123I-FP-CIT SPECT findings and its clinical relevance in prodromal dementia with Lewy bodies.

PURPOSE: Evidence for the prodromal stage of dementia with Lewy bodies (DLB) is very limited. To address this issue, we investigate the 123I-FP-CIT SPECT measure of dopamine transporter binding finding and its clinical relevance. METHODS: We enrolled subjects into a prodromal DLB group (PRD-DLB) (n = 20) and clinical DLB group (CLIN-DLB) (n = 18) and compared these groups with an Alzheimer's disease control group (AD) (n = 10). PRD-DLB was defined as patients having the non-motor symptoms associated with Lewy body disease (LBD) [i.e. REM sleep behavior disorder (RBD), olfactory dysfunction, autonomic dysfunction, and depression] and showing characteristic diffuse occipital hypometabolism in 18F-FDG PET. CLIN-DLB was defined as patients fulfilling the established criteria of probable DLB. Striatal specific binding ratio (SBR) of 123I-FP-CIT SPECT was used for objective group comparisons. The correlations between SBR and cognitive function (MMSE), motor symptoms (UPDRS3), and duration of LBD-associated non-motor symptoms were compared between the two DLB groups. RESULTS: Mean SBR scores of both PRD-DLB and CLIN-DLB were significantly lower than those of AD. No correlation was found between SBR and MMSE scores. Both in the CLIN-DLB and total DLB groups, SBR scores were negatively correlated with UPDRS3 scores, whereas no correlation was found in PRD-DLB. Among the LBD-related non-motor symptoms, duration of olfactory dysfunction, and RBD demonstrated negative correlation with SBR scores in PRD-DLB. CONCLUSION: 123I-FP-CIT SPECT may play a role for detecting DLB among the subjects in prodromal stage. During this stage, long-term olfactory dysfunction and/or RBD may indicate more severe degeneration of the nigro-striatal dopaminergic pathway.

A patient with schizophrenia presenting with post-lobotomy catatonia treated with olanzapine: a case report.

A 79-year-old Japanese woman with schizophrenia was hospitalized because of idiopathic duodenal stenosis. Three days after discontinuing ingestion, including the administration of psychotropic drugs, the patient demonstrated incoherent behaviour and strong general muscle tension, and was unable to engage in conversation. Computed tomography indicated bilateral regions of low density in the frontal lobes, subsequent to which she was diagnosed with post-lobotomy catatonia. Administration of olanzapine (10 mg/day) improved the patient's condition within a short period. Previous studies have demonstrated an association between the dysfunction of frontal circuits and catatonia; therefore, the observed catatonic episode might relate to the disconnection of nerve fibres in the prefrontal lobes induced by her lobotomy. Olanzapine was likely effective in treating catatonia because of its reported efficacy in improving frontal lobe function.

Serum insulin-like growth factor-I and amyloid beta protein in Alzheimer's disease: relationship with cognitive function.

AIMS: Previous studies have suggested that insulin-like growth factor-I (IGF-I) deficiency may lead to cognitive deficits in neurodegenerative diseases such as Alzheimer's disease. The present study aimed to investigate the possible relationship between cognitive function and concentration of IGF-I or amyloid beta protein (Aß) in serum in Alzheimer's patients. METHODS: A total of 81 Japanese patients were enrolled in this study. Concentrations of IGF-I, Aß42, and Aß40 in serum were measured. Two neuropsychological tests, Mini-Mental State Examination and Hasegawa's Dementia Scale-Revised (HDS-R), were also performed. Linear correlations among the age, serum IGF-I, serum Aß42 or Aß40, Aß42/Aß40 ratio, Mini-Mental State Examination or HDS-R total score, and the scores for six HDS-R subscales were analyzed by regression analysis. RESULTS: IGF-I showed a significant negative correlation with age (ß = -0.357, P = 0.002) and a positive correlation with Aß42/Aß40 ratio (ß = 0.318, P = 0.007). Serum IGF-I and both the Mini-Mental State Examination and the HDS-R total score also correlated (ß = 0.505, ß = 0.524, P < 0.01). Among the HDS-R subscales, 'Recall' (ρ = 0.379, P < 0.01), 'Verbal fluency' (ρ = 0.360, P < 0.01), and 'Attention and calculation' (ρ = 0.389, P < 0.01) showed significant positive correlations with serum IGF-I. CONCLUSION: The results, specifically that lower serum IGF-I was associated with cognitive impairment, suggest that metabolism of IGF-I may be involved in the pathogenesis of cognitive deficits in Alzheimer's disease.

Safety and tolerability of immune globulin intravenous (human), 10% solution in Japanese subjects with mild to moderate Alzheimer's disease.

BACKGROUND: Immune globulin intravenous (IGIV), 10% is a donor-derived polyclonal human immunoglobulin G antibody mixture that has potent immune modulatory properties and contains conformation selective anti-amyloid antibodies. We evaluated the safety and tolerability of multiple doses of IGIV, 10% in Japanese patients with mild to moderate Alzheimer's disease. METHODS: Among the 16 subjects, 12 subjects were assigned to the IGIV group and 4 subjects to the placebo group. Subjects received a total of six infusions of either IGIV at a dose of 0.2 or 0.4 g/kg, or placebo every 2 weeks. RESULTS: A total of 33 treatment-emergent adverse events (TEAE) occurred in 14 subjects: 13 TEAE in five subjects in both the IGIV 0.2 and 0.4 g/kg groups, and 7 TEAE in four subjects in the placebo group. The most common TEAE in the IGIV subjects were nasopharyngitis, injection-site swelling, and erythema. All 26 TEAE in the IGIV group were considered to be mild. Only one mild TEAE (rash) was considered to be possibly related to the study drug. There were no significant differences in incidence of TEAE between the treatment groups. Four serious TEAE were reported, and all of these were considered to be unrelated to the study treatment. Other assessments related to safety revealed neither clinically significant abnormal values nor findings in the study. CONCLUSION: IGIV is generally safe and well tolerated with multiple intravenous infusions at doses of 0.2 g/kg and 0.4 g/kg in Japanese patients with mild to moderate Alzheimer's disease.

Clinical evaluation of percutaneous endoscopic gastrostomy tube feeding in Japanese patients with dementia.

AIM: The aim of this study was to clinically evaluate percutaneous endoscopic gastrostomy (PEG) tube feeding of elderly Japanese patients with dementia. METHOD: The records of the 155 patients with dementia who underwent PEG in Juntendo Tokyo Koto Geriatric Medical Center were reviewed for pertinent clinical data, including diagnosis of dementia, place of stay before and after hospitalization, as well as survival rate, albumin levels, and incidence of aspiration pneumonia (AP) before and 6 months after PEG feeding. The latter three data of these patients were compared with those of 106 patients with dementia fed through a nasogastric (NG) tube. RESULTS: Alzheimer's disease and vascular dementia were predominant. Fifty-three percent of the patients were admitted from their home; the number of discharges to homes decreased to 21.2%. The mean (SD) of the albumin levels was 2.9 (0.4) g/dl before feeding and 2.9 (0.6) g/dl after 6 months. Among the patients with AP before PEG tube feeding, 51.6% had an AP recurrence. Conversely, AP occurred in 9.4% of the patients without AP before feeding. The patient survival rate was higher by 27 months when using PEG tube than when using an NG tube. CONCLUSION: PEG tube feeding in patients with dementia leads to preservation of status for a few years. Compared with NG tube feeding, PEG tube feeding did not induce AP due to impairment of intact swallowing function, and was associated with higher survival rate of approximately 2 years. However, PEG tube feeding does not seem to promote home medical care.

Effect of Probiotic Bifidobacterium breve in Improving Cognitive Function and Preventing Brain Atrophy in Older Patients with Suspected Mild Cognitive Impairment: Results of a 24-Week Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Probiotics have been reported to ameliorate cognitive impairment. OBJECTIVE: We investigated the effect of the probiotic strain Bifidobacterium breve MCC1274 (A1) in enhancing cognition and preventing brain atrophy of older patients with mild cognitive impairment (MCI). METHODS: In this RCT, 130 patients aged from 65 to 88 years old with suspected MCI received once daily either probiotic (B. breve MCC1274, 2×1010 CFU) or placebo for 24 weeks. Cognitive functions were assessed by ADAS-Jcog and MMSE tests. Participants underwent MRI to determine brain atrophy changes using Voxel-based Specific Regional Analysis System for Alzheimer's disease (VSRAD). Fecal samples were collected for the analysis of gut microbiota composition. RESULTS: Analysis was performed on 115 participants as the full analysis set (probiotic 55, placebo 60). ADAS-Jcog subscale "orientation" was significantly improved compared to placebo at 24 weeks. MMSE subscales "orientation in time" and "writing" were significantly improved compared to placebo in the lower baseline MMSE (< 25) subgroup at 24 weeks. VSRAD scores worsened in the placebo group; probiotic supplementation tended to suppress the progression, in particular among those subjects with progressed brain atrophy (VOI Z-score ≥1.0). There were no marked changes in the overall composition of the gut microbiota by the probiotic supplementation. CONCLUSION: Improvement of cognitive function was observed on some subscales scores only likely due to the lower sensitiveness of these tests for MCI subjects. Probiotics consumption for 24 weeks suppressed brain atrophy progression, suggesting that B. breve MCC1274 helps prevent cognitive impairment of MCI subjects.

Effect of Rikkunshi-to on appetite loss found in elderly dementia patients: a preliminary study.

BACKGROUND: Functional gastrointestinal symptoms are frequently found in elderly dementia patients. In such a case, we attempt treatment by the administration of antidepressants or second-generation antipsychotics. However, these medications have a risk of side-effects. In the present study, we carried out oral administration of Rikkunshi-to to elderly dementia patients with appetite loss, and examined its effects on food intake. METHODS: Six elderly dementia patients were recruited from inpatients. They showed appetite loss, but no organic abnormalities of the gastrointestinal organs. These patients were given Rikkunshi-to, at 7.5 g per day, t.i.d. for 4 weeks. We examined the food intake, weight, total protein, albumin and potassium in plasma before administration and for 4 weeks after administration. In statistical analyses, the percentage of food consumed for 4 weeks was analyzed by anova. We also examined the side-effects of Rikkunshi-to. RESULTS: In patient 3, we stopped investigation after 3 weeks because of the development of cholecystitis. The values of 4 weeks in patient 3 were calculated as the mean values of 4 weeks in the other five patients. anova and Tukey's multiple comparison showed a marginally significant difference in weight between before Rikkunshi-to was given and 4 weeks after. In change of food intake, there were no significant differences between before Rikkunshi-to was given and 1 day after, 1 day and 2 days after, 2 days and 3 days after, 3 days and 1 week after, and 1 week and 2 weeks after; however, there were significant increases in food intake between other times. With regard to the side-effects, mild lower limb oedema appeared in the two patients. CONCLUSION: In the present study, we showed the effect of Rikkunshi-to in improving appetite loss in elderly dementia patients. The present study suggests that Rikkunshi-to might be useful in improving functional appetite loss in elderly dementia patients, because there are no serious side-effects.

Clinical effects of high oral dose of donepezil for patients with Alzheimer's disease in Japan.

BACKGROUND: Donepezil 10 mg/day gained approval in Japan in August 2007 for the treatment of cognitive dysfunction in advanced Alzheimer's disease. METHODS: We evaluated the efficacy and adverse effects of donepezil when the dose was increased to 10 mg/day in 61 Japanese patients with Alzheimer's disease. Cognitive function was evaluated using the Revised Hasegawa Dementia Scale and mini-mental state examination at the day before starting, and at 4, 8 and 24 weeks after starting donepezil 10 mg/day. The relationship with apolipoprotein E4 was also investigated. RESULTS: The Revised Hasegawa Dementia Scale and mini-mental state examination scores were not statistically significantly different at any time after starting donepezil 10 mg/day. It can be anticipated that donepezil 10 mg/day will especially inhibit deterioration of cognitive function in advanced Alzheimer's disease. The incidence of adverse events was 11.5%, lower than the rate of 40% or higher recorded during previous clinical trials. CONCLUSIONS: The progression of cognitive dysfunction could be inhibited by increasing the dose of donepezil to 10 mg/day. It was suggested that longer-term treatment with 5 mg/day might lead to fewer adverse events when the dose is increased to 10 mg/day.

Safety and pharmacokinetics of bapineuzumab in a single ascending-dose study in Japanese patients with mild to moderate Alzheimer's disease.

AIM: To evaluate the safety, tolerability and pharmacokinetic profile of bapineuzumab after a single intravenous injection in Japanese patients with mild to moderate Alzheimer's disease. METHODS: Participants received either a placebo (n = 8), or bapineuzumab 0.15 (n = 6), 0.5 (n = 6), 1.0 (n = 6) or 2.0 (n = 6) mg/kg. Serum concentrations of bapineuzumab, antibapineuzumab antibody and total plasma ß-amyloidx-40 were assayed. RESULTS: Adverse events for bapineuzumab and placebo groups were 71% and 88%, respectively. Treatment-emergent adverse events (cataract, injection site hemorrhage, nasopharyngitis, pneumonia and muscle twitching) reported for ≥2 participants were mild or moderate in severity and unrelated to bapineuzumab dose. No deaths, serious adverse events or withdrawals were reported. Mean peak concentration for bapineuzumab increased with dose, from 3.3 ± 0.9 µg/mL with the 0.15 mg/kg dose to 61.0 ± 32.8 µg/mL with 2.0 mg/kg. Mean bapineuzumab exposure (area under the curve from time 0 to last measurable concentration; µg·h/mL) increased in a linear manner with increasing dose (mean 1260 for 0.15 mg/kg, 4264 for 0.5 mg/kg, 7818 for 1.0 mg/kg, 15 313 for 2.0 mg/kg). Mean half-life ranged from 15 to 28 days, and clearance was similar across dose groups (range 0.12-0.17 mL/h/kg). CONCLUSIONS: Plasma ß-amyloidx-40 levels increased with increasing doses of bapineuzumab. Bapineuzumab was safe and well tolerated at all doses in Japanese patients with mild to moderate Alzheimer's disease. Geriatr Gerontol Int 2016; 16: 644-650.

Development of quantitative neuropsychological tests for diagnosis of subclinical hepatic encephalopathy in liver cirrhosis patients and establishment of diagnostic criteria-multicenter collaborative study in Japanese.

At present, there are no generally accepted diagnostic criteria or methods for subclinical hepatic encephalopathy (SHE) associated with liver cirrhosis. We therefore developed an easily conducted computer-aided quantitative neuropsychiatric function test system for use in routine medical practice. We established normal values in healthy Japanese subjects and determined differences between healthy persons and liver cirrhosis patients without clinical encephalopathy in a multi-center clinical trial. The test system consists of eight tests: number connection tests A and B, a figure position test, a digit symbol test, a block design test, and reaction time tests A, B and C. The test results were affected by age, but not by gender or facility. No learning effect was noted. The results were therefore reported by 5-year quartile ranges and differences were evaluated between 542 healthy subjects and 292 cirrhotic patients. When the cut-off value was set at the 10th/90th percentile of the results in healthy subjects, the results of each of the 8 tests were abnormal in about 25% of cirrhotic patients, and at least 1 of the 8 tests gave values greater than the 10th/90th percentile cut-off value in 58.2% of the 292 liver cirrhosis patients. SHE patients were thought to be included in these 58.2% of patients. The developed test makes it possible to quantitatively assess neuropsychiatric function, and the results obtained can be used as a basis for the diagnosis of SHE.

[Limbic encephalitis caused by herpes simplex virus infection after vaccination against the influenza virus].

Various causative factors, including viral infection, autoimmunity, and paraneoplasia, are considered to be involved in the pathomechanism of limbic encephalitis. We encountered a patient who developed limbic encephalitis after vaccination against the influenza virus. In Japan, an influenza epidemic occurs every winter, and vaccination against the influenza virus is recommended. However, there have been reports of serious side effects such as the development of Guillain-Barré syndrome and acute disseminated encephalomyelitis after influenza vaccination; these findings indicate the activation of an autoimmune pathomechanism after vaccination. Here, we discuss the relationship between limbic encephalitis and influenza vaccination from the perspective of viral infection and autoimmunity. We considered that limbic encephalitis was caused by the herpes simplex virus, and hypothesized that this clinical condition rarely develops as a sole consequence of influenza vaccination but rather develops because of the activation of an autoimmune pathomechanism after vaccination.