Our aim was to test the association of vascular risk factor exposure in midlife with progression of MRI markers of brain aging and measures of cognitive decline.
A total of 1,352 participants without ...dementia from the prospective Framingham Offspring Cohort Study were examined. Multivariable linear and logistic regressions were implemented to study the association of midlife vascular risk factor exposure with longitudinal change in white matter hyperintensity volume (WMHV), total brain volume (TBV), temporal horn volume, logical memory delayed recall, visual reproductions delayed-recall (VR-d), and Trail-Making Test B-A (TrB-A) performance a decade later.
Hypertension in midlife was associated with accelerated WMHV progression (p < 0.001) and worsening executive function (TrB-A score; p = 0.012). Midlife diabetes and smoking were associated with a more rapid increase in temporal horn volume, a surrogate marker of accelerated hippocampal atrophy (p = 0.017 and p = 0.008, respectively). Midlife smoking also predicted a more marked decrease in total brain volume (p = 0.025) and increased risk of extensive change in WMHV (odds ratio = 1.58 95%confidence interval 1.07-2.33, p = 0.021). Obesity in midlife was associated with an increased risk of being in the top quartile of change in executive function (1.39 1.02-1.88, p = 0.035) and increasing waist-to-hip ratio was associated with marked decline in TBV (10.81 1.44-81.01, p = 0.021). Longitudinal changes in brain structure were significantly correlated with decline in memory and executive function.
Midlife hypertension, diabetes, smoking, and obesity were associated with an increased rate of progression of vascular brain injury, global and hippocampal atrophy, and decline in executive function a decade later.
Depression may be associated with an increased risk for dementia, although results from population-based samples have been inconsistent. We examined the association between depressive symptoms and ...incident dementia over a 17-year follow-up period.
In 949 Framingham original cohort participants (63.6% women, mean age = 79), depressive symptoms were assessed at baseline (1990-1994) using the 60-point Center for Epidemiologic Studies Depression Scale (CES-D). A cutpoint of > or = 16 was used to define depression, which was present in 13.2% of the sample. Cox proportional hazards models adjusting for age, sex, education, homocysteine, and APOE epsilon4 examined the association between baseline depressive symptoms and the risk of dementia and Alzheimer disease (AD).
During the 17-year follow-up period, 164 participants developed dementia; 136 of these cases were AD. A total of 21.6% of participants who were depressed at baseline developed dementia compared with 16.6% of those who were not depressed. Depressed participants (CES-D >/=16) had more than a 50% increased risk for dementia (hazard ratio HR 1.72, 95% confidence interval CI 1.04-2.84, p = 0.035) and AD (HR 1.76, 95% CI 1.03-3.01, p = 0.039). Results were similar when we included subjects taking antidepressant medications as depressed. For each 10-point increase on the CES-D, there was significant increase in the risk of dementia (HR 1.46, 95% CI 1.18-1.79, p < 0.001) and AD (HR 1.39, 95% CI 1.11-1.75, p = 0.005). Results were similar when we excluded persons with possible mild cognitive impairment.
Depression is associated with an increased risk of dementia and AD in older men and women over 17 years of follow-up.
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with respect to outcome. Features of the tumor microenvironment (TME) are associated with prognosis when assessed by gene expression ...profiling. However, it is uncertain whether assessment of the microenvironment can add prognostic information to the most relevant and clinically well-established molecular subgroups when analyzed by immunohistochemistry (IHC).
We carried out a histopathologic analysis of biomarkers related to TME in a very large cohort (n = 455) of DLBCL treated in prospective trials and correlated with clinicopathologic and molecular data, including chromosomal rearrangements and gene expression profiles for cell-of-origin and TME.
The content of PD1+, FoxP3+ and CD8+, as well as vessel density, was not associated with outcome. However, we found a low content of CD68+ macrophages to be associated with inferior progression-free survival (PFS) and overall survival (OS; P = 0.023 and 0.040, respectively) at both univariable and multivariable analyses, adjusted for the factors of the International Prognostic Index (IPI), MYC break and BCL2/MYC and BCL6/MYC double-hit status. The subgroup of PDL1+ macrophages was not associated with survival. Instead, secreted protein acidic and cysteine rich (SPARC)-positive macrophages were identified as the subtype of macrophages most associated with survival. SPARC-positive macrophages and stromal cells directly correlated with favorable PFS and OS (both, Plog rank <0.001, Ptrend < 0.001). The association of SPARC with prognosis was independent of the factors of the IPI, MYC double-/triple-hit status, Bcl2/c-myc double expression, cell-of-origin subtype and a recently published gene expression signature lymphoma-associated macrophage interaction signature (LAMIS).
SPARC expression in the TME detected by a single IHC staining with fair-to-good interobserver reproducibility is a powerful prognostic parameter. Thus SPARC expression is a strong candidate for risk assessment in DLBCL in daily practice.
•Content of PD1-, FoxP3- and CD8-positive T cells, as well as vessel density fail to associate with outcome in DLBCL.•Low content of CD68+ macrophages is associated with inferior outcome in DLBCL.•High content of SPARC+ macrophage and stromal cells is associated with favorable outcome in DLBCL.•SPARC+ macrophages/stromal cells prove informative regardless of molecular subtypes, including MYC and double-hit status.•SPARC expression can be assessed easily and reliably by a single IHC stain.
Previous research suggests that age of first exposure (AFE) to football before age 12 may have long-term clinical implications; however, this relationship has only been examined in small samples of ...former professional football players. We examined the association between AFE to football and behavior, mood and cognition in a large cohort of former amateur and professional football players. The sample included 214 former football players without other contact sport history. Participants completed the Brief Test of Adult Cognition by Telephone (BTACT), and self-reported measures of executive function and behavioral regulation (Behavior Rating Inventory of Executive Function-Adult Version Metacognition Index (MI), Behavioral Regulation Index (BRI)), depression (Center for Epidemiologic Studies Depression Scale (CES-D)) and apathy (Apathy Evaluation Scale (AES)). Outcomes were continuous and dichotomized as clinically impaired. AFE was dichotomized into <12 and ⩾12, and examined continuously. Multivariate mixed-effect regressions controlling for age, education and duration of play showed AFE to football before age 12 corresponded with >2 × increased odds for clinically impaired scores on all measures but BTACT: (odds ratio (OR), 95% confidence interval (CI): BRI, 2.16,1.19-3.91; MI, 2.10,1.17-3.76; CES-D, 3.08,1.65-5.76; AES, 2.39,1.32-4.32). Younger AFE predicted increased odds for clinical impairment on the AES (OR, 95% CI: 0.86, 0.76-0.97) and CES-D (OR, 95% CI: 0.85, 0.74-0.97). There was no interaction between AFE and highest level of play. Younger AFE to football, before age 12 in particular, was associated with increased odds for impairment in self-reported neuropsychiatric and executive function in 214 former American football players. Longitudinal studies will inform youth football policy and safety decisions.
Higher dietary intake and circulating levels of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have been related to a reduced risk for dementia, but the pathways underlying this ...association remain unclear. We examined the cross-sectional relation of red blood cell (RBC) fatty acid levels to subclinical imaging and cognitive markers of dementia risk in a middle-aged to elderly community-based cohort.
We related RBC DHA and EPA levels in dementia-free Framingham Study participants (n = 1575; 854 women, age 67 ± 9 years) to performance on cognitive tests and to volumetric brain MRI, with serial adjustments for age, sex, and education (model A, primary model), additionally for APOE ε4 and plasma homocysteine (model B), and also for physical activity and body mass index (model C), or for traditional vascular risk factors (model D).
Participants with RBC DHA levels in the lowest quartile (Q1) when compared to others (Q2-4) had lower total brain and greater white matter hyperintensity volumes (for model A: β ± SE = -0.49 ± 0.19; p = 0.009, and 0.12 ± 0.06; p = 0.049, respectively) with persistence of the association with total brain volume in multivariable analyses. Participants with lower DHA and ω-3 index (RBC DHA+EPA) levels (Q1 vs. Q2-4) also had lower scores on tests of visual memory (β ± SE = -0.47 ± 0.18; p = 0.008), executive function (β ± SE = -0.07 ± 0.03; p = 0.004), and abstract thinking (β ± SE = -0.52 ± 0.18; p = 0.004) in model A, the results remaining significant in all models.
Lower RBC DHA levels are associated with smaller brain volumes and a "vascular" pattern of cognitive impairment even in persons free of clinical dementia.
Abstract
Introduction:
The Ford Insomnia Response to Stress Test (FIRST) is a 9-item self-report measure of trait vulnerability to sleep reactivity. It is biologically plausible that increased stress ...reactivity can have pervasive effects on sleep and health. The FIRST has shown acceptable reliability and validity, is predictive of future sleep dysfunction, and has been related to objective measures of sleep reactivity. To date, several critical aspects of this measure remain unexplored, including: 1) normative data in an unselected population, and 2) its relation to demographic, psychiatric and medical comorbidities.
Methods:
The FIRST was administered to 2,548 individuals of the Framingham Heart Study’s Offspring and Omni cohorts (1,406 females). Descriptive statistics were conducted to determine the mean, median, standard deviation, and range of the FIRST. Between groups comparisons assessed the difference between gender and medical diagnoses: hypertension, obesity, diabetes, COPD, asthma, ischemic heart disease, stroke, congestive heart failure, anxiety, and depression. Pearson correlations assessed the relation between the FIRST and age, depression (Center for Epidemiologic Studies Depression Scale; CES-D), and quality of life (12-Item Short Form Health Survey; SF-12).
Results:
The average age of the sample was 70.0 (SD=8.5; range 44–95). FIRST scores ranged from 0–27, with a mean of 8.30 (SD=5.9) and a median of 7. There were significant differences for gender (women > men, p<.0001), COPD (p= .02), asthma (p=.03), anxiety (p<.0001), and depression (p<.0001). The FIRST correlated with age (r=-0.08), depression (r=0.34), and quality of life (r=-0.29), with all p-values <.0001.
Conclusion:
This study provides useful normative data for the FIRST. Higher sleep reactivity is related to younger age, gender, depression, and poorer quality of life. Future analysis will assess relationships with cognition, biological markers such as endothelial function and inflammation.
Support (If Any):
NHLBI N01 HC 25195.
Systemic inflammation is associated with ischemia and Alzheimer disease (AD). We hypothesized that inflammatory biomarkers would be associated with neuroimaging markers of ischemia (i.e., white ...matter hyperintensities WMH) and AD (i.e., total brain volume TCB).
MRI WMH and TCB were quantified on 1,926 Framingham Offspring participants free from clinical stroke, TIA, or dementia (mean age 60 +/- 9 years; range 35 to 85 years; 54% women) who underwent measurement of a circulating inflammatory marker panel, including CD40 ligand, C-reactive protein, interleukin-6 (IL-6), soluble intracellular adhesion molecule-1, monocyte chemoattractant protein-1, myeloperoxidase, osteoprotegerin (OPG), P-selectin, tumor necrosis factor-alpha (TNFalpha), and tumor necrosis factor receptor II. To account for head size, both TCB (TCBV) and WMH (WMH/TCV) were divided by total cranial volume. We used multivariable linear regression to relate 10 log-transformed inflammatory biomarkers to brain MRI measures.
In multivariable models, inflammatory markers as a group were associated with TCBV (p < 0.0001) but not WMH/TCV (p = 0.28). In stepwise models adjusted for clinical covariates with backwards elimination of markers, IL-6 and OPG were inversely associated with TCBV; TNFalpha was inversely related to TCBV in a subset of 1,430 participants. Findings were similar in analyses excluding individuals with prevalent cardiovascular disease. The relations between TCBV and inflammatory markers were modified by both sex and age, and generally were more pronounced in men and in older individuals.
Although our observational cross-sectional data cannot establish causality, they are consistent with the hypothesis that higher inflammatory markers are associated with greater atrophy than expected for age.
Objectives To relate cancer since entry into the Framingham Heart Study with the risk of incident Alzheimer’s disease and to estimate the risk of incident cancer among participants with and without ...Alzheimer’s disease.Design Community based prospective cohort study; nested age and sex matched case-control study. Setting Framingham Heart Study, USA.Participants 1278 participants with and without a history of cancer who were aged 65 or more and free of dementia at baseline (1986-90). Main outcome measures Hazard ratios and 95% confidence intervals for the risks of Alzheimer’s disease and cancer.Results Over a mean follow-up of 10 years, 221 cases of probable Alzheimer’s disease were diagnosed. Cancer survivors had a lower risk of probable Alzheimer’s disease (hazard ratio 0.67, 95% confidence interval 0.47 to 0.97), adjusted for age, sex, and smoking. The risk was lower among survivors of smoking related cancers (0.26, 0.08 to 0.82) than among survivors of non-smoking related cancers (0.82, 0.57 to 1.19). In contrast with their decreased risk of Alzheimer’s disease, survivors of smoking related cancer had a substantially increased risk of stroke (2.18, 1.29 to 3.68). In the nested case-control analysis, participants with probable Alzheimer’s disease had a lower risk of subsequent cancer (0.39, 0.26 to 0.58) than reference participants, as did participants with any Alzheimer’s disease (0.38) and any dementia (0.44).Conclusions Cancer survivors had a lower risk of Alzheimer’s disease than those without cancer, and patients with Alzheimer’s disease had a lower risk of incident cancer. The risk of Alzheimer’s disease was lowest in survivors of smoking related cancers, and was not primarily explained by survival bias. This pattern for cancer is similar to that seen in Parkinson’s disease and suggests an inverse association between cancer and neurodegeneration.
Abstract
Introduction:
Wearable devices for sleep assessments offer a cost-effective and convenient alternative to traditional measures of sleep. Devices are now available to measure oxygenation, ...respiration electrocardiogram, and electroencephalogram in the home environment. This study assessed standard (oximetry) and novel (cardiopulmonary coupling) measures of sleep state in a well-established epidemiology cohort.
Methods:
Data were collected from 846 participants of the Framingham Heart Study’s second generation and Omni cohort (mean age: 67.9; 484 female). Sleep studies were mailed to each participant, with a single-lead ECG device manufactured by MyCardio, LLC (www.sleepimage.com), an oximetry device manufactured by Nonin, and a brochure to direct the application of the devices. The FDA approved M1 measures electrocardiogram, body position, trunk activity, and snoring. The analysis uses cardiopulmonary coupling to generate the following measures: high and low frequency coupling (HFC and LFC, stable and unstable NREM, respectively), and a biomarker of high loop gain (narrow-band elevated low frequency coupling). The mean, standard deviation, and intra-class correlation coefficient (ICC) were calculated for HFC, LFC, oxygen desaturation index (ODI), and time with oxygen saturation below 90%.
Results:
A total of 972 participants agreed to participate. 126 participants were unable or refused to complete the study. 830 and 836 participants obtained at least 4 hours of data with the M1 and oximetry device for at least one night, respectively. 574 participants wore both devices for 2 consecutive nights (803 wore M1, 695 wore Ox for 2 consecutive nights). The mean (SD) were as follows: HFC 43.5%(18.8), LFC 37.28%(17.03), ODI 8.3(8.5), oxygen saturation below 90% 48.1(77.24) minutes, and 52.5% of the sample had narrow band coupling. The ICC for these variables ranged from 74.5%-99.9%, suggesting high night to night data and physiological signal stability. Associations with common medical co-morbidities will be presented.
Conclusion:
The results suggest that home/wearable assessment of sleep is 1) feasible, cost-effective, and yields reliable results; 2) inter-individual differences are stable; 3) measures can be readily repeated; 4) in-person visits are not required, markedly simplifying data collection. Both standard and novel measures can be collected.
Support (If Any):
NHLBI N01 HC 25195, BIDMC Chief Academic Officer’s Innovation Grant.
Abstract
Introduction:
While sleep duration has been linked to cardiovascular risk and mortality rate, there is a lack of consistent finding on the association between sleep duration and cognitive ...and mental health outcomes in the general population. The current study used a large-scale, community-based sample of middle-aged and older adults to examine the association between habitual sleep duration and depression and neuropsychological performance in the aging population.
Methods:
A total of 1,528 (mean age=60.4, 52% female) participants from the Korean Genome and Epidemiology Study (KoGES) were categorized into short sleep (<6 h), intermediate sleep (7-<8 h), and long sleep duration (≥8 h) based a self-reported sleep duration over the past month. Neuropsychological performance was measured with a test battery that contained memory (Logical Memory and Visual Reproduction), verbal fluency (Controlled Oral Word Association Test), and attention/executive function (Trail Making Test, Digit Symbol, and Stroop). Depression was measured with the Beck’s Depression Inventory (BDI).
Results:
Results from multivariate analyses of covariance indicated that there was a significant difference in Logical Memory and Visual Reproduction across the sleep duration groups after adjusting for age, sex and education. Delayed Recall on Logical Memory and Immediate and Delayed Recall on Visual Memory were significantly lower in short or long sleep, compared to intermediate sleep, after additional adjustment of medical and lifestyle factors, daytime sleepiness, and use of sleep medications (Logical Memory F=3.93, p=0.02, Visual Reproductions Immediate F=3.67, p=0.02 and Delayed F=5.40, p=0.005). The BDI was also independently associated with sleep duration groups, with short sleep exhibiting the highest level of BDI scores (F=5.18, p=0.006).
Conclusion:
The current findings indicate that short or long sleep duration are negatively associated with cognitive performance in middle-aged and older adults. Short sleep was also associated with higher depression score. These results support previous findings that demonstrated an inverted U-shaped association between sleep duration and cognitive performance and highlight the importance of maintaining a balanced sleep quantity.
Support (If Any):
This study was supported by grants from the Korean Centers for Disease Control and Prevention and the Korean Ministry for Health and Welfare (Grant 2011-E7---E71004-0 & 2012-E71005-00).
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