Dementia in Taiwan area

Transcription

1 Translational Neuroscience and Clinics ISSN print edition: ISSN electronic edition: CN print edition: /R CN electronic edition: /R DOI Vol. 2, No. 1, March 2016, pp /CN /R Dementia in Taiwan area Yuanhan Yang ( ) Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, China ABSTRACT Received: 12 January 2016 Revised: 19 February 2016 Accepted: 20 February 2016 Objective: Taiwan has an increasing aging population like other developed areas. The aging population will lead to an increased prevalence of dementia. Methods: This article will reflect the status of dementia in Taiwan, including updated epidemiology, diagnosis, subtypes, and optimal treatment of dementia. Results: The article also describes and interprets the Taiwan Dementia Policy to establish a clear, large view of the current state of management of dementia in Taiwan and future policy implementation. Conclusion: A comprehensive policy to dementia, from the basic researches to clinical care and treatment, is necessary to the increased aged population in Taiwan. The authors This article is published with open access at KEYWORDS Alzheimer s disease; ascertainment of dementia 8 (AD8); acetyl cholinesterase inhibitor; dementia Citation 1 Yang YH. Dementia in Taiwan area. Transl. Neurosci. Clin. 2016, 2(1): Introduction Dementia, including Alzheimer s disease (AD), des cribes a set of symptoms severely affecting memory, orientation, reasoning, and social abilities to interfere with activities of daily living. The risk of dementia increases with age. The percentage of the elderly is increasing in Taiwan, as in most developed areas. As the population ages, dementia has become a major public health issue. 2 Epidemiology Epidemiological studies from the 1980s and 1990s reported the prevalence of dementia in Taiwan as ranging from 1.7% to 4.3% in adults aged 65 years or more. This ratio was lower than the reported preval ence in Europe and the US (5% 10%), and may be due to underreporting, higher mortality rate, or differences in race. Specifically, family members/informants may not recognize or report cognitive deficits out of respect or treat memory decline as a normal part of the aging process. Reported mortality rates in patients with de mentia in Taiwan are higher than those in most western reports, with two population based studies reporting 32% 48%, and one hospital based study showing a mean survival time for patients with AD as 4.48 years[1]. Recently, there were two studies addressing the current prevalence of dementia in Taiwan[2, 3]. A study using the ascertainment of dementia 8 (AD8) as a screening tool to screen individuals aged greater than 50 years old has found that the estimated prevalence of very mild dementia could be higher than before. Corresponding author: Yuanhan Yang, endlessyhy@gmail.com Supported by the Review Article ARTICLE INFO

2 Transl. Neurosci. Clin. 39 That study was completed by the extensive coverage of the mentality protection center (MPC), Fo Guangshan, Taiwan, and the volunteers of MPC conducted medicine related services and screening of dementia by using the AD8 that can detect dementia even at its very mild stage in the general population throughout Taiwan. From 2011 to 2013, in total, 2,171 participants, 368 in the northern, 549 in the central, 877 in the southern, and 377 in the eastern part, were recruited with the mean age being 66.9 ± 10.2 years. The ratio of patients with suspected dementia with an AD8 score 2 was 13.6% for all recruited participants, with their mean AD8 score being 2.9 ± 1.3, mean age being 69.4 ± 10.8 years, and female predominance being 73.0% (Table 1). Although this is a screening study, it has extensive coverage of Taiwan. The AD8 is capable of screening very mild dementia and the results have provided updated information on early stage dementia in Taiwan [3]. Another recently published study has suggested the prevalence rates closer to those seen in Europe and the US. A meta analysis based on DSM IV estimated the prevalence of dementia in adults aged 65 years or more to be 5.7% (95% CI ) [4]. The whole area survey in 2014 estimated the prevalence of all cause dementia at 8.04% (95% CI ), including a 3.25% (95% CI ) prevalence of very mild dementia (VMD). Meanwhile, the study estimated the prevalence of mild cognitive impairment (MCI) at 18.76% (95% CI ) (Table 2). 3 Characteristic of patients with Alzheimer s disease Like other areas, the most demented subjects were patients with AD. Not every patient with AD has been well diagnosed and treated. Most of these patients with AD were treated at medical centers and area hospitals Table 1 Ratio of suspected very mild dementia in Taiwan after screening Northern (n = 368) Central (n = 549) Southern (n = 877) Eastern (n = 377) P value (n = 2,171) n (%) 48 (13.0%) 74 (13.5%) 126 (14.4%) 48 (12.7%) (13.6%) Age, mean ± SD 70.4 ± ± ± ± ± 10.8 Female, n (%) 36 (62.5%) 55 (74.3%) 98 (77.8%) 27 (56.3%) (73.0%) AD8 total score, mean± SD 2.7 ± ± ± ± ± 1.3 Note: Adapted from Chen CH, et al. [3] Table 2 Age specific prevalence of mild cognitive impairment (MCI) and all cause dementia including very mild dementia (VMD) Age n MCI (n = 2049) Prevalence (95% CI) VMD (n = 366) Prevalence (95% CI) Dementia with CDR 1 (n = 563) Prevalence (95% CI) All dementia (VMD plus dementia with CDR 1) (n = 929 ) Prevalence (95% CI) , ( ) 1.89 ( ) 1.51 ( ) 3.40 ( ) , ( ) 1.73 ( ) 1.73 ( ) 3.46 ( ) , ( ) 3.27 ( ) 3.92 ( ) 7.19 ( ) , ( ) 4.65 ( ) 8.38 ( ) ( ) ( ) 7.56 ( ) ( ) ( ) ( ) ( ) ( ) ( ) Total 10, ( ) 3.51 ( ) 5.40 ( ) 8.91 ( ) Age adjusted prevalence (%) * ( ) 3.25 ( ) 4.79 ( ) 8.04 ( ) Age gender adjusted prevalence (%) * ( ) 3.29 ( ) 4.84 ( ) 8.13 ( ) Note: * Age adjusted prevalence was calculated using the Taiwan census data in (Adapted from Sun Y et al. [2] )

3 40 Yuanhan Yang. Dementia in Taiwan area because the treatment of AD with acetyl cholinesterase inhibitors (AchEIs) can only be reimbursed by the National Health Institute if they are treated by neurologists or psychiatrists. We launched a study several years ago to reflect the status of AD in Taiwan, registration of Alzheimer s disease [5]. Importantly, the study was extended to Beijing and Hong Kong population [6] and to other Asian areas [7]. In Taiwan, the data came from six medical centers in the northern, central, and southern parts of Taiwan to reflect the status of patients with AD. The mean age of patients with AD was 79.3 ± 7.7 years and the mean age of informants was 57.5 ± 13.7 years. Among all informants, 69% had lived with patients and 77% of recruited patients had lived with spouse, partner, or children. Regarding family history of dementia in recruited patients, 11% had one sibling with dementia, 1.8% had two siblings with dementia, and 0.5% had three or more siblings with dementia. Some patients (2.9%) reported that their fathers were diagnosed with dementia and 6.7% reported a diagnosis of dementia in their mothers [5]. 4 Diagnostic methods Commonly used assessments in Taiwan include the mini mental state examination (MMSE) [8], Alzheimer s disease assessment scale (ADAS Cog) [9], cognitive abilities screening instrument (CASI) [10], and neuropsychiatric inventory (NPI) [11]. The clinical dementia rating (CDR) scale is also used not only for staging but also for diagnosis [12]. The AD8 is used extensively as a screening tool because of its capability in screening VMD [13]. 5 Subtypes The prevalence of subtypes of dementia was similar to other reports that AD would be higher than vascular dementia (VaD) in the general population although the prevalence would vary in relation to the characteristics of the population, community based or hospital based. Two hospital based studies found higher frequencies of VaD than AD, and one community study demonstrated a predominance of AD in women and VaD in men. The lower frequency of VaD found in the community study may be due to the lack of brain imaging data, or the higher mortality rate of patients with VaD compared to patients with AD [1]. 6 Optimal treatment There are several studies conducted and completed in Taiwan to monitor the concentration of AchEIs for clinical therapeutic response [14 16]. With donepezil, we found that 60% of recruited patients with AD had improved cognition as measured by MMSE, and 57.1% had improved global status as measured by CDR sum of boxes (CDR SB). Although donepezil has been approved for the treatment of mild to moderate AD and a higher oral dosage was suggested to have a better therapeutic response in reported results, the plasma concentration of donepezil was not examined with respect to the therapeutic outcomes in other published studies. However, our studies have examined the therapeutic responses of donepezil in patients with AD in relation to their plasma concentration of donepezil. Regarding cognition, compared to the improving group, the clinically worsening group had a significantly higher donepezil concentration (P = 0.022), odds ratio (OR = 1.024, 95% CI = ) and higher initial MMSE score (P = 0.007, OR= 1.330, 95% CI = ). For global status, the initially higher CDR SB (P = 0.028, OR= 2.318, 95% CI = ) initially higher MMSE (P = 0.036, OR = 1.201, 95% CI = ), and not donepezil concentration (P = 0.883), were significantly associated with clinical worsening [15]. These important findings have highlighted the necessity of individualized treatment with optimal dosage rather than using a uniform dose. Similarly, for rivastigmine, we found that a higher rivastigmine concentration was significantly associated with improved or preserved short term memory and worsened abstraction/judgment (P = 0.021), but not with changes in other domains (P > 0.05). Therefore, the optimal concentration of rivastigmine should be quantified for each patient because of differential cognitive responses [14]. Higher NAP concentration was significantly associated with worsened abstraction/ judgment (P = 0.027), but not with changes in other domains. These therapeutic responses in cognitive domains were also different for donepezil. Among the nine cognitive domains in the cognitive ability screening instrument, the long term memory domain

4 Transl. Neurosci. Clin. 41 had the highest improvement ratio (81.1%) compared with other domains. An increased donepezil plasma concentration (mean (SD), (32.16) ng/ml) was significantly associated with the improvement of longterm memory (P = 0.045; odds ratio, 0.959; 95% CI, ) after adjusting for age, sex, education, and apo lipoprotein E genotype [16]. In those studies, we developed an optimal treatment for patients with AD such that we had a higher adherence ratio compared to other areas. For donepezil, the mean therapeutic duration was 28.0 ± 25.9 months with a maximum of 128 months and a minimum of 0.5 months. The 12 and 24 month adherence rates were 90.1% and 84.8%, respectively [17]. 7 Clinical management The currently recommended clinical guidelines for the diagnosis, assessment, and treatment of all dementia were revised and published [18]. 7.1 Donepezil For mild or moderate AD (MMSE 10 25), the use of donepezil for 12, 24, or 52 weeks improves cognitive function and global assessment (class I, level of evidence A). Daily dosage of 10 mg/day is slightly more effective than 5 mg/day but carries higher risk for adverse events, so physicians should use discretion based on the clinical presentation in dose selection. For severe AD (MMSE 0 16), donepezil also improves cognitive function and global assessment (class I, level of evidence A), and 10 mg/day is more effective than 5 mg/day. The drug also appears to improve activities of daily living (class IIa, level of evidence A), but has no effect on dementia related behavioral disturbance. 7.2 Rivastigmine For mild or moderate AD (MMSE 10 29), the use of rivastigmine at a high (6 12 mg/day) or low (1 4 mg/day) dose improves cognitive function and global assessment, and the effect is more pronounced with the higher dose (class I, level of evidence A). Activities of daily living require the high dose for significant improvement (class I, level of evidence A). Rivastigmine has a greater effect on cognitive function in patients whose disease is progressing at a faster rate (ADAS cog increase of 4 points or more in 26 weeks) as compared to those with slow disease progression (class I, level of evidence A). Early use should have a beneficial impact on cognitive function (class IIa, level of evidence B). 7.3 Galantamine For mild or moderate AD (MMSE 10 25), the use of galantamine (16 36 mg/day) improves cognitive function and global assessment (class I, level of evidence A). In particular, 16 and 24 mg/day, both significantly improve cognitive function in patients with mild AD, while only 24 mg/day produces pronounced improvement in cognitive function in patients with moderate AD (MMSE 10 18) (class I, level of evidence B). Activities of daily living improve with mg/day, but functional benefit requires mg/day (class I, level of evidence A). Goal attainment scaling is probably improved with mg/day (class IIa, level of evidence B). Of note, in Asian ethnicities or other select patients, the use of merely 8 mg/day yields improvement in cognitive function. In terms of safety, gastrointestinal adverse effects are common and dosedependent. The use of 16 mg/day may result in treatment discontinuation due to adverse events within 6 months and 24 mg/day may result in discontinuation within 3 months (class I, level of evidence A). 7.4 Memantine For moderately severe AD (MMSE 3 14), the use of memantine can improve global performance, cognitive function, activities of daily living, and behavior (class I, evidence A). Combination therapy with donepezil is superior to donepezil monotherapy (class I, evidence B). For milder AD (MMSE 10 22), memantine only improves global performance, and combination therapy with AchEI is not superior to AchEI monotherapy (class II, evidence B). The consensus for clinical management was not to differentiate between the AchEIs in terms of clinical effectiveness or preferred order of use and not to comment on when treatment should begin, end, or be switched.

5 42 Yuanhan Yang. Dementia in Taiwan area Strength of recommendation Class I consistent evidence and/or wide consensus. Class II evidence with some controversy and/or some differing opinions. IIa evidence/opinion lean toward effectiveness. IIb limited evidence/opinion supporting effectiveness. Class III evidence and/or wide consensus for ineffectiveness or harm. Grade of evidence A evidence from multiple randomized clinical trials. B evidence from a single randomized clinical trial or multiple non randomized studies. C expert consensus. 8 Medication treatment There is limited published information about the current clinical management of dementia in Taiwan. No medications are currently capable of stopping dementia or healing the existing brain damage in patients, but the AchEIs and memantine can treat the symptoms and potentially slow the progression of the disease [15]. The goal of a pharmacological treatment is to improve patients quality of life and alleviate caregivers burden. Donepezil, rivastigmine, and galantamine are approved for the treatment of mild to moderate AD (MMSE or CDR 1 2). Memantine is approved for moderate AD (MMSE or CDR 2). Donepezil or memantine (but not in combination) is approved for the treatment of severe AD (MMSE 5 9 and CDR 3). Rivastigmine is approved for the treatment of mild to moderate Parkinson s disease dementia. Treatments for VaDs are excluded because they are not reimbursed from the national health insurance system [19]. Although these therapies have been covered by the National Health Insurance Administration since 2000 (for NINDS ADRDA, DSM, or ICD established diagnoses), prior authorization and annual reauthorization are mandatory for payment. Only neurologists and psychiatrists can prescribe these medications. A survey showed that only 66.5% to 72.6% of prior authorization cases were approved. Although an appeal process is available, the majority of appeals (89.5%) upheld the denial decision [20]. The appeals were mainly denied due to lack of appropriate exclusionary data of other possible causes of dementia [1]. Patients seeking reauthorization must be followed up with updated MMSE or CDR assessments. Treatment is to be discontinued if, at the annual evaluation, there is a decrease in MMSE score of more than 2 points or increase in CDR score of 1 or more points compared to baseline [19]. Another survey showed the average duration for AchEI therapy to be approximately 14 months and that only 9.6% of patients maintained stable cognition assessments resulting in continued drug refills for more than three years [20]. Another study indicated that for the donepezil, the mean therapeutic duration was 28.0 ± 25.9 months with a maximum of 128 months and a minimum of 0.5 months. The 12 and 24 month adherence rates were 90.1% and 84.8% [17]. Such discrepancies in clinical adherence resulted from whether the study survey was conducted throughout Taiwan [20] or by a single medical center [17]. The National Health Insurance Administration in Taiwan also covers traditional Chinese medicine (TCM). One study on the utilization of TCM among patients with dementia reported that more than 40% of patients with dementia used TCM. Youngonset dementia, higher number of behavioral and psychological symptoms of dementia (BPSD), multiple chronic diseases, and poly pharmacies were independent predictors for patients with dementia seeking TCM [21]. A number of nutritional supplements and herbs have been studied for use in treating dementia, the most well known being gingko [22]. There is no data on how often these are being used in patients with dementia in Taiwan. Clinicians and patients in Taiwan are also encouraged to utilize non pharmacologic approaches such as environmental adjustment, planned activities, change in communication patterns, cognitive training, reminiscence therapy, bright light therapy, massage, music therapy, aromatherapy, pet therapy, multisensory therapy, and art therapy [23, 24] Dementia is being recognized as a growing public health issue in Taiwan. As such, the ministry of health and welfare developed the Taiwan dementia policy: A framework for prevention and care as described below [25].

6 Transl. Neurosci. Clin Taiwan dementia policy: A framework for prevention and care 9.1 Main objectives (1) Timely diagnosis and early intervention to reduce the impact of dementia. (2) Good quality services to meet the need, maintain the dignity, and improve the quality of life of people with dementia and their family. 9.2 Purposes and scope of the Taiwan strategies for dementia care 1. To improve public awareness and understanding of dementia: (1) enhancing people s knowledge and awareness about dementia, to facilitate timely referral and assessment of those at early stage of cognitive impairment or suspected of having dementia; (2) advocating educational activities related to dementia, to increase public understanding and to reduce the stigma of dementia, in order to develop a community friendly to people with dementia; (3) implementing multi dimensional educational programs through school and community activities, to promote public awareness, understanding, and care about dementia; (4) integrating the public health and social services delivering systems to assist the public in understanding and coping effectively with dementia; (5) promoting evidence based healthy life styles and social participation to lower the risk of dementia. 2. To establish a comprehensive community care network: (1) identifying early dementia symptoms for timely diagnosis and comprehensive medical care; (2) integrating community organizations such as health care services, social welfare organizations, local activity centers, local government offices, etc., to provide information about service resources and appropriate referral; (3) developing a multi dimensional, accessible community network for prevention and care while encouraging non government organizations to join and provide services; (4) providing multi dimensional care to people with dementia according to their needs in different disease stages; (5) establishing a community network to provide counseling and support for caregivers to reduce their burden; providing caregivers with education and skill training to care for individuals with dementia; (6) encouraging collaboration between local authorities and non government organizations to facilitate early intervention programs and to provide social interaction for people with early dementia, thus delaying their functional deterioration. 3. To strengthen the primary prevention and healthcare services: (1) raising the awareness of dementia as an important part of primary healthcare; increasing primary healthcare worker s competence in evaluating dementia; (2) enhancing primary healthcare workers understanding of the need of dementia care and to provide appropriate referral; (3) integrating services within the healthcare system to implement accessible network for evaluation and treatment of dementia in rural and urban areas; (4) assisting individuals with dementia to receive early intervention and appropriate treatment based on their stage of dementia. 4. To expand human resources and enhance professional competence: (1) providing education and training for personnel and volunteers at government departments, community organizations, schools, and job settings, etc., to promote their understanding and involvement of dementia; (2) connecting local government and non government organizations to educate the seed trainers and to provide community education about dementia to enhance people s understanding and involvement; (3) incorporating knowledge and skill of prevention, treatment, and care of dementia into the professional training of medical staff, social workers, and nursing aides. 5. To strengthen inter departmental cooperation and resource integration: (1) promoting cooperation between departments to advocate prevention, treatment, and early diagnosis of dementia; (2) integrating dementia related agenda across departments to develop effective strategies; (3) establishing mechanisms to integrate resources across departments to develop multi dimensional services for individuals with dementia and their family; (4) enhancing cooperation between the government and NGOs to provide services for individuals with dementia and advocate relevant policies; (5) establishing unified service window for integrated evaluation, care plan, and referral for individuals with dementia.

7 44 Yuanhan Yang. Dementia in Taiwan area 6. To encourage dementia research and international cooperation: (1) encouraging cross disciplinary and cross institutional integrated researches and evidencebased researches in dementia prevention and management, and to develop appropriate policy according to the evidence obtained in the researches; (2) regular survey of dementia prevalence at national and community level, as well as long term follow up, for policy making and advocacy; (3) encouraging research on medical care and human rights protection for individuals with dementia, including prevention, screening instrument, etiology, clinical course, prognosis, medical and non medical interventions, etc.; (4) encouraging people in related disciplines to conduct or participate in international researches or conferences about prevention and medical care of dementia. 7. To protect human rights of individuals with dementia and their family: (1) providing services for dementia prevention and care to all individuals, regardless of age, gender, and race, with equal opportunity to access related information, support, and adequate care; (2) reviewing current law to ensure rights of individuals with dementia and their caregivers; (3) developing quality indices of dementia care and building a supervision/appraisal system for services; (4) engaging non government organizations in discussions on dementia related issues, such as ethics, law, human rights protection and promotion; (5) consulting individuals with dementia and their family while making related policy. 10 Conclusion Medical treatment of dementia is most likely underutilized in Taiwan, and the state of current clinical management is unclear. As the impact of dementia continues to increase, a holistic approach as outlined in the Taiwan dementia policy is not only crucial but its implementation also warrants careful follow up. A more comprehensive clinical guideline that addresses prevention, diagnosis, care pathways, and use of nutritional supplements, herbs, and non pharmacologic treatment approaches is needed. Research on treatment utilization patterns, including complementary and alternative therapies, as well as the type and quality of care received by institutionalized patients with dementia, will be important for establishing a clearer, larger picture of the current state of management in Taiwan and guiding evidence based clinical care and future policy implementation. References [1] Fuh JL, Wang SJ. Dementia in Taiwan: Past, present, and future. Acta Neurol Taiwan 2008, 17(3): [2] Sun Y, Lee HJ, Yang SC, Chen TF, Lin KN, Lin CC, Wang PN, Tang LY, Chiu MJ. A nationwide survey of mild cognitive impairment and dementia, including very mild dementia. PLoS One 2014, 9(6): e [3] Chen CH, Wang LC, Ma TC, Yang YH. A walk-in screening of dementia in the general population in Taiwan. Sci World J 2014, 2014: Article ID [4] Wu YT, Lee HY, Norton S, Chen CF, Chen HX, He CL, Fleming J, Matthews FE, Brayne C. Prevalence studies of dementia in Mainland China, Hong Kong and Taiwan: A systematic review and meta-analysis. PLoS One 2013, 8(6): e [5] Wang WF, Chiu PY, Lin YT, Hu CJ, Fuh JL, Yang YH. Registration of Alzheimer s disease in Taiwan: Patient and informant. Am J Alzheimers Dis Other Demen 2014, 29(1): [6] Yang YH, Wang H, Lam L, Chan WC, Yu X, Li T, Wang WF, Chiu PY, Lin YT, Hu CJ, Fuh JL, Morris JC. Characteristics of Alzheimer s disease among patients in Taiwan, Hong Kong, and Beijing. J Alzheimers Dis 2014, 42(1): [7] Yang YH, Meguro K, Kim SY, Shim YS, Yu X, Chen CL, Wang H, Lam L, Senanarong V, Dominguez J, Lu PY, Lin YT, Hu CJ, Chiu PY, Fuh JL, Wang WF, Yu BC, Li T, Wang MW, Situmeang RF, Jang JW, Zhang J, Chan WC, Zhou YY, Lou HL, Zhang L, Ye M, Chen X. Impact of Alzheimer s disease in nine Asian Countries. Gerontology, in press, DOI / [8] Folstein MF, Folstein SE, McHugh PR. Mini-mental state. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975, 12(3): [9] Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer s disease. Am J Psychiatry 1984, 141(11): [10] Lin KN, Wang PN, Liu CY, Chen WT, Lee YC, Liu HC. Cutoff scores of the cognitive abilities screening instrument, Chinese version in screening of dementia. Dement Geriatr Cogn Disord 2002, 14(4):

8 Transl. Neurosci. Clin. 45 [11] Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The neuropsychiatric inventory: Comprehensive assessment of psychopathology in dementia. Neurology 1994, 44(12): [12] Morris JC. The clinical dementia rating (CDR): Current version and scoring rules. Neurology 1993, 43(11): [13] Yang YH, Galvin JE, Morris JC, Lai CL, Chou MC, Liu CK. Application of AD8 questionnaire to screen very mild dementia in Taiwanese. Am J Alzheimers Dis Other Demen 2011, 26(2): [14] Chou MC, Chen CH, Liu CK, Chen SH, Wu SJ, Yang YH. Concentrations of rivastigmine and NAP and the cognitive response in Taiwanese Alzheimer s disease patients. J Alzheimers Dis 2012, 31(4): [15] Yang YH, Wu SL, Chou MC, Lai CL, Chen SH, Liu CK. Plasma concentration of donepezil to the therapeutic response of Alzheimer s disease in Taiwanese. J Alzheimers Dis 2011, 23(3): [16] Yang YH, Chen CH, Chou MC, Li CH, Liu CK, Chen SH. Concentration of donepezil to the cognitive response in Alzheimer disease. J Clin Psychopharmacol 2013, 33(3): [17] Chang YP, Yang CH, Chou MC, Chen CH, Yang YH. Clinical compliance of donepezil in treating Alzheimer s disease in Taiwan. Am J Alzheimers Dis Other Demen 2015, 30(4): [18] Guideline subcommittee of the Taiwan dementia society. Guidelines for the medical treatment of patients with Alzheimer s disease. Acta Neurol Taiwan 2011, 20(2): [19] National Health Insurance Administration. National Health Insurance Administration payment guidelines for drugs acting on the nervous system [Online]. National Health Insurance Administration, webdata/webdata.aspx?menu=21&menu_id=713&webdata_ id=2919. [20] Sun Y, Lai MS, Lu CJ, Chen RC. How long can patients with mild or moderate Alzheimer s dementia maintain both the cognition and the therapy of cholinesterase inhibitors: A national population-based study. Eur J Neurol 2008, 15(3): [21] Lin SK, Tsai YT, Lai JN, Wu CT. Demographic and medication characteristics of traditional Chinese medicine users among dementia patients in Taiwan: A nationwide database study. J Ethnopharmacol 2015, 161: [22] National Center for Complementary and Integrative Health. Dietary supplements and cognitive function, Dementia, and Alzheimer s disease [Online]. National Center for Complementary and Integrative Health, health/providers/digest/alzheimers.htm. [23] Taiwan Alzheimer Disease association website. [24] Li CH, Liu CK, Yang YH, Chou MC, Chen CH, Lai CL. Adjunct effect of music therapy on cognition in Alzheimer s disease in Taiwan: A pilot study. Neuropsychiatr Dis Treat 2015, 11: [25] Taiwan Ministry of Health and Welfare. Taiwan dementia policy: A framework for prevention and Care [Online]. Taiwan Ministry of Health and Welfare, http: // 475&fod_list_no=5160&doc_no=46373&rn=