Zaldy S. Tan

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 α [TNF-α]) 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-α 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-α, 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 α 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.

Association of Plasma Leptin Levels With Incident Alzheimer Disease and MRI Measures of Brain Aging

CONTEXT The adipokine leptin facilitates long-term potentiation and synaptic plasticity in the hippocampus, promotes beta-amyloid clearance, and improves memory function in animal models of aging and Alzheimer disease (AD). OBJECTIVE To relate baseline circulating leptin concentrations in a community-based sample of individuals without dementia to incident dementia and AD during follow-up and magnetic resonance imaging (MRI) measures of brain aging in survivors. DESIGN, SETTING, AND PARTICIPANTS Prospective study of plasma leptin concentrations measured in 785 persons without dementia (mean [SD] age, 79 [5] years; 62% female), who were in the Framingham original cohort at the 22nd examination cycle (1990-1994). A subsample of 198 dementia-free survivors underwent volumetric brain MRI between 1999 and 2005, approximately 7.7 years after leptin was assayed. Two measures of brain aging, total cerebral brain volume and temporal horn volume (which is inversely related to hippocampal volume) were assessed. MAIN OUTCOME MEASURE Incidence of dementia and AD during follow-up until December 31, 2007. RESULTS During a median follow-up of 8.3 years (range, 0-15.5 years), 111 participants developed incident dementia; 89 had AD. Higher leptin levels were associated with a lower risk of incident dementia and AD in multivariable models (hazard ratio per 1-SD increment in log leptin was 0.68 [95% confidence interval, 0.54-0.87] for all-cause dementia and 0.60 [95% confidence interval, 0.46-0.79] for AD). This corresponds to an absolute AD risk over a 12-year follow-up of 25% for persons in the lowest quartile (first quartile) vs 6% for persons in the fourth quartile of sex-specific leptin levels. In addition, a 1-SD elevation in plasma leptin level was associated with higher total cerebral brain volume and lower temporal horn volume, although the association of leptin level with temporal horn volume did not reach statistical significance. CONCLUSION Circulating leptin was associated with a reduced incidence of dementia and AD and with cerebral brain volume in asymptomatic older adults.

Red blood cell omega-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 = 1,575; 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: 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. 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.

Thyroid Function and the Risk of Alzheimer Disease : The Framingham Study

BACKGROUND Clinical hypothyroidism and hyperthyroidism are recognized causes of reversible dementia, but previous studies relating thyrotropin levels to cognitive performance in clinically euthyroid persons have yielded inconsistent results. METHODS We related serum thyrotropin concentrations measured at baseline (March 1977-November 1979) to the risk of Alzheimer disease (AD) in 1864 cognitively intact, clinically euthyroid Framingham original cohort participants (mean age, 71 years; 59% women). Sex-specific Cox proportional hazards models were constructed using tertiles of thyrotropin concentration (tertile 2 as the referent) and adjusting for age, apolipoprotein E epsilon4 allele status, educational level, plasma homocysteine level, current smoking, body mass index, prevalent stroke, and atrial fibrillation. RESULTS During a mean follow-up of 12.7 years (range, 1-25 years), 209 participants (142 women) developed AD. Women in the lowest (<1.0 mIU/L) and highest (>2.1 mIU/L) tertiles of serum thyrotropin concentration were at increased risk for AD (multivariate-adjusted hazard ratio, 2.39 [95% confidence interval, 1.47-3.87] [P < .001] and 2.15 [95% confidence interval, 1.31-3.52] [P = .003], respectively) compared with those in the middle tertile. Thyrotropin levels were not related to AD risk in men. Analyses excluding individuals receiving thyroid supplementation did not significantly alter these relationships. In analyses limited to participants with serum thyrotropin levels of 0.1 to 10.0 mIU/L, the U-shaped relationship between thyrotropin level and AD risk was maintained in women but not when analyses were limited to those with thyrotropin levels of 0.5 to 5.0 mIU/L. CONCLUSION Low and high thyrotropin levels were associated with an increased risk of incident AD in women but not in men.

Association of Metabolic Dysregulation With Volumetric Brain Magnetic Resonance Imaging and Cognitive Markers of Subclinical Brain Aging in Middle-Aged Adults: The Framingham Offspring Study

OBJECTIVE Diabetic and prediabtic states, including insulin resistance, fasting hyperglycemia, and hyperinsulinemia, are associated with metabolic dysregulation. These components have been individually linked to increased risks of cognitive decline and Alzheimer’s disease. We aimed to comprehensively relate all of the components of metabolic dysregulation to cognitive function and brain magnetic resonance imaging (MRI) in middle-aged adults. RESEARCH DESIGN AND METHODS Framingham Offspring participants who underwent volumetric MRI and detailed cognitive testing and were free of clinical stroke and dementia during examination 7 (1998–2001) constituted our study sample (n = 2,439; 1,311 women; age 61 ± 9 years). We related diabetes, homeostasis model assessment of insulin resistance (HOMA-IR), fasting insulin, and glycohemoglobin levels to cross-sectional MRI measures of total cerebral brain volume (TCBV) and hippocampal volume and to verbal and visuospatial memory and executive function. We serially adjusted for age, sex, and education alone (model A), additionally for other vascular risk factors (model B), and finally, with the inclusion of apolipoprotein E-ε4, plasma homocysteine, C-reactive protein, and interleukin-6 (model C). RESULTS We observed an inverse association between all indices of metabolic dysfunction and TCBV in all models (P < 0.030). The observed difference in TCBV between participants with and without diabetes was equivalent to approximately 6 years of chronologic aging. Diabetes and elevated glycohemoglobin, HOMA-IR, and fasting insulin were related to poorer executive function scores (P < 0.038), whereas only HOMA-IR and fasting insulin were inversely related to visuospatial memory (P < 0.007). CONCLUSIONS Metabolic dysregulation, especially insulin resistance, was associated with lower brain volumes and executive function in a large, relatively healthy, middle-aged, community-based cohort.

The role of inflammation in the pathogenesis of delirium and dementia in older adults: a review.

Aims: To review recent evidence that suggests inflammation plays a similar role in the pathogenesis of delirium and dementia. Methods: We performed a literature search of original research and review articles in PubMed using the keywords: delirium, dementia, and inflammation. We summarized the evidence linking inflammation to the pathogenesis of delirium and dementia. Discussion: Delirium and dementia share similarities in clinical and pathogenic features, leading to the speculation that instead of being distinct clinical entities, the two age‐related conditions may be linked by a common pathogenic mechanism. Inflammatory markers have been shown to be elevated in both delirium and dementia, thereby implicating inflammation as a possible mediating factor in their genesis. There is evidence in both basic science and clinical research literature that elevated cytokines play a crucial role in the development of cognitive dysfunction observed in both dementia and delirium. Conclusion: Mounting evidence supports the role of inflammation in the development of both dementia and delirium. Further studies are needed to elucidate the mechanisms underlying these relationships.

Thyroid Function and Alzheimer's Disease

Thyroid dysfunction has been implicated as a cause of reversible cognitive impairment and as such, the thyroid stimulating hormone has long been part of the screening laboratory test for dementia. Recently, several population-based studies demonstrated an association between hypo- or hyperthyroidism and Alzheimers disease. This review discusses the role of thyroid hormone in the normal development and regulation of central nervous system functions and summarizes the studies that have linked thyroid function and dementia risk. Finally, it explores possible biological mechanisms to explain this association, including the direct effects of thyroid hormone on cerebral amyloid processing, neurodegeneration and thyrotropin-mediated mechanisms and vascular mediated enhancement of Alzheimers disease risk.

Unmet Needs of Caregivers of Individuals Referred to a Dementia Care Program

To characterize caregiver strain, depressive symptoms, and self‐efficacy for managing dementia‐related problems and the relationship between these and referring provider type.

The University of California at Los Angeles Alzheimer's and Dementia Care Program for Comprehensive, Coordinated, Patient-Centered Care: Preliminary Data

Dementia is a chronic disease that requires medical and social services to provide high‐quality care and prevent complications. As a result of time constraints in practice, lack of systems‐based approaches, and poor integration of community‐based organizations (CBOs), the quality of care for dementia is poorer than that for other diseases that affect older persons. The University of California at Los Angeles (UCLA) Alzheimers and Dementia Care (UCLA ADC) program partners with CBOs to provide comprehensive, coordinated, patient‐centered care for individuals with Alzheimers disease and other dementias. The goals of the program are to maximize function, independence, and dignity; minimize caregiver strain and burnout; and reduce unnecessary costs. The UCLA ADC program consists of five core components: recruitment and a dementia registry, structured needs assessments of individuals in the registry and their caregivers, creation and implementation of individualized dementia care plans based on needs assessments and input from the primary care physicians, monitoring and revising care plans as needed, and around‐the‐clock access for assistance and advice. The program uses a comanagement model with a nurse practitioner Dementia Care Manager working with primary care physicians and CBOs. Based on the first 150 individuals served, the most common recommendations in the initial care plans were referrals to support groups (73%) and Alzheimers Association Safe Return (73%), caregiver training (45%), and medication adjustment (41%). The program will be evaluated on its ability to achieve the triple aim of better care for individuals, better health for populations, and lower costs.

Inflammation in the Alzheimer's disease cascade: culprit or innocent bystander?

The strongest known risk factors for late-onset Alzheimer disease (LOAD) remain a positive family history and the APOE ε4 allele. van Exel and colleagues used these known risk factors to identify high- and low-risk samples of middle-aged persons in whom they compared levels of inflammatory and vascular risk factors. They observed that, compared with controls, middle-aged offspring of families with a parental history of LOAD had higher blood pressures, lower ankle-brachial indices (measure of peripheral atherosclerosis), and increased production of proinflammatory cytokines in lipopolysaccharide-stimulated whole blood samples, associations that were independent of APOE genotype. This study adds to the growing body of evidence linking inflammatory mechanisms to Alzheimer disease risk and, especially when considered in light of the recently described association of genetic variation in the complement receptor 1 (CR1) gene with LOAD, suggests that inflammatory biomarkers (whether causal or incidental) could be measured and perhaps used to risk-stratify middle-aged persons for early preventive and therapeutic interventions.