Mark A. Sager

Hospital Admission Risk Profile (HARP): Identifying Older Patients at Risk for Functional Decline Following Acute Medical Illness and Hospitalization

OBJECTIVES: To develop and validate an instrument for stratifying older patients at the time of hospital admission according to their risk of developing new disabilities in activities of daily living (ADL) following acute medical illness and hospitalization.

The effect of body mass index on global brain volume in middle-aged adults: a cross sectional study

BackgroundObesity causes or exacerbates a host of medical conditions, including cardiovascular, pulmonary, and endocrine diseases. Recently obesity in elderly women was associated with greater risk of dementia, white matter ischemic changes, and greater brain atrophy. The purpose of this study was to determine whether body type affects global brain volume, a marker of atrophy, in middle-aged men and women.MethodsT1-weighted 3D volumetric magnetic resonance imaging was used to assess global brain volume for 114 individuals 40 to 66 years of age (average = 54.2 years; standard deviation = 6.6 years; 43 men and 71 women). Total cerebrospinal fluid and brain volumes were obtained with an automated tissue segmentation algorithm. A regression model was used to determine the effect of age, body mass index (BMI), and other cardiovascular risk factors on brain volume and cognition.ResultsAge and BMI were each associated with decreased brain volume. BMI did not predict cognition in this sample; however elevated diastolic blood pressure was associated with poorer episodic learning performance.ConclusionThese findings suggest that middle-aged obese adults may already be experiencing differentially greater brain atrophy, and may potentially be at greater risk for future cognitive decline.

Measurement of Activities of Daily Living in Hospitalized Elderly: A Comparison of Self-Report and Performance-Based Methods

To determine the accuracy of self‐reports of physical functioning by hospitalized elderly.

Risk of falls after hospital discharge.

To determine the incidence of falls within the first month after hospitalization and risk factors associated with falling during this period.

Middle-aged children of persons with Alzheimer's disease: APOE genotypes and cognitive function in the Wisconsin Registry for Alzheimer's Prevention.

Adult children of persons with Alzheimer’s disease are at increased risk of developing Alzheimer’s disease because of hereditary, environmental, and health risk factors shared with affected parents. The Wisconsin Registry for Alzheimer’s Prevention (WRAP) has completed baseline assessments on 452 middle-aged persons (mean = 53 years) who have at least 1 parent with AD. Forty-five percent had 1 or more apolipoprotein (APOE) ε4 alleles. There were few significant differences between ε4 carriers and noncarriers in demographics, health, and lifestyle measures or in neuropsychological performance. The high percentage of WRAP participants who are carriers of APOE ε4 underscores their increased risk for developing Alzheimer’s disease, but the absence of differences related to APOE status and high mean scores on cognitive tests suggests that the APOE ε4 gene has yet to have a clinical impact on cognitive functioning. The WRAP cohort may be a valuable group to follow prospectively to characterize the nature of cognitive change in relation to risk factors and to identify underlying preclinical neurobiological changes.

Early identification and treatment of Alzheimer's disease: Social and fiscal outcomes

Alzheimers disease (AD) is a progressive neurodegenerative disease that places substantial burdens on those who provide support for family members with declining cognitive and functional abilities. Many AD patients eventually require formal long‐term care services because of the absence, exhaustion, or inability of family members to provide care. The costs of long‐term care, and especially nursing home care, often deplete private financial resources, placing a substantial burden on state Medicaid programs. Current evidence suggests that pharmacological treatments and caregiver interventions can delay entry into nursing homes and potentially reduce Medicaid costs. However, these cost savings are not being realized because many patients with AD are either not diagnosed or diagnosed at late stages of the disease, and have no access to Medicare‐funded caregiver support programs.

Changes in the Location of Death after Passage of Medicare's Prospective Payment System

We reviewed age-specific national mortality data for the years 1981 through 1985 to evaluate changes in the location of death among the nations elderly after implementation of Medicares prospective payment system (PPS). Although it was unchanged in 1981 and 1982, the percentage of deaths occurring in the nations nursing homes increased from 18.9 percent in 1982 to 21.5 percent in 1985. The increases in nursing home deaths were greatest between 1983 and 1984, when 33 states showed larger-than-expected increases when compared with a base period before implementation of PPS. These changes were accompanied by a decline in the percentage of deaths that occurred in hospitals. These changes in the location of death were most pronounced in the Midwest, South, and West; they were very small in the Northeast and in states not affected by the PPS. Furthermore, the states with high population enrollments in health maintenance organizations and with large declines in the mean hospital length of stay in 1984 showed the greatest shifts in the location of death. We conclude that Medicares PPS resulted in the increased transfer of terminally ill patients from hospitals to nursing homes. Further study is required to determine whether such transfer is medically appropriate.

The Influence of Alzheimer Disease Family History and Apolipoprotein E ε4 on Mesial Temporal Lobe Activation

First-degree family history of sporadic Alzheimer disease (AD) and the apolipoprotein E ε4 (APOE4) are risk factors for developing AD. Although the role of APOE4 in AD pathogenesis has been well studied, family history remains a rarely studied and poorly understood risk factor. Both putatively cause early brain changes before symptomatic disease, but the relative contribution of each to brain function is unknown. We examined 68 middle-aged participants with a parent diagnosed with AD [family history (+FH)] and 64 age- and education-matched controls without a first-degree family history of any dementia [no family history (−FH)]. All underwent cognitive testing, APOE genotyping, and a functional magnetic resonance imaging encoding task that required discrimination of novel items from previously learned items. A 2 × 2 factorial ANOVA (presence/absence of parental family history and presence/absence of the APOE4) was used to detect group effects. A greater response to novel items was detected in the mesial temporal lobe and fusiform gyrus bilaterally among persons without a first-degree family history of AD. In hippocampal areas, the −FH +ε4 group exhibited the greatest signal change, and the +FH +ε4 group exhibited the least. These findings indicate that FH of AD is an important predictor of hippocampal activation during encoding and that FH may modulate the effect of APOE4 in these middle-aged adults, suggesting that an as yet unspecified factor embodied in first-degree family history of AD is influencing the expression of APOE4 on brain function.

Association of Insulin Resistance With Cerebral Glucose Uptake in Late Middle–Aged Adults at Risk for Alzheimer Disease

IMPORTANCE Converging evidence suggests that Alzheimer disease (AD) involves insulin signaling impairment. Patients with AD and individuals at risk for AD show reduced glucose metabolism, as indexed by fludeoxyglucose F 18-labeled positron emission tomography (FDG-PET). OBJECTIVES To determine whether insulin resistance predicts AD-like global and regional glucose metabolism deficits in late middle-aged participants at risk for AD and to examine whether insulin resistance-predicted variation in regional glucose metabolism is associated with worse cognitive performance. DESIGN, SETTING, AND PARTICIPANTS This population-based, cross-sectional study included 150 cognitively normal, late middle-aged (mean [SD] age, 60.7 [5.8] years) adults from the Wisconsin Registry for Alzheimers Prevention (WRAP) study, a general community sample enriched for AD parental history. Participants underwent cognitive testing, fasting blood draw, and FDG-PET at baseline. We used the homeostatic model assessment of peripheral insulin resistance (HOMA-IR). Regression analysis tested the statistical effect of HOMA-IR on global glucose metabolism. We used a voxelwise analysis to determine whether HOMA-IR predicted regional glucose metabolism. Finally, predicted variation in regional glucose metabolism was regressed against cognitive factors. Covariates included age, sex, body mass index, apolipoprotein E ε4 genotype, AD parental history status, and a reference region used to normalize regional uptake. MAIN OUTCOMES AND MEASURES Regional glucose uptake determined using FDG-PET and neuropsychological factors. RESULTS Higher HOMA-IR was associated with lower global glucose metabolism (β = -0.29; P < .01) and lower regional glucose metabolism across large portions of the frontal, lateral parietal, lateral temporal, and medial temporal lobes (P < .05, familywise error corrected). The association was especially robust in the left medial temporal lobe (R2 = 0.178). Lower glucose metabolism in the left medial temporal lobe predicted by HOMA-IR was significantly related to worse performance on the immediate memory (β = 0.317; t148 = 4.08; P < .001) and delayed memory (β = 0.305; t148 = 3.895; P < .001) factor scores. CONCLUSIONS AND RELEVANCE Our results show that insulin resistance, a prevalent and increasingly common condition in developed countries, is associated with significantly lower regional cerebral glucose metabolism, which in turn may predict worse memory performance. Midlife may be a critical period for initiating treatments to lower peripheral insulin resistance to maintain neural metabolism and cognitive function.

Insulin Resistance, Brain Atrophy, and Cognitive Performance in Late Middle–Aged Adults

OBJECTIVE Insulin resistance dysregulates glucose uptake and other functions in brain areas affected by Alzheimer disease. Insulin resistance may play a role in Alzheimer disease etiopathogenesis. This longitudinal study examined whether insulin resistance among late middle–aged, cognitively healthy individuals was associated with 1) less gray matter in Alzheimer disease–sensitive brain regions and 2) worse cognitive performance. RESEARCH DESIGN AND METHODS Homeostasis model assessment of insulin resistance, gray matter volume, and the Rey Auditory Verbal Learning Test (RAVLT) were acquired in 372 participants at baseline and a consecutive subset of 121 individuals ~4 years later. Voxel-based morphometry and tensor-based morphometry were used, respectively, to test the association of insulin resistance with baseline brain volume and progressive gray matter atrophy. RESULTS Higher insulin resistance predicted less gray matter at baseline and 4 years later in medial temporal lobe, prefrontal cortices, precuneus, and other parietal gyri. A region-of-interest analysis, independent of the voxel-wise analyses, confirmed that higher insulin resistance was related to medial temporal lobe atrophy. Atrophy itself corresponded to cognitive deficits in the RAVLT. Temporal lobe atrophy that was predicted by higher insulin resistance significantly mediated worse RAVLT encoding performance. CONCLUSIONS These results suggest that insulin resistance in an asymptomatic, late middle–aged cohort is associated with progressive atrophy in regions affected by early Alzheimer disease. Insulin resistance may also affect the ability to encode episodic information by negatively influencing gray matter volume in medial temporal lobe.