Stephen C. Waring

Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment

Objective: To test the hypothesis that MRI-based measurements of hippocampal volume are related to the risk of future conversion to Alzheimer’s disease (AD) in older patients with a mild cognitive impairment (MCI). Background: Patients who develop AD pass through a transitional state, which can be characterized as MCI. In some patients, however, MCI is a more benign condition, which may not progress to AD or may do so slowly.Patients:— Eighty consecutive patients who met criteria for the diagnosis of MCI were recruited from the Mayo Clinic Alzheimer’s Disease Center/Alzheimer’s Disease Patient Registry. Methods: At entry into the study, each patient received an MRI examination of the head, from which the volumes of both hippocampi were measured. Patients were followed longitudinally with approximately annual clinical/cognitive assessments. The primary endpoint was the crossover of individual MCI patients to the clinical diagnosis of AD during longitudinal clinical follow-up. Results: During the period of longitudinal observation, which averaged 32.6 months, 27 of the 80 MCI patients became demented. Hippocampal atrophy at baseline was associated with crossover from MCI to AD (relative risk [RR], 0.69, p = 0.015). When hippocampal volume was entered into bivariate models—using age, postmenopausal estrogen replacement, standard neuropsychological tests, apolipoprotein E (APOE) genotype, history of ischemic heart disease, and hypertension—the RRs were not substantially different from that found univariately, and the associations between hippocampal volume and crossover remained significant. Conclusion: In older patients with MCI, hippocampal atrophy determined by premorbid MRI-based volume measurements is predictive of subsequent conversion to AD.

Medial temporal atrophy on MRI in normal aging and very mild Alzheimer's disease.

Magnetic resonance imaging (MRI)-based volumetric measurements of medial temporal lobe (MTL) structures can discriminate between normal elderly control subjects and patients with Alzheimers disease (AD) of moderate to advanced severity. In terms of clinical utility, however, a more important issue concerns the ability of the technique to differentiate between normal elderly control subjects and AD patients with the very mildest form of the disease. We performed MRI-based volumetric measurements of the hippocampus, parahippocampal gyrus, and amygdala in 126 cognitively normal elderly control subjects and 94 patients with probable AD. The diagnosis of AD was made according to NINDS/ADRDA criteria, and disease severity was categorized by Clinical Dementia Rating (CDR) scores. Patients with CDR 0.5 were classified as very mild, CDR 1 as mild, and CDR 2 as moderate disease severity. Volumes of each structure declined with increasing age in control subjects and did so in parallel for men and women. The volume of each measured MTL structure also declined with age in patients with AD. The volume of each MTL structure was significantly smaller in AD patients than control subjects (p < 0.001). Of the several MTL measures, the total hippocampal volumetric measurements were best at discriminating control subjects from AD patients. The mean hippocampal volumes for AD patients relative to control subjects by severity of disease were as follows: very mild AD (CDR 0.5) -1.75 SD below the control mean, mild AD (CDR 1) -1.99 SD, and moderate AD (CDR 2) -2.22 SD. Age- and gender-adjusted, normalized MRI-based hippocampal volumetric measurements provide a sensitive marker of the MTL neuroanatomic degeneration in AD early in the disease process.

Aging, memory, and mild cognitive impairment

In recent years, patients who are at high risk for developing Alzheimers disease (AD) have become a focus of study. Several research groups have identified these patients, developed diagnostic criteria, and followed the patients longitudinally. These patients therefore constitute a clinical entity that is suitable for therapeutic interventions. In this article, we report our 5-year experience at the Mayo Clinic in characterizing a group of patients with mild cognitive impairment. These subjects were recruited from community-dwelling individuals who were receiving general medical care in the Department of Internal Medicine. They received the diagnosis of mild cognitive impairment if they met the following criteria: (a) complaint of defective memory, (b) normal activities of daily living, (c) normal general cognitive function, (d) abnormal memory function for age, and (e) absence of dementia. In following more than 75 of these patients, some of whom have been studied for as long as 5 years, it appears that approximately 10% to 15% of the subjects evolve to AD each year. We therefore evaluated the cognitive profiles of these patients at the time of their initial diagnosis in an attempt to predict who would remain stable and who would evolve to AD. Certain features of learning and memory performance indicated patients who were more likely to progress, but the strongest predictor was their apolipoprotein E status. The patients who possessed an epsilon 4 allele were more likely to convert to AD at a more rapid rate then those who were not carriers. Our results and similar data from other study groups indicate that diagnostic criteria can be defined for patients who are likely to convert to AD; the natural history of these patients is becoming apparent, and variables that predict ultimate conversion can be defined. Consequently, patients with mild cognitive impairment constitute an important group for study, particularly form the aspect of therapeutic interventions.

Risk of dementia among relatives of Alzheimer's disease patients in the MIRAGE study: What is in store for the oldest old?

Despite recent advances in the molecular genetics of Alzheimers disease (AD), several fundamental questions concerning risk of illness are unresolved, namely, if Mendelian factors account for the incidence of the disease, and if AD is an inevitable consequence of the aging process. This study was designed to address these issues and other aspects of familial aggregation of the disorder. A consecutive sample of 1,694 patients who met criteria for a diagnosis of probable or definite AD were ascertained in 13 centers participating in the Multi-Institutional Research in Alzheimer Genetic Epidemiology (MIRAGE) project. Lifetime risk and age at onset of AD among various strata of 12,971 first-degree relatives was estimated using survival analysis procedures. The lifetime risk of AD in first-degree relatives was 39.0% +/- 2.1% by age 96 years. Age-specific risk of AD declined after age 90 and the data set included 61 apparently unaffected persons who survived to age 96 without becoming demented. Female relatives had a higher risk of AD than male relatives at all ages. By age 80, children of conjugal AD couples had a cumulative risk of 54%, 1.5 times greater than the sum of the risks to children having affected mothers or fathers, and nearly 5 times greater than the risk to children having normal parents. Children of affected fathers had a cumulative risk that was 1.4 times the corresponding risk to children of affected mothers. Risk assessment in early-onset and late-onset families, using various strategies for determining the age cut-off, yielded contradictory results. These data suggest the following: (1) the lifetime risk among relatives does not support a simple autosomal dominant inheritance pattern of disease; (2) women are innately more susceptible to AD than men; (3) the proportion of hereditary cases may be higher in men than women; (4) distinction between early- onset and late-onset forms of AD has little meaning in the absence of a biological marker; (5) the risk of AD decreases after age 90; and (6) AD therefore may not be an inevitable concomitant of the aging process, a conclusion that has profound implications for basic and applied AD research. The age- and sex-specific lifetime risks derived from this study are sufficiently robust to be a reliable source of information for counseling relatives of AD patients.

Definition, course, and outcome of mild cognitive impairment

Abstract Mild Cognitive Impairment (MCI) is a term which can be applied to a boundary area between dementia and normal aging. Criteria which reliably describe persons falling in this range of the cognitive continuum can be defined. These persons are at very high risk for developing dementia. Biologic and cognitive parameters including Apolipoprotein E genotype help to differentiate MCI persons who will progress to dementia in 2-4 years from those who will remain free from dementia over this interval.

Nonsteroidal anti-inflammatory drug use and Alzheimer's disease: a case-control study in Rochester, Minnesota, 1980 through 1984.

OBJECTIVE To compare the frequency of use of nonsteroidal anti-inflammatory drugs (NSAIDs) among 302 incident cases of Alzheimers disease (AD) and age- and sex-matched control subjects. DESIGN We undertook a retrospective case-control study, using the resources of the Rochester Epidemiology Project. MATERIAL AND METHODS In ongoing studies of dementia in Rochester, Minnesota, we identified all incident cases of AD with onset between 1980 and 1984. From among all Rochester residents who received care at Mayo Clinic Rochester during those years, we selected one age- (within 3 years) and sex-matched control subject. For this study, exposure to a prescription NSAID was defined as prescribed use for 7 or more days during the 2-year window of time encompassing the year of onset and the year before onset among cases and the corresponding index year and the year prior for control subjects. RESULTS The odds ratio (OR) for exposure, as described, to a prescription NSAID versus no exposure to any NSAID was 0.79 (95% confidence interval [CI], 0.45 to 1.38); the OR was 1.00 (95% CI, 0.52 to 1.92) for women and 0.40 (95% CI, 0.13 to 1.29) for men. Similarly, the overall OR for aspirin exposure versus no NSAID exposure was 0.90 (95% CI, 0.54 to 1.50). CONCLUSION These data are suggestive but not confirmatory of a protective effect of NSAIDs for AD.

Predictive value of APOE genotyping in incipient Alzheimer's disease

The Mayo Alzheimers Disease Center/Alzheimers Disease Patient Registry is a prospective, longitudinal project of aging and dementia in a community setting. Over 400 pairs of individuals have been studied through this project, and extensive data on clinical, radiological, neuropathological, and biological variables have been gathered. Previous case-control studies on this group of subjects have documented the role of the apolipoprotein E (APOE) epsilon 4 as a risk factor for dementia. Subsequent analyses between APOE and the age of the patients with dementia have shown that most of the epsilon 4 effect is manifest in subjects under 75 years of age. We have also used this patient resource to study a group of individuals who are at risk for dementia by virtue of having a significant memory impairment. We have designated these patients as having a mild cognitive impairment because they have abnormal memory function but do not reach criteria for dementia. Over the course of several years of follow-up, these subjects evolve to dementia at a rate of approximately 15% per year. The presence of an APOE epsilon 4 carrier status is the best predictor of subsequent development of dementia in these individuals. These studies indicate that APOE is an important risk factor for AD, and in patients with a mild cognitive impairment, APOE may be useful in predicting who is likely to progress to dementia.

A Pilot Study of Gene/Gene and Gene/Environment Interactions in Alzheimer Disease

Background: Although some genes associated with increased risk of Alzheimer Disease (AD) have been identified, few data exist related to gene/gene and gene/environment risk of AD. The purpose of this pilot study was to explore gene/gene and gene/environment associations in AD and to obtain data for sample size estimates for larger, more definitive studies of AD. Methods: The effect of gene/gene and gene/environment interaction related to late onset Alzheimer Disease (LOAD) was investigated in 153 subjects with LOAD and 302 gender matched controls enrolled in the Personalized Medicine Research Project, a population-based bio-repository. Genetic risk factors examined included APOE, ACE, OLR1,and CYP46 genes, and environmental factors included smoking, total cholesterol, LDL, HDL, triglycerides, C-reactive protein, blood pressure, statin use, and body mass index. Results: The mean age of the cases was 78.2 years and the mean age of the controls was 87.2 years. APOE4 was significantly associated with LOAD (OR=3.55, 95%CL=1.70, 7.45). Cases were significantly more likely to have ever smoked cigarettes during their life (49.3% versus 38.4%, p=0.03). The highest recorded blood pressure and pulse pressure measurements were significantly higher in the controls than the cases (all P<0.005). Although not statistically significant in this pilot study, the relationship of the following factors was associated in opposite directions with LOAD based on the presence of an APOE4 allele: obesity at the age of 50, ACE, OLR1, and CYP46. Conclusions: These pilot data suggest that gene/gene and gene/environment interactions may be important in LOAD, with APOE, a known risk factor for LOAD, affecting the relationship of ACE and OLR1 to LOAD. Replication with a larger sample size and in other racial/ethnic groups is warranted and the allele and risk factor frequencies will assist in choosing an appropriate sample size for a definitive study.

Evaluation of obesity as an independent risk factor for medically attended laboratory‐confirmed influenza

Please cite this paper as: Coleman et al. (2013) Evaluation of obesity as an independent risk factor for medically attended laboratory‐confirmed influenza. Influenza and Other Respiratory Viruses 7(2) 160–167.

Amyotrophic Lateral Sclerosis and Polio: Is There an Association?

Because polio and ALS are both manifestations of anterior horn cell disease, consideration of some etiologic or pathogenetic relationship continues to recur. Studies that show an association are infrequent and are greatly outnumbered by negative reports in spite of possible journal bias to report positive results. Our limited studies in Guam and Rochester, Minnesota, have added to the negative list, and support the conclusion that there is no etiologic association of these two distinct diseases. The role, if any, of nonparalytic polio and polio vaccines with respect to ALS is not clear. With such a high proportion of the population having antibodies to polio, it may not be feasible to differentiate ALS with respect to the presence or absence of polio antibodies. Although the results to date do not support a polio‐ALS relationship, further long‐term studies are desirable for both the classical and the Western Pacific forms of ALS with respect to past polio outbreaks and, for the future, the unknown effect of polio vaccines on the incidence of ALS.