Authors: Marengoni, Alessandra | Fratiglioni, Laura | Bandinelli, Stefania | Ferrucci, Luigi
Article Type: Research Article
Abstract: Thousand and twelve dementia-free elderly (60–98 years old) enrolled in the InChianti Study (Italy) were evaluated at baseline (1998–2000) and at 3-year follow-up (2001–2003) with the aim of analyzing the association of lifetime socioeconomic status (SES) with prevalent and incident cognitive impairment no-dementia (CIND). SES was defined from information on formal education, longest held occupation, and financial conditions through life. CIND was defined as age-adjusted Mini-Mental State Examination score one standard deviation below the baseline mean score of participants without dementia. Logistic regression and Cox proportional-hazards models were used to estimate the association of SES with CIND. Demographics, occupation characteristics …(i.e., job stress and physical demand), cardiovascular diseases, diabetes, apolipoprotein E (APOE) genotype, smoking, alcohol consumption, depressive symptoms, and C-reactive protein were considered potential confounders. Prevalence of CIND was 17.7%. In the fully adjusted model, low education (OR = 2.1; 95% confidence intervals, CI = 1.4 to 3.2) was associated with prevalent CIND. Incidence rate of CIND was 66.0 per 1000 person-years. Low education (HR = 1.7; 95% CI = 1.04 to 2.6) and manual occupation (HR = 1.9; 95% CI = 1.0 to 3.6) were associated with incident CIND. Among covariates, high job-related physical demand was associated with both prevalent and incident CIND (OR = 1.6; 95% CI = 1.1 to 2.4 and HR = 1.5; 95% CI = 1.0 to 2.3). After stratification for education, manual occupation was still associated with CIND among participants with high education (HR = 2.2; 95% CI = 1.2 to 4.3 versus HR = 1.4; 95% CI = 0.2 to 10.4 among those with low education). Proxy markers of lifetime SES (low education, manual occupation and high physical demand) are cross-sectional correlates of CIND and predict incident CIND over a three-year follow-up. Show more
Keywords: Cognitive impairment no-dementia, epidemiology, education, finances, occupation, socioeconomic status
DOI: 10.3233/JAD-2011-101863
Citation: Journal of Alzheimer's Disease, vol. 24, no. 3, pp. 559-568, 2011
Authors: Williams, Owen A. | An, Yang | Armstrong, Nicole M. | Kitner-Triolo, Melissa | Ferrucci, Luigi | Resnick, Susan M.
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is now understood to have a long preclinical phase in which pathology starts to accumulate in the absence of clinical symptoms. Identifying the temporal stages of accelerated cognitive decline in this phase may help in developing more sensitive neuropsychological tools for early screening of preclinical cognitive decline. Change-point analyses are increasingly used to characterize the temporal stages of accelerated cognitive decline in the preclinical stages of AD. However, statistical comparisons of change-points between specific cognitive measures have not been reported. Objective: To characterize and compare the temporal stages of accelerated decline in performance on multiple cognitive …tests in a sample of participants from the Baltimore Longitudinal Study on Aging (BLSA) who later developed AD. Methods: 165 older adults (baseline age range: 61.1–91.2) from the BLSA developed AD during follow-up. Linear and non-linear mixed models were fit for 11 cognitive measures to determine change-points in rates of decline before AD diagnosis. Bootstrapping was used to compare the timing of change-points across cognitive measures. Results: Change-points followed by accelerated decline ranged from 15.5 years (Standard Error (S.E.) = 1.72) for Card Rotations to 1.9 years (S.E. = 0.68) for the Trail-Making Test Part A before AD diagnosis. Accelerated decline in Card Rotations occurred significantly earlier than all other measures, including learning and memory measures. Conclusion: Results suggest that visuospatial ability, as assessed by Card Rotations, may have the greatest utility as an early predictive tool in identifying preclinical AD. Show more
Keywords: Alzheimer’s disease, change-point analysis, cognitive decline, preclinical, prodromal, visuospatial ability
DOI: 10.3233/JAD-191268
Citation: Journal of Alzheimer's Disease, vol. 75, no. 4, pp. 1169-1180, 2020
Authors: Tian, Qu | Bilgel, Murat | Moghekar, Abhay R. | Ferrucci, Luigi | Resnick, Susan M.
Article Type: Research Article
Abstract: Background: Olfactory deficits are early features of preclinical Alzheimer’s disease (AD). Whether olfaction is associated with PET biomarkers among community-dwelling older adults is less clear. Objective: Investigate cross-sectional and longitudinal associations of olfaction with mild cognitive impairment (MCI) and amyloid-β (Aβ) and tau deposition. Methods: We analyzed 364 initially cognitively normal participants (58% women, 24% black) who had baseline olfaction data and subsequent cognitive assessments during an average 2.4-year. A subset of 129 had PET-PiB (Aβ) (n = 72 repeated) and 105 had 18 F-flortaucipir (FTP)-PET (tau) (n = 44 repeated). Olfaction was measured using a 16-item Sniffin’ Sticks Odor Identification Test. …The association of olfaction with incident MCI was examined using Cox regression. Associations with PiB-distribution volume ratio (DVR) and FTP-standardized uptake value ratio (SUVR) were examined using partial correlation. We tested whether PiB+/–status modified these associations. Analyses were adjusted for demographics and olfactory test version. Results: 17 (5%) participants developed MCI. Each unit lower odor identification score was associated with 22% higher risk of developing MCI (p = 0.04). In the PET subset, lower scores were associated with higher mean cortical DVR and DVR in orbitofrontal cortex (OFC), precuneus, and middle temporal gyrus (p ≤0.04). The “olfaction*PiB+/–” interaction in OFC DVR was significant (p = 0.03), indicating the association was limited to PiB positive individuals. Greater decline in odor identification score was associated with greater increase in anterior OFC DVR and entorhinal tau SUVR (p ≤0.03). Conclusion: Among community-dwelling older adults, poorer olfaction predicts incident MCI and is associated with overall and regional Aβ. Greater olfaction decline is associated with faster Aβ and tau accumulation in olfaction-related regions. Whether olfaction predicts AD-related neurodegenerative changes warrants further investigations. Show more
Keywords: Amyloid-β, olfaction, PET biomarkers, tau
DOI: 10.3233/JAD-210636
Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1275-1285, 2022
Authors: Gomez, Gabriela | Beason-Held, Lori L. | Bilgel, Murat | An, Yang | Wong, Dean F. | Studenski, Stephanie | Ferrucci, Luigi | Resnick, Susan M.
Article Type: Research Article
Abstract: Background: Recent studies show links between metabolic syndrome and Alzheimer’s disease (AD) neuropathology. Understanding the link between vascular-related health conditions and dementia will help target at risk populations and inform clinical strategies for early detection and prevention of AD. Objective: To determine whether metabolic syndrome is associated with global cerebral amyloid-β (Aβ) positivity and longitudinal Aβ accumulation. Methods: Prospective study of 165 participants who underwent (11)C-Pittsburgh compound B (PiB) PET neuroimaging to measure Aβ, from June 2005 to May 2016. Metabolic syndrome was defined using the revised Third Adults Treatment Panel of the National Cholesterol Education Program criteria. Participants were …classified as PiB+/–. Linear mixed effects models assessed the relationships between baseline metabolic syndrome and PiB status and regional Aβ change over time. Results: A total of 165 cognitively normal participants of the Baltimore Longitudinal Study of Aging (BLSA) Neuroimaging substudy, aged 55–92 years (mean baseline age = 76.4 years, 85 participants were male), received an average of 2.5 PET-PiB scans over an average interval of 2.6 (3.08 SD) years between first and last visits. Metabolic syndrome was not associated with baseline PiB positivity or concurrent regional Aβ. Metabolic syndrome was associated with increased rates of Aβ accumulation in superior parietal and precuneus regions over time in the PiB+ group. Elevated fasting glucose and blood pressure showed individual associations with accelerated Aβ accumulation. Conclusion: Metabolic syndrome was associated with accelerated Aβ accumulation in PiB+ individuals and may be an important factor in the progression of AD pathology. Show more
Keywords: Alzheimer’s disease, amyloid PET, brain, cholesterol, dementia, diabetes, hypertension, metabolic syndrome, vascular
DOI: 10.3233/JAD-180297
Citation: Journal of Alzheimer's Disease, vol. 65, no. 2, pp. 629-639, 2018
Authors: Beck, Justine | Ferrucci, Luigi | Sun, Kai | Walston, Jeremy | Fried, Linda P. | Varadhan, Ravi | Guralnik, Jack M. | Semba, Richard D.
Article Type: Research Article
Abstract: Aging is associated with a loss of muscle strength, and, in turn, loss of muscle strength has been associated with increased risk of frailty, disability and mortality. The factors that contribute to loss of muscle strength with aging have not been well characterized. Selenium is important in normal muscle function because of its role in selenoenzymes that protect muscle against oxidative damage. We hypothesized that low serum selenium concentrations were associated with poor grip strength. We examined the association between serum selenium and hand grip strength among 676 moderately to severely disabled community-dwelling women in the Women's Health and Aging …Study I in Baltimore, Maryland. After adjusting for age, race, body mass index, Mini-Mental Status Examination score, current smoking, hypertension, congestive heart failure and depression, serum selenium was associated with grip strength (P=0.04). This study supports the idea that selenium is important to muscle strength in older women. Show more
Keywords: Aging, muscle, sarcopenia, selenium, strength, women
Citation: BioFactors, vol. 29, no. 1, pp. 37-44, 2007
Authors: Kueider, Alexandra M. | An, Yang | Tanaka, Toshiko | Kitner-Triolo, Melissa H. | Studenski, Stephanie | Ferrucci, Luigi | Thambisetty, Madhav
Article Type: Research Article
Abstract: Serum uric acid (SUA) is an abundant natural antioxidant capable of reducing cellular oxidation, a major cause of neurodegenerative disease. In line with this, SUA levels are lower in Alzheimer’s disease; however, the association between SUA and cognition remains unclear. Results from studies examining the effects of SUA on cognition may be difficult to interpret in the context of normal versus pathological aging. This study examined sex-specific associations of baseline SUA with cognition during aging. Data from dementia-free participants initially aged 26–99 (N = 1,451) recruited for the Baltimore Longitudinal Study of Aging (BLSA), were used in the current analyses. SUA …was assessed using blood samples collected during research visits. Cognition was measured using five composite scores (verbal memory, attention, executive function, language, and visuospatial ability). At the first study visit, compared with women, men were older, more likely to be White, had more years of education, higher baseline SUA levels, and higher cardiovascular risk scores. Higher baseline SUA was associated with attenuated declines in attention (β= 0.006; p = 0.03) and visuospatial abilities (β= 0.007; p = 0.01) in men. There was a trend to suggest higher baseline SUA in men was associated with attenuated declines in language, but this finding did not reach statistical significance (p = 0.09). There were no significant findings with SUA and cognition in women. In this sample of cognitively healthy, community-dwelling adults, we found that higher SUA levels at baseline were associated with attenuated declines in attention and visuospatial abilities in men. SUA was not associated with cognition or change in cognition over time in women. Show more
Keywords: Aging, cognitive function, older adults, uric acid
DOI: 10.3233/JAD-170287
Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 699-706, 2017
Authors: Callisaya, Michele L. | Ayers, Emmeline | Barzilai, Nir | Ferrucci, Luigi | Guralnik, Jack M. | Lipton, Richard B. | Otahal, Petr | Srikanth, Velandai K. | Verghese, Joe
Article Type: Research Article
Abstract: Background: The Motoric Cognitive Risk Syndrome (MCR) is characterized by slow gait speed and cognitive complaints. Objectives: The objective of this study was to determine if the presence of MCR increases the risk of falls in older people. Methods: Individual participant data (n = 6,204) from five longitudinal studies from three countries were used for this analysis. MCR diagnosis was defined as both the presence of objectively measured slow gait speed and subjective cognitive complaints in those without dementia or mobility disability. Falls were prospectively ascertained using phone calls or questionnaires. Log binomial regression was performed to determine if MCR increased …the risk of falls separately in each cohort. Random effects meta-analysis was used to pool results from all cohorts. Results: The mean age of participants was 74.9 (SD 6.8) years and 44% (n = 2728) were male. Overall 33.9% (n = 2104) reported a fall over follow-up. Pooled relative risk of MCR with any falls was RR 1.44 95% CI 1.16, 1.79. The components of MCR, slow gait (RR 1.30 95% CI 1.14, 1.47) and cognitive complaint (RR 1.25, 95% CI 1.07, 1.46) were also associated with an increased risk of any falls. In sub-analyses MCR was associated with any fall independent of previous falls (RR 1.29 95% CI 1.09, 1.53) and with multiple falls (RR 1.77, 95% CI 1.25, 2.51). Conclusion: MCR is associated with an increased risk of falls. The increase in risk was higher than for its individual components. The simplicity of the MCR makes it an attractive falls risk screening tool for the clinic. Show more
Keywords: Cognition, dementia, falls, gait
DOI: 10.3233/JAD-160230
Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 1043-1052, 2016
Authors: Pilotto, Alberto | Sancarlo, Daniele | Panza, Francesco | Paris, Francesco | D'Onofrio, Grazia | Cascavilla, Leandro | Addante, Filomena | Seripa, Davide | Solfrizzi, Vincenzo | Dallapiccola, Bruno | Franceschi, Marilisa | Ferrucci, Luigi
Article Type: Research Article
Abstract: Aim of this study was to evaluate the usefulness of a Multidimensional Prognostic Index (MPI) based on a Comprehensive Geriatric Assessment (CGA) for predicting mortality risk in older patients with dementia. The present was a retrospective study with a year of follow-up that included 262 patients aged 65 years and older with a diagnosis of dementia. A standardized CGA that included information on clinical, cognitive, functional, and nutritional aspects, as well as comorbidity, medications, and social support network, was used to calculate MPI. The predictive value of the MPI for all-cause mortality over 1 month, 6 months, and 12 months …of follow-up was evaluated. Higher MPI values were significantly associated with higher mortality at 1 month (MPI-1, low risk = 0%, MPI-2, moderate risk = 5.2%, MPI-3, severe risk = 13.7%; p < 0.002), 6-months (MPI-1 = 2.7%, MPI-2 = 11.2%, MPI-3 = 28.8%; p < 0.001), and 12-months (MPI-1 = 2.7%, MPI-2 = 18.2%, MPI-3 = 35.6%; p < 0.001) of follow-up. The discrimination of the MPI was also good, with areas under the ROC curves of 0.77 (sensitivity = 82.9%, specificity = 66.0%, with a cut off value > 0.16) at 12-months of follow up. In conclusion, the MPI, calculated from information collected in a standardized CGA, accurately stratified hospitalized elderly patients with dementia into groups at varying risk of short- and long-term mortality. Show more
Keywords: Comprehensive Geriatric Assessment (CGA), dementia, mortality, Multidimensional Prognostic Index (MPI), prognosis, survival
DOI: 10.3233/JAD-2009-1139
Citation: Journal of Alzheimer's Disease, vol. 18, no. 1, pp. 191-199, 2009
Authors: Littlejohns, Thomas J. | Kos, Katarina | Henley, William E. | Cherubini, Antonio | Ferrucci, Luigi | Lang, Iain A. | Langa, Kenneth M. | Melzer, David | Llewellyn, David J.
Article Type: Research Article
Abstract: Background: US studies suggest that leptin, a fat-derived hormone, may be protective against the development of dementia. Objective: To investigate the complex relationship between leptin levels and cognitive decline in elderly Italians. Methods: We studied circulating fasting leptin levels in 809 elderly adults free from dementia who participated in the prospective Italian population-based InCHIANTI study between 1998 and 2009 (mean follow-up of 8.0 years). Global cognitive decline was defined as a reduction of ≥5 points on the Mini-Mental State Examination (MMSE). Trail-Making Tests A and B were also incorporated, with cognitive decline defined as discontinued testing or the worst 10% …of change from baseline. We also investigated whether any association could be explained by midlife weight and whether cognitive decline was associated with changing leptin levels. Results: The multivariate adjusted relative risk ([RR]; 95% confidence interval [CI]) of cognitive decline on the MMSE was 0.84 (95% CI 0.73–0.97) in relation to baseline sex-standardized log-leptin levels. High leptin levels showed a non-significant trend toward a reduced risk of decline on the Trail-Making Tests A (RR = 0.85, 95% CI 0.71–1.02) and B (RR = 0.90, 0.79–1.02). Adjusting for midlife weight or change in weight did not alter the pattern of results, and cognitive decline was not associated with changing leptin levels. Conclusions: High leptin levels were independently associated with a reduced risk of cognitive decline in elderly Italians. Show more
Keywords: Adipokines, cognitive decline, cohort analysis, epidemiology, leptin
DOI: 10.3233/JAD-141836
Citation: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1231-1239, 2015
Authors: Mielke, Michelle M. | Haughey, Norman J. | Han, Dingfen | An, Yang | Bandaru, Veera Venkata Ratnam | Lyketsos, Constantine G. | Ferrucci, Luigi | Resnick, Susan M.
Article Type: Research Article
Abstract: Background: Cellular and animal studies demonstrated relationships between sphingolipid metabolism and Alzheimer’s disease (AD) pathology. High blood ceramide levels have been shown to predict cognitive impairment and AD, but these studies had small sample sizes and did not assess differences in risk by sex or APOE genotype. Objective: To determine whether plasma ceramides and sphingomyelins were associated with risk of AD, and whether the association varied by sex and APOE genotype. Methods: Participants included 626 men and 366 women, aged 55 years and older, enrolled in the Baltimore Longitudinal Study of Aging. Plasma ceramides and sphingomyelins were determined using quantitative …analyses performed on a high-performance liquid chromatography coupled electrospray ionization tandem mass spectrometer. Cox proportional hazards models, stratified by sex, were used to examine the relationship of plasma ceramides and sphingomyelins with risk of AD over a mean (SD) follow-up of 15.0 (7.0) years for men and 13.1 (5.9) years for women. Results: Among men, the highest tertile of most ceramides and sphingomyelins were associated with an increased risk of AD. Among women, there were no associations between any of the ceramides and risk of AD. In contrast, women in the highest tertile of most sphingomyelins had a reduced risk of AD, which was most pronounced among APOE ɛ 4 carriers. Conclusion: These results provide further evidence for the role of sphingolipid metabolism in AD and highlight the importance of considering sex and APOE genotype in assessing this relationship. Show more
Keywords: Alzheimer’s disease, ceramides, cohort study, Epidemiology, lipids, longitudinal, sex differences
DOI: 10.3233/JAD-160925
Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 819-828, 2017