Miyako Nemoto

Quinoline and Benzimidazole Derivatives: Candidate Probes for In Vivo Imaging of Tau Pathology in Alzheimer's Disease

Neurofibrillary tangles (NFTs), neuropil threads, and neuritic elements of senile plaques predominantly comprise hyperphosphorylated tau protein and represent pathological characteristics of Alzheimers disease (AD). These lesions occur before the presentation of clinical symptoms and correlate with the severity of dementia. In vivo detection of these lesions would thus prove useful for preclinical diagnosis of AD and for tracking disease progression. The present study introduces three novel compounds, 4-[2-(2-benzoimidazolyl)ethenyl]-N,N-diethylbenzenamine (BF-126), 2-[(4-methylamino)phenyl]quinoline (BF-158), and 2-(4-aminophenyl)quinoline (BF-170), as candidate probes for in vivo imaging of tau pathology in the AD brain. When solutions of these compounds are injected intravenously into normal mice, these agents exhibit excellent brain uptake and rapid clearance from normal brain tissue. These compounds display relatively lower binding affinity to β-amyloid fibrils and higher binding affinity to tau fibrils, compared with previously reported probe BF-168. In neuropathological examination using AD brain sections, BF-126, BF-158, and BF-170 clearly visualize NFTs, neuropil threads, and paired helical filament-type neuritis. Autoradiography using 11C-labeled BF-158 further demonstrated labeling of NFTs in AD brain sections. These findings suggest the potential usefulness of quinoline and benzimidazole derivatives for in vivo imaging of tau pathology in AD.

Capsaicin Troche for Swallowing Dysfunction in Older People

Objectives: To determine whether oral capsaicin troche supplementation with every meal upregulates the impairment of upper respiratory protective reflexes such as the swallowing reflex and the cough reflex.

Cerebrospinal fluid neprilysin is reduced in prodromal Alzheimer's disease

Amyloid β peptide (Aβ) has been implicated in Alzheimers disease (AD) as an initiator of the pathological cascades. Several lines of compelling evidence have supported major roles of Aβ‐degrading enzyme neprilysin in the pathogenesis of sporadic AD. Here, we have shown a substantial reduction of cerebrospinal fluid (CSF) neprilysin activity (CSF‐NEP) in patients with AD‐converted mild cognitive impairment and early AD as compared with age‐matched control subjects. The altered CSF‐NEP likely reflects changes in neuronal neprilysin, since transfer of neprilysin from brain tissue into CSF was demonstrated by injecting neprilysin‐carrying viral vector into the brains of neprilysin‐deficient mice. Interestingly, CSF‐NEP showed an elevation with the progression of AD. Along with a close association of CSF‐NEP with CSF tau proteins, this finding suggests that presynaptically located neprilysin can be released into CSF as a consequence of synaptic disruption. The impact of neuronal damages on CSF‐NEP was further demonstrated by a prominent increase of CSF‐NEP in rats exhibiting kainate‐induced neurodegeneration. Our results unequivocally indicate significance of CSF‐NEP as a biochemical indicator to pursue a pathological process that involves decreased neprilysin activity and Aβ‐induced synaptic toxicity, and the support the potential benefits of neprilysin up‐regulation in ameliorating neuropathology in prodromal and early AD. Ann Neurol 2005;57:832–842

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.

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.

Aspiration Pneumonia and Insular Hypoperfusion in Patients with Cerebrovascular Disease

To the Editor: Gait disorders in the elderly lead to injury, fear of falling, limitation of activity, and prolonged bed rest. An interdisciplinary approach may decrease the risk of falls and reduce functional impairment, but it needs inducible efforts. We recently reported that acupuncture on two acupoints (Zusanli ST36 and Taixi K3) restored the swallowing reflex in poststroke patients. These two acupoints and Shenshu (BL23, on the lower back, below the spinous process of the second lumbar vertebra, 1.5 fingerbreadth lateral to the posterior midline) have been used in Japan and Asian countries for acupuncture treatment of gait disorders, pain, and other symptoms of lumbar regions or inferior limbs.We examined acupuncture therapy on the acupoints (ST36, K3, and BL23) and observed whether simultaneous acupuncture at the three acupoints improve gait disorders in the frail elderly. For acupuncture, six disposable stainless steel fine needles (diameter 0.16mm, length 40mm) were inserted in three acupoints bilaterally and kept at a 10-mm depth for 15minutes without any extra stimulation such as electrical or manual. The Timed Up and Go (TUG) test, which measures total time fromwhen the subject stood up from an armchair, walked a distance of 3 meters, turned, walked back to the chair, and sat down again, was measured. A TUG test score of more than 16 seconds is one of the predictors of falls. Subjects were 27 outpatients (18 women, 9 men) with a mean age standard deviation of 76 8 years and no cognitive impairment. They complained of gait disorders because of lumbago (n510), stroke (n56), Parkinsonism (n53), and combinations of these diseases (n5 8). They were selected randomly at the Tohoku University Hospital and participated in this study under written informed consent. The ethical committee of Tohoku University Hospital approved this trial. Participants were randomly assigned into two groups. At first, we practiced acupuncture on the intervention group (15 patients (11 women, 4 men), aged 75 8) and examined the TUG test before and 1 hour after the acupuncture. Twelve other patients were assigned to the control group and received usual care without acupuncture. The TUG test after the acupuncture (using three acupoints) improved significantly (18 8 vs 14 6 seconds, Po.001) (Figure 1). The TUG test without acupuncture after a 1hour interval in the control group did not change significantly (17 7 vs 17 8 seconds, P4.10). Fifteen patients in the intervention group underwent acupuncture therapy once a week for 1 year. The therapy was completed in 11 patients (9 women, 2 men, aged 75 10). The control group (7 women, 5 men, aged 76 8) received usual care without acupuncture for 1 year. The intervention group maintained their improved scores on the TUG test compared with baseline values after 1 year of follow-up (15 4 seconds, Po.001), whereas scores declined in the control group (19 6 seconds, Po.05). Activities of daily living were assessed in both groups using the Barthel Index at baseline and after 1 year of follow-up. The Barthel Index has a 100-point scale in five-point increments for healthy people. A score of 0 represents the worst state. After 1 year of follow-up, the Barthel Index declined in the control group (81 6 vs 77 10, Po.05) but improved in the intervention group (77 10 vs 93 4, Po.005). There were no adverse effects related to the acupuncture therapy. We showed that acupuncture can be a safe and inexpensive way to improve gait disorders and activities of daily living in the frail elderly. We suggest that there are beneficial effects of acupuncture to prevent limitation of activity and reduce the risk of becoming bed-ridden.

Lithium therapy and cerebrospinal fluid biomarker levels in Alzheimer's disease

Recent studies suggest that lithium may retard pathological deterioration by inhibiting aberrant phosphorylation of tau in Alzheimers disease (AD). Here, we describe three cases of AD who were treated with lithium for agitation. However, there was no obvious improvement either in global cognition, agitation or cerebrospinal fluid markers that were thought to reflect Alzheimers pathology. Increased dosages of lithium were not tolerated by the patients because of adverse effects. It is likely that AD patients do not benefit from lithium therapy as an alternative choice of treatment.