Introduction: Diabetes is prospectively associated with cognitive decline. Whether lower cognitive function and worse brain structure are prospectively associated with incident diabetes is unclear. Methods: We analyzed data for 10,133 individuals with cognitive function testing (1990–1992) and 1212 individuals with brain magnetic resonance imaging (1993–1994) from the Atherosclerosis Risk in Communities cohort. We estimated hazard ratios for incident diabetes through 2014 after adjustment for traditional diabetes risk factors and cohort attrition. Results: Higher level of baseline cognitive function was associated with lower risk for diabetes (per 1 standard deviation, hazard ratio = 0.94; 95% confidence interval = 0.90, 0.98). This association did not persist after accounting for baseline glucose level, case ascertainment methods, and cohort attrition. No association was observed between any brain magnetic resonance imaging measure and incident diabetes. Discussion: This is one of the first studies to prospectively evaluate the association between both cognitive function and brain structure and the incidence of diabetes.
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Jing Dong;
Annah Wyss;
Jingyun Yang;
T Ryan Price;
Aude Nicolas;
Michael Nalls;
Greg Tranah;
Nora Franceschini;
Zongli Xu;
Claudia Schulte;
Alvaro Alonso;
Steven R. Cummings;
Myriam Fornage;
Dmitri Zaykin;
Leping Li;
Xuemei Huang;
Stephen Kritchevsky;
Yongmei Liu;
Thomas Gasser;
Robert S. Wilson;
Philip L De Jager;
Andrew B. Singleton;
Jayant M. Pinto;
Tamara Harris;
Thomas H. Mosley Jr.;
David A. Bennett;
Stephanie London;
Lei Yu;
Honglei Chen
The human sense of smell decreases with age, and a poor sense of smell are among the most important prodromal symptoms of several neurodegenerative diseases. Recent evidence further suggests a racial difference in the sense of smell among U.S. older adults. However, no genome-wide association study (GWAS) on the sense of smell has been conducted in African-Americans (AAs). We performed the first genome-wide meta-analysis of the sense of smell among 1979 AAs and 6582 European-Americans (EAs) from three U.S. aging cohorts. In the AA population, we identified nine novel regions (KLF4-ACTL7B, RAPGEF2-FSTL5, TCF4-LOC100505474, PCDH10, KIAA1751, MYO5B, MIR320B1-CD2, NR5A2-LINC00862, SALL1-C16orf97) that were associated with the sense of smell (P < 5 × 10 −8 ). Many of these regions have been previously linked to neuropsychiatric (schizophrenia or epilepsy) or neurodegenerative (Parkinson’s or Alzheimer’s disease) diseases associated with a decreased sense of smell. In the EA population, we identified two novel loci in or near RASGRP1 and ANXA2P3 associated with sense of smell. In conclusion, this study identified several ancestry-specific loci that are associated with the sense of smell in older adults. While these findings need independent confirmation, they may lead to novel insights into the biology of the sense of smell in older adults and its relationships to neuropsychological and neurodegenerative diseases.
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Alvaro Alonso;
David S. Knopman;
Rebecca F. Gottesman;
Elsayad Z. Soliman;
Amit Shah;
Wesley T. O'Neal;
Faye L. Norby;
Thomas H. Mosley;
Lin Y. Chen
BACKGROUND: Atrial fibrillation (AF) has been associated with faster cognitive decline and increased dementia risk. Factors associated with dementia in patients with AF have been seldom studied. METHODS AND RESULTS: We studied 6432 individuals from the ARIC-NCS (Atherosclerosis Risk in Communities Neurocognitive Study). In 2011 to 2013, participants underwent a physical exam, echocardiography, detailed cognitive assessments, and a subset, brain magnetic resonance imaging. Dementia and mild cognitive impairment (MCI), as well as etiology of MCI/dementia, Alzheimer's disease-related or vascular, were adjudicated by an expert panel. AF was defined by study ECGs and past hospitalizations. We used logistic regression to estimate odds ratios and 95% CI of MCI/dementia by AF status and to assess cross-sectional correlates of MCI/dementia in patients with AF. Among 6432 participants, 611 (9.5%) had prevalent AF. AF was associated with increased odds of dementia and MCI (odds ratio, 95% CI, 2.25, 1.64-3.10, and 1.28, 1.04-1.56, respectively). Prevalence of Alzheimer's disease-related MCI/dementia and vascular MCI/dementia were higher in participants with AF than without AF (odds ratio, 95% CI, 1.29, 1.04-1.61, and 1.50, 0.99-2.25, respectively). In multivariable analyses, older age, lower body mass index, diabetes mellitus, stroke, and APOE genotype were associated with dementia prevalence in participants with AF. In models evaluating MCI/dementia subtypes, diabetes mellitus was associated with Alzheimer's disease-related MCI/dementia, whereas male sex and stroke were risk factors for vascular MCI/dementia. CONCLUSIONS: In a large, community-based study, AF was associated with higher prevalence of MCI and dementia. Controlling cardiometabolic risk factors is a potential target for prevention of adverse cognitive outcomes in AF patients.
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Pamela L. Lutsey;
Jeffrey R. Misialek;
Thomas H. Mosley;
Rebecca F. Gottesman;
Naresh M. Punjabi;
Eyal Shahar;
Richard MacLehose;
Rachel P. Ogilvie;
David Knopman;
Alvaro Alonso
Introduction This study tested the hypotheses that late-midlife obstructive sleep apnea (OSA) and short and long sleep duration are associated with dementia over 15 years of follow-up. Methods A total of 1667 Atherosclerosis Risk in Communities Study participants underwent in-home polysomnography (1996–1998) and were followed for dementia. Dementia was defined by (1) hospitalization diagnosis codes (1996–2012) and (2) a comprehensive neurocognitive examination (2011–2013) with adjudication. Results OSA and sleep duration were not associated with risk of incident dementia. When using adjudicated outcomes, severe OSA (≥30 vs. <5 apnea-hypopnea events/hour) was associated with higher risk of all-cause dementia (risk ratio [95% confidence interval], 2.35 [1.06–5.18]) and Alzheimer's disease dementia (1.66 [1.03–2.68]); associations were attenuated with cardiovascular risk factor adjustment. Sleeping <7 versus 8 to ≤9 hours was associated with higher risk of all-cause dementia (2.00 [1.03–3.86]). Discussion When adjudicated outcome definitions were used, late-midlife OSA and short sleep duration were associated with all-cause and Alzheimer's disease dementia in later life.
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Pamela L. Lutsey;
Faye L. Norby;
Rebecca F. Gottesman;
Thomas Mosley;
Richard F. MacLehose;
Naresh M. Punjabi;
Eyal Shahar;
Clifford R. Jack, Jr.;
Alvaro Alonso
Background A growing body of literature has suggested that obstructive sleep apnea (OSA) and habitual short sleep duration are linked to poor cognitive function. Neuroimaging studies may provide insight into this relation. Objective We tested the hypotheses that OSA and habitual short sleep duration, measured at ages 54-73 years, would be associated with adverse brain morphology at ages 67-89 years. Methods Included in this analysis are 312 ARIC study participants who underwent in-home overnight polysomnography in 1996-1998 and brain MRI scans about 15 years later (2012-2013). Sleep apnea was quantified by the apnea-hypopnea index and categorized as moderate/ severe (≥15.0 events/hour), mild (5.0-14.9 events/hour), or normal (<5.0 events/hour). Habitual sleep duration was categorized, in hours, as <7, 7 to ≥8, 8. MRI outcomes included number of infarcts (total, subcortical, and cortical) and white matter hyperintensity (WMH) and Alzheimer's disease signature region volumes. Multivariable adjusted logistic and linear regression models were used. All models incorporated inverse probability weighting, to adjust for potential selection bias. Results At the time of the sleep study participants were 61.7 (SD: 5.0) years old and 54% female; 19% had moderate/severe sleep apnea. MRI imaging took place 14.8 (SD: 1.0) years later, when participants were 76.5 (SD: 5.2) years old. In multivariable models which accounted for body mass index, neither OSA nor abnormal sleep duration were statistically significantly associated with odds of cerebral infarcts, WMH brain volumes or regional brain volumes. Conclusions In this community-based sample, mid-life OSA and habitually short sleep duration were not associated with later-life cerebral markers of vascular dementia and Alzheimer's disease. However, selection bias may have influenced our results and the modest sample size led to relatively imprecise associations.
Background:
Recent estimates suggest that dementia incidence is decreasing in the US possibly due to better management of cardiovascular disease (CVD) risk factors, but these studies lack repeated cross-sectional assessment among a representative US sample. Our objective was to assess temporal trends in cognitive performance in relation to CVD risk factors among older National Health and Nutrition Examination Survey (NHANES) participants.
Methods:
We used repeated cross-sectional assessment of 5711 participants ≥60 years of age from four NHANES cycles: 1999-2000, 2001-2002, 2011-2012 and 2013-2014. Cognitive function was assessed during each cycle with the Digit Symbol Substitution Test (DSST). We estimated mean DSST score at each cycle and annual trend in DSST before and after adjustment for age, sex, race/ethnicity, education, smoking status, blood pressure, glucose status and body mass index.
Results:
DSST scores was significantly higher for 2011-2012 (difference: 6.7, 95% CI 4.4 to 9.0) and 2013-2014 (difference: 6.2, 95% CI 4.0 to 8.5), but not 2001-2002 (difference: 2.3, 95% CI -0.01 to 4.6) as compared with 1999-2000 before adjustment. We observed a linear trend for higher annual DSST score before adjustment (DSST/year: 0.44, 95% CI 0.31 to 0.57) and after adjustment for age, sex, race/ethnicity, educational attainment and CVD risk factors (DSST/year: 0.17, 95% CI 0.08 to 0.26). Educational attainment was most strongly associated with the attenuation in the trend in cognitive function (77% of trend attenuation and 20% of variance in DSST).
Conclusion:
Cognitive function is improving over time for US adults aged ≥60 years. These improvements are strongly associated with greater educational attainment and irrespective of the changing US demographic and cardiovascular health profiles.
Background: There are no agreed-upon variables for predicting progression from unimpaired cognition to amnestic mild cognitive impairment (aMCI), or from aMCI to Alzheimer's disease (AD). Objective: Use ADNI data to develop a 'Framingham-like' prediction model for a 4-year period. Methods: We developed models using the strongest baseline predictors from six domains (demographics, neuroimaging, CSF biomarkers, genetics, cognitive tests, and functional ability). We chose the best predictor from each domain, which was dichotomized into more versus less harmful. Results: There were 224 unimpaired individuals and 424 aMCI subjects with baseline data on all predictors, of whom 37 (17%) and 150 (35%) converted to aMCI and AD, respectively, during 4 years of follow-up. For the unimpaired, CSF tau/Aβ ratio, hippocampal volume, and a memory score predicted progression. For those aMCI at baseline, the same predictors plus APOE4 status and functional ability predicted progression. Demographics and family history were not important predictors for progression for either group. The fit statistic was good for the unimpaired-aMCI model (C-statistic 0.80) and very good for the aMCI-AD model (C-statistic 0.91). Among the unimpaired, those with no harmful risk factors had a 4-year predicted 2% risk of progression, while those with the most harmful risk factors had a predicted 35% risk. The aMCI subjects with no harmful risk factors had a predicted 1% risk of progression those with all six harmful risk factors had a predicted 90% risk. Conclusion: Our parsimonious model accurately predicted progression from unimpaired to aMCI with three variables, and from aMCI to AD with five variables.
BACKGROUND AND PURPOSE
Atrial fibrillation (AF) is associated with dementia independent of clinical stroke. The mechanisms underlying this association remain unclear. In a community-based cohort, the ARIC study, we evaluated: (1) the longitudinal association of incident AF and (2) the cross-sectional association of prevalent AF with brain MRI abnormalities.
METHODS
The longitudinal analysis included 963 participants (mean age, 73±4.4 years, 62% women, 51% black) without prevalent stroke or AF who underwent a brain MRI in 1993–1995 and a second MRI in 2004–2006 (mean, 10.6±0.8 years). Outcomes included subclinical cerebral infarctions (SCI), sulcal size, ventricular size, and, for the cross-sectional analysis, white matter hyperintensity (WMH) volume and total brain volume (TBV).
RESULTS
In the longitudinal analysis, 29 (3.0%) participants developed AF after the first brain MRI. Those who developed AF had higher odds of increase in SCIs (OR, 3.08; 95% CI, 1.39–6.83), worsening sulcal grade (OR, 3.56; 95% CI, 1.04–12.2), and worsening ventricular grade (OR, 9.34; 95% CI 1.24–70.2). In cross-sectional analysis, of 969 participants, 35 (3.6%) had prevalent AF at the time of the 2004–2006 MRI scan. Those with AF had greater odds of higher sulcal (OR, 3.9; 95% CI, 1.7–9.1) and ventricular grade (OR, 2.4; 95% CI, 1.0–5.7) after multivariable adjustment, and no difference in WMH or TBV.
CONCLUSION
AF is independently associated with increase in SCI and worsening sulcal and ventricular grade—morphological changes associated with aging and dementia. More research is needed to define the mechanisms underlying AF-related neurodegeneration.
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Alejandra Gutierrez;
Faye L. Norby;
Ankit Maheshwari;
Mary R. Rooney;
Rebecca F. Gottesman;
Thomas H. Mosley;
Pamela L. Lutsey;
Niki Oldenburg;
Elsayed Z. Soliman;
Alvaro Alonso;
Lin Y. Chen
Background: Abnormal P-wave indices (PWIs)-reflecting underlying left atrial abnormality-are associated with increased risk of stroke independent of atrial fibrillation. We assessed whether abnormal PWIs are associated with incident dementia and greater cognitive decline, independent of atrial fibrillation and ischemic stroke.
Methods and Results: We included 13 714 participants (mean age, 57±6 years; 56% women; 23% black) who were followed for dementia through the end of 2015. (Abnormal P-wave terminal force in lead V1, ≥4000 μV×ms), abnormal P-wave axis (>75° or <0°), prolonged P-wave duration (>120 ms), and advanced interatrial block were determined from ECGs at visits 2 to 4. Dementia was adjudicated by an expert panel using data from cognitive tests and hospitalization International Classification of Diseases codes. Cognitive function was measured longitudinally using 3 neuropsychological tests. Cox proportional hazards models were used to assess the association between time-dependent abnormal PWIs with incident dementia. Linear regression models were used to evaluate PWIs with cognitive function over time. At the conclusion of the study, 19%, 16%, 28%, and 1.9% of participants had abnormal P-wave terminal force in lead V1, abnormal P-wave axis, prolonged P-wave duration, and advanced interatrial block, respectively. During mean follow-up of 18 years, there were 1390 (10%) dementia cases. All abnormal PWIs except advanced interatrial block were associated with an increased risk of dementia even after adjustment for incident atrial fibrillation and stroke: multivariable hazard ratio of abnormal P wave terminal force in lead V1=1.60, 95% CI, 1.41 to 2.83; abnormal P-wave axis, hazard ratio =1.36, 95% CI, 1.17 to 2.57; prolonged P-wave duration, hazard ratio=1.60, 95% CI, 1.42 to 1.80. Only abnormal P-wave terminal force in lead V1 was associated with greater decline in global cognition.
Conclusions: Abnormal PWIs are independently associated with an increased risk of dementia. This novel finding should be replicated in other cohorts and the underlying mechanisms should be evaluated.
Objectives: To examine the association between hospitalization, critical illness, and infection occurring during middle- and late-life and structural brain abnormalities in older adults.
Design: Prospective cohort study. Setting: Atherosclerosis Risk in Communities (ARIC) Study. Participants: A community sample of adults who were 44 to 66 years of age at study baseline.
Measurements: Active surveillance of local hospitals and annual participant contact were used to gather hospitalization information (including International Classification of Diseases, Ninth Revision, codes) on all participants over a 24-year surveillance period. Subsequently, a subset of participants underwent 3-Tesla brain magnetic resonance imaging (MRI) to quantify total and regional brain volumes, white matter hyperintensity (WMH) volume, and white matter microstructural integrity (fractional anisotropy (FA) and mean diffusivity (MD) as measured using diffusion tensor imaging (DTI)).
Results: Of the 1,689 participants included (mean age at MRI 76±5), 72% were hospitalized, 14% had a major infection, and 4% had a critical illness during the surveillance period. Using covariate-adjusted regression, hospitalization was associated with 0.12–standard deviation (SD) greater WMH volume (95% confidence interval (CI)=0.00–0.24) and poorer white matter microstructural integrity (0.17-SD lower FA, 95% CI=–0.27 to –0.06; 0.16-SD greater MD, 95% CI=0.07–0.25) than no hospitalization. There was a dose-dependent relationship between number of hospitalizations, smaller brain volumes, and lower white matter integrity (p-trends ≤.048). In hospitalized participants, critical illness was associated with smaller Alzheimer's disease (AD) signature region (–1.64 cm3, 95% CI=–3.16 to –0.12); major infection was associated with smaller AD signature region (–1.28 cm3, 95% CI=–2.21 to –0.35) and larger ventricular volume (3.79 cm3, 95% CI= 0.81–6.77).
Conclusions: Whereas all-cause hospitalization was primarily associated with lower white matter integrity, critical illness and major infection were associated with smaller brain volume, particularly within regions implicated in AD.