Alzheimer Disease: Waring SC

Waring SC, Rosenberg RN. · Department of Epidemiology, The University of Texas School of Public Health, 1200 Herman Pressler, RAS-E629, Houston, TX 77030, USA. · Arch Neurol. · Pubmed #18332245 links to  free full text

Abstract: The genetics of Alzheimer disease (AD) to date support an age-dependent dichotomous model whereby earlier age of disease onset (< 60 years) is explained by 3 fully penetrant genes (APP [NCBI Entrez gene 351], PSEN1 [NCBI Entrez gene 5663], and PSEN2 [NCBI Entrez gene 5664]), whereas later age of disease onset (> or = 65 years) representing most cases of AD has yet to be explained by a purely genetic model. The APOE gene (NCBI Entrez gene 348) is the strongest genetic risk factor for later onset, although it is neither sufficient nor necessary to explain all occurrences of disease. Numerous putative genetic risk alleles and genetic variants have been reported. Although all have relevance to biological mechanisms that may be associated with AD pathogenesis, they await replication in large representative populations. Genome-wide association studies have emerged as an increasingly effective tool for identifying genetic contributions to complex diseases and represent the next frontier for furthering our understanding of the underlying etiologic, biological, and pathologic mechanisms associated with chronic complex disorders. There have already been success stories for diseases such as macular degeneration and diabetes mellitus. Whether this will hold true for a genetically complex and heterogeneous disease such as AD is not known, although early reports are encouraging. This review considers recent publications from studies that have successfully applied genome-wide association methods to investigations of AD by taking advantage of the currently available high-throughput arrays, bioinformatics, and software advances. The inherent strengths, limitations, and challenges associated with study design issues in the context of AD are presented herein.

O'Bryant SE, Waring SC, Cullum CM, Hall J, Lacritz L, Massman PJ, Lupo PJ, Reisch JS, Doody R, Anonymous00335. · Department of Neuropsychiatry and Behavioral Science, Texas Tech University Health Sciences Center, 3601 4th St, STOP 8321, Lubbock, TX 79430, USA. · Arch Neurol. · Pubmed #18695059 links to  free full text

Abstract: BACKGROUND: The Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) score is commonly used, although the utility regarding this score in staging dementia severity is not well established. OBJECTIVE: To investigate the effectiveness of CDR-SOB scores in staging dementia severity compared with the global CDR score. DESIGN: Retrospective study. SETTING: Texas Alzheimer's Research Consortium minimum data set cohort. PARTICIPANTS: A total of 1577 participants (110 controls, 202 patients with mild cognitive impairment, and 1265 patients with probable Alzheimer disease) were available for analysis. MAIN OUTCOME MEASURES: Receiver operating characteristic curves were generated from a derivation sample to determine optimal cutoff scores and ranges, which were then applied to the validation sample. RESULTS: Optimal ranges of CDR-SOB scores corresponding to the global CDR scores were 0.5 to 4.0 for a global score of 0.5, 4.5 to 9.0 for a global score of 1.0, 9.5 to 15.5 for a global score of 2.0, and 16.0 to 18.0 for a global score of 3.0. When applied to the validation sample, kappa scores ranged from 0.86 to 0.94 (P < .001 for all), with 93.0% of the participants falling within the new staging categories. CONCLUSIONS: The CDR-SOB score compares well with the global CDR score for dementia staging. Owing to the increased range of values, the CDR-SOB score offers several advantages over the global score, including increased utility in tracking changes within and between stages of dementia severity. Interpretive guidelines for CDR-SOB scores are provided.

Waring SC, Doody RS, Pavlik VN, Massman PJ, Chan W. · Division of Epidemiology, University of Texas School of Public Health, Houston, TX 77030, USA. · Alzheimer Dis Assoc Disord. · Pubmed #16327343 No free full text.

Abstract: Survival among patients with dementia is critical information needed for planning and assessing the overall impact of dementia. Attrition from longitudinal cohorts often limits the confidence in survival estimates. For this study, we examined survival among dementia patients from a large multi-ethnic population with excellent longitudinal follow-up. Subjects were all Baylor Alzheimer's Disease Center patients residing in the greater Houston area at the time of initial diagnosis. Vital status was available for all subjects. We estimated median survival time (Kaplan-Meier) from first symptom onset and from diagnosis, and examined the effects of baseline patient characteristics on survival. Median survival time for patients with any form of dementia was 10.5 years from onset and 5.7 years from diagnosis. Similarly, median survival time for probable Alzheimer disease patients was 11.3 years from onset and 5.7 years from diagnosis. Significant trends of decreasing survival with increasing age group (<70; 70-79, > or = 80) were evident for all dementia patients and for patients with Alzheimer disease. Our findings are consistent with previous studies and provide compelling evidence that survival from onset or diagnosis of dementia depends more on age than any other factor.

Petersen RC, Jack CR, Xu YC, Waring SC, O'Brien PC, Smith GE, Ivnik RJ, Tangalos EG, Boeve BF, Kokmen E. · Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA. · Neurology. · Pubmed #10680786 No free full text.

Abstract: OBJECTIVE: To demonstrate structural-functional relationships between MRI-based volumetric measurements of medial temporal lobe structures and cognitive function. BACKGROUND: Previous work has documented the ability of MRI-based measurements of the hippocampus to discriminate between age-matched control subjects and patients with very mild AD. Relatively less is known about the correlation between medial temporal lobe structures and cognitive functions. METHOD: We evaluated structural-functional relationships among the hippocampal formation, parahippocampal gyrus, and amygdala, and measures of memory, language, and general cognitive performance in 220 probable AD patients and normal control subjects. Standardized instruments of memory and general cognitive function were used to assess subjects enrolled in a longitudinal study of aging and dementia. RESULTS: The volume of the hippocampal formation predicted performance on most acquisition and recall measures across the spectrum of normal aging and AD. If the groups were segregated, most of the expected associations between medial temporal lobe structures and memory measures were observed in the AD patients. CONCLUSION: MRI-based hippocampal volumetry accurately depicts the structural-functional relationships between memory loss and hippocampal damage across the spectrum from normal aging to dementia.

Jack CR, Petersen RC, Xu YC, O'Brien PC, Smith GE, Ivnik RJ, Boeve BF, Waring SC, Tangalos EG, Kokmen E. · Department of Diagnostic Radiology, Mayo Clinic and Foundation, Rochester, MN 55905, USA. · Neurology. · Pubmed #10227624 No free full text.

Abstract: 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.

Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. · Department of Neurology, Mayo Clinic, Rochester, Minn 55905, USA. · Arch Neurol. · Pubmed #10190820 links to  free full text

Abstract: BACKGROUND: Subjects with a mild cognitive impairment (MCI) have a memory impairment beyond that expected for age and education yet are not demented. These subjects are becoming the focus of many prediction studies and early intervention trials. OBJECTIVE: To characterize clinically subjects with MCI cross-sectionally and longitudinally. DESIGN: A prospective, longitudinal inception cohort. SETTING: General community clinic. PARTICIPANTS: A sample of 76 consecutively evaluated subjects with MCI were compared with 234 healthy control subjects and 106 patients with mild Alzheimer disease (AD), all from a community setting as part of the Mayo Clinic Alzheimer's Disease Center/Alzheimer's Disease Patient Registry, Rochester, Minn. MAIN OUTCOME MEASURES: The 3 groups of individuals were compared on demographic factors and measures of cognitive function including the Mini-Mental State Examination, Wechsler Adult Intelligence Scale-Revised, Wechsler Memory Scale-Revised, Dementia Rating Scale, Free and Cued Selective Reminding Test, and Auditory Verbal Learning Test. Clinical classifications of dementia and AD were determined according to the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition and the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria, respectively. RESULTS: The primary distinction between control subjects and subjects with MCI was in the area of memory, while other cognitive functions were comparable. However, when the subjects with MCI were compared with the patients with very mild AD, memory performance was similar, but patients with AD were more impaired in other cognitive domains as well. Longitudinal performance demonstrated that the subjects with MCI declined at a rate greater than that of the controls but less rapidly than the patients with mild AD. CONCLUSIONS: Patients who meet the criteria for MCI can be differentiated from healthy control subjects and those with very mild AD. They appear to constitute a clinical entity that can be characterized for treatment interventions.

Waring SC, Rocca WA, Petersen RC, O'Brien PC, Tangalos EG, Kokmen E. · Department of Health Sciences Research, Mayo Clinic and Mayo Foundation, Rochester, MN, USA. · Neurology. · Pubmed #10102413 No free full text.

Abstract: OBJECTIVE: To study the association between estrogen replacement therapy in postmenopausal women and AD using a case-control design. BACKGROUND: Studies of the effect of estrogen therapy on the risk of AD have been limited and have yielded conflicting results. METHODS: Case patients were all postmenopausal women who developed AD in the quinquennium 1980 through 1984 in Rochester, MN (n = 222). One control subject from the same population and free of dementia was matched to each case patient by age (+/-3 years) and length of enrollment in the records-linkage system (n = 222). Estrogen exposure was defined as any form of estrogen (oral, parenteral, topical, suppository) used for at least 6 months after the onset of menopause and before the onset of AD (or corresponding year in the matched control subject). Information on dose and duration of use was abstracted. Consistent with the matched design, analyses entailed conditional logistic regression. RESULTS: AD patients and control subjects had identical age at menarche (median: 13.0 versus 13.0 years) and age at menopause (median: 50.0 versus 50.0 years). The frequency of estrogen use was higher among control subjects than AD patients (10% versus 5%; odds ratio = 0.42; 95% confidence interval 0.18 to 0.96; p = 0.04). There was a significant trend of decreasing odds ratios with increasing duration of use. The inverse association between estrogen therapy and AD remained significant after adjustment for education and age at menopause. CONCLUSION: These results from a population-based study suggest that estrogen replacement therapy is associated with a reduced risk of AD in postmenopausal women.