Aki Nakanishi

Randomized double-blind placebo-controlled multicenter trial of Yokukansan for neuropsychiatric symptoms in Alzheimer's disease.

Yokukansan (YKS), a traditional herbal medicine, has been used to treat behavioral and psychological symptoms of dementia (BPSD). The present study is the first double‐blind, randomized, placebo‐controlled trial to determine the efficacy and safety of YKS for the treatment of BPSD in Alzheimers disease (AD).

Protein Disulfide Isomerase P5-Immunopositive Inclusions in Patients with Alzheimer's Disease

Amyloid plaques and neurofibrillary tangles (NFTs) are the major pathological characteristics of Alzheimers disease (AD). NFTs are composed of tubular filaments and paired helical filaments containing polymerized hyperphosphorylated tau protein. Another feature of AD is excessive generation of nitric oxide (NO). Protein disulfide isomerase (PDI) is a chaperon protein located in the endoplasmic reticulum (ER). It was recently reported that NO-induced S-nitrosylation of PDI inhibits its enzymatic activity, leading to the accumulation of polyubiquitinated proteins, and activates the unfolded protein response. In addition, we previously reported the presence of PDI-immunopositive NFTs in AD. Here, we found that protein disulfide isomerase P5 (P5), which is a member of the PDI protein family, was co-localized with tau in NFTs. To our knowledge, this is the first report of P5-immunopositive inclusion in AD. Furthermore, we showed that S-nitrosylated P5 was present and the expression level of P5 was decreased in AD brains compared with that of control brains. We also demonstrated that the knock-down of PDI or P5 by siRNA could affect the viability of SH-SY5Y cells under ER stress. Previously, the observation of S-nitrosylated PDI in AD was reported. NO may inhibit P5 by inducing S-nitrosylation in the same manner as PDI, which inhibits its enzymatic activity allowing protein misfolding to occur in AD. The accumulation of misfolded proteins induces ER stress and may cause apoptosis of neuronal cells through S-nitrosylation and down-regulation of PDI and P5 in AD.

Two cases of dementias with motor neuron disease evaluated by Pittsburgh compound B-positron emission tomography

We described the cases of two patients with dementia associated with motor neuron disease, the former with frontotemporal dementia (FTD) and the latter with Alzheimer’s disease (AD), studied by the Pittsburgh compound B-positron emission tomography (PIB-PET). In the FTD patient, the PIB-PET revealed no amyloid accumulation in the cortex, whilst in the AD patient showed amyloid accumulation mainly in the frontal, parietal and lateral temporal lobes, besides the posterior cingulate gyrus and the precuneus. Thus, PIB-PET might facilitate the discrimination of different proteinopathies that cause neurodegenerative diseases, as dementia associated with ALS.

Derlin-1-immunopositive inclusions in patients with Alzheimer's disease.

&NA; Amyloid plaques and neurofibrillary tangles are the major pathological hallmarks of Alzheimers disease. Neurofibrillary tangles are composed of filaments and paired helical filaments containing polymerized hyperphosphorylated tau protein. Derlin proteins are a family of proteins that are conserved in all eukaryotes, in which they function in endoplasmic reticulum‐associated degradation. Protein disulfide isomerase (PDI) is a member of the thioredoxin superfamily and is believed to accelerate the folding of disulfide‐bonded proteins in the luminal space of the endoplasmic reticulum. In this study, we found that derlin‐1 and PDI were colocalized in neurofibrillary tangles in the brain of patients with Alzheimers disease. Derlin‐1 and PDI may work as partners to avoid the accumulation of unfolded proteins in Alzheimers disease. Furthermore, we found that derlin‐1 was immunopositive for neurofibrillary tangles and upregulated in Alzheimers disease and that derlin‐1 may play an important role in endoplasmic reticulum‐associated degradation during the pathogenesis of Alzheimers disease. We hypothesize that derlin‐1 was upregulated to avoid the aggregation of unfolded proteins. Despite the upregulation of derlin‐1, the functions of chaperone proteins and Alzheimer tau protein were lost and these proteins were also accumulated. Finally, they were involved in neurofibrillary tangles. These results suggest that derlin‐1 may be associated with endoplasmic reticulum stress in neuronal cells in Alzheimers disease.

The Relationship Between Medial Temporal Lobe Atrophy and Cognitive Impairment in Patients With Dementia With Lewy Bodies

Background: The relationship between medial temporal lobe atrophy (MTA) and cognitive impairment in patients with dementia with Lewy bodies (DLB) remains unclear. We examined this relationship using voxel-based specific regional analysis system for Alzheimer disease (VSRAD) advance software, which allowed us to quantify the degree of MTA on images obtained from magnetic resonance imaging (MRI) scans. Methods: Thirty-seven patients diagnosed with DLB were recruited and scanned with a 1.5 Tesla MRI scanner. All MRI data were analyzed using VSRAD advance. The target volume of interest (VOI) included the entire region of the entorhinal cortex, hippocampus, and amygdala. The degree of MTA was obtained from the averaged positive z-score (Z score) on the target VOI, with higher scores indicating more severe MTA. Mini-Mental State Examination (MMSE) and the Revised Hasegawa Dementia Scale (HDS-R), which strengthened the measures of memory and language more than MMSE, were used to assess the presence of cognitive impairment. Results: A negative correlation was found between the Z score and MMSE total scores or the HDS-R total scores. A stepwise multiple regression analysis performed to adjust the covariate effects of sex, age, the onset age of the disease, duration of DLB, years of education, and donepezil treatment showed that the HDS-R total scores were independently associated with the Z score, whereas MMSE total scores were not. Conclusions: These results suggest that MTA is related to cognitive impairment in patients with DLB, particularly the regions of orientation, immediate and delayed recall, and word fluency.

PiB negative dementia: Pitfall of clinical diagnosis of Alzheimer's disease

Background: The relative utility of the positron emission tomography (PET) radioligand N-methyl-11C-2-(4-methylaminophenyl)-6-hydroxybenzothiazole (also known as 11C-6-OH-BTA-1 or 11C-PIB) and 18F-fluorodeoxyglucose (18F-FDG) in distinguishing Alzheimer’s Disease (AD), mild cognitive impairment (MCI) and controls (CTR) is not fully established. Methods: Patients with mild AD (n 1⁄4 18), MCI (n 1⁄4 24) and CTR subjects (n 1⁄4 18) were studied. A diagnostic evaluation, neuropsychological tests, 11C-PIB PET, 18F-FDG PET, and structural MRI were done. For 11C-PIB, region of interest (ROI) binding potentials (BPND) from the Logan graphical method were obtained, using cerebellar reference. For 18F-FDG, regional cerebral metabolic rate for glucose (rCMRGlu) was obtained using an arterial input function. Results: The three subject groups (n 1⁄4 59) differed in 11C-PIB BPND in prefrontal cortex (p < .001), cingulate (p < .001), parietal cortex (p < .001), precuneus (p < .001) and parahippocampal gyrus (p < .004), but not hippocampus. These differences occurred in the AD-CTR and AD-MCI comparisons, with no significant differences between MCI and CTR. For 18F-FDG (n 1⁄4 51), rCMRGlu differed across the three groups in the precuneus (p 1⁄4 0.004) and parietal cortex (p 1⁄4 0.02). These differences occurred in the AD-CTR and AD-MCI comparisons, with no significant differences between MCI and CTR. Mean 11C-PIB BPND was higher in AD compared to CTR, and MCI compared to CTR. Mean 18F-FDG rCMRGlu did not differ among the groups. 11C-PIB BPND showed strong inverse correlations with cognitive test scores in prefrontal, cingulate, parietal and precuneus, but not hippocampus. 18F-FDG rCMRGlu showed less robust positive correlations with cognitive test scores, primarily in parietal cortex and precuneus. For each ROI, when both 11C-PIB BPND and 18F-FDG rCMRGlu were entered into logistic regression models, 11C-PIB BPND significantly differed between AD and CTR in prefrontal, cingulate, parietal and parahippocampal gyrus, and between AD and MCI in prefrontal, cingulate, parietal and precuneus. 18F-FDG rCMRGlu was not significant in these analyses. Conclusions: When evaluated simultaneously, 11C-PIB BPND but not 18F-FDG rCMRGlu had group discriminating ability. The ability of 11C-PIB PET to distinguish AD, MCI and CTR underlines its potential use in differential diagnosis, and patient selection and monitoring in treatment trials.