Alzheimer Disease: Rocca WA

Viswanathan A, Rocca WA, Tzourio C. · Department of Neurology and Clinical Trials Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. · Neurology. · Pubmed #19171835 No free full text.

Abstract: In recent years, accumulating evidence has suggested that vascular risk factors contribute to Alzheimer disease (AD). Vascular dementia had been traditionally considered secondary to stroke and vascular disease. It has been traditionally distinguished from AD, considered to be a purely neurodegenerative form of dementia. However, in light of this more recent literature, it appears that there is a spectrum: ranging from patients with pure vascular dementia to patients with pure AD and including a large majority of patients with contributions from both Alzheimer and vascular pathologies. In this article, we discuss the impact of vascular risk factors on AD and its consequences at the individual level and at the population level by highlighting the concept of attributable risk. We then discuss the key questions and next steps involved in designing a therapeutic trial to control vascular risk factors for the prevention of dementia.

Gorelick PB, Erkinjuntti T, Hofman A, Rocca WA, Skoog I, Winblad B. · Department of Neurological Sciences, Rush Medical College, Chicago, Illinois, USA. · Alzheimer Dis Assoc Disord. · Pubmed #10609692 No free full text.

Abstract: Stroke is an important public health problem worldwide. Those at high risk of stroke may be at high risk of cognitive impairment and dementia after stroke. Modifiable cardiovascular risk factors in midlife including hypertension, alcohol use, cigarette smoking, and certain dietary factors may be important targets for prevention of vascular causes of cognitive impairment. These same types of factors may also be associated with Alzheimer disease. Better control of cardiovascular disease risk factors might lead to delay or prevention of vascular dementia and Alzheimer disease.

Geda YE, Roberts RO, Knopman DS, Petersen RC, Christianson TJ, Pankratz VS, Smith GE, Boeve BF, Ivnik RJ, Tangalos EG, Rocca WA. · Department of Psychiatry and Psychology, College of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA. · Arch Gen Psychiatry. · Pubmed #18838636 No free full text.

Abstract: CONTEXT: Little is known about the population-based prevalence of neuropsychiatric symptoms in mild cognitive impairment (MCI). OBJECTIVE: To estimate the prevalence of neuropsychiatric symptoms in MCI and normal cognitive aging in a defined population. DESIGN: Cross-sectional study derived from an ongoing population-based prospective cohort study. SETTING: The Mayo Clinic Study of Aging. PARTICIPANTS: We studied a random sample of 1969 individuals without dementia from the target population of 9965 elderly persons residing in Olmsted County (Minnesota) on the prevalence date (October 1, 2004). Neuropsychiatric data were available for 319 of 329 subjects with MCI (97.0%) and 1590 of 1640 subjects with normal cognition (97.0%). Neurologic, cognitive, and neuropsychiatric data were obtained from the study participants. A classification of MCI, dementia, and normal cognitive aging was adjudicated by an expert consensus panel. Accordingly, 329 subjects were classified as having MCI and the remaining 1640 subjects were classified as having normal cognition. MAIN OUTCOME MEASURE: Neuropsychiatric Inventory Questionnaire score. RESULTS: Multivariate logistic regression analyses were conducted after adjusting for age, sex, and educational status. By considering both the odds ratio (OR) and the frequency of a symptom, the most distinguishing features between the 2 groups were apathy (OR, 4.53; 95% confidence interval [CI], 3.11-6.60; P < .001), agitation (3.60; 2.18-5.92; P < .001), anxiety (3.00; 2.01-4.48; P < .001), irritability 2.99; 2.11-4.22; P < .001), and depression (2.78; 2.06-3.76; P < .001). The OR was highest for delusion (8.12; 95% CI, 2.92-22.60; P < .001); however, it was rare in both subjects with MCI (11 of 319 [3.4%]) and those with normal cognition (6 of 1590 [0.4%]). Thus, the population attributable risk for delusion was only 2.62% compared with 14.60% for apathy. CONCLUSIONS: Nonpsychotic symptoms affected approximately 50% of subjects with MCI and 25% of subjects with normal cognition. In contrast, psychotic symptoms were rare.

Lesnick TG, Papapetropoulos S, Mash DC, Ffrench-Mullen J, Shehadeh L, de Andrade M, Henley JR, Rocca WA, Ahlskog JE, Maraganore DM. · Division of Biostatistics, Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America. · PLoS Genet. · Pubmed #17571925 links to  free full text

Abstract: While major inroads have been made in identifying the genetic causes of rare Mendelian disorders, little progress has been made in the discovery of common gene variations that predispose to complex diseases. The single gene variants that have been shown to associate reproducibly with complex diseases typically have small effect sizes or attributable risks. However, the joint actions of common gene variants within pathways may play a major role in predisposing to complex diseases (the paradigm of complex genetics). The goal of this study was to determine whether polymorphism in a candidate pathway (axon guidance) predisposed to a complex disease (Parkinson disease [PD]). We mined a whole-genome association dataset and identified single nucleotide polymorphisms (SNPs) that were within axon-guidance pathway genes. We then constructed models of axon-guidance pathway SNPs that predicted three outcomes: PD susceptibility (odds ratio = 90.8, p = 4.64 x 10(-38)), survival free of PD (hazards ratio = 19.0, p = 5.43 x 10(-48)), and PD age at onset (R(2) = 0.68, p = 1.68 x 10(-51)). By contrast, models constructed from thousands of random selections of genomic SNPs predicted the three PD outcomes poorly. Mining of a second whole-genome association dataset and mining of an expression profiling dataset also supported a role for many axon-guidance pathway genes in PD. These findings could have important implications regarding the pathogenesis of PD. This genomic pathway approach may also offer insights into other complex diseases such as Alzheimer disease, diabetes mellitus, nicotine and alcohol dependence, and several cancers.

Roberts RO, Cha RH, Knopman DS, Petersen RC, Rocca WA. · Divisions of Epidemiology, Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, USA. · Alzheimer Dis Assoc Disord. · Pubmed #16917183 No free full text.

Abstract: An inverse association between estrogen therapy (ET) and Alzheimer disease (AD) has been reported in some, but not in all studies. We investigated the association between ET and AD in postmenopausal women using a population-based case-control design. Women who developed AD from 1985 through 1989 in Rochester, MN (cases, n=264) were individually matched by age (+/-1 y) to control women free of dementia from the same population (controls, n=264). ET exposure (>/=6 mo after menopause) was ascertained by abstracting the complete medical records archived in the records-linkage system of the Rochester Epidemiology Project. The frequency of ET use was similar in cases (11.4%) and controls [10.6%; odds ratio=1.10; 95% confidence interval (CI)=0.63-1.93]. However, cases who used ET had a suggestive trend for an earlier age at start of ET compared with controls (median, 49.0 vs. 50.5 y; P=0.06). Although smoking (ever vs. never) was not associated with AD overall, we observed an interaction between smoking and ET. The odds ratio of AD in ET users was 4.55 (95% CI=1.33-15.53) among smokers, but was 0.68 (95% CI=0.35-1.32) among never-smokers (P for interaction=0.01). Our findings do not confirm a significant association between ET and AD overall; however, the possible interaction with smoking deserves further study.

Knopman DS, Petersen RC, Cha RH, Edland SD, Rocca WA. · The Mayo Alzheimer Disease Research Center, Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN, USA. · Neurology. · Pubmed #16217048 No free full text.

Abstract: 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.

Knopman DS, Petersen RC, Edland SD, Cha RH, Rocca WA. · Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. · Neurology. · Pubmed #14872045 No free full text.

Abstract: 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.

Knopman DS, Parisi JE, Boeve BF, Cha RH, Apaydin H, Salviati A, Edland SD, Rocca WA. · Department of Neurology, Mayo Clinic and Foundation, Rochester, MN 55905, USA. · Arch Neurol. · Pubmed #12707071 links to  free full text

Abstract: BACKGROUND: The validity of the clinical diagnosis of vascular dementia (VaD) remains suboptimal. OBJECTIVE: To investigate clinicopathologic correlations in VaD. METHODS: We used the medical records-linkage system of the Rochester Epidemiology Project to identify incident cases of dementia in Rochester, Minn, from January 1, 1985, through December 31, 1989. Dementia and Alzheimer disease (AD) were defined by the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Vascular dementia was defined by criteria including imaging results. Pathological characteristics of AD were quantified by means of standard scoring methods for neurofibrillary tangles and neuritic plaques. Vascular pathological findings were assessed by expert neuropathological opinion. RESULTS: Of 419 patients with dementia who died before the study, neuropathological examination results were available in 89 (21%) with median age at onset of 80 years (range, 50-96 years; 52 [58%] women). Pathological diagnoses were AD in 45 patients (51%), pure VaD in 12 (13%), combined AD and VaD in 11 (12%), and other diagnoses in the remaining 21 patients. Criteria for VaD that required either a temporal relationship between a stroke and dementia onset or worsening, or bilateral infarctions in specified locations demonstrated on imaging results (Mayo Clinic criteria) had 75% sensitivity and 81% specificity for pure VaD (positive likelihood ratio, 3.9; 95% confidence interval, 2.2-6.7). Five cases of pure VaD lacked the temporal relationship and accounted for the imperfect sensitivity of the criteria. CONCLUSIONS: In this population-based autopsy study, the presence of vascular pathological characteristics in the absence of major AD pathological findings was common. Pure VaD without overt clinical strokes remains a challenge for antemortem diagnosis.

Knopman DS, Rocca WA, Cha RH, Edland SD, Kokmen E. · Department of Neurology, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA. · Arch Neurol. · Pubmed #12533093 links to  free full text

Abstract: OBJECTIVE: To investigate the relationship between features and definitions of vascular dementia (VaD) and survival. DESIGN: We used the medical records linkage system of the Rochester Epidemiology Project to identify incident cases of dementia in Rochester from January 1, 1985, through December 31, 1989. Dementia and Alzheimer disease were defined using the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Vascular dementia was defined by ad hoc criteria, including imaging. Each patient with dementia was matched by age and sex to a referent subject free of dementia. Patients with dementia and referent subjects were followed from the onset of dementia (or index year) through death, censoring, or the end of the study. RESULTS: We included 479 patients with incident dementia and 479 referent subjects. Overall, patients with VaD had worse mortality than referent subjects (relative risk [RR], 2.7; 95% confidence interval [CI], 1.9-3.9). Among patients with VaD, those with dementia temporally related to a stroke had a worse relative mortality (RR, 4.5; 95% CI, 2.7-7.4) than those with only imaging evidence of bilateral infarctions in gray matter structures (RR, 2.4; 95% CI, 1.5-3.8). Relative mortality estimates varied by using 3 sets of published diagnostic criteria for VaD. Patients with VaD had a higher RR of death (RR, 2.7; 95% CI, 1.9-3.9) than patients with dementia overall (RR, 1.8; 95% CI, 1.6-2.1) or patients with Alzheimer disease (RR, 1.4; 95% CI, 1.2-1.7). CONCLUSIONS: The relative mortality of patients with VaD varied depending on the set of diagnostic criteria used. A temporal relationship to a stroke was the strongest predictive feature for poor survival in patients with dementia.

Edland SD, Rocca WA, Petersen RC, Cha RH, Kokmen E. · Department of Health Sciences Research, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA. · Arch Neurol. · Pubmed #12374497 links to  free full text

Abstract: BACKGROUND: Incidence rates of Alzheimer disease (AD) were higher in women than in men in several recent European and Asian studies. Cohort studies in the United States, on the other hand, have consistently reported no difference in incidence across sex. OBJECTIVE: To measure age- and sex-specific incidence rates of dementia and AD for persons aged 50 years and older residing in Rochester, Minn, during 1985 to 1989. SUBJECTS AND METHODS: Cases were ascertained through the medical records linkage system of the Rochester Epidemiology Project, which encompasses the records of all medical care providers (including outpatient clinics, hospitals, general practitioners, and nursing homes) in Rochester. Computer indices of clinical diagnoses, histologic diagnoses, and medical procedures were screened for indications of dementia. All medical records of potential cases were reviewed and abstracted by a trained nurse abstractor. A neurologist (E.K.) confirmed the presence of dementia and established a differential diagnosis of AD using the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and estimated the year of onset. RESULTS: A total of 482 incident cases of dementia were identified; 356 of them (73.9%) had AD. For both dementia and AD, incidence rates increased steeply with age, and there were no consistent differences between men and women. The sex pattern for AD did not change after removing cases with silent bilateral infarcts on imaging. CONCLUSIONS: Contrary to observations from European and Asian populations, women were not at increased risk of incident AD in Rochester. Our findings, based on a medical records linkage system, corroborate findings from several other US studies that involved the direct contact of cohort members. The consistency of findings across study designs suggests that sex or sex-related exposures do not consistently play a major role in AD causation in American populations.

Bower JH, Dickson DW, Taylor L, Maraganore DM, Rocca WA. · Department of Neurology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA. · Mov Disord. · Pubmed #12360539 No free full text.

Abstract: We correlated the clinical features with pathological findings in an autopsy series of cases of incident parkinsonism. We used the medical records-linkage system of the Rochester Epidemiology Project to identify all incident cases of parkinsonism in Olmsted County, MN, for the years 1976 to 1990. Medical histories were abstracted in a standardized manner. Included in this study were those incident cases who died and underwent autopsy. Brain sections were studied with routine histology and special stainings. A neuropathologist blinded to any clinical information assigned cases to neuropathological categories. We found 364 incident cases of parkinsonism of which 235 were deceased at the time of this study; there were 39 autopsied brains available for analysis (17% of deceased cases). Of the 16 patients diagnosed pathologically with Lewy body disease, documentation indicated that 8 had an early dementia, 3 had prominent dysautonomia, and 2 had prominent ataxia. Of the 7 patients diagnosed pathologically with progressive supranuclear palsy, 4 had no documentation of supranuclear gaze palsy, and 3 had no documentation of early falls. Of the 3 patients diagnosed pathologically with multiple system atrophy, none had prominent ataxia or dysautonomia documented. Of the 5 patients with vascular disease at pathology, none had been given the clinical diagnosis of vascular parkinsonism. Of the 8 cases given the clinical diagnosis of drug-induced parkinsonism, 6 were found to have basal ganglia pathology. The autopsied cases in this study were not representative of all patients with parkinsonism, because atypical cases are more likely to come to autopsy than typical ones. Despite this selection bias, the retrospective data collection, and the small sample size, we made several observations that illustrate the difficulty in achieving an accurate antemortem diagnosis of parkinsonism.

Rocca WA. · Department of Health Sciences Research, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA. · Neurology. · Pubmed #10854361 No free full text.

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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.