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Epidemiology of Dementia in Rochester, Minnesota
Subject Review Epidemiology of Dementia in Rochester, Minnesota C. MARY BEARD, R.N., M.P.H., PETER C. O'BRIEN, PH.D., T. KURLAND, M.D., DR.P.H.
EMRE KOKMEN, M.D., AND LEONARD
• Objective: To present the results of several retrospective epidemiologic studies of dementia in Rochester, Minnesota. • Material and Methods: These studies were done by using the medical records-linkage resources of the Rochester Epidemiology Project. • Results: The incidence and prevalence of dementia increase sharply with advancing age. No difference is noted in overall age-adjusted incidence rates by gender. Rochester studies provide the only 25-year time trend analyses of the incidence of dementia in the United States. Time trends over three prevalence dates indicate an increase in prevalence in this community. Survival is decreased among patients with dementing illness. Case-control studies of Alzheimer's disease (AD) show that general medical conditions, previous head injury, thyroid disease, expoStudies of the frequency and characteristics of diseases in a defined community population provide information on the incidence and prevalence rates of the disorder and help determine whether certain characteristics differ in affected and unaffected persons. The resources of the Rochester Epidemiology Project' were used to complete several descriptive, historical cohort and case-control studies of dementing illness in Rochester, Minnesota. Herein we present a succinct review of those epidemiologic studies of dementia. Recently, many studies of Alzheimer's disease (AD) have been conducted in various populations; the common finding in all such studies is that advancing age is the most important risk factor for AD. Rochester, a city of about 70,000 people (1990 US census), is in southeastern Minnesota, approximately 90 miles from the closest large population center, the twin cities of From the Department of Neurology (E.K.), Section of Clinical Epidemiology (C.M.B., L.T.K.), and Section of Biostatistics (P.C.O.), Mayo Clinic Rochester, Rochester, Minnesota. This study was supported in part by Grants AR 30582, AG 06786, and AG 08031 from the National Institutes of Health, Public Health Service. Address reprint requests to Dr. Emre Kokmen, Department of Neurology, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905. Mayo Clin Proc 1996; 71:275-282
sure to therapeutic radiation, anesthesia, and blood transfusion are generally not risk factors for AD. Patients with depression may have an increased risk for the development of AD. Sociodemographic factors such as education, occupation, marital status, and type of dwelling were not significantly different among patients with AD and their age- and gendermatched control subjects. • Conclusion: The Rochester Epidemiology Project has proved to be an excellent resource for the study of the incidence, prevalence, and risk factors for dementia. (Mayo Clin Proc 1996; 71:275-282) AD = Alzheimer's disease; CI = confidence intervals; OR = odds ratios
Minneapolis and St. PauL Since the early years of this century, the Mayo Clinic has provided most of the primary health care and almost all secondary and tertiary health care for the population in this community. Detailed health-care records, including physicians' notes for outpatient and inpatient care, laboratory and diagnostic test results, and correspondence, have been preserved in their original form. Since 1966, the Rochester Epidemiology Project' has provided access to the medical records of other health-care providers in and around the community (Olmsted Community Hospital, Olmsted Medical Group, the University of Minnesota and Department of Veterans Affairs hospitals in Minneapolis, the former Rochester State Hospital, and, more recently, individual medical practitioners and nursing homes). Diagnostic information from all these sources has been coded and indexed and is updated annually.
INCIDENCE STUDIES For the period 1960 through 1984, we identified all healthcare records that contained a diagnostic rubric (the list included 112 codes from the International Classification of Diseases, Adopted Code for Hospitals [H-ICDA]) that might indicate dementia. Each health-care record was then reviewed and evaluated by a nurse-abstractor and a neurologist 275
© 1996 Mayo Foundation for Medical Education and Research
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EPIDEMIOLOGY OF DEMENTIA IN ROCHESTER, MINNESOTA
Table I.-Diagnostic Rubrics Used in Medical Record Reviews for Dementing Illnesses Alzheimer's disease Atherosclerosis or arteriosclerosis Acute brain syndrome Brain atrophy Brain degeneration Brain syndrome Brain damage Brain sclerosis Brain softening Brain disease Chronic brain syndrome Cerebral arteriosclerosis Cerebrovascular disease Creutzfeldt-Jakob disease
Cortical atrophy-cortical degeneration Dementia-delirium-encephalopathy Encephalitis Encephalomalacia Generalized brain atrophy Huntington's disease Lesions of central nervous system Inflammation of brain Depression Pick's disease Personality disorder Mental changes Senility-senile brain diseasesenescence
(E.K.) for the presence of descriptive terms suggestive of dementia and AD (Table 1).2-5 This process was implemented by reviewing the designated medical records for evidence of any ongoing decline in mental ability, and each was classified for the likelihood of dementia. The criteria for AD (Table 2) are comparable to the criteria from the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA).6 Using all available data from local health-care records, we established a year of onset for the symptoms of dementia for each patient. Diagnostic categories for dementia included dementia alone or with infarcts, alcoholism, parkinsonism and Parkinson's disease, head trauma, tumors, and Huntington's disease. Residence in Rochester for at least I year before onset of dementia was confirmed; thus, patients who had moved to Rochester for management of a previously diagnosed dementing illness were not included in the incidence study.>' Patients whose condition did not fulfill the criterion of irreversible decline were excluded from the study. In order to estimate incidence rates, the number of cases served as the numerator, and the population of Rochester (from the US decennial census) was the denominator.i? Straight-line interpolation was used for intercensal years, and incidence rates were age-adjusted to the US white population from the decennial census as appropriate for comparison by gender. Ninety-five percent confidence intervals (CI) were based on the Poisson distribution. During the 25-year period 1960 through 1984, 1,262 incidence cases (859 women and 403 men) of dementia occurred. For each 5-year interval during this period, the median age at onset for men was 76, 76, 80, 79, and 80 years, and for women it was 80, 81, 82, 82, and 83 years.i? Agespecific incidence rates for dementia (Fig. 1) indicated an exponential increase with advancing age. During the 25-
Mayo Clio Proc, March 1996, Vol 71
year period, the rates for dementia remained stable, with only a modest increase among the very old during the most recent 10 years. Similarly, the incidence rates for AD increased exponentially with advancing age. The assessment of incidence rates over time necessitated uniform case ascertainment and may have been nonexistent until this project. The trend of such rates over time may provide valuable etiologic clues.
PREVALENCE STUDIES Prevalence rates indicate the extent of disease on a specified date or "prevalence day" and are important for planning the professional staff and resources needed for the care of patients with dementing illness. These rates may vary due to changes in incidence, survival, or migration patterns (or all three) of patients with the conditions of interest. Prevalence studies of the Rochester population were done after incidence cases had been defined. Included as prevalence cases were all surviving patients (incidence cases) who still resided in Rochester on prevalence day, as well as those with dementia who had moved to the community and were in residence on prevalence day. Prevalence rates were estimated by using the number of living affected residents as the numerator and decennial census data as the denominator. 7-9 Throughout the years of these studies, January 1 was speciTable 2.-Diagnostic Criteria for Dementia and Alzheimer's Disease Diagnostic criteria for dementia Documented evidence of: Previously normal intellectual and social function Irreversible decline in intellectual and social function Dementia as a predominant symptom Definite evidence of memory impairment Documentation of at least 2 of the following (patient must be completely alert): Disorientation Decline in personality and/or behavior Dyscalculia Apraxia and/or agnosia Problems with language Impairment in judgment and/or abstract thinking If diagnosis is based on clinical information only (that is, without autopsy confirmation), dementia must have been present for 6 months Clinical diagnosis ofAlzheimer's disease Dementia as previously defined Insidious onset Slow progression Other causes for dementia ruled out Pathologic diagnosis ofAlzheimer's disease Dementia as previously defined Presence of abundant neuritic plaques and/or neurofibrillary tangles in one or more cortical regions other than the hippocampus
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EPIDEMIOLOGY OF DEMENTIA IN ROCHESTER, MINNESOTA
Mayo Clio Proc, March 1996, Vol 71
Dementia
Alzheimer's
3,000
2,500
~
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~
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3,000 01960-1964 -1965-1969 1970-1974 -o- 1975-1979 "'1980-1984
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8
277
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~~~~~~
Fig. 1. Incidence rates of dementia and Alzheimer's disease in Rochester, Minnesota, population, stratified by age, for five quinquennial periods (1960 through 1984). pyrs = person-years.
fied as prevalence day in 1975, 1980, and 1985. The numbers affected were 201 in 1975, 361 in 1980, and 521 in 1985. Median ages stratified by gender are shown in Table 3. Age-specific prevalence rates for men and women (Fig. 2) showed an increase with advancing age for both genders. Prevalence was similar for the first two dates; a significant increase was noted in the rates in 1985 in comparison with those in 1980 (P<0.05).9
CASE·CONTROL STUDIES Incidence cases of AD formed the cohort for retrospective case-control studies that evaluated risk factors such as prior exposure to therapeutic radiation,'? anesthesia, II blood transfusion," thyroid disease," and head injury with loss of consciousness.!' Approximately 20 other medical and psychiatric conditions 15 and sociodemographic characteristics, including education," were also assessed in these same cohorts. Retrospective case-control studies in other populations have suggested that head injury, low educational level, and thyroid disease may be risk factors for AD.17 In the Rochester AD case-control study, each case was matched by age and gender to a control subject who registered for medical care at the Mayo Clinic during the year of onset of AD for the case. All community medical records for each control were reviewed to determine whether the person
was free of dementing illness before and during the corresponding index year. Odds ratios (OR) for risk factors were estimated by using the logistic regression techniques of Breslow and Day.18 The 95% CI were also estimated for the OR. The power of the study to detect a difference in the occurrence of risk factors for cases and controls was evaluated separately for each potential risk factor. 15 Sociodemographic information, including date of birth, gender, marital status, modal occupation, education, living arrangement, date and status of last follow-up, as well as other specific medical diagnostic information, was collected for cases and controls from the same community data source by a nurse-abstractor." Diagnostic information abstracted included history of stroke, Huntington's disease, Parkinson's disease, Creutzfeldt-Jakob disease, other multisystem atrophy, brain tumors, hydrocephalus, head injury, multiple sclerosis, chronic alcoholism, amyotrophic lateral sclerosis, peripheral neuropathy, epilepsy, radiculopathy, narcolepsy, vertigo of unknown cause, any myopathy, vitamin B I2 deficiency, depression, mania, paranoid psychosis, personality disorder, meningitis, encephalitis, neurosyphilis, herpes zoster, systemic cancers, leukemia, lymphoma, head and neck cancers, diabetes mellitus, thyroid disease, liver disease, kidney disease, anemia, lung disease, hypertension, coronary artery disease, other arteriosclerotic occlusive dis-
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278
EPIDEMIOLOGY OF DEMENTIA IN ROCHESTER, MINNESOTA
Table 3.-Prevalence Cases of Dementia on Jan. 1 in 1975, 1980, and 1985 in Rochester, Minnesota Prevalence day (Jan. 1)
Men
1975 1980 1985
87 93 135
No. Women 214 268 386
Median age (yr) Men
Women
81 81 81
86 84 86
ease, myasthenia gravis, fractures, surgical treatment that necessitated general anesthesia, number of blood transfusions, and therapeutic radiation.P'P:" We evaluated the importance of several medical, neurologic, and psychiatric conditions as potential risk factors for AD. 15 The results suggested that episodic depression may be important as a risk factor (OR, 1.71; 95% CI, 1.03 to 2.83). The only other increased OR in our case-control study is the one for personality disorder. No significant association was noted for the other risk factors studied." When multiple comparisons such as these are made, an occasional increased OR may occur by chance; thus, a cautious interpretation of the findings is necessary. Sociodemographic variables from our population-based studies included the putative association between low educational level and AD. 16 No association was noted between
Mayo Clio Proc, March 1996, Vol 71
AD and gender, education, modal occupation, living arrangement, type of dwelling, and marital status (Table 4). The effects of anesthesia and blood transfusion were studied as possible risk factors for all incident cases of AD from 1975 through 1984. 1I · 12 In order to ensure adequate information about prior operations, patients and their matched control subjects must have resided in the county for 40 or more years. Neither exposure to six or more episodes of general anesthesia (OR, 1.44; 95% CI, 0.77 to 2.7) nor cumulative exposure to 600 or more minutes of general anesthesia (OR, 1.63; 95% CI, 0.53 to 5.04) was significantly associated with an increased risk for AD. Neither prior blood transfusions nor therapeutic radiation was found to be a risk factor for AD (Table 5).10.12
COHORT STUDIES Cohort studies provide a powerful means for evaluating the relationship-association of a suspected risk factor and subsequent diseases. Thus, the additional opportunity to evaluate head trauma and Hashimoto's thyroiditis as risk factors for AD by using a cohort study design was exceptional.P:" All community patients in these cohort studies were followed up through a review of their medical records for subsequent AD. By applying the age- and gender-specific incidence rates for AD to the appropriate person-years of follow-up in
Dementia
Alzheimer's
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21,000
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January 1, 1975 January 1, 1980
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Fig. 2. Prevalence rates of dementia and Alzheimer's disease in Rochester, Minnesota, population, stratified by age, for two prevalence dates: January 1, 1975,and January 1, 1980. pyrs =person-years.
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EPIDEMIOLOGY OF DEMENTI A IN ROCHES TER , MINNESOTA
Mayo Clin Proc, March 1996, Vol 71
279
Table 4.-Univariate Odds Ratios for Sociodemographic Variables Among Cases of Alzheimer's Disease and Controls in Rochester, Minnesota, From 1975 Through 1979* Women
Men
Cases]
ControIst
No
Yes
No
Yes
Education ~9 yr Ever married
20
16
22
14
3
60
2
61
Type of dwelling:j: Living arrangement§
51
12
57
6
57
6
53
10
Odds ratio (95% CI) 1.33 (0.46-3 .84) 0.67 (0.11-3 .99) 2.50 (0.78-7.97) 0.56 (0.19-1.66)
Cases ]
Controls]
No
Yes
No
Yes
78
35
80
33
40
138
41
137
124
54
125
53
104
74
106
72
Total Odds ratio (95% CI) 1.08 (0.62- I.89) 1.03 (0.63-1.71) 1.03 (0.64- 1.65) 1.04 (0.69-1.57)
Casest
Controls'[
No
Yes
No
Yes
98
51
102
47
43
198
43
198
175
66
182
59
161
80
159
82
Odds ratio (95% CI) 1.13 (0.69-1.85) 1.00 (0.62-1.62) 1.18 (0.77-1.82) 0.96 (0.66-1.4 1)
*CI =confidence interval. t Matched pairs with any missing information were excluded. :j:Living somewhere other than in own home versus living in own home . §Living alone versus living with someone.
these cohorts, we could estimate an expected number of cases of AD to compare with the number observed. Standardized incidence ratios and 95% confidence limits were calculated to facilitate comparis ons. Historical cohort studies of prior head trauma (N = 821) and Hashimoto 's thyroiditis (N = 198) in this population suggest that neither is a risk factor for AD. The OR for AD after head trauma was 1.25 (95% CI, 0.34 to 4.66), and for biopsy-proven Hashimoto's thyroiditis, it was 0.92 (95% CI, 0.65 to 1.31).13.19 A retrospective (historical) cohort study of 543 Rochester residents with AD (onset 1975 through 1984) and their matched control subjects showed that the risk of fracture was not increased before the onset of AD. The risk ratio for any subsequent fracture was l.l (95% CI, 0.9 to 1.3), and this slight increase was accounted for entirely by a 2.7-fold (95% CI, 1.8 to 4.2) increase in the risk of hip fracture."
SURVIVAL To evaluate survival, we reviewed all incidence cases of AD between 1960 and 1984 (N =960) to obtain date and status at last follow-up. Only 127 patients were still alive. Death certificates for all those deceased were obtained. The measurement of survival from recognized onset of dementing illness is of interest; therefore, we used the Cox proportional hazards model to evaluate survival and included age at onset, year of onset, and gender, taking into account that patients were not at risk of death until diagnosed with AD. We also evaluated the possibility of interaction. Survival of patients with AD is decreased in comparison with that of the general population.i ':" Survival of patients with AD (Fig. 3) seemed to increase in the more recent time period (1975 through 1984); the relative hazard decreased by a factor of 0.82 for each decade. We also reconfirmed that
women with AD have a longer survival after onset of AD than do men with AD.22
CONCLUSION The availability of extensive health-care record information for a delineated population has provided the unique opportunity for comprehen sive epidemiologic studies of dementing illnesses in Rochester. Performing various studies throughout several decades in a single, relatively stable population has advantages. The ability to confirm in-depth medical diagnoses from health-care records by using physicians' notes, laboratory data, other ancillary diagnoses and reports, and correspondence is important. Our records often encompass the entire adult life of patients, with documentation of inpatient and outpatient care, nursing home care, as well as death certificate notations and autopsy results . The median duration of medical records available for the cases of AD and controls in the incidence and case-control studies was 44 years. Table 5.-Specific Risk Factors for Alzheimer's Disease St udied in Rochester, Minnesota Factor Case-control studies Head trauma 15 Thyroid disease" Therapeutic radiation'? Anesthesia" Blood transfusion " Cohort studies Head trauma'? Hashimoto's thyroiditis 13
Odds ratio
95 % confidence
interval
1.25 0.92 0.95 1.28 1.25
0.34-4.66 0.65-1.31 0.66-1.37 0.82-7 .00 0.82-1 .88
1.00* 1.37 *
0.63- 1.50 0.59-2.70
*Standardized morbidity ratio.
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280
EPIDEMIOLOGY OF DEMENTIA IN ROCHESTER, MINNESOTA
Alzheimers 1960 - 1974
veers (Age
~=
80)
Years{Age70·79j
Mayo Clio Proc, March 1996, Vol 71
Alzheimers 1975 - 1984
Years (Age:>= 80j
Ye3rs(Age70-79)
~\4
.
Yfl3rs(Age < 70j
veers (Age < 70)
Fig.3. Comparison of survival curves for incidence casesof Alzheimer's disease, stratified by gender, for two periods (1960 through 1974and 1975 through 1984) in Rochester, Minnesota. Dashed line represents men, and solid line represents women. (From Beard and associates." By permission.) For incidence and prevalence studies, use of a medical records-linkage system offers distinct advantages over the sampling methods used in most community-based studies. In medical records-linkage studies, the quality of medical information reflects the continuous updating due to repeated examinations in conjunction with documentation by different health-care providers. In community-sampling studies, surrogate informants provide information that is subject to recall bias and data that are often incomplete and difficult to confirm. Additionally, the refusal rate for such inquiries may be high. Medical records-linkage studies can be far more complete, relatively unbiased, and far less costly to conduct. Certain disadvantages are inherent in epidemiologic studies performed by using medical record information, even when complete health-care records are available: some patients may not receive medical attention, and some may obtain their health care elsewhere. We estimate, however, that virtually all Rochester residents who are 65 years of age or older have at least one health-care contact at the Mayo Clinic in any 3-year period (unpublished data). Another possible disadvantage of using medical records data is the
lack of uniformity in available information. All patients with dementia do not undergo the same work-up; therefore, desired details of a neuropsychologic examination or specific findings in neuroimaging cannot be evaluated for every patient. Until the most recent quinquennium, a family history of dementing or other neurologic illness and the use or abuse of alcohol and drugs were recorded inconsistently. Measures are being taken to decrease these shortcomings in the medical records in Rochester. Availability and reliability of longitudinal information in health-care records should not differ between cases and controls, a fact that may override some of the objections to this type of investigation. Even if a patient does not undergo a detailed neuropsychologic assessment, the accretion of data in the medical record about cognition and behavior year after year and examination after examination often provides a clear picture of the severity and progression of dementing illness. Because the Rochester population is predominantly of northern European origin, our studies have been unable to address putative differences between races or major ethnic groups. Nevertheless, the Rochester database is unusual in that it allows estimation of secular trends in the incidence
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EPIDEMIOLOGY OF DEMENTIA IN ROCHESTER, MINNESOTA
Mayo Clio Proc, March 1996, Vol 71
and prevalence of dementing illness; therefore, additional studies in the future are feasible and may be of paramount importance. Very few incidence studies of dementia have been done in the United States. Nonuniform studies from diverse regions of the world still provide remarkably similar incidence and prevalence rates (Fig. 4 and 5).23 The highest prevalence rates reported in the United States are from studies in a retirement community in California and from studies in eastern Boston in Massachusetts. This occurrence is likely attributable to the unusual case definition criteria used in the two studies.i':" A historical cohort study is the most powerful study design for determining disease associations. Such studies can be criticized if different criteria are used to determine evolving disease among the defined cohort than were used to define incidence cases. The studies reported herein were done with use of the same case finding and case definition procedures for both cases and controls. Similar findings from both case-control and cohort studies strengthen our conclusion.
35
-c-
Our experience with case-control and cohort studies has not confirmed that head injury, thyroid disease, or lower levels of education are risk factors for AD. Our case-control studies have the advantage of being free of selection and recall biases, inasmuch as all the data were collected from health-care records and were documented long before dementia occurred. Many of the studies that suggest an association between low educational levels and AD were done in populations with rather low literacy rates and were based on prevalence surveys. In the Rochester study, the educational level among control subjects was similar to the decennial census data for this population. The Rochester Epidemiology Project data resource was utilized to conduct several studies of AD by using various study designs. The potential influence of certain genetic characteristics, such as the apolipoprotein E-IV allele, cannot be addressed in retrospective studies at this time. The frequency of various apoprotein alleles in patients with AD and their age-matched control subjects in the AD Patient Registry has been reported." Additional studies of anemia and exposure to estrogens, nonsteroidal anti-inflammatory
50
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.-. 65
70
75
80
85
90
Age (years)
Fig. 5. Comparison of age-specific prevalence rates of Alzheimer's disease in selected studies from United States (US), Europe, and Japan. (From Breteler and associates.P By permission.)
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282
Mayo Clio Proc, March 1996, Vol 71
EPIDEMIOLOGY OF DEMENTIA IN ROCHESTER, MINNESOTA
agents, and reserpine are under way with use of this unique database. ACKNOWLEDGMENT Many investigators have collaborated and contributed to the study of dementing illness in Rochester. We are grateful to the following persons: John A. Anderson, B.S.; John F. Annegers, Ph.D.; Frances M. Baker, M.D.; David J. Ballard, M.D., Ph.D.; Erik J. Bergstralh, M.S.; Nicolaas I. L. 1. Bohnen, M.D., Ph.D.; Vijay Chandra, M.D., Ph.D.; John D. Earle, M.D.; Lavonne A. Gates, R.N.; Virginia A. Hanson, R.N.; Ian D. Hay, M.B., Ph.D.; L. Joseph Melton III, M.D.; Kenneth P. Offord, M.S.; Haruo Okazaki, M.D.; Yasef Ozsarfati, M.D.; Walter A. Rocca, M.D., M.P.H.; Bruce S. Schoenberg, M.D., M.P.H. (deceased); Jack P. Whisnant, M.D.; David M. Williams, M.B.,B.S., Ph.D.; and Fumio Yoshimasu, M.D.
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10. 11. 12. 13.
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16.
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25. 26.
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EMRE KOKMEN, M.D., AND LEONARD
• Objective: To present the results of several retrospective epidemiologic studies of dementia in Rochester, Minnesota. • Material and Methods: These studies were done by using the medical records-linkage resources of the Rochester Epidemiology Project. • Results: The incidence and prevalence of dementia increase sharply with advancing age. No difference is noted in overall age-adjusted incidence rates by gender. Rochester studies provide the only 25-year time trend analyses of the incidence of dementia in the United States. Time trends over three prevalence dates indicate an increase in prevalence in this community. Survival is decreased among patients with dementing illness. Case-control studies of Alzheimer's disease (AD) show that general medical conditions, previous head injury, thyroid disease, expoStudies of the frequency and characteristics of diseases in a defined community population provide information on the incidence and prevalence rates of the disorder and help determine whether certain characteristics differ in affected and unaffected persons. The resources of the Rochester Epidemiology Project' were used to complete several descriptive, historical cohort and case-control studies of dementing illness in Rochester, Minnesota. Herein we present a succinct review of those epidemiologic studies of dementia. Recently, many studies of Alzheimer's disease (AD) have been conducted in various populations; the common finding in all such studies is that advancing age is the most important risk factor for AD. Rochester, a city of about 70,000 people (1990 US census), is in southeastern Minnesota, approximately 90 miles from the closest large population center, the twin cities of From the Department of Neurology (E.K.), Section of Clinical Epidemiology (C.M.B., L.T.K.), and Section of Biostatistics (P.C.O.), Mayo Clinic Rochester, Rochester, Minnesota. This study was supported in part by Grants AR 30582, AG 06786, and AG 08031 from the National Institutes of Health, Public Health Service. Address reprint requests to Dr. Emre Kokmen, Department of Neurology, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905. Mayo Clin Proc 1996; 71:275-282
sure to therapeutic radiation, anesthesia, and blood transfusion are generally not risk factors for AD. Patients with depression may have an increased risk for the development of AD. Sociodemographic factors such as education, occupation, marital status, and type of dwelling were not significantly different among patients with AD and their age- and gendermatched control subjects. • Conclusion: The Rochester Epidemiology Project has proved to be an excellent resource for the study of the incidence, prevalence, and risk factors for dementia. (Mayo Clin Proc 1996; 71:275-282) AD = Alzheimer's disease; CI = confidence intervals; OR = odds ratios
Minneapolis and St. PauL Since the early years of this century, the Mayo Clinic has provided most of the primary health care and almost all secondary and tertiary health care for the population in this community. Detailed health-care records, including physicians' notes for outpatient and inpatient care, laboratory and diagnostic test results, and correspondence, have been preserved in their original form. Since 1966, the Rochester Epidemiology Project' has provided access to the medical records of other health-care providers in and around the community (Olmsted Community Hospital, Olmsted Medical Group, the University of Minnesota and Department of Veterans Affairs hospitals in Minneapolis, the former Rochester State Hospital, and, more recently, individual medical practitioners and nursing homes). Diagnostic information from all these sources has been coded and indexed and is updated annually.
INCIDENCE STUDIES For the period 1960 through 1984, we identified all healthcare records that contained a diagnostic rubric (the list included 112 codes from the International Classification of Diseases, Adopted Code for Hospitals [H-ICDA]) that might indicate dementia. Each health-care record was then reviewed and evaluated by a nurse-abstractor and a neurologist 275
© 1996 Mayo Foundation for Medical Education and Research
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276
EPIDEMIOLOGY OF DEMENTIA IN ROCHESTER, MINNESOTA
Table I.-Diagnostic Rubrics Used in Medical Record Reviews for Dementing Illnesses Alzheimer's disease Atherosclerosis or arteriosclerosis Acute brain syndrome Brain atrophy Brain degeneration Brain syndrome Brain damage Brain sclerosis Brain softening Brain disease Chronic brain syndrome Cerebral arteriosclerosis Cerebrovascular disease Creutzfeldt-Jakob disease
Cortical atrophy-cortical degeneration Dementia-delirium-encephalopathy Encephalitis Encephalomalacia Generalized brain atrophy Huntington's disease Lesions of central nervous system Inflammation of brain Depression Pick's disease Personality disorder Mental changes Senility-senile brain diseasesenescence
(E.K.) for the presence of descriptive terms suggestive of dementia and AD (Table 1).2-5 This process was implemented by reviewing the designated medical records for evidence of any ongoing decline in mental ability, and each was classified for the likelihood of dementia. The criteria for AD (Table 2) are comparable to the criteria from the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA).6 Using all available data from local health-care records, we established a year of onset for the symptoms of dementia for each patient. Diagnostic categories for dementia included dementia alone or with infarcts, alcoholism, parkinsonism and Parkinson's disease, head trauma, tumors, and Huntington's disease. Residence in Rochester for at least I year before onset of dementia was confirmed; thus, patients who had moved to Rochester for management of a previously diagnosed dementing illness were not included in the incidence study.>' Patients whose condition did not fulfill the criterion of irreversible decline were excluded from the study. In order to estimate incidence rates, the number of cases served as the numerator, and the population of Rochester (from the US decennial census) was the denominator.i? Straight-line interpolation was used for intercensal years, and incidence rates were age-adjusted to the US white population from the decennial census as appropriate for comparison by gender. Ninety-five percent confidence intervals (CI) were based on the Poisson distribution. During the 25-year period 1960 through 1984, 1,262 incidence cases (859 women and 403 men) of dementia occurred. For each 5-year interval during this period, the median age at onset for men was 76, 76, 80, 79, and 80 years, and for women it was 80, 81, 82, 82, and 83 years.i? Agespecific incidence rates for dementia (Fig. 1) indicated an exponential increase with advancing age. During the 25-
Mayo Clio Proc, March 1996, Vol 71
year period, the rates for dementia remained stable, with only a modest increase among the very old during the most recent 10 years. Similarly, the incidence rates for AD increased exponentially with advancing age. The assessment of incidence rates over time necessitated uniform case ascertainment and may have been nonexistent until this project. The trend of such rates over time may provide valuable etiologic clues.
PREVALENCE STUDIES Prevalence rates indicate the extent of disease on a specified date or "prevalence day" and are important for planning the professional staff and resources needed for the care of patients with dementing illness. These rates may vary due to changes in incidence, survival, or migration patterns (or all three) of patients with the conditions of interest. Prevalence studies of the Rochester population were done after incidence cases had been defined. Included as prevalence cases were all surviving patients (incidence cases) who still resided in Rochester on prevalence day, as well as those with dementia who had moved to the community and were in residence on prevalence day. Prevalence rates were estimated by using the number of living affected residents as the numerator and decennial census data as the denominator. 7-9 Throughout the years of these studies, January 1 was speciTable 2.-Diagnostic Criteria for Dementia and Alzheimer's Disease Diagnostic criteria for dementia Documented evidence of: Previously normal intellectual and social function Irreversible decline in intellectual and social function Dementia as a predominant symptom Definite evidence of memory impairment Documentation of at least 2 of the following (patient must be completely alert): Disorientation Decline in personality and/or behavior Dyscalculia Apraxia and/or agnosia Problems with language Impairment in judgment and/or abstract thinking If diagnosis is based on clinical information only (that is, without autopsy confirmation), dementia must have been present for 6 months Clinical diagnosis ofAlzheimer's disease Dementia as previously defined Insidious onset Slow progression Other causes for dementia ruled out Pathologic diagnosis ofAlzheimer's disease Dementia as previously defined Presence of abundant neuritic plaques and/or neurofibrillary tangles in one or more cortical regions other than the hippocampus
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EPIDEMIOLOGY OF DEMENTIA IN ROCHESTER, MINNESOTA
Mayo Clio Proc, March 1996, Vol 71
Dementia
Alzheimer's
3,000
2,500
~
>-
Q.
8 ~
~
CD
3,000 01960-1964 -1965-1969 1970-1974 -o- 1975-1979 "'1980-1984
01960-1964 _ 1965·1969 2,500
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-1970-1974 1975-1979 "'1980-1984 ~
2,000
8
277
2,000
Tolal=M+F
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1,000
1,000
500
500
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0
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.=
~~~~~~
Age groups
~~~~~~
Fig. 1. Incidence rates of dementia and Alzheimer's disease in Rochester, Minnesota, population, stratified by age, for five quinquennial periods (1960 through 1984). pyrs = person-years.
fied as prevalence day in 1975, 1980, and 1985. The numbers affected were 201 in 1975, 361 in 1980, and 521 in 1985. Median ages stratified by gender are shown in Table 3. Age-specific prevalence rates for men and women (Fig. 2) showed an increase with advancing age for both genders. Prevalence was similar for the first two dates; a significant increase was noted in the rates in 1985 in comparison with those in 1980 (P<0.05).9
CASE·CONTROL STUDIES Incidence cases of AD formed the cohort for retrospective case-control studies that evaluated risk factors such as prior exposure to therapeutic radiation,'? anesthesia, II blood transfusion," thyroid disease," and head injury with loss of consciousness.!' Approximately 20 other medical and psychiatric conditions 15 and sociodemographic characteristics, including education," were also assessed in these same cohorts. Retrospective case-control studies in other populations have suggested that head injury, low educational level, and thyroid disease may be risk factors for AD.17 In the Rochester AD case-control study, each case was matched by age and gender to a control subject who registered for medical care at the Mayo Clinic during the year of onset of AD for the case. All community medical records for each control were reviewed to determine whether the person
was free of dementing illness before and during the corresponding index year. Odds ratios (OR) for risk factors were estimated by using the logistic regression techniques of Breslow and Day.18 The 95% CI were also estimated for the OR. The power of the study to detect a difference in the occurrence of risk factors for cases and controls was evaluated separately for each potential risk factor. 15 Sociodemographic information, including date of birth, gender, marital status, modal occupation, education, living arrangement, date and status of last follow-up, as well as other specific medical diagnostic information, was collected for cases and controls from the same community data source by a nurse-abstractor." Diagnostic information abstracted included history of stroke, Huntington's disease, Parkinson's disease, Creutzfeldt-Jakob disease, other multisystem atrophy, brain tumors, hydrocephalus, head injury, multiple sclerosis, chronic alcoholism, amyotrophic lateral sclerosis, peripheral neuropathy, epilepsy, radiculopathy, narcolepsy, vertigo of unknown cause, any myopathy, vitamin B I2 deficiency, depression, mania, paranoid psychosis, personality disorder, meningitis, encephalitis, neurosyphilis, herpes zoster, systemic cancers, leukemia, lymphoma, head and neck cancers, diabetes mellitus, thyroid disease, liver disease, kidney disease, anemia, lung disease, hypertension, coronary artery disease, other arteriosclerotic occlusive dis-
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278
EPIDEMIOLOGY OF DEMENTIA IN ROCHESTER, MINNESOTA
Table 3.-Prevalence Cases of Dementia on Jan. 1 in 1975, 1980, and 1985 in Rochester, Minnesota Prevalence day (Jan. 1)
Men
1975 1980 1985
87 93 135
No. Women 214 268 386
Median age (yr) Men
Women
81 81 81
86 84 86
ease, myasthenia gravis, fractures, surgical treatment that necessitated general anesthesia, number of blood transfusions, and therapeutic radiation.P'P:" We evaluated the importance of several medical, neurologic, and psychiatric conditions as potential risk factors for AD. 15 The results suggested that episodic depression may be important as a risk factor (OR, 1.71; 95% CI, 1.03 to 2.83). The only other increased OR in our case-control study is the one for personality disorder. No significant association was noted for the other risk factors studied." When multiple comparisons such as these are made, an occasional increased OR may occur by chance; thus, a cautious interpretation of the findings is necessary. Sociodemographic variables from our population-based studies included the putative association between low educational level and AD. 16 No association was noted between
Mayo Clio Proc, March 1996, Vol 71
AD and gender, education, modal occupation, living arrangement, type of dwelling, and marital status (Table 4). The effects of anesthesia and blood transfusion were studied as possible risk factors for all incident cases of AD from 1975 through 1984. 1I · 12 In order to ensure adequate information about prior operations, patients and their matched control subjects must have resided in the county for 40 or more years. Neither exposure to six or more episodes of general anesthesia (OR, 1.44; 95% CI, 0.77 to 2.7) nor cumulative exposure to 600 or more minutes of general anesthesia (OR, 1.63; 95% CI, 0.53 to 5.04) was significantly associated with an increased risk for AD. Neither prior blood transfusions nor therapeutic radiation was found to be a risk factor for AD (Table 5).10.12
COHORT STUDIES Cohort studies provide a powerful means for evaluating the relationship-association of a suspected risk factor and subsequent diseases. Thus, the additional opportunity to evaluate head trauma and Hashimoto's thyroiditis as risk factors for AD by using a cohort study design was exceptional.P:" All community patients in these cohort studies were followed up through a review of their medical records for subsequent AD. By applying the age- and gender-specific incidence rates for AD to the appropriate person-years of follow-up in
Dementia
Alzheimer's
21,000
21,000
o 18,000
I
8 :3
15,000
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o
January 1,1975 January 1,1980
18,000
, ,,
•
January 1, 1975 January 1, 1980
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9,000
6,000
6,000
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c:: iii >
lD
!
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Age groups
Fig. 2. Prevalence rates of dementia and Alzheimer's disease in Rochester, Minnesota, population, stratified by age, for two prevalence dates: January 1, 1975,and January 1, 1980. pyrs =person-years.
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EPIDEMIOLOGY OF DEMENTI A IN ROCHES TER , MINNESOTA
Mayo Clin Proc, March 1996, Vol 71
279
Table 4.-Univariate Odds Ratios for Sociodemographic Variables Among Cases of Alzheimer's Disease and Controls in Rochester, Minnesota, From 1975 Through 1979* Women
Men
Cases]
ControIst
No
Yes
No
Yes
Education ~9 yr Ever married
20
16
22
14
3
60
2
61
Type of dwelling:j: Living arrangement§
51
12
57
6
57
6
53
10
Odds ratio (95% CI) 1.33 (0.46-3 .84) 0.67 (0.11-3 .99) 2.50 (0.78-7.97) 0.56 (0.19-1.66)
Cases ]
Controls]
No
Yes
No
Yes
78
35
80
33
40
138
41
137
124
54
125
53
104
74
106
72
Total Odds ratio (95% CI) 1.08 (0.62- I.89) 1.03 (0.63-1.71) 1.03 (0.64- 1.65) 1.04 (0.69-1.57)
Casest
Controls'[
No
Yes
No
Yes
98
51
102
47
43
198
43
198
175
66
182
59
161
80
159
82
Odds ratio (95% CI) 1.13 (0.69-1.85) 1.00 (0.62-1.62) 1.18 (0.77-1.82) 0.96 (0.66-1.4 1)
*CI =confidence interval. t Matched pairs with any missing information were excluded. :j:Living somewhere other than in own home versus living in own home . §Living alone versus living with someone.
these cohorts, we could estimate an expected number of cases of AD to compare with the number observed. Standardized incidence ratios and 95% confidence limits were calculated to facilitate comparis ons. Historical cohort studies of prior head trauma (N = 821) and Hashimoto 's thyroiditis (N = 198) in this population suggest that neither is a risk factor for AD. The OR for AD after head trauma was 1.25 (95% CI, 0.34 to 4.66), and for biopsy-proven Hashimoto's thyroiditis, it was 0.92 (95% CI, 0.65 to 1.31).13.19 A retrospective (historical) cohort study of 543 Rochester residents with AD (onset 1975 through 1984) and their matched control subjects showed that the risk of fracture was not increased before the onset of AD. The risk ratio for any subsequent fracture was l.l (95% CI, 0.9 to 1.3), and this slight increase was accounted for entirely by a 2.7-fold (95% CI, 1.8 to 4.2) increase in the risk of hip fracture."
SURVIVAL To evaluate survival, we reviewed all incidence cases of AD between 1960 and 1984 (N =960) to obtain date and status at last follow-up. Only 127 patients were still alive. Death certificates for all those deceased were obtained. The measurement of survival from recognized onset of dementing illness is of interest; therefore, we used the Cox proportional hazards model to evaluate survival and included age at onset, year of onset, and gender, taking into account that patients were not at risk of death until diagnosed with AD. We also evaluated the possibility of interaction. Survival of patients with AD is decreased in comparison with that of the general population.i ':" Survival of patients with AD (Fig. 3) seemed to increase in the more recent time period (1975 through 1984); the relative hazard decreased by a factor of 0.82 for each decade. We also reconfirmed that
women with AD have a longer survival after onset of AD than do men with AD.22
CONCLUSION The availability of extensive health-care record information for a delineated population has provided the unique opportunity for comprehen sive epidemiologic studies of dementing illnesses in Rochester. Performing various studies throughout several decades in a single, relatively stable population has advantages. The ability to confirm in-depth medical diagnoses from health-care records by using physicians' notes, laboratory data, other ancillary diagnoses and reports, and correspondence is important. Our records often encompass the entire adult life of patients, with documentation of inpatient and outpatient care, nursing home care, as well as death certificate notations and autopsy results . The median duration of medical records available for the cases of AD and controls in the incidence and case-control studies was 44 years. Table 5.-Specific Risk Factors for Alzheimer's Disease St udied in Rochester, Minnesota Factor Case-control studies Head trauma 15 Thyroid disease" Therapeutic radiation'? Anesthesia" Blood transfusion " Cohort studies Head trauma'? Hashimoto's thyroiditis 13
Odds ratio
95 % confidence
interval
1.25 0.92 0.95 1.28 1.25
0.34-4.66 0.65-1.31 0.66-1.37 0.82-7 .00 0.82-1 .88
1.00* 1.37 *
0.63- 1.50 0.59-2.70
*Standardized morbidity ratio.
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280
EPIDEMIOLOGY OF DEMENTIA IN ROCHESTER, MINNESOTA
Alzheimers 1960 - 1974
veers (Age
~=
80)
Years{Age70·79j
Mayo Clio Proc, March 1996, Vol 71
Alzheimers 1975 - 1984
Years (Age:>= 80j
Ye3rs(Age70-79)
~\4
.
Yfl3rs(Age < 70j
veers (Age < 70)
Fig.3. Comparison of survival curves for incidence casesof Alzheimer's disease, stratified by gender, for two periods (1960 through 1974and 1975 through 1984) in Rochester, Minnesota. Dashed line represents men, and solid line represents women. (From Beard and associates." By permission.) For incidence and prevalence studies, use of a medical records-linkage system offers distinct advantages over the sampling methods used in most community-based studies. In medical records-linkage studies, the quality of medical information reflects the continuous updating due to repeated examinations in conjunction with documentation by different health-care providers. In community-sampling studies, surrogate informants provide information that is subject to recall bias and data that are often incomplete and difficult to confirm. Additionally, the refusal rate for such inquiries may be high. Medical records-linkage studies can be far more complete, relatively unbiased, and far less costly to conduct. Certain disadvantages are inherent in epidemiologic studies performed by using medical record information, even when complete health-care records are available: some patients may not receive medical attention, and some may obtain their health care elsewhere. We estimate, however, that virtually all Rochester residents who are 65 years of age or older have at least one health-care contact at the Mayo Clinic in any 3-year period (unpublished data). Another possible disadvantage of using medical records data is the
lack of uniformity in available information. All patients with dementia do not undergo the same work-up; therefore, desired details of a neuropsychologic examination or specific findings in neuroimaging cannot be evaluated for every patient. Until the most recent quinquennium, a family history of dementing or other neurologic illness and the use or abuse of alcohol and drugs were recorded inconsistently. Measures are being taken to decrease these shortcomings in the medical records in Rochester. Availability and reliability of longitudinal information in health-care records should not differ between cases and controls, a fact that may override some of the objections to this type of investigation. Even if a patient does not undergo a detailed neuropsychologic assessment, the accretion of data in the medical record about cognition and behavior year after year and examination after examination often provides a clear picture of the severity and progression of dementing illness. Because the Rochester population is predominantly of northern European origin, our studies have been unable to address putative differences between races or major ethnic groups. Nevertheless, the Rochester database is unusual in that it allows estimation of secular trends in the incidence
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EPIDEMIOLOGY OF DEMENTIA IN ROCHESTER, MINNESOTA
Mayo Clio Proc, March 1996, Vol 71
and prevalence of dementing illness; therefore, additional studies in the future are feasible and may be of paramount importance. Very few incidence studies of dementia have been done in the United States. Nonuniform studies from diverse regions of the world still provide remarkably similar incidence and prevalence rates (Fig. 4 and 5).23 The highest prevalence rates reported in the United States are from studies in a retirement community in California and from studies in eastern Boston in Massachusetts. This occurrence is likely attributable to the unusual case definition criteria used in the two studies.i':" A historical cohort study is the most powerful study design for determining disease associations. Such studies can be criticized if different criteria are used to determine evolving disease among the defined cohort than were used to define incidence cases. The studies reported herein were done with use of the same case finding and case definition procedures for both cases and controls. Similar findings from both case-control and cohort studies strengthen our conclusion.
35
-c-
Our experience with case-control and cohort studies has not confirmed that head injury, thyroid disease, or lower levels of education are risk factors for AD. Our case-control studies have the advantage of being free of selection and recall biases, inasmuch as all the data were collected from health-care records and were documented long before dementia occurred. Many of the studies that suggest an association between low educational levels and AD were done in populations with rather low literacy rates and were based on prevalence surveys. In the Rochester study, the educational level among control subjects was similar to the decennial census data for this population. The Rochester Epidemiology Project data resource was utilized to conduct several studies of AD by using various study designs. The potential influence of certain genetic characteristics, such as the apolipoprotein E-IV allele, cannot be addressed in retrospective studies at this time. The frequency of various apoprotein alleles in patients with AD and their age-matched control subjects in the AD Patient Registry has been reported." Additional studies of anemia and exposure to estrogens, nonsteroidal anti-inflammatory
50
France-Bordeaux
-A- Sweden-Gothenburg 30
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SWeden-Lundby
...-
UK-Liverpool
45
25
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,... :::::.. CD 0
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-...& US-East Boston
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US-Rochester 1965-74
......
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0
65
70
75
80
85
90
Age (years)
Fig. 4. Comparison of age-specific incidence rates of Alzheimer's disease in community-based studies from United States (US) and Europe. pyrs = person-years; UK = United Kingdom. (From Breteler and associates." By permission.)
.-. 65
70
75
80
85
90
Age (years)
Fig. 5. Comparison of age-specific prevalence rates of Alzheimer's disease in selected studies from United States (US), Europe, and Japan. (From Breteler and associates.P By permission.)
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
282
Mayo Clio Proc, March 1996, Vol 71
EPIDEMIOLOGY OF DEMENTIA IN ROCHESTER, MINNESOTA
agents, and reserpine are under way with use of this unique database. ACKNOWLEDGMENT Many investigators have collaborated and contributed to the study of dementing illness in Rochester. We are grateful to the following persons: John A. Anderson, B.S.; John F. Annegers, Ph.D.; Frances M. Baker, M.D.; David J. Ballard, M.D., Ph.D.; Erik J. Bergstralh, M.S.; Nicolaas I. L. 1. Bohnen, M.D., Ph.D.; Vijay Chandra, M.D., Ph.D.; John D. Earle, M.D.; Lavonne A. Gates, R.N.; Virginia A. Hanson, R.N.; Ian D. Hay, M.B., Ph.D.; L. Joseph Melton III, M.D.; Kenneth P. Offord, M.S.; Haruo Okazaki, M.D.; Yasef Ozsarfati, M.D.; Walter A. Rocca, M.D., M.P.H.; Bruce S. Schoenberg, M.D., M.P.H. (deceased); Jack P. Whisnant, M.D.; David M. Williams, M.B.,B.S., Ph.D.; and Fumio Yoshimasu, M.D.
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10. 11. 12. 13.
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