@article {1212, title = {Cognition and the risk of hospitalization for serious falls in the elderly: results from the Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {65}, year = {2010}, month = {2010 Nov}, pages = {1242-9}, abstract = {

BACKGROUND: Many elderly adults fall every year, sometimes resulting in serious injury and hospitalization. Although impaired cognition is a risk factor for injurious falls, little is known about cognitive decline above the threshold of impairment and risk of serious falls in community-dwelling seniors.

METHODS: In total, 702 of 5,356 older adults participating in the Cardiovascular Health Study experienced an injurious fall between 1990 and 2005, as indicated by hospitalization records. General cognition was measured annually with the Modified Mini-Mental State Examination and processing speed with the Digit Symbol Substitution Test. The Cox regression model was used to calculate hazard ratio and 95\% confidence interval with and without time-dependent covariates and adjusted for known risk factors.

RESULTS: Participants with slightly decreased Digit Symbol Substitution Test scores were at increased risk for a serious fall (hazard ratio = 1.58, 95\% confidence interval = 1.15-2.17). The risk continued to increase with each quartile decrease in Digit Symbol Substitution Test score. Participants without prevalent cardiovascular disease at baseline and decreased Modified Mini-Mental State Examination scores (80-89) had a 45\% increased risk for a serious fall and those at high risk for dementia (<80) were at twice the risk as participants scoring above 90 (hazard ratio = 2.16, 95\% confidence interval = 1.60-2.91).

CONCLUSIONS: Both decreased general cognition and decreased processing speed appear to be potential risk factors for serious falls in the elderly. When assessing the risk of serious falls in elderly patients, clinicians should consider usual factors like gait instability and sensory impairment as well as less obvious ones such as cardiovascular disease and cognitive function in nondemented adults.

}, keywords = {Accidental Falls, Aged, Aged, 80 and over, Chi-Square Distribution, Cognition Disorders, Female, Follow-Up Studies, Geriatric Assessment, Hospitalization, Humans, Male, Mental Status Schedule, Physical Examination, Proportional Hazards Models, Risk Assessment, Risk Factors, Surveys and Questionnaires}, issn = {1758-535X}, doi = {10.1093/gerona/glq115}, author = {Welmerink, Diana B and Longstreth, W T and Lyles, Mary F and Fitzpatrick, Annette L} } @article {1398, title = {Comparing years of healthy life, measured in 16 ways, for normal weight and overweight older adults.}, journal = {J Obes}, volume = {2012}, year = {2012}, month = {2012}, pages = {894894}, abstract = {

Introduction. The traditional definitions of overweight and obesity are not age specific, even though the relationship of weight to mortality is different for older adults. Effects of adiposity on aspects of health beside mortality have not been well investigated. Methods. We calculated the number of years of healthy life (YHL) in the 10 years after baseline, for 5,747 older adults. YHL was defined in 16 different ways. We compared Normal and Overweight persons, classified either by body mass index (BMI) or by waist circumference (WC). Findings. YHL for Normal and Overweight persons differed significantly in 25\% of the comparisons, of which half favored the Overweight. Measures of physical health favored Normal weight, while measures of mental health and quality of life favored Overweight. Overweight was less favorable when defined by WC than by BMI. Obese persons usually had worse outcomes. Discussion. Overweight older adults averaged as many years of life and years of healthy life as those of Normal weight. There may be no outcome based reason to distinguish Normal from Overweight for older adults. Conclusion. The "Overweight paradox" appears to hold for nonmortality outcomes. New adiposity standards are needed for older adults, possibly different by race and sex.

}, issn = {2090-0716}, doi = {10.1155/2012/894894}, author = {Diehr, Paula and Thielke, Stephen and O{\textquoteright}Meara, Ellen and Fitzpatrick, Annette L and Newman, Anne} } @article {7245, title = {Changes in Depressive Symptoms and Subsequent Risk of Stroke in the Cardiovascular Health Study.}, journal = {Stroke}, year = {2016}, month = {2016 Dec 06}, abstract = {

BACKGROUND AND PURPOSE: Depression is associated with stroke, but the effects of changes in depressive symptoms on stroke risk are not well understood. This study examined whether depressive symptom changes across 2 successive annual assessments were associated with incident stroke the following year.

METHODS: We used visit data from 4319 participants of the Cardiovascular Health Study who were stroke free at baseline to examine whether changes in depressive symptoms classified across 2 consecutive annual assessments predicted incident first stroke during the subsequent year. Depressive symptoms were assessed using the 10-item Center for Epidemiologic Studies Depression scale (high versus low at >=10). Survival models were inverse probability weighted to adjust for demographics, health behaviors, medical conditions, past depressive symptoms, censoring, and survival.

RESULTS: During follow-up, 334 strokes occurred. Relative to stable low scores of depressive symptoms, improved depression symptoms were associated with almost no excess risk of stroke (adjusted hazards ratio, 1.02; 95\% confidence interval, 0.66-1.58). New-onset symptoms were nonsignificantly associated with elevated stroke risk (adjusted hazards ratio, 1.44; 95\% confidence interval, 0.97-2.14), whereas persistently high depressive symptoms were associated with elevated adjusted hazard of all-cause stroke (adjusted hazards ratio, 1.65; 95\% confidence interval, 1.06-2.56). No evidence for effect modification by race, age, or sex was found.

CONCLUSIONS: Persistently high symptoms of depression predicted elevated hazard of stroke. Participants with improved depressive symptoms had no elevation in stroke risk. Such findings suggest that strategies to reduce depressive symptoms may ameliorate stroke risk.

}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.116.013554}, author = {Gilsanz, Paola and Kubzansky, Laura D and Tchetgen Tchetgen, Eric J and Wang, Qianyi and Kawachi, Ichiro and Patton, Kristen K and Fitzpatrick, Annette L and Kop, Willem J and Longstreth, W T and Glymour, M Maria} } @article {7563, title = {Concordance With Prevention Guidelines and Subsequent Cancer, Cardiovascular Disease, and Mortality: A Longitudinal Study of Older Adults.}, journal = {Am J Epidemiol}, volume = {186}, year = {2017}, month = {2017 Nov 15}, pages = {1168-1179}, abstract = {

Reports on the associations between multiple clinical and behavioral health indicators and major health outcomes among older adults are scarce. We prospectively examined concordance with guidelines from the American Cancer Society and American Heart Association for disease prevention in relation to cancer, cardiovascular disease (CVD), and mortality among Cardiovascular Health Study enrollees aged 65-98 years who, at baseline assessment in 1989-1996 (n = 3,491), were free of CVD and cancer. Total and cause-specific mortality, as well as incidence of cancer and CVD, were lower with higher guideline concordance. Independent of body mass index, blood pressure, total cholesterol, and fasting plasma glucose, better health behaviors (diet, physical activity, and alcohol consumption) were associated with lower mortality (2-sided P < 0.0001). Among individuals with ideal levels for 3-4 of these 4 cardiometabolic biomarkers, those with poor concordance with health behavior recommendations had higher mortality compared with those who had the highest concordance with these behavioral recommendations (adjusted mortality hazard ratio = 1.82, 95\% confidence interval: 1.25, 2.67). Older adults who are concordant with recommendations for cancer and CVD prevention have reduced rates of chronic disease and mortality. Interventions to achieve and maintain healthy lifestyle behaviors may offer benefits both in the presence and absence of adverse traditional clinical risk factors.

}, keywords = {Aged, Aged, 80 and over, American Cancer Society, American Heart Association, Body Mass Index, Cardiovascular Diseases, Cause of Death, Diet, Exercise, Female, Guideline Adherence, Healthy Lifestyle, Humans, Incidence, Longitudinal Studies, Male, Neoplasms, Practice Guidelines as Topic, Prospective Studies, United States}, issn = {1476-6256}, doi = {10.1093/aje/kwx150}, author = {Greenlee, Heather and Strizich, Garrett and Lovasi, Gina S and Kaplan, Robert C and Biggs, Mary L and Li, Christopher I and Richardson, John and Burke, Gregory L and Fitzpatrick, Annette L and Fretts, Amanda M and Psaty, Bruce M and Fried, Linda P} } @article {8632, title = {Coagulation factor VIII, white matter hyperintensities and cognitive function: Results from the Cardiovascular Health Study.}, journal = {PLoS One}, volume = {15}, year = {2020}, month = {2020}, pages = {e0242062}, abstract = {

OBJECTIVE: To investigate the relationship between high FVIII clotting activity (FVIII:C), MRI-defined white matter hyperintensities (WMH) and cognitive function over time.

METHODS: Data from the population-based Cardiovascular Health Study (n = 5,888, aged >=65) were used. FVIII:C was measured in blood samples taken at baseline. WMH burden was assessed on two cranial MRI scans taken roughly 5 years apart. Cognitive function was assessed annually using the Modified Mini-Mental State Examination (3MSE) and Digit Symbol Substitution Test (DSST). We used ordinal logistic regression models adjusted for demographic and cardiovascular factors in cross-sectional and longitudinal WMH analyses, and adjusted linear regression and linear mixed models in the analyses of cognitive function.

RESULTS: After adjustment for confounding, higher levels of FVIII:C were not strongly associated with the burden of WMH on the initial MRI scan (OR>p75 = 1.20, 95\% CI 0.99-1.45; N = 2,735) nor with WMH burden worsening over time (OR>p75 = 1.18, 95\% CI 0.87-1.59; N = 1,527). High FVIII:C showed no strong association with cognitive scores cross-sectionally (3MSE>p75 β = -0.06, 95\%CI -0.45 to 0.32, N = 4,005; DSST>p75 β = -0.69, 95\%CI -1.52 to 0.13, N = 3,954) or over time (3MSE>p75 β = -0.07,95\% CI -0.58 to 0.44, N = 2,764; DSST>p75 β = -0.22, 95\% CI -0.97 to 0.53, N = 2,306) after confounding adjustment.

INTERPRETATION: The results from this cohort study of older adult participants indicate no strong relationships between higher FVIII:C levels and WMH burden or cognitive function in cross-sectional and longitudinal analyses.

}, keywords = {Aged, Blood Coagulation, Cognition, Cross-Sectional Studies, Factor VIII, Female, Humans, Logistic Models, Longitudinal Studies, Magnetic Resonance Imaging, Male, Mental Status and Dementia Tests, Up-Regulation, White Matter}, issn = {1932-6203}, doi = {10.1371/journal.pone.0242062}, author = {Rohmann, Jessica L and Longstreth, W T and Cushman, Mary and Fitzpatrick, Annette L and Heckbert, Susan R and Rice, Kenneth and Rosendaal, Frits R and Sitlani, Colleen M and Psaty, Bruce M and Siegerink, Bob} } @article {9252, title = {CD133 as a Biomarker for an Autoantibody-to-ImmunoPET Paradigm for the Early Detection of Small Cell Lung Cancer.}, journal = {J Nucl Med}, volume = {63}, year = {2022}, month = {2022 Nov}, pages = {1701-1707}, abstract = {

Small cell lung cancer (SCLC) is a deadly neuroendocrine tumor for which there are no screening methods sensitive enough to facilitate early, effective intervention. We propose targeting the neuroendocrine tumor neoantigen CD133 via antibody-based early detection and PET (immunoPET) to facilitate earlier and more accurate detection of SCLC. RNA sequencing datasets, immunohistochemistry, flow cytometry, and Western blots were used to quantify CD133 expression in healthy and SCLC patients. CD133 was imaged using near-infrared fluorescence (NIRF) immunoimaging, and Zr immunoPET. Anti(α)-CD133 autoantibody levels were measured in SCLC patient plasma using antibody microarrays. Across 6 publicly available datasets, CD133 messenger RNA was found to be higher in SCLC tumors than in other tissues, including healthy or normal adjacent lung and non-SCLC samples. Critically, the upregulation of CD133 messenger RNA in SCLC was associated with a significant increase (hazard ratio, 2.62) in death. CD133 protein was expressed in primary human SCLC, in SCLC patient-derived xenografts, and in both SCLC cell lines tested (H82 and H69). Using an H82 xenograft mouse model, we first imaged CD133 expression with NIRF. Both and NIRF clearly showed that a fluorophore-tagged αCD133 homed to lung tumors. Next, we validated the noninvasive visualization of subcutaneous and orthotopic H82 xenografts via immunoPET. An αCD133 antibody labeled with the positron-emitting radiometal Zr demonstrated significant accumulation in tumor tissue while producing minimal uptake in healthy organs. Finally, plasma αCD133 autoantibodies were found in subjects from cohort studies up to 1 year before SCLC diagnosis. In light of these findings, we conclude that the presence of αCD133 autoantibodies in a blood sample followed by CD133-targeted Zr-immunoPET could be an effective early detection screening strategy for SCLC.

}, keywords = {Animals, Autoantibodies, Biomarkers, Cell Line, Tumor, Disease Models, Animal, Early Detection of Cancer, Humans, Lung Neoplasms, Mice, Mice, Nude, Neuroendocrine Tumors, Positron-Emission Tomography, RNA, Messenger, Small Cell Lung Carcinoma}, issn = {1535-5667}, doi = {10.2967/jnumed.121.263511}, author = {Kunihiro, Andrew G and Sarrett, Samantha M and Lastwika, Kristin J and Solan, Joell L and Pisarenko, Tatyana and Kein{\"a}nen, Outi and Rodriguez, Cindy and Taverne, Lydia R and Fitzpatrick, Annette L and Li, Christopher I and Houghton, A McGarry and Zeglis, Brian M and Lampe, Paul D} } @article {9704, title = {Circulating sphingolipids and subclinical brain pathology: the cardiovascular health study.}, journal = {Front Neurol}, volume = {15}, year = {2024}, month = {2024}, pages = {1385623}, abstract = {

BACKGROUND: Sphingolipids are implicated in neurodegeneration and neuroinflammation. We assessed the potential role of circulating ceramides and sphingomyelins in subclinical brain pathology by investigating their association with brain magnetic resonance imaging (MRI) measures and circulating biomarkers of brain injury, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in the Cardiovascular Health Study (CHS), a large and intensively phenotyped cohort of older adults.

METHODS: Brain MRI was offered twice to CHS participants with a mean of 5 years between scans, and results were available from both time points in 2,116 participants (mean age 76 years; 40\% male; and 25\% ε4 allele carriers). We measured 8 ceramide and sphingomyelin species in plasma samples and examined the associations with several MRI, including worsening grades of white matter hyperintensities and ventricular size, number of brain infarcts, and measures of brain atrophy in a subset with quantitative measures. We also investigated the sphingolipid associations with serum NfL and GFAP.

RESULTS: In the fully adjusted model, higher plasma levels of ceramides and sphingomyelins with a long (16-carbon) saturated fatty acid were associated with higher blood levels of NfL [β = 0.05, false-discovery rate corrected () = 0.004 and β = 0.06, = < 0.001, respectively]. In contrast, sphingomyelins with very long (20- and 22-carbon) saturated fatty acids tended to have an inverse association with levels of circulating NfL. In secondary analyses, we found an interaction between ceramide d18:1/20:0 and sex ( for interaction = <0.001), such that ceramide d18:1/20:0 associated with higher odds for infarcts in women [OR = 1.26 (95\%CI: 1.07, 1.49), = 0.03]. We did not observe any associations with GFAP blood levels, white matter grade, ventricular grade, mean bilateral hippocampal volume, or total brain volume.

CONCLUSION: Overall, our comprehensive investigation supports the evidence that ceramides and sphingomyelins are associated with increased aging brain pathology and that the direction of association depends on the fatty acid attached to the sphingosine backbone.

}, issn = {1664-2295}, doi = {10.3389/fneur.2024.1385623}, author = {Moseholm, Kristine F and Horn, Jens W and Fitzpatrick, Annette L and Djouss{\'e}, Luc and Longstreth, W T and Lopez, Oscar L and Hoofnagle, Andrew N and Jensen, Majken K and Lemaitre, Rozenn N and Mukamal, Kenneth J} } @article {9743, title = {Circulating sphingolipids in relation to cognitive decline and incident dementia: The Cardiovascular Health Study.}, journal = {Alzheimers Dement (Amst)}, volume = {16}, year = {2024}, month = {2024 Jul-Sep}, pages = {e12623}, abstract = {

INTRODUCTION: Whether circulating levels of sphingolipids are prospectively associated with cognitive decline and dementia risk is uncertain.

METHODS: We measured 14 sphingolipid species in plasma samples from 4488 participants (mean age 76.2 years; 40\% male; and 25\% apolipoprotein E ( ε4 allele carriers). Cognitive decline was assessed annually across 6 years using modified Mini-Mental State Examination (3MSE) and Digital Symbol Substitution Test (DSST). Additionally, a subset of 3050 participants were followed for clinically adjudicated dementia.

RESULTS: Higher plasma levels of sphingomyelin-d18:1/16:0 (SM-16) were associated with a faster cognitive decline measured with 3MSE, in contrast, higher levels of sphingomyelin-d18:1/22:0 (SM-22) were associated with slower decline in cognition measured with DSST. In Cox regression, higher levels of SM-16 (hazard ration [HR]~=~1.24 [95\% confidence interval [CI]: 1.08-1.44]) and ceramide-d18:1/16:0 (Cer-16) (HR~=~1.26 [95\% CI: 1.10-1.45]) were associated with higher risk of incident dementia.

DISCUSSION: Several sphingolipid species appear to be involved in cognitive decline and dementia risk.

HIGHLIGHTS: Plasma levels of sphingolipids were associated with cognitive decline and dementia risk.Ceramides and sphingomyelins with palmitic acid were associated with faster annual cognitive decline and increased risk of dementia.The direction of association depended on the covalently bound saturated fatty acid chain length in analysis of cognitive decline.

}, issn = {2352-8729}, doi = {10.1002/dad2.12623}, author = {Moseholm, Kristine F and Cronj{\'e}, H{\'e}l{\'e}ne T and Koch, Manja and Fitzpatrick, Annette L and Lopez, Oscar L and Otto, Marcia C de Oliveira and Longstreth, W T and Hoofnagle, Andrew N and Mukamal, Kenneth J and Lemaitre, Rozenn N and Jensen, Majken K} } @article {9913, title = {Circulating non-esterified fatty acids, risk of dementia and cognitive decline: The cardiovascular health study and multi-ethnic study of atherosclerosis.}, journal = {Neurobiol Aging}, volume = {148}, year = {2025}, month = {2025 Apr}, pages = {71-79}, abstract = {

Circulating non-esterified fatty acids (NEFAs) have toxic effects on a variety of organs central to cardiometabolic disease and can cross the blood-brain barrier. Whether NEFAs associate with cognitive decline or dementia remains unknown. Circulating total NEFA levels were measured in 3242 participants without dementia among older adults of the Cardiovascular Health Study (CHS) and related to adjudicated dementia over 6 years (n = 456 cases) and annually assessed cognitive decline. For confirmation, we related circulating NEFAs to cognition assessed 10 years later among 4361 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). In CHS participants, each SD higher NEFA levels were associated with a hazard ratio (HR) for all-cause dementia of 1.11 (95 \% CI: 1.01; 1.22). Baseline NEFA levels were also associated with more rapid decline in cognition over 6 years of follow-up. In MESA, circulating NEFA measurements were associated with lower cognitive scores measured 10 years later.{\textquoteright}

}, keywords = {Aged, Aged, 80 and over, Atherosclerosis, Cognition, Cognitive Dysfunction, Cohort Studies, Dementia, Fatty Acids, Nonesterified, Female, Follow-Up Studies, Humans, Male, Middle Aged, Risk, Risk Factors}, issn = {1558-1497}, doi = {10.1016/j.neurobiolaging.2025.01.009}, author = {Moseholm, Kristine F and Jensen, Majken K and B{\r u}zkov{\'a}, Petra and Aroner, Sarah A and Fitzpatrick, Annette L and Longstreth, W T and Lopez, Oscar and Siscovick, David S and Kizer, Jorge R and Ix, Joachim H and Hughes, Timothy M and Hayden, Kathleen M and Nomura, Sarah and Tsai, Michael Y and McClelland, Robyn and Djouss{\'e}, Luc and Mukamal, Kenneth J} }