失智症之暴露危險因子與相關保護因子研究:以慢性C型肝炎感染、高血壓與糖尿病患者為例 (2015)

Background: Dementia is a syndrome of chronic, progressive cognitive impairment involving multiple domains of cognition, significant enough to cause functional impairment and not due to a medically reversible cause. The clinical hallmark of dementia is a gradual decline in cognitive function, and patients with assessments that indicate cognitive impairment should be further evaluated to determine an appropriate diagnosis or identify other causes. Although not all subjects with cognitive impairment develop dementia, cognitive deficits have been proposed to be able to identify patients at risk of developing dementia in the pre-clinical stage. The early detection of cognition decline and risk factors are important to prevent the progression of dementia. 
The reimbursement database of the National Health Insurance program in Taiwan provides an opportunity for research. There were three objectives to this research; (1) to investigate the potential increased risk for dementia in patients infected with hepatitis C virus (HCV) in Taiwan; (2) to investigate the effects of antihypertensive drugs, especially angiotensin receptor blockers (ARBs) on dementia and its subtypes; (3) to determine if there is a relationship between the severity of diabetes and the risk of dementia in Taiwanese patients.
Methods: We conducted three population-based cohort studies based on the Taiwan National Health Insurance Research Database. 
(1) In the HCV cohort study, a total of 58,570 matched (1:1) pairs of HCV-infected patients and non-HCV-infected patients were included from all potential participants aged 50 years or more.
(2) In the ARB study, a total of 24,531 matched pairs (1:1) of ARB-exposed and non-ARB-exposed subjects were included. 
(3) In the diabetes study, a total of 431,178 new-onset diabetic patients were included as the diabetes cohort. The severity of diabetes was evaluated using the adapted Diabetes Complications Severity Index (aDCSI). 
Each subject was individually tracked from 1997 to 2010 (2009 in the HCV cohort) to identify incident cases of dementia (onset in 1999 or later). Cox proportional hazard regression analysis was used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between HCV infection and dementia, ARBs and dementia, and the severity of diabetes and dementia.
Results: 
(1) There were 2,989 dementia cases in the HCV-infected cohort during the follow-up period of 533,861.1 person-years; the overall incidence rate of dementia was significantly different from the non-HCV cohort (56.0 vs. 47.7 cases per 10,000 person-years, p < 0.05). The adjusted HR for dementia was 1.36 (95% CI, 1.27-1.42) for the HCV-infected patients after adjusting for alcohol-related disease, liver cirrhosis, hepatic encephalopathy and hepatocellular carcinoma. 
(2) There were 1,322 cases (5.4%) of dementia in the ARB cohort and 2,181 cases (8.9%) in the non-ARB cohort during the eleven-year follow-up period. The multivariate-adjusted HRs for dementia, Alzheimer’s disease and vascular dementia were 0.54 (95% CI, 0.51-0.59), 0.53 (95% CI, 0.43-0.64) and 0.63 (95% CI, 0.54-0.73) for the subjects who received ARB treatment, respectively. In terms of cumulative dosage, the subjects with more than 1460 defined daily doses (DDD) of ARBs had a lower risk than those who received less than 1460 DDD (HR 0.37 vs. 0.61; p < 0.05). 
(3) A total of 431,178 new-onset diabetic patients were included, 6.2% of whom were diagnosed with dementia. At the end of the follow-up period, the HRs for dementia were 1.04 (95% CI, 0.99-1.09), 1.40 (95% CI, 1.34-1.46, p < 0.001), 1.54 (95% CI, 1.47-1.61, p < 0.001) and 1.70 (95% CI, 1.63-1.78, p < 0.001) with an aDCSI score of 1, 2, 3 and more than 3, respectively. Compared with the patients with mild progressive, the adjusted HRs increased with aDCSI change (two-year HRs: 1.30, 1.53, 1.97; final HRs 2.38, 6.95, 24.0 with an increase in aDCSI score per year of 0.51-1.00, 1.01-2.00 and more than 2.00, respectively, vs. less than 0.50; p < 0.001 for trend). 
Conclusions: These results suggest that HCV infection may increase the risk of dementia, and that the use of ARBs may be associated with a reduced risk of dementia in patients at high vascular risk. Diabetic patients with rapid progression and exacerbated severity had a higher risk of dementia. Further mechanistic research is needed to validate our findings.