Digital Clock Drawing as an Alzheimer's Disease Susceptibility Biomarker: Associations with Genetic Risk Score and APOE in Older Adults.

BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia in older adults, but most people are not diagnosed until significant neuronal loss has likely occurred along with a decline in cognition. Non-invasive and cost-effective digital biomarkers for AD have the potential to improve early detection. OBJECTIVE: We examined the validity of DCTclockTM (a digitized clock drawing task) as an AD susceptibility biomarker. DESIGN: We used two primary independent variables, Apolipoprotein E (APOE) ε4 allele carrier status and polygenic risk score (PRS). We examined APOE and PRS associations with DCTclockTM composite scores as dependent measures. SETTING: We used existing data from the Framingham Heart Study (FHS), a community-based study with the largest dataset of digital clock drawing data to date. PARTICIPANTS: The sample consisted of 2,398 older adults ages 60-94 with DCTclockTM data (mean age of 72.3, 55% female and 92% White). MEASUREMENTS: PRS was calculated using 38 variants identified in a recent large genome-wide association study (GWAS) and meta-analysis of late-onset AD (LOAD). RESULTS: Results showed that DCTclockTM performance decreased with advancing age, lower education, and the presence of one or more copies of APOE ε4. Lower DCTclockTM Total Score as well as lower composite scores for Information Processing Speed (both command and copy conditions) and Drawing Efficiency (command condition) were significantly associated with higher PRS levels and more copies of APOE ε4. APOE and PRS associations displayed similar effect sizes in both men and women. CONCLUSIONS: Our results indicate that higher AD genetic risk is associated with poorer DCTclockTM performance in older adults without dementia. This is the first study to demonstrate significant differences in clock drawing performance on the basis of APOE status or PRS.

Reproductive Markers in Alzheimer's Disease Progression: The Framingham Heart Study.

BACKGROUND: Reproductive status, such as the age of menarche or menopause, may be linked to cognitive abilities and risk for incident Alzheimer's disease (AD) but the evidence is conflicting. It is also not fully known if these factors interact with cortical beta-amyloid deposition. OBJECTIVES: To study the relationship between reproductive risks, sex hormone markers and risk for decline in specific cognitive domains in women. DESIGN, SETTING AND PARTICIPANTS: We analyzed the association of reproductive markers (age at menarche, number of births, age at menopause, sex hormone-binding globulin, estradiol, estrone, total testosterone, free testosterone) with incident AD and annualized cognitive decline in the community-based longitudinal Framingham Heart Study (FHS) Offspring women 60 years and older (n=772, mean age 68 years, mean follow-up 10.7 ± 3 years). We used the Cox proportional hazards regression model and linear regression model, adjusting for covariates. OUTCOME MEASURES: Incident AD dementia as well as the annualized change in memory, language, attention and executive functions. RESULTS: Older age at menopause was associated with a lower risk of incident AD dementia (p = 0.047, 6% lower risk per older year) after adjusting for baseline age, education, hormone therapy status, and MMSE score. Older age at menopause was significantly associated with a slower annualized decline in memory (beta = 0.085, p = 0.00059). The lower level of plasma Aß42 was also associated with a higher risk of incident AD (HR = 0.97, 95% CI = 0.95, 0.99; p = 0.0039) but there was no significant interaction effect with age at menarche, age at menopause or plasma sex hormone levels. CONCLUSION: Younger age at menopause is a risk factor for late-life memory decline and incident AD. This risk appears to be independent of Aß42 pathology. Further studies to understand the biological and social mechanisms underlying the differential effects of reproductive risks are warranted.

Cognitive Digital Biomarkers from Automated Transcription of Spoken Language.

BACKGROUND: Although patients with Alzheimer's disease and other cognitive-related neurodegenerative disorders may benefit from early detection, development of a reliable diagnostic test has remained elusive. The penetration of digital voice-recording technologies and multiple cognitive processes deployed when constructing spoken responses might offer an opportunity to predict cognitive status. OBJECTIVE: To determine whether cognitive status might be predicted from voice recordings of neuropsychological testing. DESIGN: Comparison of acoustic and (para)linguistic variables from low-quality automated transcriptions of neuropsychological testing (n = 200) versus variables from high-quality manual transcriptions (n = 127). We trained a logistic regression classifier to predict cognitive status, which was tested against actual diagnoses. SETTING: Observational cohort study. PARTICIPANTS: 146 participants in the Framingham Heart Study. MEASUREMENTS: Acoustic and either paralinguistic variables (e.g., speaking time) from automated transcriptions or linguistic variables (e.g., phrase complexity) from manual transcriptions. RESULTS: Models based on demographic features alone were not robust (area under the receiver-operator characteristic curve [AUROC] 0.60). Addition of clinical and standard acoustic features boosted the AUROC to 0.81. Additional inclusion of transcription-related features yielded an AUROC of 0.90. CONCLUSIONS: The use of voice-based digital biomarkers derived from automated processing methods, combined with standard patient screening, might constitute a scalable way to enable early detection of dementia.

Using Digital Tools to Advance Alzheimer's Drug Trials During a Pandemic: The EU/US CTAD Task Force.

The 2020 COVID-19 pandemic has disrupted Alzheimer's disease (AD) clinical studies worldwide. Digital technologies may help minimize disruptions by enabling remote assessment of subtle cognitive and functional changes over the course of the disease. The EU/US Clinical Trials in Alzheimer's Disease (CTAD) Task Force met virtually in November 2020 to explore the opportunities and challenges associated with the use of digital technologies in AD clinical research. While recognizing the potential of digital tools to accelerate clinical trials, improve the engagement of diverse populations, capture clinically meaningful data, and lower costs, questions remain regarding the stability, validity, generalizability, and reproducibility of digital data. Substantial concerns also exist regarding regulatory acceptance and privacy. Nonetheless, the Task Force supported further exploration of digital technologies through collaboration and data sharing, noting the need for standardization of digital readouts. They also concluded that while it may be premature to employ remote assessments for trials of novel experimental medications, remote studies of non-invasive, multi-domain approaches may be feasible at this time.

Age of first exposure to American football and long-term neuropsychiatric and cognitive outcomes.

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.

GWAS for executive function and processing speed suggests involvement of the CADM2 gene.

To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32,070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.

Job strain and cognitive decline: a prospective study of the framingham offspring cohort.

BACKGROUND: Workplace stress is known to be related with many behavioral and disease outcomes. However, little is known about its prospective relationship with measures of cognitive decline. OBJECTIVE: To investigate the association of job strain, psychological demands and job control on cognitive decline. METHODS: Participants from Framingham Offspring cohort (n=1429), were assessed on job strain, and received neuropsychological assessment approximately 15 years and 21 years afterwards. RESULTS: High job strain and low control were associated with decline in verbal learning and memory. Job strain was associated with decline in word recognition skills. Active job and passive job predicted decline in verbal learning and memory relative to low strain jobs in the younger subgroup. Active job and demands were positively associated with abstract reasoning skills. CONCLUSIONS: Job strain and job control may influence decline in cognitive performance.

Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949).

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10(-9), MIR2113; rs17522122, P=2.55 × 10(-8), AKAP6; rs10119, P=5.67 × 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.

Pulmonary tuberculosis and lung cancer mortality in a historical cohort of workers with asbestosis.

OBJECTIVES: To examine pulmonary tuberculosis (PTB) infection and lung cancer mortality among workers with asbestosis in Hong Kong. STUDY DESIGN: Historical cohort study. METHODS: All 124 male incident cases of asbestosis registered at the Pneumoconiosis Clinic of the Tuberculosis and Chest Service of the Department of Health between 1981 and 2008 were recruited and followed-up until 2008 to ascertain vital status and underlying causes of death. Standardized mortality ratios (SMRs) were calculated using the person-year method. Axelson's indirect method was used to adjust for the potential confounding effect of cigarette smoking. RESULTS: Forty-five patients (36.29%) had a history of PTB at the time of asbestosis diagnosis. The SMR of lung cancer was 5.22 [95% confidence interval (CI) 1.08-15.25] for subjects with a history of PTB, and this was reduced to 2.35 (95% CI 0.49-6.85) after indirect adjustment for smoking. Among asbestosis workers without a history of PTB, the SMR after indirect adjustment for smoking was 4.25 (95% CI 1.55-9.25) and 5.92 (95% CI 1.92-13.79) for those with comorbidities and those without comorbidities, respectively. Compared with other workers, those with a history of PTB had the highest all-cause SMR (6.73, 95% CI 4.55-9.63) and very high mortality due to heart diseases. CONCLUSIONS: This historical cohort study revealed that the prevalence of PTB infection was high among workers with asbestosis in Hong Kong. An excess risk of lung cancer mortality was observed among workers with a history of PTB, but the risk was lower than that seen among workers without a history of PTB. These interesting findings need to be confirmed by future studies.

Red blood cell ω-3 fatty acid levels and markers of accelerated brain aging.

OBJECTIVE: 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. METHODS: 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). RESULTS: 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: ß ± 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 (ß ± SE = -0.47 ± 0.18; p = 0.008), executive function (ß ± SE = -0.07 ± 0.03; p = 0.004), and abstract thinking (ß ± SE = -0.52 ± 0.18; p = 0.004) in model A, the results remaining significant in all models. CONCLUSION: Lower RBC DHA levels are associated with smaller brain volumes and a "vascular" pattern of cognitive impairment even in persons free of clinical dementia.

Midlife vascular risk factor exposure accelerates structural brain aging and cognitive decline.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Early detection of central airway lung cancer in smokers with silicosis.

BACKGROUND: Smokers with silicosis are at increased risk of lung cancer. OBJECTIVE: To evaluate the feasibility of using autofluorescence bronchoscopy after sputum examination for early detection of large airway lung cancer and factors associated with the presence of cancerous and pre-cancerous lesions among smokers with silicosis. METHODS: Subjects at the pneumoconiosis clinic were recruited if they fulfilled the following criteria: 1) age ≥40 years, 2) smoking history of ≥20 pack-years and 3) confirmed diagnosis of silicosis. Sputum specimens were collected for cytology/cytometry examination and autofluorescence bronchoscopy was performed in subjects with an abnormal sputum result. RESULTS: A total of 48 subjects were recruited during the study period. The mean age and smoking history were respectively 63 ± 10 years and 51 ± 30 pack-years. Intraepithelial lung cancers and pre-neoplastic lesions (squamous metaplasia or above) were detected in respectively 2 (4.2%) and 14 (29.2%) subjects. The proportions of current smokers (75.0% vs. 40.6%, P = 0.03) and asbestos exposure (37.5% vs. 9.4%, P = 0.04) were significantly higher in subjects with the above lesions compared with those without. CONCLUSIONS: Sputum examination followed by autofluorescence bronchoscopy may be a useful way of identifying cancerous/pre-cancerous lesions among silicotic smokers. Current smoking and asbestos exposure were associated with these lesions.

Depressive symptoms and risk of dementia: the Framingham Heart Study.

OBJECTIVES: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: Depression is associated with an increased risk of dementia and AD in older men and women over 17 years of follow-up.

Association of parental dementia with cognitive and brain MRI measures in middle-aged adults.

OBJECTIVES: Studies of autosomal dominant Alzheimer disease (AD) have shown structural and cognitive changes in mutation carriers decades prior to clinical disease. Whether such changes are detectable in offspring of persons with sporadic dementia remains unknown. We related prospectively verified parental dementia to brain MRI and cognitive testing in the offspring, within a 2-generational community-based cohort. METHODS: A total of 717 Framingham offspring (mean age: 59 +/- 8 years) were studied. In multivariate analyses, we compared offspring with and without verified parental dementia (and AD) for 1) performance on tests of memory, abstract reasoning, and cognitive flexibility, and 2) volumetric brain MRI measures of total cerebral brain volume (TCBV), hippocampal volume (HV), and white matter hyperintensity volume (WMHV), assessed cross-sectionally and longitudinally. RESULTS: When testing the association of parental dementia and AD with baseline cognitive performance, we observed an interaction of parental dementia and AD with APOE epsilon4 status (p < 0.002). In APOE epsilon4 carriers only (n = 165), parental dementia was associated with poorer scores on tests of verbal memory (beta = -1.81 +/- 0.53, p < 0.001) and visuospatial memory (beta = -1.73 +/- 0.47, p < 0.001). These associations were stronger for parental AD (beta = -1.97 +/- 0.52, p < 0.001, beta = -1.95 +/- 0.48, p < 0.001), equivalent to 14-16 years of brain aging. Among APOE epsilon4 carriers, offspring of participants with dementia were also more likely to show an annual decline in TCBV in the top quartile (odds ratio = 4.67 [1.26-17.30], p = 0.02). Regardless of APOE epsilon4 status, participants with parental dementia were more likely to be in the highest quartile of decline in executive function test scores (odds ratio = 1.61 [1.02-2.53], p = 0.04). CONCLUSIONS: Among middle-aged carriers of the APOE epsilon4 allele, parental dementia and Alzheimer disease were associated with poorer verbal and visuospatial memory and a higher rate of global brain atrophy.

Avocado soybean unsaponifiables (ASU) suppress TNF-alpha, IL-1beta, COX-2, iNOS gene expression, and prostaglandin E2 and nitric oxide production in articular chondrocytes and monocyte/macrophages.

OBJECTIVE: To evaluate the effects of avocado soybean unsaponifiables (ASU) on proinflammatory mediators in chondrocytes and monocyte/macrophage-like cells. DESIGN: To determine the dose response of ASU, chondrocytes (5 x 10(5) cells/well) were incubated at 5% CO(2), 37 degrees C for 72 h with (1) control media alone or (2) ASU at concentrations of 0.3, 0.9, 2.7, 8.3, and 25 microg/ml. Cells were activated with 20 ng/ml lipopolysaccharide (LPS) for 24 h and cell supernatants were analyzed for prostaglandin E(2) (PGE(2)) and nitrite content. Chondrocytes and THP-1 monocyte/macrophages (5 x 10(5) cells/well) were incubated at 5% CO(2), 37 degrees C for 72 h with (1) control media alone or (2) ASU (25 mug/ml). One set of cells was activated for 1 h with LPS (20 ng/ml) for both reverse-transcriptase PCR and real-time PCR analysis of tumor necrosis factor-alpha (TNF-alpha), interleukin-1-beta (IL-1beta), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) expression. One set of cells was activated for 24 h to analyze secreted PGE(2) and nitrite levels in the cellular supernatant. RESULTS: ASU reduced TNF-alpha, IL-1beta, COX-2, and iNOS expression in LPS-activated chondrocytes to levels similar to nonactivated control levels. The suppression of COX-2 and iNOS expression was paralleled by a significant reduction in PGE(2) and nitrite, respectively, in the cellular supernatant. ASU also reduced TNF-alpha and IL-1beta expression in LPS-activated monocyte/macrophage-like cells. CONCLUSION: The present study demonstrates that the anti-inflammatory activity of ASU is not restricted to chondrocytes, but also affects monocyte/macrophage-like cells that serve as a prototype for macrophages in the synovial membrane. These observations provide a scientific rationale for the pain-reducing and anti-inflammatory effects of ASU observed in osteoarthritis patients.

Inflammatory markers and the risk of Alzheimer disease: the Framingham Study.

OBJECTIVE: To examine whether serum cytokines and spontaneous production of peripheral blood mononuclear cell (PBMC) cytokines are associated with the risk of incident Alzheimer disease (AD). METHODS: We followed 691 cognitively intact community-dwelling participants (mean age 79 years, 62% women) and related PBMC cytokine production (tertiles of spontaneous production of interleukin 1 [IL-1], IL-1 receptor antagonist, and tumor necrosis factor alpha [TNF-alpha]) and serum C-reactive protein and interleukin 6 (IL-6) to the risk of incident AD. RESULTS: Adjusting for clinical covariates, individuals in the top two tertiles (T2 and T3) of PBMC production of IL-1 or the top tertile (T3) of PBMC production of TNF-alpha were at increased risk of developing AD (multivariable-adjusted hazard ratio [HR] for IL-1 T2 = 2.84, 95% CI 1.09 to 7.43; p = 0.03 and T3 = 2.61, 95% CI 0.96 to 7.07; p = 0.06; for TNF-alpha, adjusted HR for T2 = 1.30, 95% CI 0.53 to 3.17; p = 0.57 and T3 = 2.59, 95% CI 1.09 to 6.12; p = 0.031]) compared with those in the lowest tertile (T1). INTERPRETATION: Higher spontaneous production of interleukin 1 or tumor necrosis factor alpha by peripheral blood mononuclear cells may be a marker of future risk of Alzheimer disease (AD) in older individuals. These data strengthen the evidence for a pathophysiologic role of inflammation in the development of clinical AD.

Inflammatory biomarkers are associated with total brain volume: the Framingham Heart Study.

BACKGROUND: 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]). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Stroke risk profile, brain volume, and cognitive function: the Framingham Offspring Study.

BACKGROUND: Mid-life stroke risk factors have been related to late-life cognitive impairment. This association may result not only from clinical strokes but also from subclinical brain injury, such as a global atrophy demonstrable on quantitative brain MRI. METHODS: The authors evaluated the community-based cohort of Framingham Offspring Study participants. A total of 1,841 subjects (mean age, 62 years; 857 men, 984 women) who underwent quantitative MRI and cognitive testing between 1999 and 2001 and were free of clinical stroke and dementia constituted our study sample. The authors used age- and sex-adjusted linear regression models to relate previous (1991 to 1995) and recent (1998 to 2001) Framingham Stroke Risk Profile (FSRP) scores to the total cerebral brain volume ratio (TCBVr) on follow-up MRI, and further to relate the TCBVr with education-adjusted scores on neuropsychological tests administered at the time of imaging. RESULTS: There was an inverse association between FSRP scores and TCBVr. The TCBVr also showed a significant positive association with performance on tests of attention (Trails A), executive function (Trails B), and visuospatial function (visual reproduction, Hooper visual organization), but not with performance on tests of verbal memory or naming. CONCLUSIONS: The Framingham Stroke Risk Profile may identify subjects with smaller brains and poorer cognitive function among stroke- and dementia-free subjects, reinforcing the importance of managing stroke risk factors.

The preclinical phase of alzheimer disease: A 22-year prospective study of the Framingham Cohort.

OBJECTIVES: To relate performance on tests of cognitive ability to the subsequent development of probable Alzheimer disease (pAD) and to identify the pattern of earliest changes in cognitive functioning associated with a diagnosis of pAD. DESIGN: From May 1975 to November 1979, a screening neuropsychological battery was administered to Framingham Study participants. They were followed up prospectively for 22 years and examined at least every 2 years for the development of pAD. SETTING: A community-based center for epidemiological research. PARTICIPANTS: Subjects were 1076 participants of the Framingham Study aged 65 to 94 years who were free of dementia and stroke at baseline (initial) neuropsychological testing. MAIN OUTCOME MEASURE: Presence or absence of pAD during a 22-year surveillance period was related to test performance at initial neuropsychological testing. RESULTS: Lower scores for measures of new learning, recall, retention, and abstract reasoning obtained during a dementia-free period were associated with the development of pAD. Lower scores for measures of abstract reasoning and retention predicted pAD after a dementia-free period of 10 years. CONCLUSIONS: The "preclinical phase" of detectable lowering of cognitive functioning precedes the appearance of pAD by many years. Measures of retention of information and abstract reasoning are among the strongest predictors of pAD when the interval between initial assessment and the development of pAD is long. Arch Neurol. 2000.

Docetaxel (Taxotere) in combination with anthracyclines in the treatment of breast cancer.

Considering the single-agent activity of docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) and doxorubicin in breast cancer and their potential non-cross-resistance, several docetaxel/anthracycline-based combination chemotherapies were developed in phase I and II programs for metastatic breast cancer patients. The rationale for these combinations was also reinforced by the fact that docetaxel showed significant activity in phase III trials in patients previously exposed or having failed anthracycline chemotherapy. In a pivotal randomized phase III study of doxorubicin plus docetaxel versus doxorubicin plus cyclophosphamide as first-line chemotherapy for 429 patients with metastatic breast cancer, doxorubicin/docetaxel emerged as the more effective regimen. Despite a lower-dose intensity of doxorubicin, patients receiving doxorubicin/docetaxel experienced a higher response rate as well as a significantly longer time to progression and time to treatment failure. This difference was seen even in patients with poor-prognosis disease. Febrile neutropenia was more common in doxorubicin/docetaxel-treated patients. However, there were no septic deaths among 213 patients receiving doxorubicin/ docetaxel. Extrahematologic toxicity appeared mild for both regimens and the combination docetaxel/doxorubicin did not increase the cardiac toxicity expected for an anthracycline-containing regimen. Docetaxel plus doxorubicin is the first regimen, involving a newly developed agent, proven superior to a standard anthracycline-containing combination in metastatic breast cancer and its potential is now being investigated in the adjuvant setting.