Palta, Priya

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: Among older adults with diabetes, cognitive dysfunction is of particular concern as it has implications for treatment adherence and diabetes self-management. The prevalence of cognitive dysfunction has not been well characterized in this population. Methods: We conducted a cross-sectional analysis of 5509 participants (1815 with diabetes) from visit 5 (2011-2013) of the ARIC Study. Diabetes was defined based on self-reported physician diagnosis, diabetes medication use, or HbA1c ≥ 6.5%. Cognitive function was measured using 8 neuropsychological tests, which were grouped into three cognitive domains representing memory, executive function, and language. Participants were categorized as having cognitive dysfunction if test scores were more than 1.5 standard deviations below age-, race-, and education-adjusted scores derived from a cognitively healthy population. We calculated crude prevalence estimates and used Poisson regression to estimate adjusted prevalence ratios (PRs), comparing cognitive dysfunction in persons with and without diabetes. We adjusted for demographic and clinical characteristics. Results: The mean age of participants was 75 years, 59% were female, 79% were white, and 33% had diabetes. In each domain, the prevalence of cognitive dysfunction among persons with diabetes ranged from 14% to 27%. Persons with diabetes were more likely than persons without diabetes to have dysfunction in multiple domains (PR = 1.29, 95% CI: 1.12, 1.49). Prevalence of cognitive dysfunction was significantly higher in persons with versus without diabetes for memory (PR=1.13, 95% CI: 1.02, 1.25), language (PR=1.24, 95% CI: 1.09, 1.45), and executive function (PR=1.10, 95% CI: 1.00, 1.22)(Figure). PRs were similar in crude models. Conclusions: The prevalence of cognitive dysfunction among older adults with diabetes is high. These results have implications for how physicians educate patients in appropriate self-management practices and for the prevention of diabetes-related complications.

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.

Background: Most patients receive a diagnosis of dementia late in the course of the disease. In an effort to learn more about the potential for earlier detection, we examined comorbidity burden preceding a diagnosis of dementia in a cohort of older adults. Methods: Cognitive status of ARIC Study cohort participants (n=6,538) was adjudicated at Visit 5 (2011-2013) by a classification committee of physicians and neuropsychologists using a battery of neurocognitive tests, functional assessments, and neurologic exam. Additionally, cognitive status of participants who did not attend the Visit 5 examination, but were alive at the time of the visit (n= 2,289) was ascertained through a Telephone Interview for Cognitive Status-Modified (TICS) or Clinical Dementia Rating (CDR) informant interview. We examined the presence of dementia diagnostic codes in claims for inpatient and outpatient services occurring during the years 1991-2013 and preceding dementia diagnoses among all ARIC cohort participants with a dementia classification. In a sample of study participants who were enrolled in continuous fee-for-service (FFS) Medicare for at least 5 years prior to dementia ascertainment, we examined the comorbidity profile preceding the date of dementia ascertainment using ICD9 diagnostic codes obtained from inpatient records and claims for outpatient office visits. Results: Of the 7,283 ARIC participants enrolled in FFS Medicare at the time of ARIC dementia ascertainment (39.6% men, 26.4% black, mean age 76.7 years (SD 5.4)), 901 (12.4%) were classified as having dementia. Only 41.3% of those classified with dementia and 2.6% of those classified as cognitively intact had dementia diagnostic codes in any position in claims for inpatient or outpatient care preceding the ascertainment of cognitive status. In analyses limited to participants with 5 years of continuous FFS Medicare enrollment prior to the cognitive status ascertainment, we observed a consistently greater frequency of hospitalizations among study participants with a subsequent dementia classification, as compared to those with no cognitive impairment (1.62 (SD 0.08) vs. 1.10 (SD 0.05) hospitalizations per participant in the year preceding dementia diagnosis, respectively). No difference in the frequency of outpatient visits was observed. In addition to a greater frequency of diagnostic codes for cerebrovascular disease and cerebral degeneration, those with a positive dementia classification had a greater prior frequency of ICD9 codes for depression, heart failure, acute renal failure, and fluid and electrolyte disorders, as compared to those with no cognitive impairment. Conclusion: Dementia patients may have distinct comorbidity profiles in the years preceding a diagnosis. A greater understanding of these profiles is important for characterizing patient factors that may enable early detection and management.

Introduction: Several studies report late-life physical activity (PA) to be associated with less brain atrophy. Associations of PA and subclinical brain markers evaluated at older ages may be subject to reverse causality due to comorbidity, age-related changes in lifestyle, or incipient cognitive impairment. Therefore, we aimed to compare late-life cross-sectional estimates of PA and ROI brain volumes to those using prospective PA measures from mid- to late-life. Methods: Participants (n=1549, mean age: 75, 39% male, 20% Black) with repeat assessments of PA from visit 1 (1987-1989) and a brain magnetic resonance imaging (MRI) in 2011-2013 were included. Total volume of PA in metabolic equivalent-min/week was estimated using the Baecke Physical Activity Questionnaire and classified as no, low, middle or high at each visit. Based on visit 1 and 3 (1993-1995) PA assessments, a subset of participants (n=663) were further categorized as habitually inactive or having habitually low, middle, or high PA in mid-life. Brain MRI using 3D-1.5T equipment quantified ROI volumes following a standardized protocol. Weighted linear regression adjusted for intracranial volume, demographics, select cardiovascular risk factors and ApoE4 estimated the standardized difference in ROI volumes. Results: Compared to no PA, high PA was associated with larger ROI brain volumes cross-sectionally in late-life (Table). High mid-life PA was only modestly associated with larger frontal cortical and deep gray matter volumes in late-life (Table). Habitually high PA in mid-life was not associated with less atrophy across brain regions in late-life. Conclusions: Our results do not support a causal interpretation of the cross-sectional associations between PA and brain volumes reported in late-life. Drawing on long-term population-based data, this study provides novel information on the associations of PA across life epochs with brain health, which can inform translational and intervention efforts to reduce age-related cognitive impairment.

Background: Vascular aging is associated with cognitive decline. Aortic stiffness is a hallmark of vascular aging. We tested the hypothesis that greater aortic stiffness is associated with a faster rate of cognitive decline over 5 years among older adults. Methods: A prospective cohort study at the 5th (2011-2013) and 6th (2016-2017) examinations of the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS) was conducted to quantify the association between baseline aortic stiffness and cognitive decline over 5 years. A total of 4639 participants (mean age: 75 years, 41% men, 22% Black) with baseline measures of aortic stiffness and cognitive function were included in the analysis. Aortic stiffness was measured as carotid-femoral pulse wave velocity (cfPWV) using the Omron VP-1000 Plus device and analyzed continuously per 1 standard deviation meter/second (3.20 m/s). Elevated aortic stiffness was defined as the upper 25th percentile of cfPWV (13.39 m/s). Cognitive function was based on ten neuropsychological tests across multiple domains of cognition, including memory, executive function/processing speed, and language. A global cognitive performance factor score was estimated based on all cognitive tests at both visits. Multivariable linear regression was used to examine the associations of each standard deviation (SD) increment in cfPWV and elevated cfPWV with annual cognitive decline over 5 years. Interactions with baseline cognitive status were assessed. To account for attrition (35% over 5 years), multiple imputation by chained equations was used to impute missing global cognitive performance factor scores at visit 6. Results: Each 1 SD increase in cfPWV was associated with 0.008 SD (Beta (β)=-0.008, 95% confidence interval (CI): -0.010, -0.003) annual rate of decline in cognitive function after adjustment for age, sex, education, race-center and ApoE4. With additional adjustment for ever smoking, total weekly physical activity time, mean arterial pressure, diabetes, and body mass index, each SD higher cfPWV was associated with 0.005 SD (β=-0.005, 95% CI: -0.010, -0.001) annual rate of decline in cognitive function. Elevated cfPWV was associated with 0.015 SD (β=-0.015, 95% CI: -0.024, -0.005) annual decline in cognitive function, and with 0.010 SD (β=-0.010, 95% CI: -0.020, 0.0001) annual decline after additional adjustment. Conclusion: Higher aortic stiffness is associated with the rate of decline in global cognitive function among community-dwelling older adults. The hemodynamic sequelae of aortic stiffening may contribute to cognitive decline among older adults.

Background Changes 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 Results We 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. Conclusions High 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.

Introduction: Stiffening of the aorta is associated with greater pulse pressure and transmission of pulsatile energy into the cerebral circulation, which can increase susceptibility to microvascular damage in the brain. We tested the hypothesis that higher aortic stiffness measured in late-life is associated with a greater prevalence odds of dementia measured ~5 years later. Methods: Dementia-free ARIC-NCS participants (n=4753; mean age: 75 years; 42% male; 21% black) with measures of aortic stiffness at the visit 5 (2011-2013) examination were included. Aortic stiffness was measured by carotid-femoral pulse wave velocity (cfPWV) using the VP-1000 Plus device (Omron Co., Japan) and modeled as continuous (per standard deviation (SD)), categorical into distribution-based quartiles, and as elevated vs. non-elevated cfPWV according to the upper 25 th percentile (13.34 m/s). Cognitive status (normal/mild cognitive impairment (MCI)/dementia) was ascertained at the visit 5 and 6 (2016-2017) examinations with expert review by an adjudication committee of in-person cognitive testing. A multivariable logistic regression model estimated the adjusted association of cfPWV with 5-year odds of dementia. Results: Among dementia-free participants, a 1 SD higher cfPWV was associated with a greater odds of dementia (Odds Ratio (OR): 1.19 (95% Confidence Interval (CI): 1.03, 1.39). Elevated cfPWV (upper 25 th percentile) was also associated with a greater odds of dementia (OR: 1.54, 95% CI: 1.08, 2.19) in this sample. This association was stronger among participants who were cognitively normal at visit 5 (n=3758, Table): the multivariable-adjusted OR of dementia = 2.16 (95% CI: 1.35, 3.47) for elevated vs. non-elevated cfPWV. The risk of dementia among those with baseline MCI (n=955) was not associated with cfPWV levels. Results were robust to adjustment for vascular risk factors. Conclusions: Among older adults, especially when MCI is not present, greater central aortic stiffness is associated with dementia risk.

Introduction: Low levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) among older adults are associated with mortality, and reportedly with lower cognitive performance, biomarkers of neurodegeneration, and dementia. We tested the associations of liver enzymes with cognition in ARIC-NCS. Methods: We studied 3191 participants (mean age 79 years, 59% female, 23% black) free of chronic liver disease and cirrhosis, and with AST:ALT ratio ≤2 at visit in 2016-2017. Serum ALT and AST were examined continuously and by quintiles, with the 3 rd quintile as the distribution-based modal reference range. Cognitive status (normal, mild cognitive impairment [MCI], dementia) was ascertained by an expert adjudication panel. A composite global cognition score was estimated from memory, executive function, and language tests. We used demographic and ApoE4 adjusted multinomial logistic and linear regressions. Results: Participants were classified as cognitively unimpaired (2375), MCI (602) or dementia (214). Lower levels of ALT and AST, and a higher AST:ALT ratio were associated with higher prevalence of dementia and lower global cognition scores ( Figure ). The prevalence odds ratio of dementia and MCI for the 1 st quintile, vs 3 rd quintile of ALT, were 1.73 (95% CI:1.06-2.81) and 1.27 (0.92-1.76), respectively. The corresponding estimates for AST were 1.71 (1.03-2.84) and 1.17 (0.87-1.59). Global cognition scores were lower in the 1 st vs 3 rd quintiles of ALT and AST by 0.13 (0.06-0.21) and 0.08 (0-0.15) standard deviation units, respectively. Additional adjustment for alcohol intake did not change the results. Conclusions: Liver hypometabolism is linked to reduced brain glucose metabolism, impaired production of neurotransmitters and synaptic maintenance, systemic insulin resistance and inflammation, while hepatic metabolite profiles are altered in dementia. Prospective assessments are warranted to characterize the role of hepatic metabolic dysfunction in cognitive impairment among older adults.