NEUROLOGY/2016/757526 2

Supplemental methods (appendix e-1)

Title: Trends in dementia prevalence, incidence, and survival rate in a Japanese community

Authors: Tomoyuki Ohara, M.D., Ph.D.1,2, Jun Hata, M.D., Ph.D.2,3,5, Daigo Yoshida, Ph.D.2,3, Naoko Mukai, M.D., Ph.D.2,3,5, Masaharu Nagata, M.D., Ph.D.2,5, Toru Iwaki M.D., Ph.D.4, Takanari Kitazono, M.D., Ph.D.3,5, Shigenobu Kanba, M.D., Ph.D.1, Yutaka Kiyohara, M.D., Ph.D.6, and Toshiharu Ninomiya, M.D., Ph.D.2,3

Affiliations:

1.  Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

2.  Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

3.  Department of Center for Cohort Studies, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

4.  Department of Neuropathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

5.  Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

6.  Hisayama Research Institute for Lifestyle Diseases, Fukuoka, Japan.

Corresponding Author:

Tomoyuki Ohara, M.D., Ph.D.

Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University

3-1-1Maidashi, Higashi-ku, Fukuoka 812-8582, Japan

Tel: (+81) 92-652-3080

Fax: (+81) 92-652-3075

E-mail:

Supplemental methods (appendix e-1)

Diagnosis of dementia

In the cross-sectional surveys, the diagnosis of dementia and its subtypes was made clinically based on the guidelines of the Diagnostic and Statistical Manual of Mental Disorders, third edition (DSM-III)1 in 1985 and those of the DSM-III revised version (DSM-III-R)2 in 1992, 1998, 2005, and 2012.

In the follow-up surveys, the diagnosis of dementia was made based on the guidelines of the DSM-III-R.2 Patients diagnosed with AD met the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association criteria (NINCDS-ADRDA),3 and patients diagnosed with vascular dementia (VaD) met the National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l’Enseignement en Neurosciences criteria (NINDS-AIREN).4 Clinical information, including neuroimaging, was used to diagnose possible and probable dementia subtypes. Definite dementia subtypes were also determined on the basis of clinical and neuropathological information in dementia patients who underwent autopsy. The diagnostic procedure for autopsy cases has been previously reported.5 Each case of dementia was adjudicated by expert stroke physicians and psychiatrists. We used neuropathological findings only for determining dementia subtypes, and modified the clinical diagnosis of dementia subtypes to a definitive diagnosis for cases with autopsy as necessary.

During the follow-up, 134 individuals (40 men and 94 women) in the 1988 cohort and 334 individuals (114 men and 220 women) in the 2002 cohort developed dementia. In the 1988 cohort, 122 of these patients (91.0%) underwent brain imaging evaluation, 46 (34.3%) underwent autopsy, and 38 underwent both. Similarly, in the 2002 cohort, 296 patients (88.6%) underwent brain imaging, 71 (21.3%) underwent autopsy, and 61 underwent both. Therefore, 130 patients (97.0%) in the 1988 cohort and 306 patients (91.6%) in the 2002 cohort underwent some kind of morphological examination. Among dementia cases, 7 cases in the 1988 cohort and 15 cases in the 2002 cohort were a mixed type of AD and VaD. These cases were counted as events in the analysis for each subtype. Finally, 73 individuals in the 1988 cohort and 222 in the 2002 cohort experienced AD, 48 and 87 VaD, and 20 and 40 other/unclassified dementia, respectively.

Risk factor measurements

At the baseline survey of both cohorts, a self-administered questionnaire concerning lifestyle, including smoking habits, alcohol consumption, educational status, medical history, and treatment of hypertension, diabetes, and hypercholesterolemia was checked by trained interviewers. The mean of three measurements of blood pressure was used for the analysis. Hypertension was defined as blood pressure ≥140/90 mmHg or current use of antihypertensive agents. Electrocardiogram abnormalities were defined as left ventricular hypertrophy (Minnesota Code 3-1), ST depression (4-1, 2, or 3), or atrial fibrillation (8-3). Body mass index (BMI, kg/m2) was calculated as an indicator of adiposity, and obesity was defined as BMI ≥25 kg/m2. Diabetes mellitus was defined by fasting glucose concentrations ≥126 mg/dl, 2-hour postload glucose or postprandial glucose concentrations ≥200 mg/dl, and/or use of oral hypoglycemic agents or insulin. Serum total cholesterol levels were measured enzymatically, and hypercholesterolemia was defined as serum total cholesterol ≥220 mg/dL or current use of lipid-lowering agents. History of stroke was defined on the basis of all clinical data available in the Hisayama Study. A low educational level was defined as ≤9 years of formal education. Smoking status and alcohol consumption were classified as either current use or not. Regular exercise was defined as engaging in sports more than three times a week during leisure time.

Statistical analysis

The age-standardized prevalence of dementia was estimated by the direct method using the WHO World Standard Population with 5-year age groups. Trends in the crude and adjusted prevalence of dementia were estimated by using the logistic regression model. The difference of crude mean values and frequencies of risk factors were estimated by using Student’s t-test or the Chi-square test, respectively. The age- and sex-adjusted mean values of risk factors as continuous variables were calculated and compared between the two cohorts by using the linear regression model. The frequencies of risk factors were adjusted for age and sex and tested with logistic regression analysis. The incidence of dementia and its subtypes and all-cause mortality were calculated by the person-year method with adjustment for age and sex by the direct method with 5-year age groups. In this adjustment, the age and sex distribution in the 1988 cohort was used as a standard population. The age- and sex-adjusted incidence was compared between the two cohorts using the Cox proportional hazards model, and the adjusted hazard ratio (HR) with its 95% confidence intervals (CI) was also estimated using the Cox model. The competing risk of death was examined by using the method proposed by Fine JP and Gray RJ.6 Patients who developed dementia were followed-up for the subsequent 5 years after the disease onset or to the end of the follow-up period in each cohort, and survival curves were drawn using the Cox model with adjustment for age and sex. In each cohort, we also selected dementia cases which developed during the follow-up and age- and sex-matched control participants randomly selected from those without incident dementia and compared the 5-year mortality rate after the onset of dementia between these two groups. The heterogeneity in the influence of incident dementia on the mortality between cohorts was tested by adding the interaction terms to the relevant Cox model. All statistical analyses were performed with SAS (version 9.3; SAS Institute, Cary, NC). Two-sided p<0.05 was considered statistically significant in all analyses.

REFERENCES (for the supplemental methods)

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2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 3rd ed, revised. Washington, DC: American Psychiatric Association, 1987.

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4. Román GC, Tatemichi TK, Erkinjuntti T, Cummings JL, Masdeu JC, Garcia JH, et al. Vascular dementia: diagnostic criteria for research studies. report of the NINDS-AIREN International Workshop. Neurology 1993;43:250-260.

5. Fujimi K, Sasaki K, Noda K, Wakisaka Y, Tanizaki Y, Matsui Y, et al. Clinicopathological outline of dementia with Lewy bodies applying the revised criteria: the Hisayama Study. Brain Pathol 2008;18:317-325.

6. Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999;94:496-509.