differential item functioning (DIF) can detect group differences in responses to individual items (e.g., bias). IRT and DIF-detection methods have been used increasingly often to identify bias in cognitive test performance by characteristics (DIF grouping variables) such as hearing impairment, race, and educational attainment. Previous analyses have not considered the effect of missing data on inferences, although levels of missing cognitive data can be substantial in epidemiologic studies.MethodsWe used data from Visit 6 (2016–2017) of the Atherosclerosis Risk in Communities Neurocognitive Study (N = 3,580) to explicate the effect of artificially imposed missing data patterns and imputation on DIF detection.ResultsWhen missing data was imposed among individuals in a specific DIF group but was unrelated to cognitive test performance, there was no systematic error. However, when missing data was related to cognitive test performance and DIF group membership, there was systematic error in DIF detection. Given this missing data pattern, the median DIF detection error associated with 10%, 30%, and 50% missingness was -0.03, -0.08, and -0.14 standard deviation (SD) units without imputation, but this decreased to -0.02, -0.04, and -0.08 SD units with multiple imputation.ConclusionsIncorrect inferences in DIF testing have downstream consequences for the use of cognitive tests in research. It is therefore crucial to consider the effect and reasons behind missing data when evaluating bias in cognitive testing.

Associations of Serum Magnesium with Brain Morphology and Subclinical Cerebrovascular Disease: The Atherosclerosis Risk in Communities-Neurocognitive Study.

Circulating magnesium has been associated with a lower risk of dementia, but the physiologic effects by which magnesium may prevent neurological insults remain unclear. We studied 1466 individuals (mean age 76.2 ± 5.3, 28.8% black, 60.1% female) free of prevalent stroke, with measured serum magnesium and with available MRI scans obtained in 2011–2013, participating in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). Cross-sectional differences in frontal, temporal, parietal, and occipital lobe volume, along with deep grey matter, total brain, and white matter hyperintensity volume across serum magnesium (categorized into quintiles and per standard deviation increases) were assessed using multiple linear regression. We also examined associations of magnesium with the prevalence of cortical, subcortical, and lacunar infarcts using multiple logistic regression. After adjusting for demographics, biomarkers, medications, and cardiometabolic risk factors, higher circulating magnesium was associated with greater total brain volume and frontal, temporal, and parietal lobe volumes (volumes 0.14 to 0.19 standard deviations higher comparing Q5 to Q1). Elevated magnesium was also associated with lower odds of subcortical infarcts (OR (95%CI): 0.44 (0.25, 0.77) comparing Q5 to Q1) and lacunar infarcts (OR (95%CI): 0.40 (0.22, 0.71) comparing Q5 to Q1). Elevated serum magnesium was cross-sectionally associated with greater brain volumes and lower odds of subclinical cerebrovascular disease, suggesting beneficial effects on pathways related to neurodegeneration and cerebrovascular damage. Further exploration through prospective analyses is needed to assess increasing circulating magnesium as a potential neuroprotective intervention.

The effect of missing cognitive data on the detection of bias due to hearing impairment in cognitive testing

AbstractBackgroundMethods for the detection of bias in cognitive testing disentangle underlying cognitive ability from cognitive test performance. These methods have been previously used to understand how language of administration, sex, education, or sensory impairment status might bias cognitive test scores. Although missing data is common in cognitive testing, prior research on bias in cognitive testing has not addressed or accounted for missing data. This work aims to describe and understand how missing data effects the detection of bias in cognitive testing.MethodWe utilized real‐world data from Visit 6 (2017‐2019) of the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC‐NCS) (N = 3580), which included a thorough neuropsychological battery. We used item response theory methods to test for item‐level biases (differential item functioning) by hearing impairment (PTA&gt;25 db in 4 speech frequencies). We examined the effect of imposing 10%, 30%, or 50% missingness in cognitive test items that was either (1) random or (2) related to cognitive performance, among those with hearing impairment.ResultIn the ARIC‐NCS sample (mean age: 79.9, 60% female), 73% had hearing impairment. When we imposed missingness that was unrelated to cognitive status, we saw no systematic error in the detection of item‐level biases. However, imposing missingness that was related to cognitive status did result in systematic error in item‐level bias detection. The magnitude of this error was larger with greater amounts of missing data, such that the median error across all cognitive items in the detection of item‐level bias considered for the scenarios with 10%, 30%, and 50% missing data was 0.03, 0.07 and 0.13 logits respectively, resulting in flipped inferences for 21%, 32% and 44% of tests.ConclusionMissing data related to cognitive status may lead to error and incorrect conclusions regarding bias in cognitive testing. This has the potential to result in incorrect decisions regarding the construction and analysis of cognitive testing data in epidemiologic studies of cognition and cognitive decline. When evaluating for item‐level biases in cognitive testing, careful consideration regarding the amount and patterns of missingness present in cognitive test data is necessary.

Associations of central auditory processing with brain volumes in the aging and cognitive health evaluation in elders and the atherosclerosis risk in communities neurocognitive study

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.