Mari Ootsuki

Dementia caregivers’ burdens and use of public services

Background:  The objectives of the present study are to examine risk factors for the heavy burden of caring for demented patients as well as factors that may affect on the level of utilization by carers of public services under current long‐term care insurance in Japan.

BENEFITS OF COMBINING DONEPEZIL PLUS TRADITIONAL JAPANESE HERBAL MEDICINE ON COGNITION AND BRAIN PERFUSION IN ALZHEIMER'S DISEASE: A 12-WEEK OBSERVER-BLIND, DONEPEZIL MONOTHERAPY CONTROLLED TRIAL

To the Editor: Although many attempts have been made to demonstrate its cognitive benefits in Alzheimer’s disease (AD), donepezil, one of the cholinesterase (ChE) inhibitors, is still a standard therapeutic agent. Because of a limited benefit of a single drug alone, several clinical trials of combination regimen have been reported. One study demonstrated that an inhibition of ChE leads to a marked reduction of choline acetyltransferase (ChAT) levels in the rat brain. A negative feedback mechanism may explain this finding, supporting the use of a ChAT activator in combination with donepezil in AD. Kami-Untan-To (KUT), a traditional Japanese herbal medicine, is known to upregulate the expression of ChAT at the messenger ribonucleic acid level. It also increases acetylcholine levels and the number of ChAT-positive neurons in aged mice. Finally, Suzuki et al. conducted a clinical trial of KUT to evaluate safety and efficacy in patients with mild to moderate AD. Therefore, we designed an observer-blind, donepezil monotherapy controlled clinical trial of a combination of donepezil plus KUT. A 12-week, observer-blind, donepezil monotherapy controlled clinical trial was conducted at the Tohoku University hospital outpatient clinic for dementia from October 2003 through January 2005. Thirty-eight eligible AD patients (National Institute of Neurological and Communicative Disorders and StrokeFAlzheimer’s Disease and Related Disorders Association criteria) were randomly assigned to receive donepezil alone (n 5 20, mean age standard deviation 74.6 3.9; men, n 5 4; women n 5 16) or a combination of donepezil and KUT (n 5 18, aged 73.7 5.6; men, n 5 4; women n 5 14). In both groups, patients received a 3-mg daily dose of donepezil for the first 14 days followed by an escalation to 5 mg thereafter. The 13 herbs of KUT were purchased from Tsumura Co. Ltd, Tokyo, Japan. The quality of the herbs was standardized based on the Good Manufacturing Practice defined by the Ministry of Health and Welfare of Japan. Cognitive function was measured using the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) and Mini-Mental State Examination (MMSE), as well as regional cerebral blood flow (rCBF) using I-IMP-ARG single photon emission computed tomography, with SPM99 software package (Wellcome Department of Imaging Neuroscience, London, UK) implemented in MATLAB 5.3 system (Mathworks Inc., Natick, MA). At baseline, there was no significant difference in age, sex distribution, MMSE score (19.6 4.1 vs 18.9 4.9 points), ADAS-cog score (19.5 6.8 vs 21.0 7.6 points), prevalence of silent brain infarction (38% vs 44%), or grade for deep white matter lesions (0.9 0.6 vs 1.1 0.2) and for periventricular hyperintensity (0.7 0.8 vs 0.7 0.8) (as previously defined) between the treatment groups (chi-square test, P4.05). Two patients in the donepezil monotherapy group had intractable diarrhea, conceivably due to cholinergic adverse effects by donepezil. No such event was observed in the combination group. Analyses were performed using the last observation carried forward method. Differences in the MMSE and ADAScog scores between baseline and posttreatment were analyzed using a paired t test and repeated measure analysis of variance. As shown in Figure 1A, relative to baseline, posttreatment MMSE scores significantly improved only in the combination group (from 18.9 4.9 to 21.6 4.2 points, P 5.001; 4.17o95% confidence interval (CI) o 1.28) but not in the donepezil monotherapy group (from 19.6 4.1 to 20.4 4.5). As shown in Figure 1B, ADAScog scores also improved significantly in the combination group (from 21.0 7.6 to 16.8 7.1, Po.001; 2.54o 95% CIo5.80) but not in the monotherapy group (from 19.5 6.8 to 18.2 7.0). Furthermore, as shown in Figure 1C, the rCBF in frontal regions significantly increased in the combination group alone (Po.05 corrected: Brodmann’s area (BA) 9, (x, y, z) 5 (8, 50, 24), Z 5 5.19; BA 8, (x, y, z) 5 (26, 28, 46), Z 5 5.04; BA 9, (x, y, z) 5 (8, 54, 36), Z 5 4.99; kE 5 6,029). Despite a small sample size and a short observation period, we demonstrated that the combined use of donepezil plus KUT was more beneficial than donepezil alone in cognition and brain perfusion. Although cholinergicrelated adverse effects might be expected, such events did not occur in the combination group. Therefore, it is likely that donepezil and KUT worked synergistically in a safe fashion to enhance availability of acetylcholine. In our study, the prevalence of silent brain infarction was 38% in the donepezil monotherapy group and 44% in the combination group. This was comparable with results of studies with serially enrolled autopsy-confirmed AD cases by Heyman et al. (30.2%). Therefore, it should be noted that our study was conducted in a mixed population of pure AD and AD with cerebrovascular diseases. In summary, KUT might be used as a complementary regimen to enhance treatment success of current cholinergic therapy for AD.

Exacerbation of dementia after the earthquake and tsunami in Japan

On Friday, March 11, 2011, a magnitude 9.0 earthquake hit Japan, which was followed by enormous tsunamis that caused numerous casualties and serious damage in the coastal cities [1]. After the disaster, many elderly people including patients with dementia were evacuated to asylums such as gymnasiums and halls because their houses were destroyed. Many of the patients visited our clinic after evacuation, and most of them got significantly worse with their dementia symptoms including behavioral and psychological symptoms of dementia (BPSD). We here examined changes in cognitive functions and BPSD with minimental state examination (MMSE) and neuropsychiatric inventory-questionnaire (NPI-Q), respectively, in patients with Alzheimer’s disease after the earthquake. We analyzed three groups including subjects who did not suffer from the disaster (group 1, M/F = 9/11, age 74.3 ± 8.3), subjects who had experienced the disaster but did not stay at an evacuation site (group 2, M/F = 9/9, age 75.6 ± 7.8), and subjects who were forced to stay at an evacuation site (group 3, M/F = 8/9, age 77.8 ± 8.5). We compared the altered values (after-before) of each test in the three groups. Both groups 2 and 3 showed a decline in MMSE compared to group 1 although a significant difference was observed only between ‘‘group 1 and 2’’ and ‘‘group 1 and 3’’. Concerning the NPI-Q both group 2 and 3 exhibited exacerbation of BPSD and the significant difference was observed between ‘‘group 1 and 2’’, ‘‘group 1 and 3’’ and ‘‘group 2 and 3’’ (Fig. 1). Disasters such as earthquakes, tsunamis, hurricanes, and tornados must be extremely stressful to elderly people. On the other hand, to change their circumstances to inferior conditions such as evacuation sites should affect their mental and cognitive condition more severely [2]. Nobody likes to live together with many other people in a big hall with people having poor hygiene. Not only physical but also mental care to the elderly who suffered from the disaster is now needed.

Plasma Homocysteine and Risk of Coexisting Silent Brain Infarction in Alzheimer’s Disease

Background: Cerebrovascular disease is common in Alzheimer’s disease (AD). Elevated plasma homocysteine (pHcy) levels are reported to be associated with an increased risk of poor cognition and dementia. Objective: To determine whether high pHcy levels are associated with an increased risk of coexisting silent brain infarctions (SBIs) in AD. Methods: Study population comprising 143 outpatients with clinical diagnosis of probable AD (73.3 ± 7.0 years) were classified into 2 groups according to the presence or absence of SBIs on magnetic resonance imaging. Results: SBIs were noted in 32.9% (47/143) of the AD patients. The pHcy levels in the AD with SBIs (14.0 ± 4.5 µmol/l) were significant ly elevated compared with the AD without SBIs (11.7 ± 4.7 µmol/l, p = 0.007). After adjusting for age and gender, high pHcy (>12.4 µmol/l), but not hypertension, was associated with an increased risk of developing SBIs in AD (OR = 4.61, 95% CI = 1.74–12.2, p = 0.002). However, age at onset, cognitive function, cerebrospinal tau or amyloid β-peptide1–42 levels were not significantly correlated with pHcy levels in AD. Conclusion: SBIs commonly coexist with AD, and may be a unique vascular condition in which homocysteine plays an important role. Homocysteine-lowering therapy rather than antihypertensive medication might be an appropriate strategy to prevent stroke associated with AD.

Aggravation of Alzheimer's disease symptoms after the earthquake in Japan: A comparative analysis of subcategories

We recently reported that patients with Alzheimer’s disease (AD) experienced a significant worsening of symptoms after the earthquake and tsunami that occurred in Japan on 11 March 2011. Our previous analysis showed that patients with AD who experienced the disaster had deteriorated with regard to both cognitive functions, and behavioral and psychological symptoms of dementia (BPSD) compared with those

Long‐term cognitive benefits of donepezil in Alzheimer’s disease: A retrospective comparison between 1994–1999 and 2000–2004

Objective:  In order to address an issue of how long Alzheimer’s disease (AD) patients should receive donepezil, we estimated long‐term effect of donepezil on cognition as well as its influential factors. We also evaluated the additional effect of cerebrospinal fluid (CSF)‐tau protein levels on diagnosis.