Cardiovascular Health Study-Cognition Study Research Articles

CogDrisk, ANU-ADRI, CAIDE, and LIBRA Risk Scores for Estimating Dementia Risk.

While the Australian National University-Alzheimer Disease Risk Index (ANU-ADRI), Cardiovascular Risk Factors, Aging, and Dementia (CAIDE), and Lifestyle for Brain Health (LIBRA) dementia risk tools have been widely used, a large body of new evidence has emerged since their publication. Recently, Cognitive Health and Dementia Risk Index (CogDrisk) and CogDrisk for Alzheimer disease (CogDrisk-AD) risk tools have been developed for the assessment of dementia and AD risk, respectively, using contemporary evidence; comparison of the relative performance of these risk tools is limited. To evaluate the performance of CogDrisk, ANU-ADRI, CAIDE, LIBRA, and modified LIBRA (LIBRA with age and sex estimates from ANU-ADRI) in estimating dementia and AD risks (with CogDrisk-AD and ANU-ADRI). This population-based cohort study obtained data from the Rush Memory and Aging Project (MAP), the Cardiovascular Health Study Cognition Study (CHS-CS), and the Health and Retirement Study-Aging, Demographics and Memory Study (HRS-ADAMS). Participants who were free of dementia at baseline were included. The factors were component variables in the risk tools that included self-reported baseline demographics, medical risk factors, and lifestyle habits. The study was conducted between November 2021 and March 2023, and statistical analysis was performed from January to June 2023. Risk scores were calculated based on available factors in each of these cohorts. Area under the receiver operating characteristic curve (AUC) was calculated to measure the performance of each risk score. Multiple imputation was used to assess whether missing data may have affected estimates for dementia risk. Among the 6107 participants in 3 validation cohorts included for this study, 2184 participants without dementia at baseline were available from MAP (mean [SD] age, 80.0 [7.6] years; 1606 [73.5%] female), 548 participants without dementia at baseline were available from HRS-ADAMS (mean [SD] age, 79.5 [6.3] years; 288 [52.5%] female), and 3375 participants without dementia at baseline were available from CHS-CS (mean [SD] age, 74.8 [4.9] years; 1994 [59.1%] female). In all 3 cohorts, a similar AUC for dementia was obtained using CogDrisk, ANU-ADRI, and modified LIBRA (MAP cohort: CogDrisk AUC, 0.65 [95% CI, 0.61-0.69]; ANU-ADRI AUC, 0.65 [95% CI, 0.61-0.69]; modified LIBRA AUC, 0.65 [95% CI, 0.61-0.69]; HRS-ADAMS cohort: CogDrisk AUC, 0.75 [95% CI, 0.71-0.79]; ANU-ADRI AUC, 0.74 [95% CI, 0.70-0.78]; modified LIBRA AUC, 0.75 [95% CI, 0.71-0.79]; CHS-CS cohort: CogDrisk AUC, 0.70 [95% CI, 0.67-0.72]; ANU-ADRI AUC, 0.69 [95% CI, 0.66-0.72]; modified LIBRA AUC, 0.70 [95% CI, 0.68-0.73]). The CAIDE and LIBRA also provided similar but lower AUCs than the 3 aforementioned tools (eg, MAP cohort: CAIDE AUC, 0.50 [95% CI, 0.46-0.54]; LIBRA AUC, 0.53 [95% CI, 0.48-0.57]). The performance of CogDrisk-AD and ANU-ADRI in estimating AD risks was also similar. CogDrisk and CogDrisk-AD performed similarly to ANU-ADRI in estimating dementia and AD risks. These results suggest that CogDrisk and CogDrisk-AD, with a greater range of modifiable risk factors compared with other risk tools in this study, may be more informative for risk reduction.

Longitudinal Patterns of Brain Changes in a Community Sample in Relation to Aging and Cognitive Status.

Aging and Alzheimer's disease (AD) are characterized by widespread cortical and subcortical atrophy. Though atrophy patterns between aging and AD overlap considerably, regional differences between these two conditions may exist. Few studies, however, have investigated these patterns in large community samples. Elaborate longitudinal changes in brain morphometry in relation to aging and cognitive status in a well-characterized community cohort. Clinical and neuroimaging data were compiled from 72 participants from the Cardiovascular Health Study-Cognition Study, a community cohort of healthy aging and probable AD participants. Two time points were identified for each participant with a mean follow-up time of 5.36 years. MRI post-processing, morphometric measurements, and statistical analyses were performed using FreeSurfer, Version 7.1.1. Cortical volume was significantly decreased in the bilateral superior frontal, bilateral inferior parietal, and left superior parietal regions, among others. Cortical thickness was significantly reduced in the bilateral superior frontal and left inferior parietal regions, among others. Overall gray and white matter volumes and hippocampal subfields also demonstrated significant reductions. Cortical volume atrophy trajectories between cognitively stable and cognitively declined participants were significantly different in the right postcentral region. Observed volume reductions were consistent with previous studies investigating morphometric brain changes. Patterns of brain atrophy between AD and aging may be different in magnitude but exhibit widespread spatial overlap. These findings help characterize patterns of brain atrophy that may reflect the general population. Larger studies may more definitively establish population norms of aging and AD-related neuroimaging changes.

Abstract 44: Plasma Sphingolipids in Relation to Cognitive Decline and Incident Dementia

Introduction: Sphingolipids are fundamental components of brain structure and function. They are located in the myelin sheath insulating neuronal axons and in the cell membranes of neurons, astrocytes, and microglia involved in signal transduction. Although circulating sphingolipid profiles reflect clinical neurodegeneration, few prospective studies have investigated their utility as pre-clinical risk markers in community-based cohorts. For heart disease and diabetes, themselves risk factors for dementia, associations with sphingolipids differed across species and the length of the saturated fatty acid carried. Hypothesis: We hypothesized that plasma levels of sphingolipid species containing palmitic acid (16:0) would be positively associated with incident dementia risk and cognitive decline, while those with arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) would be associated with lower risk. Methods: We measured 18 sphingolipid species in plasma samples from 4612 participants of the Cardiovascular Health Study (CHS) (mean age 76.2 years; 40% male; and 25% APOE ε4 allele carriers). Cognitive decline was assessed across 6 years using annual 100-point modified Mini-Mental State Examination (3MSE) and Digital Symbol Substitution Test (DSST) scores. A total of 3088 non-demented participants were enrolled in the CHS Cognition Study and followed with adjudication for dementia. To correct the analyses for multiple comparisons, we applied a false discovery rate (FDR) correction and used a significance threshold of 0.05. Results: Higher baseline levels of lactosylceramide-24:0 (LacCer-24) were associated with a faster 6-year cognitive decline (time x sphingolipid interaction p=0.04 for 3MSE and 0.03 for DSST). Conversely, higher baseline plasma levels of hexosylceramide -16:0 (HexCer-16) and sphingomyelin-22:0 (SM-22) were associated with slower cognitive decline measured with DSST (time x sphingolipid interaction p=0.02 for HexCer and p=0.05 for SM-22). During a median follow-up of 4.5 years, we identified 366 incident dementia cases. In proportional Cox regression analyses, higher plasma levels of ceramide-16:0 (Cer-16) were positively associated with incident dementia upon adjustment for demographics, lifestyle factors, medical history, C-reactive protein, and lipids [hazard ratio per SD: 1.18 (95% CI, 1.06; 1.31)]. Conclusions: In older adults without dementia, higher plasma levels of Cer-16, a species previously associated with cardiovascular disease and mortality, were associated with higher risk of clinical dementia as we hypothesized. LacCer-24 was associated with faster, and HexCer-16 and SM-22 with slower, cognitive decline, but these species were not statistically associated with dementia risk. These novel and inconsistent findings will need to be replicated in other longitudinal studies.

Prospective Longitudinal Perfusion in Probable Alzheimer's Disease Correlated with Atrophy in Temporal Lobe.

Reduced cerebral blood flow (CBF) in the temporoparietal region and gray matter volumes (GMVs) in the temporal lobe were previously reported in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). However, the temporal relationship between reductions in CBF and GMVs requires further investigation. This study sought to determine if reduced CBF is associated with reduced GMVs, or vice versa. Data came from 148 volunteers of the Cardiovascular Health Study Cognition Study (CHS-CS), including 58 normal controls (NC), 50 MCI, and 40 AD who had perfusion and structural MRIs during 2002-2003 (Time 2). Sixty-three of the 148 volunteers had follow-up perfusion and structural MRIs (Time 3). Forty out of the 63 volunteers received prior structural MRIs during 1997-1999 (Time 1). The relationships between GMVs and subsequent CBF changes, and between CBF and subsequent GMV changes were investigated. At Time 2, we observed smaller GMVs (p<0.05) in the temporal pole region in AD compared to NC and MCI. We also found associations between: (1) temporal pole GMVs at Time 2 and subsequent declines in CBF in this region (p=0.0014) and in the temporoparietal region (p=0.0032); (2) hippocampal GMVs at Time 2 and subsequent declines in CBF in the temporoparietal region (p=0.012); and (3) temporal pole CBF at Time 2 and subsequent changes in GMV in this region (p = 0.011). Therefore, hypoperfusion in the temporal pole may be an early event driving its atrophy. Perfusion declines in the temporoparietal and temporal pole follow atrophy in this temporal pole region.

Abstract P007: Arterial Stiffness is Associated With Increased Risk of Incident Dementia in the Older Elderly: The Cardiovascular Health Study Cognition Study

Introduction: Arterial stiffness is related to aging, hypertension, and obesity, and higher carotid-femoral pulse wave velocity (PWV) is associated with brain amyloid deposition. We hypothesized that higher cfPWV was associated with incident dementia in older adults (mean age 78) of the Cardiovascular Health Study Cognition Study (CHS-CS). Methods: Pittsburgh CHS-CS participants (n=532) without dementia at baseline (1998-99) had annual cognitive exams through 2013. CfPWV (m/sec) was measured from pulse velocity waveforms on 356 participants between 1996-2000, who were slightly younger, more educated, with less mild cognitive impairment (MCI) than those not included. Associations of cfPWV [continuous (transformed: -1/cfPWV) and quartile] with time-to-event [cfPWV measurement to dementia or death (competing event), or end of follow-up] were assessed in Cox proportional hazards model with competing risk of death. Results: Over 15-year follow-up, 212 (59.6%) dementia cases (median onset time=4 years) and 87 (24.4%) deaths occurred prior to dementia diagnosis. Adjusted for age and sex, incident dementia was related to higher cfPWV [hazard ratio (HR)=1.52 per -1/cfPWV, 95%CI=1.04, 2.24] (Table). Results were similar when further adjusted for education, race, ApoE4 , hypertension, diabetes, MCI, and abnormal white matter (WMG) or ventricular grade (VG). Results persisted in separate models that excluded those with ApoE4 + (n=79), diabetes (n=40), MCI (n=65) or abnormal WMG or VG (n=136). In stratified models, results were stronger for age ≥80 vs. &lt;80 and for hypertension vs. no hypertension. Pulse pressure (PP), another index of arterial stiffness, was not associated with incident dementia (age- and sex-adjusted HR=1.01 per mmHg PP, 95%CI=0.99, 1.01). Conclusions: Higher cfPWV, but not higher PP, was significantly associated with incident dementia in the older adults. Interventions to slow arterial stiffness with aging may reduce the risk of dementia among older individuals.

Subclinical Cardiovascular Disease and Death, Dementia, and Coronary Heart Disease in Patients 80+ Years

BackgroundThe successful prevention and treatment of coronary heart disease (CHD) and stroke has resulted in a substantial increase in longevity, with subsequent growth in the population of older people at risk for dementia. ObjectivesThe authors evaluated the relationship of coronary and other peripheral atherosclerosis to risk of death, dementia, and CHD in the very elderly. Because the extent of vascular disease differs substantially between men and women, sex- and race-specific analyses were included, with a specific focus on women with low coronary artery calcium (CAC) Agatston scores. MethodsWe evaluated the relationship between measures of subclinical cardiovascular disease (CAC, carotid intimal medial thickness, stenosis, and ankle brachial index) and risk of dementia, CHD, and total mortality in 532 participants of the Cardiovascular Health Study-Cognition Study from 1998/1999 (mean age, 80 years) to 2012/2013 (mean age, 93 years). ResultsThirty-six percent of participants had CAC scores >400. Women and African-Americans had lower CAC scores. Few men had low CAC scores. CAC score and number of coronary calcifications were directly related to age-adjusted total mortality and CHD. The age-specific incidence of dementia was higher than for CHD. Only about 25% of deaths were caused by CHD and 16% by dementia. Approximately 64% of those who died had a prior diagnosis of dementia. White women with low CAC scores had a significantly decreased incidence of dementia. ConclusionsIn subjects 80+ years of age, there is a greater incidence of dementia than of CHD. CAC, as a marker of atherosclerosis, is a determinant of mortality, and risk of CHD and myocardial infarction. White women with low CAC scores had a significantly decreased risk of dementia. A very important unanswered question, especially in the very elderly, is whether prevention of atherosclerosis and its complications is associated with less Alzheimer disease pathology and dementia. (Cardiovascular Health Study [CHS]; NCT00005133)

Incidence of mild cognitive impairment in the Pittsburgh Cardiovascular Health Study-Cognition Study.

The purpose of this study was to examine the incidence of mild cognitive impairment (MCI) and patterns of progression from incident MCI to dementia in 285 cognitively normal subjects (mean age, 78.9 years) in the Cardiovascular Health Study-Cognition Study from 1998-1999 to 2010-2011. Two hundred (70%) of the participants progressed to MCI; the age-adjusted incidence of MCI was 111.09 (95% confidence interval, 88.13-142.95) per 1,000 person-years. A total of 107 (53.5%) of the incident MCI subjects progressed to dementia. The mean time from MCI to dementia was 2.8 ± 1.8 years. Forty (20%) of the incident MCI cases had an "unstable" course: 19 (9.5%) converted to MCI and later returned to normal; 10 (5%) converted to MCI, to normal, and later back to MCI; 7 (3.5%) converted to MCI, to normal, to MCI, and later to dementia; and 4 (2%) converted to MCI, to normal, and later to dementia. There was an increased mortality rate among the cognitively normal group (110.10 per 1,000 person-years) compared to those with incident MCI who converted to dementia (41.32 per 1,000 person-years). The majority of the subjects aged >80 years developed an MCI syndrome, and half of them progressed to dementia. Once the MCI syndrome was present, the symptoms of dementia appeared within 2 to 3 years. Progression from normal to MCI or from normal to MCI to dementia is not always linear; subjects who developed MCI and later returned to normal can subsequently progress to dementia. Competing mortality and morbidity influence the study of incident MCI and dementia in population cohorts.

Incidence of Mild Cognitive Impairment in the CHS Cognition Study (S24.001)

Objective: To examine the incidence of mild cognitive impairment (MCI) in the Cardiovascular Health Study-Cognition Study. Background Older subjects with MCI have an increased risk of developing dementia. Design/Methods: We examined the incidence of MCI and patterns of progression from incident MCI to dementia in 285 normal subjects (mean age: 78.9) participating in the CHS-CS from 1998-99 to 2010-2011. Results: 200 (70%) of the participants progressed to MCI; the age-adjusted incidence of MCI was 112.09 (95% CI: 88.1 – 142.95) per/1000 persons-years. 110 (55%) of the incident MCI subjects progressed to dementia. The mean time to MCI was 5.9 + 2.7 years and from the MCI to dementia 2.8 + 1.8 years. 40 (20%) of the incident MCI cases had an “unstable” course: 19 (9.5%) converted to MCI and later returned to normal, 10 (5%) converted to MCI to normal and later went back to MCI, 7 (3.5%) converted to MCI to normal to MCI and later to dementia, and 4 (2%) converted to MCI to normal and later to dementia. Conclusions: The majority of the subjects older than age 80 developed an MCI syndrome and half progressed to dementia. Progression from normal to MCI or from normal to MCI to dementia is not always linear; 20% of the subjects had a fluctuating course. Subjects who developed MCI and later returned to normal can progress to dementia during follow-up. Importantly, once the MCI syndrome is present, the symptoms of dementia appear within 2-3 years. This suggests that the window to detect symptomatic pre-dementia cases is narrow in this age group, which has important implications for the development of prevention therapies. Supported by: The research reported in this article was supported by contracts N01-HC-85079 through N01-HC-85086, N01-HC-35129, and N01-HC-15103 from the National Heart, Lung, and Blood Institute, and grants AG15928 and AG20098 from the National Institute on Aging. Disclosure: Dr. Lopez has received personal compensation for activities with Lundbeck and Johnson & Johnson as a consultant. Dr. Becker has nothing to disclose. Dr. Chang has nothing to disclose. Dr. Sweet has nothing to disclose. Dr. DeKosky has received personal compensation in an editorial capacity for Up-to-Date, Inc. Dr. Gach has nothing to disclose. Dr. Carmichael has nothing to disclose. Dr. McDade has nothing to disclose. Dr. Kuller has nothing to disclose.

The effects of physical activity, education, and body mass index on the aging brain

Normal human aging is accompanied by progressive brain tissue loss and cognitive decline; however, several factors are thought to influence brain aging. We applied tensor-based morphometry to high-resolution brain MRI scans to determine whether educational level or physical activity was associated with brain tissue volumes in the elderly, particularly in regions susceptible to age-related atrophy. We mapped the 3D profile of brain volume differences in 226 healthy elderly subjects (130F/96M; 77.9 ± 3.6 SD years) from the Cardiovascular Health Study-Cognition Study. Statistical maps revealed the 3D profile of brain regions whose volumes were associated with educational level and physical activity (based on leisure-time energy expenditure). After controlling for age, sex, and physical activity, higher educational levels were associated with ~2-3% greater tissue volumes, on average, in the temporal lobe gray matter. After controlling for age, sex, and education, greater physical activity was associated with ~2-2.5% greater average tissue volumes in the white matter of the corona radiata extending into the parietal-occipital junction. Body mass index (BMI) was highly correlated with both education and physical activity, so we examined BMI as a contributing factor by including physical activity, education, and BMI in the same model; only BMI effects remained significant. This is one of the largest MRI studies of factors influencing structural brain aging, and BMI may be a key factor explaining the observed relationship between education, physical activity, and brain structure. Independent contributions to brain structure could not be teased apart as all these factors were highly correlated with one another.

Depressed Mood is Not a Risk Factor for Incident Dementia in a Community-Based Cohort

To determine the relationship between depressed mood and the development of Alzheimer disease in cognitively normal individuals. Longitudinal and observational. Community-based cohort study. A total of 288 participants in the Cardiovascular Health Study-Cognition Study (mean age: 77.52, SD =3.65, range: 70-89). All of the participants were adjudicated as cognitively normal in 1998/1999, and all had at least three visits before 1998/1999 with measures of cognition and mood state. The mean length of follow-up from 1998-1999 to 2007 was 7.1 years (range: 1-9 years, median =9 years). The Center for Epidemiological Studies-Depression Scale (CESD) was used to index mood state, and the Modified Mini-Mental State Examination (3MSE) was the index of cognitive function among participants before 1998/1999. These measures were considered in two ways: participants were classified according to: 1) whether they showed a high-negative correlation between their CESD and 3MSE scores (i.e., indicating that greater depression was linked to poorer cognition) and 2) whether they showed persistently elevated CESD scores. The study outcome, development of dementia (N = 48), was based on consensus classifications, which was based on detailed neuropsychological and neurological exams. The authors could find no consistent relationship between mood state, either alone or in relation to cognitive status, and the subsequent development of dementia. Those individuals whose cognitive functions were highly correlated with their mood state were no more likely to develop dementia than other participants. Those who had persistently depressed mood were also no more likely to develop dementia than those without persistently depressed mood. Within the confines of this prospective, community-based study of elderly adults, the authors could not find strong evidence to support the hypothesis that mood disturbance was linked with the development of dementia.

Prevalence and classification of mild cognitive impairment in the Cardiovascular Health Study Cognition Study: part 1.

To examine the prevalence of mild cognitive impairment (MCI) and its diagnostic classification in the Cardiovascular Health Study (CHS) Cognition Study. The CHS Cognition Study is an ancillary study of the CHS that was conducted to determine the presence of MCI and dementia in the CHS cohort. Multicenter population study. We examined 3608 participants in the CHS who had undergone detailed neurological, neuropsychological, neuroradiological, and psychiatric testing to identify dementia and MCI. The prevalence of MCI was determined for the whole cohort, and specific subtypes of MCI were examined in detail only at the Pittsburgh, Pa, center (n = 927). Mild cognitive impairment was classified as either MCI amnestic-type or MCI multiple cognitive deficits-type. The overall prevalence of MCI was 19% (465 of 2470 participants); prevalence increased with age from 19% in participants younger than 75 years to 29% in those older than 85 years. The overall prevalence of MCI at the Pittsburgh center was 22% (130 of 599 participants); prevalence of the MCI amnesic-type was 6% and of the MCI multiple cognitive deficits-type was 16%. Twenty-two percent of the participants aged 75 years or older had MCI. Mild cognitive impairment is a heterogeneous syndrome, where the MCI amnestic-type is less frequent than the MCI multiple cognitive deficits-type. Most of the participants with MCI had comorbid conditions that may affect their cognitive functions.