Atherosclerosis Risk In Communities Neurocognitive Study Research Articles

Associations of Prior Head Injury With Mild Behavioral Impairment Domains.

This study investigated associations of prior head injury and number of prior head injuries with mild behavioral impairment (MBI) domains. The Atherosclerosis Risk in Communities (ARIC) Study. A total of 2534 community-dwelling older adults who took part in the ARIC Neurocognitive Study stage 2 examination were included. This was a prospective cohort study. Head injury was defined using self-reported and International Classification of Diseases, Ninth Revision ( ICD -9) code data. MBI domains were defined using the Neuropsychiatric Inventory Questionnaire (NPI-Q) via an established algorithm mapping noncognitive neuropsychiatric symptoms to the 6 domains of decreased motivation, affective dysregulation, impulse dyscontrol, social inappropriateness, and abnormal perception/thought content. The primary outcome was the presence of impairment in MBI domains. Participants were a mean age of 76 years, with a median time from first head injury to NPI-Q administration of 32 years. The age-adjusted prevalence of symptoms in any 1+ MBI domains was significantly higher among individuals with versus without prior head injury (31.3% vs 26.0%, P = .027). In adjusted models, a history of 2+ head injuries, but not 1 prior head injury, was associated with increased odds of impairment in affective dysregulation and impulse dyscontrol domains, compared with no history of head injury (odds ratio [OR] = 1.83, 95% CI = 1.13-2.98, and OR = 1.74, 95% CI = 1.08-2.78, respectively). Prior head injury was not associated with symptoms in MBI domains of decreased motivation, social inappropriateness, and abnormal perception/thought content (all P > .05). Prior head injury in older adults was associated with greater MBI domain symptoms, specifically affective dysregulation and impulse dyscontrol. Our results suggest that the construct of MBI can be used to systematically examine the noncognitive neuropsychiatric sequelae of head injury; further studies are needed to examine whether the systematic identification and rapid treatment of neuropsychiatric symptoms after head injury is associated with improved outcomes.

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.

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 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.

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.

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.

Accuracy of self- and proxy-rated hearing among older adults with and without cognitive impairment.

Hearing loss is highly prevalent among older adults with cognitive impairment and may exacerbate neuropsychiatric symptoms and affect interactions with others. Although audiometry is the gold standard for measuring hearing, it is not always used in research or clinical settings focused on the care of individuals with cognitive impairment. Subjective assessments of hearing, both self- and proxy-rated, are widespread but may not adequately capture the presence of hearing loss as compared to audiometry. This study investigates the concordance between subjective and objective hearing assessments among older adults with and without cognitive impairment and evaluates factors associated with concordance. Participants were a subset of the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS), a prospective cohort study representing four US communities with adjudicated cognitive diagnoses and audiometric data, totaling 3326 self-rated and 520 proxy-rated hearing assessments. Sensitivity and specificity were calculated, and multivariable logistic regression estimated the magnitude of the association between the concordance of hearing assessments and variables of interest. Sensitivity and specificity for self-rated hearing status were 71.2% and 85.9% among cognitively normal older adults, 61.1% and 84.9% among persons with MCI, and 52.6% and 81.2% among persons with dementia, respectively. For proxy-rated hearing, sensitivity and specificity were 65.7% and 83.3% for persons with MCI and 73.3% and 60.3% for persons with dementia, respectively. Female sex was positively associated with concordance for self-rated hearing assessments. The low sensitivity of self- and proxy-rated hearing assessments compared to audiometry suggests that hearing loss among older adults with cognitive impairment may go underreported and unaddressed in subjective assessments. Clinicians and researchers should recognize the limitations of using self- and proxy-rated hearing assessments as measures of hearing status and incorporate objective audiometric evaluation whenever possible.

Abstract P283: CCL5 Acts As A Vasoconstrictor On Penetrating Arterioles In The Cerebral Circulation By Enhancing 20-HETE Activity

20-HETE is synthesized from arachidonic acid by cytochrome P450 (CYP) enzymes 4A and 4F. Inactivating mutations in the CYP enzymes that produce 20-HETE are associated with hypertension and stroke in man. We previously revealed that inactivating variants of CYP4A/F enzymes are associated with dementia in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NS) population. 20-HETE is involved with sodium regulation in the kidney and is a powerful vasoconstrictor. It was recently discovered that CCL5 and 20-HETE share the same receptor, GPR75. We previously found that 20-HETE constricts and augments the myogenic response (MR) of the middle cerebral artery (MCA) and renal afferent arteriole. However, whether CCL5 has any effect on penetrating arterioles (PAs) and interacts with 20-HETE is unknown. We found that GPR75 is expressed in PAs and pericytes in the brain. CYP4A is also expressed in pericytes and is inversely proportional to levels of GPR75 in the brain. In the present study, we found that 20-HETE contributes to the basal myogenic tone of PAs in SD rats. Administration of HET0016, a 20-HETE synthesis inhibitor, dilated the PA by 34 ± 3% (n = 6) under 10 mmHg perfusion pressure. Administration of WIT003, a 20-HETE agonist, constricted the vessel by 23 ± 4% (n = 6) under the same perfusion pressure. We found that CCL5 also reduced PA diameter by 20 ± 4% (n = 7) in SD rats under 10 mmHg perfusion pressure. Moreover, we compared the response to CCL5 in SS rats that are 20-HETE deficient and SS.CYP4A1 transgenic rats in which 20-HETE production is restored. PAs isolated from SS rats treated with 0.1 nM CCL5 constricted by 9 ± 5% (n = 6) while those treated with 10 nM constricted by 12 ± 3% (n = 6). CCL5 had a greater response in PAs from the SS.CYP4A1 strain, and the diameter of the PAs constricted by 14 ± 2% (n = 5) and 24 ± 5% (n = 5) in response to 0.1 and 10 nM CCL5, respectively. These results demonstrate that CCL5 has a direct effect on PAs similar to 20-HETE that acts via the GPR75 receptor. However, further study is needed to determine how CCL5 and 20-HETE interact to promote vasoconstriction. These studies would help further understand the involvement of 20-HETE in disease and potentially identify novel drug targets.

Abstract 35: Gamma Adducin Dysfunction Leads To Cerebrovascular Distention, Blood Brain Barrier Leakage, And Cognitive Deficits In The Fawn-hooded Hypertensive Rats

We have previously identified an inactivating mutation of ADD3 in FHH rats which is associated with impaired myogenic reactivity of renal arterioles and podocyte function, and contributes to the development of CKD. We have found that SNPs in human ADD1 or ADD3 in the same region as Add3 in FHH rats are linked to reductions in brain volumes and impaired performance on cognitive tests in 4,286 elderly patients (67-90 years old) in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS), but the mechanisms of these pathologies are unclear. The present study examined cerebral hemodynamics and cognitive function in FHH versus FHH.1BN and FHH. Add3 rats that express the WT Add3 gene. The myogenic responses of the middle cerebral artery (MCA) and parenchymal arterioles (PA) were impaired in FHH rats. MCA diameter decreased by 15-20% in FHH.1BN (n = 27) and FHH. Add3 (n = 10) transgenic rats, but increased by 9 ± 3% in FHH rats (n = 15) when perfusion pressure was increased from 40 to 160 mmHg. PA diameter increased by 3.16 ± 2.79% in FHH (n = 5) rats versus a 19 ± 3% and 13 ± 2% decrease FHH. Add3 (n = 4) and FHH.1BN (n = 6), respectively, when pressure was increased from 10 to 40 mmHg. Autoregulation of surface and deep cortical blood flow was impaired in FHH rats and rose by 48 ± 3% (n = 22) and 41 ± 3% (n = 12), respectively, versus 32 ± 3% (n = 7) and 16 ± 5% (n = 6) in FHH. Add3 rats when MAP was increased from 100 to 160 mmHg. By using a fluorescent microscope to examine 60 μm brain sections, it was revealed that the outer diameters of PAs were distended in FHH in comparison to FHH.1BN and FHH. Add3 transgenic rats when systemic pressure was increased to 160 mmHg. Blood brain barrier leakage was also greater in FHH rats than in FHH.1BN and FHH. Add3 rats after acute elevations in pressure. FHH (n=16) rats took 40- 50% longer to navigate an eight-arm water maze than FHH. Add3 (n=11) and FHH.1BN (n=7) rats. These results indicate that variants that alter Add3 function promote cognitive dysfunction in FHH rats by altering cerebral hemodynamics and may play a similar role in cognitive deficits in elderly patients in the ARIC-NCS study. This study suggests that blood pressure should be strictly controlled in hypertensive patients identified with ADD3 variants to prevent dementia.

Assessing Bias in Cognitive Testing for Older Adults with Sensory Impairment: An Analysis of Differential Item Functioning in the Baltimore Longitudinal Study on Aging (BLSA) and the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS).

Vision and hearing impairments affect 55% of people aged 60+ years and are associated with lower cognitive test performance; however, tests rely on vision, hearing, or both. We hypothesized that scores on tests that depend on vision or hearing are different among those with vision or hearing impairments, respectively, controlling for underlying cognition. Leveraging cross-sectional data from the Baltimore Longitudinal Study of Aging (BLSA) and the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS), we used item response theory to test for differential item functioning (DIF) by vision impairment (better eye presenting visual acuity worse than 20/40) and hearing impairment (better ear .5-4kHz pure-tone average > 25 decibels). We identified DIF by vision impairment for tests whose administrations do not rely on vision [e.g., Delayed Word Recall both in ARIC-NCS: .50 logit difference between impaired and unimpaired (p=.04) and in BLSA: .62 logits (p=.02)] and DIF by hearing impairment for tests whose administrations do not rely on hearing [Digit Symbol Substitution test in BLSA: 1.25 logits (p=.001) and Incidental Learning test in ARIC-NCS: .35 logits (p=.001)]. However, no individuals had differences between unadjusted and DIF-adjusted measures of greater than the standard error of measurement. DIF by sensory impairment in cognitive tests was independent of administration characteristics, which could indicate that elevated cognitive load among persons with sensory impairment plays a larger role in test performance than previously acknowledged. While these results were unexpected, neither of these samples are nationally representative and each has unique selection factors; thus, replication is critical.

Hearing Loss and Frailty Among Older Adults: The ARIC Neurocognitive Study

Hearing Loss (HL) is common among older adults and is associated with factors (e.g., walking speed and social isolation) that may mediate an association with frailty. In the Atherosclerosis Risk in Communities (ARIC) study, frailty was defined as a composite variable (unintentional weight loss, energy expenditure, walking speed, low energy, and grip strength) while HL was measured using pure-tone audiometry. Among, 3179 participants in 2015-2017, 251 (7.9%) were frail. In a model adjusted for demographic and clinical risk factors, mild HL (n=1263; Odds Ratio[OR]=1.42; 95%Confidence Interval[CI]=1.01-2.01) and moderate HL (n=854; OR=1.67; 95%CI=1.09-2.55) were associated with higher odds of frailty relative to those without HL (n=1063). Among participants who completed an ARIC visit 2-years later, the odds of developing frailty tended to be higher among those with mild (OR=1.46; 95%CI=0.91-2.33) and moderate HL (OR=1.43; 95%CI=0.77-2.67). Future research should focus on mechanisms underlying association and determine the impact of treatment of HL. Part of a symposium sponsored by Sensory Health Interest Group.

Hearing loss and hearing care disparities among older adults with cognitive impairment

AbstractBackgroundAlthough both age‐related and highly prevalent, little is known regarding the prevalence of hearing loss among persons with dementia (PwD). Current understanding is based on convenience samples primarily from specialized memory clinics. The Atherosclerosis Risk in Communities Neurocognitive Study (ARIC‐NCS) is a large, prospective study of a population‐based cohort from 4 U.S. community sites with audiometric and neurocognitive testing and bi‐racial representation. We examined the prevalence of hearing loss and hearing aid use among older adults with cognitive impairment and whether cognitive status influences hearing aid use.MethodWe analyzed audiometric and hearing care data from ARIC‐NCS Visit 6 (2016‐2018). Participants underwent a full neurocognitive battery and audiometric evaluation at Visit 6. Participants with complete audiometric data and an adjudicated diagnosis of cognitively normal, mild cognitive impairment (MCI), or dementia were included in the analytical cohort (N=3,385). Differences in participant characteristics by cognitive status were descriptively compared using Chi‐square tests or one‐way ANOVAs. We performed a series of logistic regression models to estimate the odds of hearing aid non‐use by cognitive status.ResultPrevalence of hearing loss was greater with increasing cognitive impairment (cognitively normal:64.7%; MCI:71.3%; dementia:83.3%). Prevalence of hearing aid use among those with hearing loss and cognitive impairment varied by race (African Americans 7.2%; whites 32.8%). In a multivariable‐adjusted model, cognitive impairment was independently associated with higher odds of non‐use of hearing aids (MCI odds ratio (OR):1.4 (95%CI:1.0‐1.8); dementia OR:1.8 (95%CI:1.2‐2.9) versus cognitively normal). The strongest risk factor for non‐use of hearing aids was race, where African Americans have almost a 5 times higher odds of not using hearing aids compared to whites (95% CI:2.9‐7.4).ConclusionHearing loss is highly prevalent but vastly untreated among older adults with cognitive impairment, particularly African Americans, and cognitive impairment is independently associated with hearing aid use. These estimates are some of the first population‐based estimates of audiometric hearing loss among diverse older adults with adjudicated diagnoses of MCI or dementia. With increased calls to address ethnic/racial disparities, we must include hearing loss, as one of the most common co‐morbidities, in order to optimize health and well‐being among all PwD.

Abstract 13193: Association of Abnormal P-wave Indices With Brain MRI Infarcts: The Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS)

Introduction: We recently reported that abnormal P-wave indices (PWI)—ECG markers of atrial cardiomyopathy (AC)—are associated with an increased risk of dementia, independent of atrial fibrillation (AF) and clinical ischemic stroke. The mechanisms, however, remain unclear, but may include silent ischemia. Hypothesis: Abnormal PWI are associated with higher prevalence of cortical infarcts on MRI, suggesting cardioembolism as a potential mechanism. Methods: ARIC-NCS participants (mean age, 72.2±5.3 years; 60% women; 29% black) who underwent 3T brain MRI scans in 2011-2013 were included. Abnormal PWI included P-wave terminal force in lead V1 [(PTFV1) defined as ≥4000 μV*ms] and P-wave duration [(PWD) defined as &gt;120 ms], which were measured from standard 12-lead ECGs. Brain MRI outcomes included cortical infarcts, cerebral microbleeds (CMB), and markers of small vessel disease [white matter hyperintensities (WMH) and lacunar infarcts]. We used weighted multivariable logistic and linear regression analyses. Results: Of the 1,850 participants, 464 had abnormal PTFV1 and 415 had prolonged PWD. After multivariable adjustment including AF, abnormal PTFV1 and PWD were significantly associated with 26-44% increased odds of cortical and lacunar infarcts (Table) . Although PWD was associated with CMB in Model 1, the association was no longer significant after multivariable adjustment. Finally, abnormal PWIs were not associated with WMH after adjusting for stroke and AF (P &gt;0.5). Conclusions: Abnormal PWI are associated with higher prevalence of cortical infarcts, suggesting cardioembolism with silent ischemia as a possible mechanism underlying the association of AC with dementia. More research is needed to evaluate other mechanisms such as cerebral small vessel disease.

Association between kidney disease measures and intracranial atherosclerosis: The ARIC study.

To test the association between reduced kidney function (assessed by estimated glomerular filtration rate [eGFR] and cystatin C [CysC]) and kidney damage (assessed by urinary albumin-to-creatinine ratio [ACR]) and intracranial atherosclerotic disease (ICAD) by high-resolution vessel wall MRI (VWMRI) in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). We conducted a cross-sectional analysis of ARIC participants with data on kidney measures and VWMRI in 2011 to 2013. The main outcomes were presence of intracranial plaques and luminal stenosis. Multivariable models were adjusted for demographics, cardiovascular risk factors, and use of antithrombotic medications. A total of 1,762 participants (mean ± SD age, 76.3 ± 5.3) were included. eGFR based on CysC (eGFRcysc) <60 mL/min/1.73 m2 (vs ≥60 mL/min/1.73 m2) was associated with plaque presence (adjusted odds ratio [OR] 1.29, 95% confidence interval [CI] 1.04-1.60), any detectable stenosis (adjusted OR 1.31, 95% CI 1.04-1.63), and >70% stenosis or occlusion (adjusted OR 2.15, 95% CI 1.32-3.50). Neither ACR nor CysC showed statistically significant associations with ICAD features in adjusted models. In adjusted multinomial models, participants with eGFRcysc <60 mL/min/1.73 m2 (vs ≥60 mL/min/1.73 m2) had an increased OR of 1.41 (95% CI 1.06-1.87) for having 1 plaque (vs none) but no significant increase for multiple plaques; ACR ≥30 was associated with moderate (50%-70%) stenosis (OR 2.01, 95% CI 1.14-3.55) vs absent or less than 50% stenosis. In community-dwelling older adults, reduced kidney function or elevated kidney damage was associated with ICAD measured by VWMRI. This finding may help to better identify a population at high risk for ICAD.

Aortic Stiffness and White Matter Microstructural Integrity Assessed by Diffusion Tensor Imaging: The ARIC-NCS.

BackgroundChanges in white matter microstructural integrity are detectable before appearance of white matter lesions on magnetic resonance imaging as a manifestation of cerebral small‐vessel disease. The information relating poor white matter microstructural integrity to aortic stiffness, a hallmark of aging, is limited. We aimed to examine the association between aortic stiffness and white matter microstructural integrity among older adults.Methods and ResultsWe conducted a cross‐sectional study to examine the association between aortic stiffness and white matter microstructural integrity among 1484 men and women (mean age, 76 years) at the 2011 to 2013 examination of the ARIC‐NCS (Atherosclerosis Risk in Communities Neurocognitive Study). Aortic stiffness was measured as carotid‐femoral pulse wave velocity. Cerebral white matter microstructural integrity was measured as fractional anisotropy and mean diffusivity using diffusion tensor imaging. Multivariable linear regression was used to examine the associations of carotid‐femoral pulse wave velocity with fractional anisotropy and mean diffusivity of the overall cerebrum and at regions of interest. Each 1‐m/s higher carotid‐femoral pulse wave velocity was associated with lower overall fractional anisotropy (β=−0.03; 95% CI, −0.05 to −0.02) and higher overall mean diffusivity (β=0.03; 95% CI, 0.02–0.04). High carotid‐femoral pulse wave velocity (upper 25th percentile) was associated with lower fractional anisotropy (β=−0.40; 95% CI, −0.61 to −0.20) and higher overall mean diffusivity (β=0.27; 95% CI, 0.10–0.43). Similar associations were observed at individual regions of interest.ConclusionsHigh aortic stiffness is associated with low cerebral white matter microstructural integrity among older adults. Aortic stiffness may serve as a target for the prevention of poor cerebral white matter microstructural integrity.