Yokukansan in the treatment of behavioral and psychological symptoms of dementia: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES: There is currently no meta-analysis of the efficacy and tolerability of Yokukansan in the treatment of behavioral and psychological symptoms of dementia. METHOD: We used information obtained from the PubMed and Cochrane Library databases until October 2012. We conducted a systematic review and meta-analysis of individual patient data from randomized controlled trials comparing Yokukansan with usual care (UC, i.e., controls). Standardized mean difference and weighted mean difference were calculated. All studies used the Neuropsychiatric Inventory (NPI) for the evaluation of behavioral and psychological symptoms of dementia. RESULTS: Four relevant studies (total n = 236) were identified. Yokukansan was superior to UC in the reduction of total NPI scores (p = 0.0009, weighted mean difference = -7.20, I(2) = 0%). In addition, Yokukansan was more efficacious in reducing scores on the NPI subscale (delusions, hallucinations, and agitation/aggression) than UC (p < 0.00001-0.0009). Yokukansan treatment also improved activities of daily living scores compared with UC (p = 0.04, standardized mean difference = -0.32, I(2) = 0%). Mini-mental state examination scores did not differ between the Yokukansan and UC treatment groups. Yokukansan was not different from UC regarding discontinuation due to any cause. CONCLUSION: Our results suggest that Yokukansan has a beneficial effect on NPI and on ADL scores and that Yokukansan seems to be a well-tolerated treatment.

Clinicopathological study of diffuse neurofibrillary tangles with calcification. With special reference to TDP-43 proteinopathy and alpha-synucleinopathy.

Diffuse neurofibrillary tangles with calcification (DNTC) is a relatively rare presenile dementia that clinically shows overlapping symptoms of Alzheimer's disease and frontotemporal lobar degeneration (FTLD). DNTC is pathologically characterized by localized temporal or frontotemporal atrophy with massive neurofibrillary tangles, neuropil threads and Fahr's-type calcification without senile plaques. We tried to clarify the molecular basis of DNTC by immunohistochemically examining the appearance and distribution of accumulated alpha-synuclein (aSyn) and TAR DNA-binding protein of 43kDa (TDP-43) in the brains of 10 Japanese autopsy cases. We also investigated the clinically characteristic symptoms from the clinical charts and previous reports, and the correlations with neuropathological findings. The characteristic symptoms were evaluated using the Neuropsychiatric Inventory Questionnaire (NPI-Q). As a result, we confirmed the high frequency of neuronal cytoplasmic accumulation of aSyn (80%) and phosphorylated TDP-43 (90%) in DNTC cases. There was a significant correlation between some selected items of NPI-Q scores and the severity of the limbic TDP-43 pathology. The pathology of DNTC included TDP-43 and aSyn pathology with high frequency. These abnormal accumulations of TDP-43 might be involved in the pathological process of DNTC, having a close relationship to the FTLD-like psychiatric symptoms during the clinical course.

A case of dementia with Lewy bodies that temporarily showed symptoms similar to Creutzfeldt-Jakob disease.

We discuss a case of a 67-year-old male with dementia with Lewy bodies (DLB) that was initially suspected as Creutzfeldt-Jakob disease (CJD) or another type of encephalopathy, because he showed rapidly progressive deterioration, myoclonus, gait disturbance and a decline in activities of daily living. The present study describes a clinically atypical case with probable DLB and reviews similar cases in the literature, and we propose a rapidly progressive clinical subtype of DLB.

Distribution of neurofibrillary tangles in diffuse neurofibrillary tangles with calcification.

AIMS: In this study, the appearance and distribution of neurofibrillary tangles (NFT) in diffuse neurofibrillary tangles with calcification (DNTC) were investigated neuropathologically in order to elucidate the detailed distribution pattern in this disease. METHODS: The distribution of NFT in six cases neuropathologically diagnosed as DNTC (two men and four women) was studied using Gallyas-Braak silver stain. The age at death ranged from 56 to 73, with an average of 63.5 +/- 7.5 years. RESULTS: NFT were seen throughout the cerebral cortex, and were especially marked in the temporal and limbic cortices. The distribution pattern of NFT in the limbic lobe was similar to that in Alzheimer's disease as reported in the previous studies. In the temporal lobe, more NFT were distributed in the anterior than in the posterior area, which was confirmed in all six cases. The temporal pole showed the highest density of NFT including ghost tangles. CONCLUSIONS: The diffuse appearance of NFT in the cerebral cortex with the highest severity in the temporal pole was found to be a neuropathological characteristic of DNTC.

[Development of a brief communication ability scale for Japanese demented elderly].

We developed a brief scale to evaluate communication ability of the demented elderly. This scale assesses not only abilities related to overall communication such as verbal function, judgment and emotional function, but also non-verbal communication such as eye-contact, nodding and smiling. The scale places little burden on the demented elderly subject and takes only a few minutes to perform, even if the dementia is severe. We evaluated 106 demented elderly residents of nursing homes using this brief communication ability scale, and the following results were obtained. The validity of this scale was confirmed by the high correlation coefficient between this scale and the formal caregiver questionnaire scores concerning communication ability, and the high-correlation coefficient between this scale and intellectual functions (r = -0.904), emotional functions (r = -0.841) and motor functions (r = -0.679) of dementia syndromes rating scale (Gottfries, Bråne, Steen scale; GBS scale), Hasegawa's Dementia Scale-Revised (HDS-R) (r = 0.625) and the Mini-Mental State Examination (MMS) (r = 0.733). The reliability of this scale was confirmed by the high interrater reliability coefficient of 0.828, test-retest reliability coefficient of 0.940 and Cronbach alpha coefficient of 0.938. These results indicate that the new scale is useful in the assessment of communication ability among the demented elderly.

Glial fibrillary tangles in diffuse neurofibrillary tangles with calcification.

In the present study the occurrence and distribution of glial fibrillary tangles (GFT) and their related structures in diffuse neurofibrillary tangles with calcification (DNTC) were investigated using Gallyas-Braak (GB) stain. Six cases neuropathologically diagnosed as DNTC were studied (two males and four females). The age at death ranged from 56 to 73 years, with an average of 63.5+/-7.5 years. GFT were classified morphologically, and their immunoreactivites for tau and ubiquitin were examined. Glial cells with GFT were identified with astrocytes and oligodendrocytes by immunostain for glial fibrillary acidic protein and transferrin, respectively. A small number of coiled bodies detected within the oligodendrocytes in the white matter of the cerebrum were positive for tau and ubiquitin. Cell clusters of thorn-shaped astrocytes were detected in the subcortical and subpial regions where gliosis occurred. Thorn-shaped astrocytes were positive for tau, but negative for ubiquitin. A small number of tuft-shaped astrocytes detected prominently in the temporal cortex and amygdala with numerous neurofibrillary tangles were positive for tau and ubiquitin. All three types of GFT were detected, especially in the temporal and limbic lobes, which were the most severely affected sites in DNTC. Moreover, various-shaped neurofibrillary tangles, aggregated rods and some argyrophilic threads were differentiated from GFT. They were positive for GB, but not detected within the glial cells.

Two distinct subgroups of senile dementia of Alzheimer type: quantitative study of neurofibrillary tangles.

The heterogeneity of senile dementia of Alzheimer type (SDAT) has been suggested by some authors clinically and neuropathologically. The heterogeneity of SDAT was investigated based on quantification of NFT combining Braak and Braak's neuropathological staging and the density of NFT in various areas of the cerebral cortex. Brain tissues were examined from 16 autopsy cases with clinically late onset dementia (> age 65) and neuropathologically diagnosed dementia of Alzheimer type (DAT). Gallyas-Braak staining was used for the quantification of NFT. The density of NFT was examined in the precentral gyrus, middle temporal gyrus (T2), parahippocampal gyrus and the amygdaloid nucleus. The 16 cases studied were divided into two groups depending on the number of NFT in the cortex (cut-off score: 5/mm2): the AD-like group (NFT > or = 5/mm2) and the common group (NFT < 5/mm2). The density of NFT in the precentral gyrus (t(3.225) = -9.007, P = 0.002) and T2 (t(3.365) = -3.774, P = 0.027) in the AD-like group was significantly higher than those in the common group. However, no significant difference was observed in the parahippocampal gyrus between the two groups (t(14) = -0.318, NS). Moreover, there were no significant differences between the two groups as regards age at onset and the duration of the illness. The present study revealed the possible existence of two subgroups in SDAT having significantly different NFT densities in various areas of the cerebral cortex without any significant difference in their duration of illness. This classification has no relationship to Braak and Braak's staging, which depends only on the distribution of NFT, irrespective of their density. Arai et al. revealed that the NFT density in AD was significantly higher than in SDAT. We suggest that the neuropathological findings of the AD-like group in SDAT resemble those of presenile AD.