Hippocampal atrophy correlates with clinical features of Alzheimer disease in African Americans.

CONTEXT: Imaging measurements may aid in the characterization and diagnosis of patients with Alzheimer disease (AD). Most research studies, however, have been performed on predominantly white study groups despite the fact that there may be biological differences in AD between African American and white patients. OBJECTIVE: To measure hippocampal volume in African American patients with AD and to correlate these measurements with the presence of AD and neuropsychological test performance. DESIGN: Survey study. SETTING: Academic center. PARTICIPANTS: Fifty-four healthy African American subjects and 32 African American patients with AD were studied. Hippocampal volumes were measured in all subjects from magnetic resonance images using established methods. MAIN OUTCOME MEASURE: Correlations were assessed between hippocampal volume and demographic variables, clinical group membership, and neuropsychological performance. RESULTS: The hippocampi of patients were atrophic with respect to those of healthy subjects (P<.01). Significant direct correlations were present between hippocampal volumes and performance on several different neuropsychological tests (r>0.5 and P<.01 for every test evaluated) when patients and healthy subjects were combined. CONCLUSIONS: Hippocampal atrophy is a feature of AD in African Americans as it is in white subjects. The neuropsychological-hippocampal volume correlations indicate that hippocampal volume measurements do represent a measure of the structural substrate of functional impairment in AD.

Levodopa therapy and survival in idiopathic Parkinson's disease: Olmsted County project.

We studied survival in all Olmsted County Parkinson's disease (PD) patients seen at the Mayo Clinic from 1964 to 1978, attempting to answer two questions: (1) What effect does levodopa have on survival in PD? and (2) Does the timing of levodopa administration influence survival? We chose this period because it allowed us to study patient records with a spectrum of disease durations before levodopa treatment; in many patients, the treatment delay was exclusively due to levodopa being unavailable prior to 1969. Mortality of the entire PD cohort (N = 179; 61% levodopa-treated) was greater than that of the general population (matched chronologically, geographically, and by age and gender). Lower age at onset of motor symptoms, lower Hoehn and Yahr stage at first neurologic visit for parkinsonism, and treatment with levodopa were all independent predictors of improved survival. Using a time-dependent Cox regression model, we assessed the impact of the timing of levodopa administration during the course of illness on mortality, while statistically controlling for other factors (ie, patient selection for levodopa treatment, and independent predictors of survival). Risk of death following initiation of levodopa was significantly reduced (p < 0.001), regardless of pre-levodopa duration of illness. This reduction gradually diminished over a period of 4 years on levodopa, but continued to be significantly reduced. After 4 years, increasing survival benefit again progressively accrued over time to at least 17 years of levodopa treatment (p < 0.001). At no point in time was levodopa treatment associated with increased mortality, arguing against substantial levodopa toxicity. However, despite levodopa-improved survival, mortality continues to be increased in PD relative to the general population.

Antemortem MRI findings correlate with hippocampal neuropathology in typical aging and dementia.

OBJECTIVES: To assess the diagnostic specificity of MRI-defined hippocampal atrophy for AD among individuals with a variety of pathologically confirmed conditions associated with dementia as well as changes attributable to typical aging, and to measure correlations among premortem MRI measurements of hippocampal atrophy, mental status examination performance, and the pathologic stage of AD. METHODS: An unselected series of 67 individuals participating in the Mayo Alzheimer's Disease Research Center/Alzheimer's Disease Patient Registry who had undergone a standardized antemortem MRI study and also postmortem examination were identified. Hippocampal volumes were measured from antemortem MRI. Each postmortem specimen was assigned a pathologic diagnosis and in addition, the severity of AD pathology was staged using the method of Braak and Braak. RESULTS: Individuals with an isolated pathologic diagnosis of AD, hippocampal sclerosis, frontotemporal degeneration, and neurofibrillary tangle--only degeneration usually had substantial hippocampal atrophy, while those with changes of typical aging did not. Among all 67 subjects, correlations (all p < 0.001) were observed between hippocampal volume and Braak and Braak stage (r = -0.39), between hippocampal volume and Mini-Mental State Examination (MMSE) score (r = 0.60), and between MMSE score and Braak and Braak stage (r = -0.41). CONCLUSIONS: Hippocampal atrophy, while not specific for AD, was a fairly sensitive marker of the pathologic AD stage (particularly among subjects with isolated AD pathology [r = -0.63, p = 0.001]) and consequent cognitive status.

Variability in anticoagulation control predicts thromboembolism after mechanical cardiac valve replacement: a 23-year population-based study.

OBJECTIVE: To assess optimal control of blood anticoagulation to maximize antithrombotic protection after mechanical cardiac valve replacement. DESIGN: A population-based study of 96 patients with a mean follow-up of 7.7 years (range, 1 month to 23 years) was performed in Olmsted County, Minnesota, and 10,301 prothrombin time (PT) ratios were determined after mechanical heart valve replacement. MATERIAL AND METHODS: PT ratios were analyzed in a new time-dependent Cox proportional-hazards model by defining an algorithm for comparing variability in PT ratios at each month of follow-up and relating these to thromboembolic events. The new method was compared with several conventional time-independent definitions. RESULTS: During 740 person-years of follow-up, 19 of 96 patients (20%) had 27 thromboembolic events. Of these 19 patients, 8 (42%) had events within 3 months after valve replacement. Freedom from any thromboembolic event was 72% at 15 years. The event rate was high (7.5% per year) during high variability and low (0.9% per year) during low variability in the PT ratio. This relationship was lost when time dependence was removed. More PT ratios were less than 1.5 during high (27%) than during low (19%) variability. Several conventional definitions of adequacy of anticoagulation that averaged PT ratios before a thromboembolic event or throughout follow-up or that compared the proportion of PT ratios above or below a fixed ratio did not define or only partially defined different thromboembolic risks. CONCLUSION: Periods of high and low variability of PT ratios define high and low risk of thromboembolism, respectively.

Protein-losing enteropathy after the Fontan operation.

Patients were observed after the Fontan operation to determine the frequency and severity of protein-losing enteropathy. A total of 427 patients who survived for 30 days after the Fontan operation, performed between 1973 and January 1987, were analyzed and, thus far, protein-losing enteropathy has developed in 47 of 427. The cumulative risk for the development of protein-losing enteropathy by 10 years was 13.4% among 30-day survivors, and 5-year survival after the diagnosis was 46%. Hemodynamic studies done coincident with the diagnosis of protein-losing enteropathy have shown increased systemic venous pressure, decreased cardiac index, increased pulmonary vascular resistance, and increased ventricular end-diastolic pressure. Medical management of protein-losing enteropathy was only partially successful. Statistical analysis has shown that factors related to protein-losing enteropathy were ventricular anatomy, increased preoperative ventricular end-diastolic pressure, longer operative bypass time, increased length of hospital stay, and postoperative renal failure. This study suggests that scrupulous selection of cases for the Fontan operation is mandatory and that certain perioperative factors may predispose to this serious complication of the Fontan procedure.

The incidence of MCI differs by subtype and is higher in men: the Mayo Clinic Study of Aging.

OBJECTIVE: Although incidence rates for mild cognitive impairment (MCI) have been reported, few studies were specifically designed to measure the incidence of MCI and its subtypes using published criteria. We estimated the incidence of amnestic MCI (aMCI) and nonamnestic MCI (naMCI) in men and women separately. METHODS: A population-based prospective cohort of Olmsted County, MN, residents ages 70-89 years on October 1, 2004, underwent baseline and 15-month interval evaluations that included the Clinical Dementia Rating scale, a neurologic evaluation, and neuropsychological testing. A panel of examiners blinded to previous diagnoses reviewed data at each serial evaluation to assess cognitive status according to published criteria. RESULTS: Among 1,450 subjects who were cognitively normal at baseline, 296 developed MCI. The age- and sex-standardized incidence rate of MCI was 63.6 (per 1,000 person-years) overall, and was higher in men (72.4) than women (57.3) and for aMCI (37.7) than naMCI (14.7). The incidence rate of aMCI was higher for men (43.9) than women (33.3), and for subjects with ≤12 years of education (42.6) than higher education (32.5). The risk of naMCI was also higher for men (20.0) than women (10.9) and for subjects with ≤12 years of education (20.3) than higher education (10.2). CONCLUSIONS: The incidence rates for MCI are substantial. Differences in incidence rates by clinical subtype and by sex suggest that risk factors for MCI should be investigated separately for aMCI and naMCI, and in men and women.

Prevalence of mild cognitive impairment is higher in men. The Mayo Clinic Study of Aging.

OBJECTIVE: We investigated the prevalence of mild cognitive impairment (MCI) in Olmsted County, MN, using in-person evaluations and published criteria. METHODS: We evaluated an age- and sex-stratified random sample of Olmsted County residents who were 70-89 years old on October 1, 2004, using the Clinical Dementia Rating Scale, a neurologic evaluation, and neuropsychological testing to assess 4 cognitive domains: memory, executive function, language, and visuospatial skills. Information for each participant was reviewed by an adjudication panel and a diagnosis of normal cognition, MCI, or dementia was made using published criteria. RESULTS: Among 1,969 subjects without dementia, 329 subjects had MCI, with a prevalence of 16.0% (95% confidence interval [CI] 14.4-17.5) for any MCI, 11.1% (95% CI 9.8-12.3) for amnestic MCI, and 4.9% (95% CI 4.0-5.8) for nonamnestic MCI. The prevalence of MCI increased with age and was higher in men. The prevalence odds ratio (OR) in men was 1.54 (95% CI 1.21-1.96; adjusted for age, education, and nonparticipation). The prevalence was also higher in subjects who never married and in subjects with an APOE epsilon3epsilon4 or epsilon4epsilon4 genotype. MCI prevalence decreased with increasing number of years of education (p for linear trend <0.0001). CONCLUSIONS: Our study suggests that approximately 16% of elderly subjects free of dementia are affected by MCI, and amnestic MCI is the most common type. The higher prevalence of MCI in men may suggest that women transition from normal cognition directly to dementia at a later age but more abruptly.

Incident dementia in women is preceded by weight loss by at least a decade.

BACKGROUND: Although several studies reported weight loss preceding the onset of dementia, other studies suggested that obesity in midlife or even later in life may be a risk factor for dementia. METHODS: The authors used the records-linkage system of the Rochester Epidemiology Project to ascertain incident cases of dementia in Rochester, MN, for the 5-year period 1990 to 1994. The authors defined dementia using the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV). Each case was individually matched by age (+/-1 year) and sex to a person drawn randomly from the same population, and free from dementia in the index year (year of onset of dementia in the matched case). Weights were abstracted from the medical records in the system. RESULTS: There were no differences in weight between cases and controls 21 to 30 years prior to the onset of dementia. However, women with dementia had lower weight than controls starting at 11 to 20 years prior to the index year, and the difference increased over time through the index year. We found a trend of increasing risk of dementia with decreasing weight in women both at the index year (test for linear trend; p < 0.001) and 9 to 10 years before the index year (test for linear trend; p = 0.001). CONCLUSIONS: Even accounting for delays in diagnosis, weight loss precedes the diagnosis of dementia in women but not in men by several years. This loss may relate to predementia apathy, loss of initiative, and reduced olfactory function.

Coronary artery bypass grafting is not a risk factor for dementia or Alzheimer disease.

OBJECTIVE: To study coronary artery bypass grafting (CABG) as a risk factor for dementia and Alzheimer disease (AD) using a case-control design. METHODS: The authors used the records-linkage system of the Rochester Epidemiology Project to ascertain incident cases of dementia in Rochester, MN, for the 5-year period 1990 to 1994. The authors defined dementia and AD using the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV). Each case was individually matched by age (+/-1 year) and sex to a person drawn randomly from the same population, and free of dementia in the index year (year of onset of dementia in the matched case). RESULTS: Among 557 dementia cases, 24 (4.3%) had undergone a CABG prior to the onset of dementia with a median lag time of 5.5 years (range = 0.1 to 15.9). Among 557 controls, 28 subjects (5.0%) had undergone a CABG prior to the index year with a median lag time 3.9 years (range = 0.1 to 12.3); OR = 0.85 (95% CI = 0.49 to 1.49; p = 0.57) for dementia and OR = 0.78 (95% CI = 0.39 to 1.56; p = 0.48) for AD. The findings did not change after adjustment for education. The perioperative courses of cases and controls were comparable. Analyses including only the 481 cases of dementia with presumed neurodegenerative or cerebrovascular etiology were also negative. CONCLUSIONS: This population-based case-control study suggests that coronary artery bypass grafting is not a major risk factor for dementia overall, or for Alzheimer disease.

Incidence of dementia and Alzheimer's disease: a reanalysis of data from Rochester, Minnesota, 1975-1984.

For both dementia and Alzheimer's disease (AD), data regarding incidence rates in the oldest old and time trends in incidence are limited. The authors reanalyzed previously reported data on the incidence of dementia and AD in Rochester, Minnesota, from 1975 through 1984, using three new strategies. First, incidence rates were corrected by removing age-, sex-, and calendar year-specific prevalent cases from the census-derived denominator figures. Second, incidence figures for persons above age 84 years were disaggregated. Third, time trends were investigated graphically using age-specific curves and birth cohort curves. Dementia diagnosis and AD diagnosis followed defined ad hoc criteria. Analyses were conducted for men, women, and both sexes combined, and for dementia and AD separately. The age-specific incidence rates were similar in men and women, continued to increase after age 84 years, and remained stable over time for both dementia and AD. No birth cohort effect was present for either dementia or AD. The similar risks seen in men and women, the continuing increase in incidence after age 84 years, and the stability of incidence over time have important implications for etiologic research on AD.

The incidence of frontotemporal lobar degeneration in Rochester, Minnesota, 1990 through 1994.

The records-linkage system of the Rochester Epidemiology Project was used to ascertain incident cases of frontotemporal lobar degeneration (FTLD) in Rochester, MN, from 1990 through 1994. Four cases of FTLD were identified (all women); two were confirmed neuropathologically. All were of the behavioral-dysexecutive type and had onset before age 70. The incidence rates (new cases per 100,000 person-years) were 2.2 for ages 40 to 49, 3.3 for ages 50 to 59, and 8.9 for ages 60 to 69. For comparison, the corresponding rates for Alzheimer disease were 0.0, 3.3, and 88.9.

Comparison of different MRI brain atrophy rate measures with clinical disease progression in AD.

OBJECTIVE: To correlate different methods of measuring rates of brain atrophy from serial MRI with corresponding clinical change in normal elderly subjects, patients with mild cognitive impairment (MCI), and patients with probable Alzheimer disease (AD). METHODS: One hundred sixty subjects were recruited from the Mayo Clinic Alzheimer's Disease Research Center and Alzheimer's Disease Patient Registry Studies. At baseline, 55 subjects were cognitively normal, 41 met criteria for MCI, and 64 met criteria for AD. Each subject underwent an MRI examination of the brain at the time of the baseline clinical assessment and then again at the time of a follow-up clinical assessment, 1 to 5 years later. The annualized changes in volume of four structures were measured from the serial MRI studies: hippocampus, entorhinal cortex, whole brain, and ventricle. Rates of change on several cognitive tests/rating scales were also assessed. Subjects who were classified as normal or MCI at baseline could either remain stable or convert to a lower-functioning group. AD subjects were dichotomized into slow vs fast progressors. RESULTS: All four atrophy rates were greater among normal subjects who converted to MCI or AD than among those who remained stable, greater among MCI subjects who converted to AD than among those who remained stable, and greater among fast than slow AD progressors. In general, atrophy on MRI was detected more consistently than decline on specific cognitive tests/rating scales. With one exception, no differences were found among the four MRI rate measures in the strength of the correlation with clinical deterioration at different stages of the disease. CONCLUSIONS: These data support the use of rates of change from serial MRI studies in addition to standard clinical/psychometric measures as surrogate markers of disease progression in AD. Estimated sample sizes required to power a therapeutic trial in MCI were an order of magnitude less for MRI than for change measures based on cognitive tests/rating scales.

Comparison of memory fMRI response among normal, MCI, and Alzheimer's patients.

OBJECTIVE: To determine whether an fMRI memory encoding task distinguishes among cognitively normal elderly individuals, patients with mild cognitive impairment (MCI), and patients with early Alzheimer's disease (AD). METHODS: Twenty-nine subjects (11 normal, 9 MCI, 9 AD) were studied with an fMRI memory encoding task. A passive sensory task was also performed to assess potential intergroup differences in fMRI responsiveness. Activation in the medial temporal lobe for the memory task and in the anatomic rolandic area for the sensory task was studied. Intergroup comparisons were performed using receiver operating characteristic (ROC) analyses. The ROC method provides rigorous control of artifactual false-positive "activation." Subjects were tested for recall and recognition of the encoding task stimuli following the fMRI study. RESULTS: Medial temporal lobe activation was greater in normal subjects than MCI and AD patients (p = 0.03 and p = 0.04). There was no difference between AD and MCI patients in fMRI memory performance [corrected]. There was an association between fMRI memory activation (area under the ROC curve) and post-fMRI performance on recognition and free recall. There was no difference among the three groups on the sensory task. CONCLUSIONS: MCI and AD patients had less medial temporal lobe activation on the memory task than the normal subjects but similar activation as normal subjects on the sensory task. These findings suggest decreased medial temporal activation may be a specific marker of limbic dysfunction due to the neurodegenerative changes of AD. In addition, fMRI is sufficiently sensitive to detect changes in the prodromal, MCI, phase of the disease.