Walter A. Rocca

High-resolution whole-genome association study of Parkinson disease.

We performed a two-tiered, whole-genome association study of Parkinson disease (PD). For tier 1, we individually genotyped 198,345 uniformly spaced and informative single-nucleotide polymorphisms (SNPs) in 443 sibling pairs discordant for PD. For tier 2a, we individually genotyped 1,793 PD-associated SNPs (P<.01 in tier 1) and 300 genomic control SNPs in 332 matched case-unrelated control pairs. We identified 11 SNPs that were associated with PD (P<.01) in both tier 1 and tier 2 samples and had the same direction of effect. For these SNPs, we combined data from the case-unaffected sibling pair (tier 1) and case-unrelated control pair (tier 2) samples and employed a liberalization of the sibling transmission/disequilibrium test to calculate odds ratios, 95% confidence intervals, and P values. A SNP within the semaphorin 5A gene (SEMA5A) had the lowest combined P value (P=7.62 x 10(-6)). The protein encoded by this gene plays an important role in neurogenesis and in neuronal apoptosis, which is consistent with existing hypotheses regarding PD pathogenesis. A second SNP tagged the PARK11 late-onset PD susceptibility locus (P=1.70 x 10(-5)). In tier 2b, we also selected for genotyping additional SNPs that were borderline significant (P<.05) in tier 1 but that tested a priori biological and genetic hypotheses regarding susceptibility to PD (n=941 SNPs). In analysis of the combined tier 1 and tier 2b data, the two SNPs with the lowest P values (P=9.07 x 10(-6); P=2.96 x 10(-5)) tagged the PARK10 late-onset PD susceptibility locus. Independent replication across populations will clarify the role of the genomic loci tagged by these SNPs in conferring PD susceptibility.

The cost of epilepsy in the United States: an estimate from population-based clinical and survey data.

Summary: Purpose: To provide 1995 estimates of the lifetime and annual cost of epilepsy in the United States using data from patients with epilepsy, and adjusting for the effects of comorbidities and socioeconomic conditions.

Incidence and distribution of parkinsonism in Olmsted County, Minnesota, 1976-1990.

Objective: Limited information is available on the frequency and distribution of parkinsonism as a syndrome. We studied the incidence of parkinsonism and its specific types among residents of Olmsted County, MN, for the period from 1976 through 1990. Methods: We used the medical records linkage-system of the Rochester Epidemiology Project to identify all individuals whose records contained documentation of any form of parkinsonism, related neurodegenerative diseases, or tremor of any type. A nurse abstractor screened the records, and, when applicable, a neurologist reviewed them to determine the presence of parkinsonism using specified diagnostic criteria and to define the year of onset. Results: We found 364 incident cases of parkinsonism: 154 with PD (42%), 72 with drug-induced parkinsonism (20%), 61 unspecified (17%), 51 with parkinsonism in dementia (14%), and 26 with other causes (7%). The average annual incidence rate of parkinsonism (per 100,000 person-years) in the age group 50 to 99 years was 114.7; incidence increased steeply with age from 0.8 in the age group 0 to 29 years to 304.8 in the age group 80 to 99 years. The cumulative incidence of parkinsonism assuming no competing causes of death was 7.5% to age 90 years. PD was the most common type of parkinsonism, followed by parkinsonism in dementia in men and drug-induced parkinsonism in women. Men had higher incidence than women at all ages for all types of parkinsonism except drug-induced. Conclusions: Parkinsonism is a common disease among the elderly; its incidence increases steeply with advancing age and is consistently higher in men. The distribution by type changes with age and gender.

Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause

Objective: There is increasing laboratory evidence for a neuroprotective effect of estrogen; however, the clinical and epidemiologic evidence remains limited and conflicting. We studied the association of oophorectomy performed before the onset of menopause with the risk of subsequent cognitive impairment or dementia. Methods: We included all women who underwent unilateral or bilateral oophorectomy before the onset of menopause for a non-cancer indication while residing in Olmsted County, MN, from 1950 through 1987. Each member of the oophorectomy cohort was matched by age to a referent woman from the same population who had not undergone oophorectomy. In total, we studied 813 women with unilateral oophorectomy, 676 women with bilateral oophorectomy, and 1,472 referent women. Women were followed through death or end of study using either direct or proxy interviews. Results: Women who underwent either unilateral or bilateral oophorectomy before the onset of menopause had an increased risk of cognitive impairment or dementia compared to referent women (hazard ratio [HR] = 1.46; 95% CI 1.13 to 1.90; adjusted for education, type of interview, and history of depression). The risk increased with younger age at oophorectomy (test for linear trend; adjusted p < 0.0001). These associations were similar regardless of the indication for the oophorectomy, and for women who underwent unilateral or bilateral oophorectomy considered separately. Conclusions: Both unilateral and bilateral oophorectomy preceding the onset of menopause are associated with an increased risk of cognitive impairment or dementia. The effect is age-dependent and suggests a critical age window for neuroprotection.

An operational approach to National Institute on Aging–Alzheimer's Association criteria for preclinical Alzheimer disease

A workgroup commissioned by the Alzheimers Association (AA) and the National Institute on Aging (NIA) recently published research criteria for preclinical Alzheimer disease (AD). We performed a preliminary assessment of these guidelines.

Anxiety disorders and depressive disorders preceding Parkinson's disease: a case-control study.

We studied the association between preceding psychiatric disorders and Parkinsons disease (PD) using a case‐control design. We used the medical records‐linkage system of the Rochester Epidemiology Project to identify 196 subjects who developed PD in Olmsted County, Minnesota, during the years 1976–1995. Each case was matched by age (±1 yr) and sex to a general population control. We reviewed the complete medical records of cases and control subjects to detect preceding psychiatric disorders. The frequency of psychiatric disorders was higher in cases than in control subjects; the odds ratio was 2.2 for anxiety disorders (95% confidence interval [95% CI] = 1.4–3.4; p = 0.0003), 1.9 for depressive disorders (95% CI = 1.1–3.2; p = 0.02), and 2.4 for both anxiety disorders and depressive disorders occurring in the same individual (95% CI = 1.2–4.8; p = 0.02). When we restricted analyses to disorders present 5 years or more before the onset of motor symptoms of PD, the association with depressive disorders lost statistical significance. However, the association with anxiety disorders remained significant for disorders present 5, 10, or 20 years before onset of motor symptoms. Our results suggest that anxiety disorders and depressive disorders are associated with PD and that the causative process or the risk factors underlying PD are present many years before the appearance of motor symptoms.

Use of a Medical Records Linkage System to Enumerate a Dynamic Population Over Time: The Rochester Epidemiology Project

The Rochester Epidemiology Project (REP) is a unique research infrastructure in which the medical records of virtually all persons residing in Olmsted County, Minnesota, for over 40 years have been linked and archived. In the present article, the authors describe how the REP links medical records from multiple health care institutions to specific individuals and how residency is confirmed over time. Additionally, the authors provide evidence for the validity of the REP Census enumeration. Between 1966 and 2008, 1,145,856 medical records were linked to 486,564 individuals in the REP. The REP Census was found to be valid when compared with a list of residents obtained from random digit dialing, a list of residents of nursing homes and senior citizen complexes, a commercial list of residents, and a manual review of records. In addition, the REP Census counts were comparable to those of 4 decennial US censuses (e.g., it included 104.1% of 1970 and 102.7% of 2000 census counts). The duration for which each person was captured in the system varied greatly by age and calendar year; however, the duration was typically substantial. Comprehensive medical records linkage systems like the REP can be used to maintain a continuously updated census and to provide an optimal sampling framework for epidemiologic studies.

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 ε3ε4 or ε4ε4 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.

Premature menopause or early menopause: Long-term health consequences

OBJECTIVE To review and summarize current evidence on the health consequences of premature menopause and early menopause. METHODS We reviewed existing literature and combined graphically some results from the Mayo Clinic Cohort Study of Oophorectomy and Aging. RESULTS Premature menopause or early menopause may be either spontaneous or induced. Women who experience premature menopause (before age 40 years) or early menopause (between ages 40 and 45 years) experience an increased risk of overall mortality, cardiovascular diseases, neurological diseases, psychiatric diseases, osteoporosis, and other sequelae. The risk of adverse outcomes increases with earlier age at the time of menopause. Some of the adverse outcomes may be prevented by estrogen treatment initiated after the onset of menopause. However, estrogen alone does not prevent all long-term consequences, and other hormonal mechanisms are likely involved. CONCLUSIONS Regardless of the cause, women who experience hormonal menopause and estrogen deficiency before reaching the median age of natural menopause are at increased risk for morbidity and mortality. Estrogen treatment should be considered for these women, but may not eliminate all of the adverse outcomes.

History of the Rochester Epidemiology Project: Half a Century of Medical Records Linkage in a US Population

The Rochester Epidemiology Project (REP) has maintained a comprehensive medical records linkage system for nearly half a century for almost all persons residing in Olmsted County, Minnesota. Herein, we provide a brief history of the REP before and after 1966, the year in which the REP was officially established. The key protagonists before 1966 were Henry Plummer, Mabel Root, and Joseph Berkson, who developed a medical records linkage system at Mayo Clinic. In 1966, Leonard Kurland established collaborative agreements with other local health care providers (hospitals, physician groups, and clinics [primarily Olmsted Medical Center]) to develop a medical records linkage system that covered the entire population of Olmsted County, and he obtained funding from the National Institutes of Health to support the new system. In 1997, L. Joseph Melton III addressed emerging concerns about the confidentiality of medical record information by introducing a broad patient research authorization as per Minnesota state law. We describe how the key protagonists of the REP have responded to challenges posed by evolving medical knowledge, information technology, and public expectation and policy. In addition, we provide a general description of the system; discuss issues of data quality, reliability, and validity; describe the research team structure; provide information about funding; and compare the REP with other medical information systems. The REP can serve as a model for the development of similar research infrastructures in the United States and worldwide.