Increased Total Homocysteine Levels Predict the Risk of Incident Dementia Independent of Cerebral Small-Vessel Diseases and Vascular Risk Factors

Article type: Research Article

Authors: Miwa, Kaori^{a; *} | Tanaka, Makiko^b | Okazaki, Shuhei^a | Yagita, Yoshiki^c | Sakaguchi, Manabu^a | Mochizuki, Hideki^a | Kitagawa, Kazuo^d

Affiliations: [a] Department of Neurology and Stroke Center, Osaka University Graduate School of Medicine, Osaka, Japan | [b] Department of Strokology, Stroke Center, Hoshigaoka Medical Center, Osaka, Japan | [c] Department of Stroke Medicine, Kawasaki Medical University, Kurashiki, Japan | [d] Department of Neurology, Tokyo Women’s Medical University, Tokyo, Japan

Correspondence: [*] Correspondence to: Kaori Miwa, MD, PhD, Department of Neurology and Stroke Center, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan. Tel.:+81 6 6879 3576; Fax: +81 6 6878 6574; E-mail: miwa@osaka-njm.net

Abstract: Background:Homocysteine has been identified as a potential risk factor for stroke, cerebral small-vessel diseases (SVD), and dementia. Objective:The present study aimed to investigate the predictive value of homocysteine levels on incident dementia while simultaneously controlling for MRI findings and vascular risk factors. Methods:Within a Japanese cohort of participants with vascular risk factors in an observational study, we evaluated the association between baseline total homocysteine (tHcy) levels (per 1 μmol/L and the tertile of tHcy), the prevalence of MRI-findings at baseline, and incident all-cause dementia. Baseline brain MRI was used to determine SVD (lacunas, white matter hyperintensities, and cerebral microbleeds [CMBs]) and atrophy (medial-temporal lobe atrophy and bicaudate ratio). Logistic regression analyses were used to estimate the cross-sectional association between tHcy and each of MRI findings. Cox proportional hazards analyses were performed to estimate the longitudinal association between tHcy and dementia. Results:In the 643 subjects (age: 67.2 ± 8.4 years, male: 59% ; education: 12.9 ± 2.6 years), multivariable analyses adjusted for several potential confounders, including estimated glomerular filtration rate (eGFR) and intima-media thickness, showed that highest tHcy tertile was associated with lacunas, CMBs, and strictly deep CMBs. During the mean 7.3-year follow-up (range: 2–13), 47 patients were diagnosed with dementia (Alzheimer’s disease: 24; vascular dementia: 18; mixed-type: 3; other: 2). After adjusting for age, gender, APOE ɛ4, education, BMI, MMSE, hypertension, cerebrovascular events, eGFR, and MRI-findings, tHcy level (hazard ratios [HR]: 1.08, p = 0.043) and the highest tertile of tHcy (HR: 2.50, p = 0.047) for all-cause dementia remained significant. Conclusions:Our results provide additional evidence of tHcy that contributes to increased susceptibility to dementia risk.

Keywords: Alzheimer’s disease, cerebral small-vessel disease, dementia, estimated glomerular filtration rate, homocysteine, microbleeds, vascular dementia

DOI: 10.3233/JAD-150458

Journal: Journal of Alzheimer's Disease, vol. 49, no. 2, pp. 503-513, 2016