Search

Background: Brain ageing is highly heterogeneous, as it is driven by a variety of normal and neuropathological processes. These processes may differentially affect structural and functional brain ageing across individuals, with more pronounced ageing (older brain age) during midlife being indicative of later development of dementia. Here, we examined whether brain-ageing heterogeneity in unimpaired older adults related to neurodegeneration, different cognitive trajectories, genetic and amyloid-beta (Aβ) profiles, and to predicted progression to Alzheimer's disease (AD)., Methods: Functional and structural brain age measures were obtained for resting-state functional MRI and structural MRI, respectively, in 3460 cognitively normal individuals across an age range spanning 42-85 years. Participants were categorised into four groups based on the difference between their chronological and predicted age in each modality: advanced age in both (n = 291), resilient in both (n = 260) or advanced in one/resilient in the other (n = 163/153). With the resilient group as the reference, brain-age groups were compared across neuroimaging features of neuropathology (white matter hyperintensity volume, neuronal loss measured with Neurite Orientation Dispersion and Density Imaging, AD-specific atrophy patterns measured with the Spatial Patterns of Abnormality for Recognition of Early Alzheimer's Disease index, amyloid burden using amyloid positron emission tomography (PET), progression to mild cognitive impairment and baseline and longitudinal cognitive measures (trail making task, mini mental state examination, digit symbol substitution task)., Findings: Individuals with advanced structural and functional brain-ages had more features indicative of neurodegeneration and they had poor cognition. Individuals with a resilient brain-age in both modalities had a genetic variant that has been shown to be associated with age of onset of AD. Mixed brain-age was associated with selective cognitive deficits., Interpretation: The advanced group displayed evidence of increased atrophy across all neuroimaging features that was not found in either of the mixed groups. This is in line with biomarkers of preclinical AD and cerebrovascular disease. These findings suggest that the variation in structural and functional brain ageing across individuals reflects the degree of underlying neuropathological processes and may indicate the propensity to develop dementia in later life., Funding: The National Institute on Aging, the National Institutes of Health, the Swiss National Science Foundation, the Kaiser Foundation Research Institute and the National Heart, Lung, and Blood Institute., Competing Interests: Declaration of interests TB has received investigator-initiated research awards from the NIH, the Alzheimer’s Association, the Foundation at Barnes-Jewish Hospital, Siemens Healthineers, Hyperfine and Avid Radiopharmaceuticals (a wholly-owned subsidiary of Eli Lilly and Company). She participates as a site investigator in clinical trials sponsored by Eli Lilly and Company, Biogen, Eisai, Jaansen, and Roche. She has served as a paid and unpaid consultant to Eisai, Siemens, Biogen, Janssen, Hyperfine, Merck Lilly, and Bristol-Myers Squibb. JCM has served as a paid consultant to the Barcelona Brain Research Center and the Native Alzheimer Disease-related Resource Center in Minority Aging Research. He also received payments for presentations at the AAIM meeting, Longer Life Foundation and the International Brain Health Symposium. JCM has received travel support to attend meetings including: AAIM, DIAN, AD/PD, ATRI/ADNI, ADRC, ADC, the International conference on Health Aging & Biomarkers and the International Brain Health Symposium. He has served on the advisory board for the Cure Alzheimer’s Fund and LEADS at Indiana University. IMN has received payments from Premier, Inc for participating in an advisory board, from Peerview for an educational talk, and from Subtle Medical, Inc for consulting. DW has served as a paid consultant to Qynapse, Beckman Coulter and Eli Lilly. He also received grants from the NIH and Biogen paid to his institution and received travel support from the Alzheimer's Association. SR is an NIA IRP employee and has served on the advisory board of Dementia Platforms, UK, the Canadian Consortium on Neurodegeneration in Aging and the Adult Aging Brain Connectome. She has received travel support from the McKnight Foundation to attend an annual meeting., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: This study aimed to investigate how skeletal muscle attenuation and adipose tissue (AT) attenuation of the quadriceps, hamstrings, paraspinal muscle groups and the psoas muscle vary according to the targeted muscles, sex, and age., Design: Population-based cross-sectional study., Setting: Community-dwelling old population in Reykjavik, Iceland., Subjects: A total of 5331 older adults (42.8% women), aged 66-96 years from the Age, Gene/Environment Susceptibility (AGES)- Reykjavik Study, who participated in the baseline visit (between 2002 and 2006) and had valid thigh and abdominal computed tomography (CT) scans were studied., Methods: Muscle attenuation and AT attenuation of the quadriceps, hamstrings, paraspinal muscle groups and the psoas muscle were determined using CT. Linear mixed model analysis of variance was performed for each sex, with skeletal muscle or AT attenuation as the dependent variable., Results: Muscle attenuation decreased, and AT attenuation increased with age in both sexes, and these differences were specific for each muscle, although not in all age groups. Age-related differences in muscle and AT attenuation varied with specific muscle. In general, for both sexes, skeletal muscle attenuation of the hamstrings declined more than average with age. Men and women displayed a different pattern in the age differences in AT attenuation for each muscle., Conclusions: Our data support the hypotheses that skeletal muscle attenuation decreases, and AT attenuation increases with aging. In addition, our data add new evidence, supporting that age-related differences in skeletal muscle and AT attenuation vary between muscles., (Copyright © 2021 Elsevier Inc. All rights reserved.)

In this case-cohort study, we used data-driven computational anatomy approaches to assess within and between sex spatial differences in proximal femoral bone characteristics in relation to incident hip fracture. One hundred male and 234 female incident hip fracture cases, and 1047 randomly selected noncase subcohort participants (562 female) were chosen from the population-based AGES-Reykjavik study (mean age of 77 years). The baseline -i.e. before hip fracture- hip quantitative computed tomography scans of these subjects were analyzed using voxel-based morphometry, tensor-based morphometry, and surface-based statistical parametric mapping to assess the spatial distribution of volumetric bone mineral density (vBMD), internal structure, and cortical bone properties (thickness, vBMD and trabecular vBMD adjacent to the endosteal surface) of the proximal femur, respectively, in relation to incident hip fracture. Results showed that in both men and women: 1) the superior aspect of the femoral neck and the trochanteric region (except for cortical bone thickness) were consistently identified as being associated with incident hip fracture, and 2) differences in bone properties between noncases and incident hip fracture cases followed similar trends, were located at compatible regions, and manifested heterogeneity in the spatial distribution of their magnitude with focal regions showing larger differences. With respect to sex differences, most of the regions with a significant interaction between fracture group and sex showed: 1) differences of greater magnitude in men between noncases and incident hip fracture cases with different spatial distributions for all bone properties with the exception of cortical bone thickness, and 2) that while most of these regions showed better bone quality in male cases than in female cases, female cases showed higher vBMD in the principal compressive group and higher endotrabecular vBMD at several regions including the anterior, posterior, and lateral aspects of the proximal femur. These findings indicate the value of these image analysis techniques by providing unique information about the specific patterns of bone deterioration associated with incident hip fracture and their sex differences, highlighting the importance of looking to men and women separately in the assessment of hip fracture risk., (Copyright © 2018. Published by Elsevier Inc.)

Background: Atrophy and fatty infiltration of muscle with aging are associated with fractures and falls, however, their direct associations with muscle function are not well described. It was hypothesized that participants with lower quadriceps muscle attenuation, area, and greater intramuscular adipose tissue (IMAT) will exhibit slower rates of torque development (RTD) and lower peak knee extension torques., Methods: Data from 4,842 participants (2,041 men, 2,801 women) from the Age Gene/Environment Susceptibility Reykjavik Study (mean age 76 ± 0.1 years) with complete thigh computed tomography and isometric knee testing. Regression models were adjusted for health, behavior, and comorbidities. Muscle attenuation was further adjusted for muscle area and IMAT; muscle area adjusted for IMAT and attenuation; and IMAT adjusted for muscle area and attenuation. Standardized betas (β) indicate association effect sizes., Results: In the fully-adjusted models, attenuation (men β = 0.06, 95% CI: 0.01, 0.11; women β = 0.07, 95% CI: 0.03, 0.11) and muscle area (men β = 0.13, 95% CI: 0.07, 0.19; women β = 0.10, 95% CI: 0.06, 0.15) were associated with knee RTD. Attenuation (men β = 0.12, 95% CI: 0.08, 0.16; women β = 0.12, 95% CI: 0.09, 0.16) and muscle area (men β = 0.38, 95% CI: 0.33, 0.43; women β = 0.33, 95% CI: 0.29, 0.37) were associated with peak torque., Conclusions: These data suggest that muscle attenuation and area are independently associated with RTD and peak torque; and that area and attenuation demonstrate similar contributions to RTD.

Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N=78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P<5 × 10 -8 ), we found suggestive evidence (P<5 × 10 -6 ) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (for example, NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions.

We aimed to investigate if trajectory components (baseline level, slope, and variability) of peripheral interleukin-6 (IL-6) over time were related to cognitive impairment and smaller hippocampal volume and if hippocampal volume explained the associations between IL-6 and cognitive impairment. Multivariable regression models were used to test the association between IL-6 trajectory components with change in neuroimaging measures of the hippocampus and with cognitive impairment among 135 older adults (70-79 years at baseline) from the Healthy Brain Project over 14 years. IL-6 variability was positively associated with cognitive impairment (odds ratio [OR] = 5.86, 95% confidence interval [CI]: 1.24, 27.61) and with greater decrease per year of gray matter volume of the hippocampus (β = -0.008, standard error = 0.004, p = 0.03). After adjustment for hippocampal volume, the OR of cognitive impairment decreased for each unit of IL-6 variability and CIs widened (OR = 4.36, 95% CI: 0.67, 28.29). Neither baseline levels nor slopes of IL-6 were related to cognitive impairment or hippocampal volume. We believe this has potential clinical and public health implications by suggesting adults with stable levels of peripheral IL-6 may be better targets for intervention studies for slowing or preventing cognitive decline., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Chronic kidney disease (CKD) is common in the elderly, but the cause is often not identifiable. Some posit that age-related reductions in glomerular filtration rate (GFR) and increases in albuminuria are normal, whereas others suggest that they are a consequence of vascular disease., Study Design: Cross-sectional analysis of a substudy of a prospective cohort., Setting & Participants: AGES (Age, Gene/Environment Susceptibility)-Reykjavik Study., Predictor: Exposure to higher blood pressure in midlife., Outcomes & Measurements: Measured GFR using plasma clearance of iohexol and urine albumin-creatinine ratio., Results: GFR was measured in 805 participants with mean age in midlife and late life of 51.0±5.8 and 80.8±4.0 (SD) years, respectively. Mean measured GFR was 62.4±16.5 mL/min/1.73 m(2) and median albuminuria was 8.0 (IQR, 5.4-16.5) mg/g. Higher midlife systolic and diastolic blood pressures were associated with lower later-life GFRs. Associations persisted after adjustment. Higher midlife systolic and diastolic blood pressures were also associated with higher albumin-creatinine ratios, and associations remained significant even after adjustment., Limitations: This is a study of survivors, and people who agreed to participate in this study were healthier than those who refused. Blood pressure may encompass effects of the other risk factors. Results may not be generalizable to populations of other races. We were not able to adjust for measured GFR or albuminuria at the midlife visit., Conclusions: Factors other than advanced age may account for the high prevalence of CKD in the elderly. Midlife factors are potential contributing factors to late-life kidney disease. Further studies are needed to identify and treat midlife modifiable factors to prevent the development of CKD., (Copyright © 2015 National Kidney Foundation, Inc. All rights reserved.)

Background: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting., Methods: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults., Results: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10(-10)) and replication cohorts (p = 5.65 × 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10(-8), and rs6813517 [SPOCK3], p = 2.58 × 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism., Conclusions: This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways., (Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: To quantify racial differences in brain structural characteristics in white and black octogenarians, and to examine whether these characteristics contribute to cognition., Methods: Cross-sectional study of 283 adults 79-89 years old (59.4% white;42.0% women) with data on gray matter integrity via diffusion tensor imaging (mean diffusivity), gray matter atrophy (GMA), white matter hyperintensities (WMH), literacy, smoking, drinking, income, hypertension and diabetes. Participants were recruited from an ongoing epidemiological study of older adults living in the community with a range of chronic conditions, physical and cognitive function. Standardized betas (sβ) of neuroimaging markers predicting Digit Symbol Substitution Test (DSST) and Modified Mini-Mental State Examination (3MS) scores were computed in multivariable regression models stratified by race., Results: Compared to whites, blacks had lower DSST (p=0.001) and lower 3MS (p=0.006), but also lower mean diffusivity (i.e. higher gray matter microstructural integrity, p=0.032), independent of gender, income, literacy, body mass index, diabetes and drinking habits. Racial differences were not significant for WMH (p=0.062) or GMA (p=0.4). Among blacks, mean diffusivity and WMH were associated with DSST (sβ=-.209, p=0.037 and -.211, p=.038, respectively) independent of each other and other covariates; among whites, mean diffusivity, but not WMH, was significantly associated with DSST and 3MS (sβ =-.277, p=.002 and -.250, p=0.029, respectively)., Conclusions: In this cohort of octogenarians living in the community, blacks appeared to have higher microstructural integrity of gray matter as compared to whites. This neuroimaging marker was related to higher cognition even in the presence of WMH and other cardiovascular conditions. If confirmed, these findings suggest microstructural gray matter integrity may be a target to improve cognition, especially among blacks who survive to very old age with a range of chronic cardiovascular conditions., Competing Interests: The authors report no conflicts of interest.

Experimental mild heat shock is widely known as an intervention that results in extended longevity in various models along the evolutionary lineage. Heat shock proteins (HSPs) are highly upregulated immediately after a heat shock. The elevation in HSP levels was shown to inhibit stress-mediated cell death, and recent experiments indicate a highly versatile role for these proteins as inhibitors of programmed cell death. In this study, we examined common genetic variations in 31 genes encoding all members of the HSP70, small HSP, and heat shock factor (HSF) families for their association with all-cause mortality. Our discovery cohort was the Rotterdam study (RS1) containing 5,974 participants aged 55 years and older (3,174 deaths). We assessed 4,430 single nucleotide polymorphisms (SNPs) using the HumanHap550K Genotyping BeadChip from Illumina. After adjusting for multiple testing by permutation analysis, three SNPs showed evidence for association with all-cause mortality in RS1. These findings were followed in eight independent population-based cohorts, leading to a total of 25,007 participants (8,444 deaths). In the replication phase, only HSF2 (rs1416733) remained significantly associated with all-cause mortality. Rs1416733 is a known cis-eQTL for HSF2. Our findings suggest a role of HSF2 in all-cause mortality.

Although organochlorines have been reported more frequently in Parkinson's disease (PD) brains than in controls, the association with brain Lewy pathology is unknown. Honolulu-Asia Aging Study (HAAS) participants, exposed to organochlorines from a variety of sources during midlife, represent a population well suited to determining the relationship of brain organochlorines with Lewy pathology in decedents from the longitudinal HAAS. The study design included the measurement of 21 organochlorine levels in frozen occipital lobe samples from HAAS decedents. Alpha-synuclein immunostaining performed on 225 brains was used to identify Lewy bodies and Lewy neurites. With the potential for spurious associations to appear between Lewy pathology and 17 organochlorine compounds found in at least 1 brain, initial assessments identified heptachlor epoxide isomer b, methoxychlor, and benzene hexachloride b as being most important. The prevalence of Lewy pathology was 75% (6 of 8) among brains with any 2 of the 3 compounds, 48.8% (79 of 162) among those with 1, and 32.7% (18 of 55) for those with neither (P = .007 test for trend). Although findings persisted after removing cases with PD and dementia with Lewy bodies and after adjustment for age at death, body mass index, pack-years of cigarette smoking, and coffee intake (P = .013), the results were insignificant when correcting for multiple testing. Although consistent with earlier accounts of an association between organochlorines and clinical PD, associations with Lewy pathology warrant further study., (Copyright © 2012 Movement Disorder Society.)

Unlabelled: We examined if lifelong physical activity is important for maintaining bone strength in the elderly. Associations of quantitative computerized tomography-acquired bone measures (vertebral and femoral) and self-reported physical activity in mid-life (mean age, 50 years), in old age (≥65 years), and throughout life (recalled during old age) were investigated in 2,110 men and 2,682 women in the AGES-Reykjavik Study. Results conclude lifelong physical activity with continuation into old age (≥65 years) best maintains better bone health later in life., Introduction: Skeletal loading is thought to modulate the loss of bone in later life, and physical activity is a chief means of affecting bone strength by skeletal loading. Despite much discussion regarding lifelong versus early adulthood physical activity for preventing bone loss later in life, inconsistency still exists regarding how to maintain bone mass later in life (≥65 years)., Methods: We examined if lifelong physical activity is important for maintaining bone strength in the elderly., Results: The associations of quantitative computerized tomography-acquired vertebral and femoral bone measures and self-reported physical activity in mid-life (mean age, 50 years), in old age (≥65 years), and throughout life (recalled during old age) were investigated in 2,110 men and 2,682 women in the AGES-Reykjavik Study., Conclusion: Our findings conclude that lifelong physical activity with continuation into old age (≥65 years) best maintains better bone health in the elderly.

Aims/hypothesis: We aimed to describe the prevalence of retinopathy in an aged cohort of Icelanders with and without diabetes mellitus., Methods: The study population consisted of 4,994 persons aged ≥ 67 years, who participated in the Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-R). Type 2 diabetes mellitus was defined as HbA(1c) ≥ 6.5% (>48 mmol/mol). Retinopathy was assessed by grading fundus photographs using the modified Airlie House adaptation of the Early Treatment Diabetic Retinopathy Study protocol. Associations between retinopathy and risk factors were estimated using odds ratios obtained from multivariate analyses., Results: The overall prevalence of retinopathy in AGES-R was 12.4%. Diabetes mellitus was present in 516 persons (10.3%), for 512 of whom gradable fundus photos were available, including 138 persons (27.0%, 95% CI 23.2, 31.0) with any retinopathy. Five persons (1.0%, 95% CI 0.3, 2.3) had proliferative retinopathy. Clinically significant macular oedema was present in five persons (1.0%, 95% CI 0.3, 2.3). Independent risk factors for retinopathy in diabetic patients in a multivariate model included HbA(1c), insulin use and use of oral hypoglycaemic agents, the last two being indicators of longer disease duration. In 4478 participants without diabetes mellitus, gradable fundus photos were available for 4,453 participants, with retinopathy present in 476 (10.7%, 95% CI 9.8, 11.6) and clinically significant macular oedema in three persons. Independent risk factors included increasing age and microalbuminuria., Conclusions/interpretation: Over three-quarters (78%) of retinopathy cases were found in persons without diabetes and a strong association between microalbuminuria and non-diabetic retinopathy was found. These results may have implications for patient management of the aged.

Objective: Several studies report that diabetes increases risk of cognitive impairment; some have hypothesized that advanced glycation end products (AGEs) underlie this association. AGEs are cross-linked products that result from reactions between glucose and proteins. Little is known about the association between peripheral AGE concentration and cognitive aging., Methods: We prospectively studied 920 elders without dementia, 495 with diabetes and 425 with normal glucose (mean age 74.0 years). Using mixed models, we examined baseline AGE concentration, measured with urine pentosidine and analyzed as tertile, and performance on the Modified Mini-Mental State Examination (3MS) and Digit Symbol Substitution Test (DSST) at baseline and repeatedly over 9 years. Incident cognitive impairment (a decline of >1.0 SD on each test) was analyzed with logistic regression., Results: Older adults with high pentosidine level had worse baseline DSST score (p=0.05) but not different 3MS score (p=0.32). On both tests, there was a more pronounced 9-year decline in those with high and mid pentosidine level compared to those in the lowest tertile (3MS 7.0, 5.4, and 2.5 point decline, p overall <0.001; DSST 5.9, 7.4, and 4.5 point decline, p=0.03). Incident cognitive impairment was higher in those with high or mid pentosidine level than those in the lowest tertile (3MS: 24% vs 17%, odds ratio=1.55; 95% confidence interval 1.07-2.26; DSST: 31% vs 22%, odds ratio=1.62; 95% confidence interval 1.13-2.33). There was no interaction between pentosidine level, diabetes status, and cognitive decline. Multivariate adjustment for age, sex, race, education, hypertension, cardiovascular disease, estimated glomerular filtration rate, and diabetes diminished results somewhat but overall patterns remained similar., Conclusion: High peripheral AGE level is associated with greater cognitive decline in older adults with and without diabetes.

Objective: To determine if levels of serum estradiol and testosterone can predict stroke in a population-based sample of elderly men., Methods: Serum 17beta estradiol and testosterone were measured in 2,197 men aged 71 to 93 years who participated in the Honolulu-Asia Aging Study from 1991 to 1993. All were free of prevalent stroke, coronary heart disease, and cancer. Participants were followed to the end of 1998 for thromboembolic and hemorrhagic events., Results: During the course of follow-up, 124 men developed a stroke (9.1/1,000 person-years). After age adjustment, men in the top quintile of serum estradiol (> or =125 pmol/L [34.1 pg/mL]) experienced a twofold excess risk of stroke vs men whose estradiol levels were lower (14.8 vs 7.3/1,000 person-years, p < 0.001). Among the lower quintiles, there were little differences in the risk of stroke. Findings were also significant and comparable for bioavailable estradiol and for thromboembolic and hemorrhagic events. After additional adjustment for hypertension, diabetes, adiposity, cholesterol concentrations, atrial fibrillation, and other characteristics, men in the top quintile of serum estradiol continued to have a higher risk of stroke vs those whose estradiol levels were lower (relative hazards = 2.2; 95% CI = 1.5 to 3.4, p < 0.001). Testosterone was not related to the risk of stroke., Conclusions: High levels of serum estradiol may be associated with an elevated risk of stroke in elderly men.

We investigated the association between MRI detected brain lesions and levels of endogenous sex hormones in Japanese-American men aged 74-95 years. Logistic regression was used to estimate the association (OR (95% CI)) of MRI outcome with tertiles of bioavailable testosterone, 17beta estradiol and sex hormone binding globulin (SHBG). There was a significantly increased risk for cerebral atrophy in the highest tertile of testosterone (3.1 (1.2-7.8)) compared to the lowest. We also found that men with the highest estradiol had a higher risk of lacunes (1.92 (1.1-3.2)). These relationships did not change with adjustment for the other sex hormones, cardiovascular risk factors, or other brain lesions. In contrast, men with the highest SHBG had a lower risk both of cerebral atrophy and lacunes, after adjusting for sex hormones and cardiovascular risk factors. There were no associations between sex hormones and hippocampal atrophy, white matter lesions, and large infarcts. Because the levels of hormone were measured close in time to the acquisition of the MRI, these associations may reflect neurodegeneration in brain regions regulating hormone levels.

As population-based epidemiologic studies may acquire images from thousands of subjects, automated image post-processing is needed. However, error in these methods may be biased and related to subject characteristics relevant to the research question. Here, we compare two automated methods of brain extraction against manually segmented images and evaluate whether method accuracy is associated with subject demographic and health characteristics. MRI data (n = 296) are from the Honolulu Asia Aging Study, a population-based study of elderly Japanese-American men. The intracranial space was manually outlined on the axial proton density sequence by a single operator. The brain was extracted automatically using BET (Brain Extraction Tool) and BSE (Brain Surface Extractor) on axial proton density images. Total intracranial volume was calculated for the manually segmented images (ticvM), the BET segmented images (ticvBET) and the BSE segmented images (ticvBSE). Mean ticvBSE was closer to that of ticvM, but ticvBET was more highly correlated with ticvM than ticvBSE. BSE had significant over (positive error) and underestimated (negative error) ticv, but net error was relatively low. BET had large positive and very low negative error. Method accuracy, measured in percent positive and negative error, varied slightly with age, head circumference, presence of the apolipoprotein eepsilon4 polymorphism, subcortical and cortical infracts and enlarged ventricles. This epidemiologic approach to the assessment of potential bias in image post-processing tasks shows both skull-stripping programs performed well in this large image dataset when compared to manually segmented images. Although method accuracy was statistically associated with some subject characteristics, the extent of the misclassification (in terms of percent of brain volume) was small.

Based on many experimental and observational studies we now understand that neurodegenerative brain changes begin by middle age. Characteristics of the risk factors for these brain changes may also change with age. A review is conducted of studies that report on the association of mid-life risk factors to late cognitive impairment and dementia. Issues related to the interpretation of the data are discussed. The studies suggest that mid-life cardiovascular risk factors, and in particular elevated levels of blood pressure, increase the risk for late-life cognitive impairment and dementia. Our understanding the contribution of cardiovascular risk factors to late age brain disease has been helped tremendously by prospective studies with long follow-up. To better understand which risk factors lead to disease initiation, progression and prognosis, a life course approach to the epidemiologic study of dementia is needed.

Longitudinal data from the MacArthur Study of Successful Aging were used to test for interactions between education and apolipoprotein E (APOE) genotype with respect to time trends in cognitive performance. Interactions between education, APOE-e4 status, and time were found for overall cognitive function, and for subscales measuring memory and naming: The presence of the e4 allele was associated with steeper declines in cognition for those with a greater than eighth-grade education. For those with an eighth-grade education or less, time trends did not differ by APOE genotype. A measure of cognitive impairment (i.e., scores of < or = 7 on the Short Portable Mental Status Questionnaire) yielded parallel though weaker evidence for a similar interaction with respect to risk of cognitive impairment. These findings suggest that the presence of at least one e4 allele appears to reduce the protective effects of education for those with at least a ninth-grade education or more, resulting in steeper cognitive declines with age.

Objectives: To evaluate the association between insulin resistance (IR) and executive dysfunction in a large, population-based study of older persons without diabetes mellitus (DM) or dementia., Design: Cross-sectional study., Setting: Outpatient clinic in Greve in Chianti and Bagno a Ripoli, Italy., Participants: A total of 597 subjects aged 65 to 93 without DM or dementia., Measurements: Anthropometric measurements; plasma fasting levels of glucose, insulin, cholesterol (total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol), and insulin-like growth factor-1 (IGF-1); homeostasis model assessment (HOMA) to estimate degree of IR; Trail Making Test (TMT) A; TMT-B; TMT-B minus TMT-A (DIFF B-A); and Mini-Mental State Examination (MMSE)., Results: IR (HOMA) was associated with longer TMT-B (correlation coefficient (r)=0.11; P=.006) and DIFF B-A times (r=0.10; P=.022). Subjects in the upper tertile of IR were older and had longer TMT-B and DIFF B-A than participants in the lowest tertile. After adjusting for age, sex, and years of formal education, IR was significantly correlated with TMT-A, TMT-B, and DIFF B-A. After adjusting for age, sex, education, body mass index, waist:hip girth ratio, HDL-C, triglycerides, IGF-1, hypertension, drug intake, and physical activity, the results did not significantly change. After introducing MMSE score into the model, IR continued to be an independent determinant of TMT-A (beta=11.005; P=.021), TMT-B (beta=28.379; P<.001), and DIFF B-A (beta=17.374; P=.011)., Conclusion: IR is independently associated with frontal cortex function evidenced by poor TMT times in older persons without DM or dementia.

Substantia nigra (SN) neurons were counted on single, transverse caudal midbrain sections from 217 male participants in the Honolulu-Asia Aging Study, aged 74-97 years at death. Quadrants areas within the SN were determined with a planimeter and neuronal density was expressed as neurons/mm(2) for 10 Parkinson's disease (PD) cases, 29 incidental Lewy body cases, and 178 controls with neither condition. Mean densities in all quadrants were significantly lower in the PD group compared with the other groups (p = 0.006). This relationship was strongest in the ventrolateral quadrant. In a subgroup of 50 controls who were examined with the Unified Parkinson's Disease Rating Scale an average of 2.1 years prior to death, there was an association of stooped posture (p = 0.009), postural instability (p = 0.013), body bradykinesia (p = 0.048), and gait disturbance (p = 0.05) with neuron density in the dorsolateral quadrant; and impaired speech (p = 0.014), abnormal facial expression (p = 0.022), and difficulty rising from a chair (p = 0.032) with neuron density in the dorsomedial quadrant. There was a significant association of increasing number of signs present with decreasing neuron density in both quadrants (p = 0.001 for trend). Low SN neuron density may be the basis for parkinsonian signs in the elderly without PD.

Background: While a genetic risk factor for late-onset AD, the effects of the epsilon4 allele of the APOE gene on cognitive functioning more generally remain unclear., Objective: To assess the role of the epsilon4 allele of the APOE gene in longitudinal cognitive decline., Methods: Multiple measures of cognitive function were assessed longitudinally in the MacArthur Successful Aging Study, a population-based cohort free of frank impairment at baseline. Subjects were 965 Caucasian and African American men and women from Durham NC, East Boston, MA, and New Haven, CT, aged 70 to 79 years, recruited in 1988 through 1989, who completed two follow-up evaluations, one at 3 years and another at 7 years., Results: At the first follow-up, modest but significant declines in naming and spatial ability were associated with the APOE-epsilon4 genotype. By the second follow-up, more pronounced and significant associations were noted between the APOE-epsilon4 genotype and cognitive decline from six of the eight cognitive outcomes. After 7 years, APOE-epsilon4 allele carriers were twice as likely to have declined on a global cognitive score (odds ratio = 2.0; 95% CI: 1.1, 3.6) as noncarriers., Conclusions: APOE-epsilon4 is associated with cognitive decline among a high-functioning elderly cohort, with effects most pronounced after 7 years of follow-up. Hence, the epsilon4 allele either may function as a risk factor for cognitive impairment in normal aging across a broad spectrum of domains or may exert detectable effects early in a long prodromal AD trajectory.

Background: Clinical and subclinical hypothyroidism is associated with cognitive impairment., Objective: This study investigated the association between thyroxine (T(4)) and thyroid-stimulating hormone (TSH) level and change over time in cognitive performance in a sample of older women with normal thyroid gland function., Methods: T(4) and TSH were measured at baseline in 628 women (> or = 65 years) enrolled in the Women's Health and Aging Study, a community-based study of physically impaired women. Cognitive function was assessed at baseline and after 1, 2, and 3 years, using the Mini-Mental State Examination (MMSE). Incident cognitive decline was defined as a decrease of more than one point/year in MMSE score between baseline and the end of the follow-up. The analysis included 464 subjects with normal thyroid gland function with a baseline and at least one follow-up MMSE., Results: At baseline there was no association between T(4) and TSH level and cognitive function. In longitudinal analysis, adjusting for age, race, level of education, and other covariates, compared with women in the highest T(4) tertile (8.1 to 12.5 microg/dL), those in the lowest tertile (4.5 to 6.5 microg/dL) had a greater decline in MMSE score (-0.25 point/year vs -0.12 point/year; p = 0.04). A total of 95 women (20.5%) had cognitive decline during the study period (mean MMSE decline, 5.5 points). Compared with women in the highest T(4) tertile, those in the lowest tertile had a twofold risk of cognitive decline (adjusted relative risk, 1.97; 95% CI, 1.10 to 3.50). The results were not modified by baseline cognitive and physical function. There was no association between baseline TSH level and change in cognitive function., Conclusions: In older women, low T(4) levels, within the normal range, were associated with a greater risk of cognitive decline over a 3-year period. Thyroid hormone levels may contribute to cognitive impairment in physically impaired women.

Objectives: To assess the longitudinal association between sleep disturbances (insomnia and daytime sleepiness) and incidence of dementia and cognitive decline in older men., Design: Community-based longitudinal cohort study., Setting: The Honolulu-Asia Aging Study of dementia that is linked to the Honolulu Heart Program's fourth examination, conducted 1991-1993, and the 3-year follow-up fifth examination, conducted 1994-1996., Participants: Two thousand three hundred forty-six Japanese-American men age 71 to 93 years who screened negative for prevalent dementia at baseline and were screened again for dementia incidence in a 3-year follow-up examination., Measurements: Baseline self-reports of trouble falling asleep or early morning awakening (insomnia) and being sleepy during the day (daytime sleepiness); Cognitive Abilities Screening Instrument (CASI) scores from baseline and followup; clinical diagnosis of incident dementia; and other baseline measures including age, years of education, body mass index, depressive symptoms, and history of hypertension, heart disease, diabetes mellitus, asthma, and use of benzodiazepines., Results: After adjusting for age and other factors, persons reporting excessive daytime sleepiness at baseline (8%) were twice as likely to be diagnosed with incident dementia than were those not reporting daytime sleepiness (odds ratio (OR)=2.19, 95% confidence interval (CI)=1.37-3.50) and about 40% more likely to have >or=9 point drop in their CASI score between examinations (OR=1.44, 95% CI=1.01-2.08). In contrast, insomnia was not associated with cognitive decline or incidence of dementia., Conclusions: Daytime sleepiness in older adults may be an early indicator of decline in cognitive functioning and onset of dementia.

Background and Purpose: The aim of this study was to explore the joint effect of the APOE epsilon4 allele and midlife systolic blood pressure (SBP) on the risk for poor cognitive function in late life., Methods: The study includes 3605 surviving members of the cohort of the Japanese-American men followed prospectively over 26 years (1965-1991) as a part of the Honolulu Heart Program. In 1965 men were aged 45 to 68 years and were living in the island of Oahu, Hawaii. For this study the sample was divided into 4 categories: normal SBP (<160 mm Hg)/No epsilon4, as the reference category; normal SBP/epsilon4; high SBP/no epsilon4; high SBP/epsilon4. The relative risk (RR) of late-life intermediate and poor cognitive function relative to good function was measured by the Cognitive Abilities Screening Instrument (CASI) test., Results: After adjusting for age, education, smoking, alcohol use, and body mass index, the RR for poor cognitive function (CASI <74) compared with good cognitive function (CASI >/=82) in never-treated subjects was 1.3 (95% CI 0.9 to 1.9) for the normal SBP/epsilon4 category, 2.6 (0.7 to 10.0) for the high SBP/no epsilon4, and 13.0 (1.9 to 83.8) for the high SBP/epsilon4. Adjustment for diabetes, prevalent stroke, coronary disease, and ankle-brachial index reduced the RR of poor cognition by 25.5% (RR 13.0 to 10.8) in those with both risk factors. In the treated group, the RR was 1.9 (0.7 to 4.5) for those with both risk factors., Conclusions: The results suggest that midlife high SBP has a stronger adverse effect on cognitive function in persons with higher genetic susceptibility, but this effect may be modified by antihypertensive treatment.

Purpose: The purpose of this study was to investigate the association between level of physical activity and risk of cognitive decline at older age and its variation across carriers and noncarriers of the apolipoprotein e4 allele., Methods: The association was studied in a cohort of 347 elderly Dutch men. Mean age of the study subjects was 74.6 +/- 4.3 yr in 1990. Physical activity was categorized in "maximal 1 h per day" versus "more than 1 h per day." Cognitive decline was defined as a drop MMSE score > 3 points between 1990 and 1993., Results: After adjusting for age, education, alcohol consumption, smoking and cognitive functioning at baseline, subjects with maximal 1 h of physical activity per day had a two-fold increased risk of cognitive decline (OR 2.0, 95% CI: 0.9-4.8) as compared with the rest. Risk of cognitive decline was particularly strong in carriers of the APOE*4 allele (adjusted OR 3.7, 95% CI: 1.1-12.6)., Conclusion: The authors conclude that promotion of physical activity at older age may reduce the risk of cognitive decline. The existence of subgroups with a particularly high risk may have important implications for prevention strategies.

Cardiovascular risk factors often cluster into a metabolic syndrome that may increase the risk of dementia. The objective of the present study was to assess the long-term association between clustered metabolic cardiovascular risk factors measured at middle age and the risk of dementia in old age. This prospective cohort study of cardiovascular disease was started in 1965 and was extended to a study of dementia in 1991. The subjects were Japanese-American men with an average age of 52.7+/-4.7 (mean+/-SD) years at baseline. Dementia was diagnosed in 215 men, according to international criteria, and was based on a clinical examination, neuropsychological testing, and an informant interview. The z scores were calculated for 7 risk factors (random postload glucose, diastolic and systolic blood pressures, body mass index, subscapular skinfold thickness, random triglycerides, and total cholesterol). The relative risk (RR [95% CI]) of dementia (subtypes) per 1 SD increase in the sum of the z scores was assessed after adjustment for age, education, occupation, alcohol consumption, cigarette smoking, and years of childhood lived in Japan. The z-score sum was higher in demented subjects than in nondemented subjects, indicating a higher risk factor burden (0.74 versus -0.06, respectively; P=0. 008). Per SD increase in the z-score sum, the risk of dementia was increased by 5% (RR 1.05, 95% CI 1.02 to 1.09). The z-score sum was specifically associated with vascular dementia (RR 1.11, 95% CI 1.05 to 1.18) but not with Alzheimer's disease (RR 1.00, 95% CI 0.94 to 1.05). Clustering of metabolic cardiovascular risk factors increases the risk of dementia (mainly, dementia of vascular origin).

We studied the association of mid-life blood pressure to late age dementia, specifically Alzheimer's disease and vascular dementia. Data are from the cohort of 3703 Japanese-American men who were followed in the Honolulu Heart Program (HHP;1965-1971), and subsequently re-examined in 1991 for dementia. We assessed the risk (odds ratio (95% CI)) for dementia associated with categories of systolic (SBP) and diastolic blood pressure (DBP), stratified by never/ever treatment with anti-hypertensive medications, and adjusting for age, education, apolipoprotein epsilon allele, smoking and alcohol intake. Among those never treated (57% sample), the risk for dementia was OR 95% CI 3.8 (1.6-8.7) for DBP of 90-94 mm Hg, and 4. 3 (1.7-10.8) for DBP of 95 mmHg and over compared to those with DBP of 80 to 89 mm Hg. Compared to those with SBP of 110 to 139 mm Hg, the risk for dementia was 4.8 (2.0-11.0) in those with SBP 160 mm Hg and higher. Blood pressure was not associated with the risk for dementia in treated men. These results were consistent for Alzheimer's disease and vascular dementia. This study suggests elevated levels of blood pressure in middle age can increase the risk for late age dementia in men never treated with anti-hypertensive medication.

Background: Smoking is reported to be positively related to abdominal fat in young and middle-aged persons; however, it is unclear whether this relationship exists in elderly persons. Behavioral influence on fat distribution is of importance because of the accumulation of abdominal fat with age and its associated health risks., Methods: The relationship was investigated in a population-based sample of 1,178 men and 1,163 women aged 55-85 years, representative of the Dutch older population in 1992-1993. Waist and hip circumference and their ratio were used as indices of fat distribution. Past and current smoking habits were obtained by questionnaire., Results: Smoking was associated with waist/hip-ratio (WHR) in men, with current smokers having the highest WHR and never smokers the lowest. A dose-response relationship between the daily number of cigarettes smoked and WHR was observed in men. These associations remained significant after adjustment for confounding due to age, education, body mass index, health status, alcohol intake, and sports activity. The dose-response relationship did not change after additional adjustment for duration of smoking. Among former male smokers, recent quitters had a higher WHR compared to long-term quitters. Additional analysis showed that smoking was more strongly associated with waist than with hip circumference. In women the relationship between smoking and fat distribution was not clear., Conclusions: Past and current smoking habits are positively associated with abdominal fat in older men, but not in older women.

Objectives: To study the association between cognitive status and plasma concentrations of various antioxidants in middle-aged and older individuals without neuropsychiatric disease., Design: Evaluation of cross-sectional data from a cohort study., Setting: The Austrian Stroke Prevention Study., Participants: A total of 1769 subjects aged 50 to 75 years, with no history or signs of neuropsychiatric disease, selected randomly from the community register., Measurements: The score on the Mattis Dementia Rating Scale (MDRS) was dichotomized according to age-and education-specific lowest quartile cut-off points. Reversed-phase high performance liquid chromatography measurements of the plasma concentrations of lutein/zeaxanthin, cryptoxanthin, canthaxanthin, lycopene, alpha-carotene, beta-carotene, retinol, gamma-tocopherol, alpha-tocopherol, and ascorbate were measured., Results: Individuals with MDRS results below the lowest quartile cut-off point had lower levels of beta-carotene and alpha-tocopherol than their counterparts with test performance above this limit (0.44+/-.33 micromol/L vs 0.51+/-.48 micromol/L, P < .001; and 29.50+/-7.98 micromol/L vs 30.93+/-11.10 micromol/L, P < .001, respectively). Only alphatocopherol remained significantly associated with cognitive functioning when logistic regression analysis was used to adjust for possible confounders including age, sex, month of blood sampling, years of education, smoking, lipid status, and major risk factors for stroke (P = .019)., Conclusion: These observations are compatible with the view that some dietary antioxidants may protect against cognitive impairment in older people.

The objective of this study was to investigate the relation between the peripheral concentrations of the adrenal steroid hormones cortisol and dehydroepiandrosterone sulfate (DHEAS) and cognitive impairment and decline. A prospective study design was used. The setting was a suburb of Rotterdam, The Netherlands. The study population consisted of a sample of 189 healthy participants from the population-based Rotterdam Study, aged 55-80 yr, who were invited for an additional examination. Follow-up examinations took place 1.9 yr after baseline, on the average. We determined fasting blood levels of DHEAS before dexamethasone administration and of cortisol and corticosteroid-binding globulin before and after the administration of 1 mg dexamethasone overnight. The 30-point Mini-Mental State Examination (MMSE) was used to assess cognition. The associations with cognitive impairment (MMSE score of <26; 6% of the sample) and cognitive decline (drop in MMSE score of >1 point/yr; 24%) were estimated using logistic regression, with adjustment for age, sex, education, and depressive symptoms. An increase of 1 SD in the estimate of free cortisol (SD = 30.3) was associated with cognitive impairment, although not significantly [odds ratio (OR) = 1.5; 95% confidence interval (CI), 0.9-2.4]. A 1 SD increase in the natural logarithm of cortisol after the administration of 1 mg dexamethasone (SD = 0.68) was associated with an OR for cognitive decline of 1.5 (95% CI, 1.0-2.3). A 1 SD increase in DHEAS (SD = 2.10 micromol/L) was inversely, but nonsignificantly, related to cognitive impairment (OR = 0.5; 95% CI, 0.2-1.1) and cognitive decline (OR = 0.6; 95% CI, 0.4-1.1). The ratio of free cortisol over DHEAS was significantly related to cognitive impairment (OR = 1.8; 95% CI, 1.0-3.2). This prospective study among healthy elderly subjects suggested that basal free cortisol levels were positively related to cognitive impairment, and cortisol levels after dexamethasone treatment were related to cognitive decline. There was an inverse, but nonsignificant, association between DHEAS and cognitive impairment and decline.

Objective: To study the relation between birth weight and systolic blood pressure in infancy and early childhood., Design: Longitudinal study of infants from birth to 4 years of age., Setting: A middle class community in the Netherlands., Participants: 476 Dutch infants born in 1980 to healthy women after uncomplicated pregnancies., Main Outcome Measures: Systolic blood pressure and body weight measured at birth and at 3 months and 4 years of age; the relation between systolic blood pressure and birth weight as estimated by multiple regression models that include current weight and previous blood pressure and control for gestational age, length at birth, and sex., Results: Complete data were available on 392 infants. At 4 years of age the relation between blood pressure and birth weight appeared to be U shaped; low and high birthweight infants had raised blood pressure. Current weight and previous blood pressure were also positively associated with blood pressure at that age. Low birthweight infants (birth weight < 3100 g) had a greater gain in blood pressure and weight in early infancy. High birthweight infants (birth weight > or = 3700 g) had high blood pressure at birth, and weight and blood pressure tended to remain high thereafter., Conclusions: Even among normal infants there seem to be subgroups defined by birth weight in which blood pressure is regulated differently. Future investigations are needed to examine the physiological basis of these differences. Studies of correlates of adult disease related to birth weight should investigate mechanisms related to increased risk separately in infants of low and high birth weight.

We examined the effects of selected health conditions and sensory functions, socioeconomic status, age, and education on cognitive functioning in 3,974 community-dwelling individuals aged 65-84 years. Logistic regression analysis was used to examine the independent and joint effects of these variables on borderline (Mini-Mental State Exam [MMSE] of 22-25) and poor (MMSE of < or = 21) functioning relative to adequate functioning (MMSE of 26-30). The effect of age and of education on MMSE performance was relatively stable, even after adjusting for age- and education-related health conditions and sensory impairments that also influenced level of cognitive functioning. These conditions included poor vision, Parkinson's disease, diabetes, depression, stroke (in 65-74-year-olds), and low socioeconomic status (in 75-84-year-olds). Education did not modify the effect of these variables on MMSE performance. Additional studies elucidating further the mechanisms that relate these sociodemographic factors to cognitive performance are warranted, as are studies of the relationship between these factors and the incidence of cognitive impairment.

UNLABELLED: Association between serum bone formation and resorption markers and cortical and trabecular bone loss and the concurrent periosteal apposition in a population-based cohort of 1069 older adults was assessed. BTM levels moderately reflect the cellular events at the endosteal and periosteal surfaces but are not associated with fracture risk. INTRODUCTION: We assessed whether circulating bone formation and resorption markers (BTM) were individual predictors for trabecular and cortical bone loss, periosteal expansion, and fracture risk in older adults aged 66 to 93 years from the AGES-Reykjavik study. METHODS: The sample for the quantitative computed tomography (QCT)-derived cortical and trabecular BMD and periosteal expansion analysis consisted of 1069 participants (474 men and 595 women) who had complete baseline (2002 to 2006) and follow-up (2007 to 2011) hip QCT scans and serum baseline BTM. During the median follow-up of 11.7 years (range 5.4-12.5), 54 (11.4 %) men and 182 (30.6 %) women sustained at least one fracture of any type. RESULTS: Increase in BTM levels was associated with faster cortical and trabecular bone loss at the femoral neck and proximal femur in men and women. Higher BTM levels were positively related with periosteal expansion rate at the femoral neck in men. Markers were not associated with fracture risk. CONCLUSION: This data corroborates the notion from few previous studies that both envelopes are metabolically active and that BTM levels may moderately reflect the cellular events at the endosteal and periosteal surfaces. However, our results do not support the routine use of BTM to assess fracture risk in older men and women. In light of these findings, further studies are justified to examine whether systemic markers of bone turnover might prove useful in monitoring skeletal remodeling events and the effects of current osteoporosis drugs at the periosteum.

Association between serum bone formation and resorption markers and cortical and trabecular bone loss and the concurrent periosteal apposition in a population-based cohort of 1069 older adults was assessed. BTM levels moderately reflect the cellular events at the endosteal and periosteal surfaces but are not associated with fracture risk.IntroductionWe assessed whether circulating bone formation and resorption markers (BTM) were individual predictors for trabecular and cortical bone loss, periosteal expansion, and fracture risk in older adults aged 66 to 93 years from the AGES-Reykjavik study.MethodsThe sample for the quantitative computed tomography (QCT)-derived cortical and trabecular BMD and periosteal expansion analysis consisted of 1069 participants (474 men and 595 women) who had complete baseline (2002 to 2006) and follow-up (2007 to 2011) hip QCT scans and serum baseline BTM. During the median follow-up of 11.7 years (range 5.4-12.5), 54 (11.4 %) men and 182 (30.6 %) women sustained at least one fracture of any type.ResultsIncrease in BTM levels was associated with faster cortical and trabecular bone loss at the femoral neck and proximal femur in men and women. Higher BTM levels were positively related with periosteal expansion rate at the femoral neck in men. Markers were not associated with fracture risk.ConclusionThis data corroborates the notion from few previous studies that both envelopes are metabolically active and that BTM levels may moderately reflect the cellular events at the endosteal and periosteal surfaces. However, our results do not support the routine use of BTM to assess fracture risk in older men and women. In light of these findings, further studies are justified to examine whether systemic markers of bone turnover might prove useful in monitoring skeletal remodeling events and the effects of current osteoporosis drugs at the periosteum.

UnlabelledAssociation between serum bone formation and resorption markers and bone mineral, structural, and strength variables derived from quantitative computed tomography (QCT) in a population-based cohort of 1745 older adults was assessed. The association was weak for lumbar spine and femoral neck areal and volumetric bone mineral density.IntroductionThe aim of this study was to examine the relationship between levels of bone turnover markers (BTMs; osteocalcin (OC), C-terminal cross-linking telopeptide of type I collagen (CTX), and procollagen type 1N propeptide (P1NP)) and quantitative computed tomography (QCT)-derived bone density, geometry, and strength indices in the lumbar spine and femoral neck (FN).MethodsA total of 1745 older individuals (773 men and 972 women, aged 66-92 years) from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik cohort were studied. QCT was performed in the lumbar spine and hip to estimate volumetric trabecular, cortical, and integral bone mineral density (BMD), areal BMD, bone geometry, and bone strength indices. Association between BTMs and QCT variables were explored using multivariable linear regression.ResultsMajor findings showed that all BMD measures, FN cortical index, and compressive strength had a low negative correlation with the BTM levels in both men and women. Correlations between BTMs and bone size parameters were minimal or not significant. No associations were found between BTMs and vertebral cross-sectional area in women. BTMs alone accounted for only a relatively small percentage of the bone parameter variance (1-10 %).ConclusionSerum CTX, OC, and P1NP were weakly correlated with lumbar spine and FN areal and volumetric BMD and strength measures. Most of the bone size indices were not associated with BTMs; thus, the selected bone remodeling markers do not reflect periosteal bone formation. These results confirmed the limited ability of the most sensitive established BTMs to predict bone structural integrity in older adults.

We investigated the genetic overlap between Alzheimer's disease (AD) and Parkinson's disease (PD). Using summary statistics (P-values) from large recent genome-wide association studies (GWAS) (total n=89 904 individuals), we sought to identify single nucleotide polymorphisms (SNPs) associating with both AD and PD. We found and replicated association of both AD and PD with the A allele of rs393152 within the extended MAPT region on chromosome 17 (meta analysis P-value across five independent AD cohorts=1.65 × 10(-7)). In independent datasets, we found a dose-dependent effect of the A allele of rs393152 on intra-cerebral MAPT transcript levels and volume loss within the entorhinal cortex and hippocampus. Our findings identify the tau-associated MAPT locus as a site of genetic overlap between AD and PD, and extending prior work, we show that the MAPT region increases risk of Alzheimer's neurodegeneration.