Shinobu Kawakatsu

Correlation of regional cerebral blood flow with performance on neuropsychological tests in schizophrenic patients

Regional cerebral blood flow (rCBF) was determined by the 133Xe inhalation technique (Headtome II: ring detection SPECT) in 53 DSM-III schizophrenic patients. The rCBF values were corrected by using end-tidal carbon dioxide concentration values (PECO2). After rCBF measurement, neuropsychological tests--Word Fluency Test, Maze Test and Wisconsin Card Sorting Test--were performed. There were significant correlations between frontal rCBF and scores on each neuropsychological test. In particular, a moderate correlations between the frontal rCBF and the performance on the Wisconsin Card Sorting Test was noted. It seems likely that decrease of rCBF in prefrontal regions at rest reflects a disturbance of frontal lobe function in schizophrenic patients.

Sequence analysis of presenilin-1 gene mutation in Japanese Alzheimer's disease patients

The mutations of presenilins (PSs) gene and their clinicopathological correlations to Alzheimers disease (AD) have lately attracted considerable attention. In this report we analyzed fifteen Japanese familial Alzheimers disease (FAD) including 12 early-onset FAD and 13 sporadic AD patients for the mutation of PS-1 gene by direct sequence analysis. We found the mutations, G384A, E280A in two FAD and H163R in one sporadic AD patient, and no N1411 or M239V mutation in PS-2 gene, and no mutation in exons 16 and 17 in amyloid precursor protein (APP) gene. Families in which we failed to find the mutation by this screening may have mutations elsewhere in PSs or in APP gene, or yet unidentified other AD loci may exist. This is the first report to find a sporadic AD patient having PS-1 mutation.

Effects of genetic defects in the CYP2C19 gene on the N-demethylation of imipramine, and clinical outcome of imipramine therapy

Abstract  The relationship between the genetic polymorphism of S‐mephenytoin 4′‐hydroxylation catalyzed by CYP2C19 and the N‐demethylation of imipramine was examined in 10 Japanese depressed patients. Five patients, who were poor metabolizers of S‐mephenytoin, were determined to be either homozygous for a mutation in exon 5 or heterozygous for mutations in exon 4 and exon 5 of the CYP2C19 gene. In contrast, five patients, who were extensive metabolizers, had no mutations. The demethylation index (the desipramine/imipramine ratio) was significantly lower in patients with genetic defects. Plasma levels of imipramine and 2‐hydroxyimipramine normalized by the daily dose (mg) per weight (kg) were significantly higher in patients with genetic defects. This suggests that the N‐demethylation of imipramine is impaired in patients with genetic defects in the CYP2C19 gene, and that genotype determination may be useful in preventing side effects induced by unexpectedly elevated levels of imipramine.

Possible association between delusional disorder, somatic type and reduced regional cerebral blood flow

1. A 78-year-old female with DDST and pain disorder was treated by clomipramine 20-100 mg/day. The hypochondriacal delusion was completely resolved, while the pains were partially resolved. 2. The SPECT using Xe-133 taken at the early stage of clomipramine treatment, when she still had hypochondriacal delusions, showed markedly reduced rCBF in the temporal and parietal lobes, with predominance on the left hemisphere. Meanwhile, the SPECT taken after resolution of the hypochondriacal delusions showed a marked improvement in the reduced rCBF. 3. This report suggests that DDST has some association with reduced rCBF in the temporal and parietal lobes.

Acetylcholinesterase activities and monoamine metabolite levels in the cerebrospinal fluid of patients with alzheimer's disease

We measured cholinesterase (ChE) activity and monoamine metabolite levels in the cerebrospinal fluid (CSF) of 22 patients with early-onset Alzheimer type dementia (Alzheimers disease; AD) and of 32 controls. Acetylcholinesterase (AChE) activity, 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) levels were significantly lower in AD patients than in controls. However, there was an overlap in values of each CSF parameter. The measurement of various CSF parameters rather than one alone was more useful as a diagnostic aid. CSF ChE activities correlated with scores on the GBS rating scale, Hasegawa dementia scale, and Wechsler Adult Intelligence Scale, but the monoamine metabolite levels did not. Although cholinergic and monoaminergic deficits may coexist in AD patients, cholinergic deficits tend to be more often associated with cognitive decline than the monoaminergic deficits.

A human granin-like neuroendocrine peptide precursor (proSAAS) immunoreactivity in tau inclusions of Alzheimer's disease and parkinsonism-dementia complex on Guam

The deposition of tau inclusions is one of the neuropathological hallmarks in neurodegenerative disorders with dementia. We have reported that the N-terminal fragment of a human granin-like neuroendocrine peptide precursor (N-proSAAS) is accumulated in Pick bodies. However, it is unknown whether N-proSAAS is widely accumulated in tau inclusions in other tauopathies. Here, we performed an immunohistochemical examination using antibodies against both the N- and C-terminal sequence of proSAAS in the brains of patients with Alzheimers disease and parkinsonism-dementia complex on Guam. The antibody against N-proSAAS immunostained neurofibrillary tangles and neuritic plaques in both diseases, whereas the antibody against the C-terminal sequence of proSAAS did not. The results of the present study suggest that N-proSAAS or proSAAS-like molecules were trapped within the tau fibrils and accumulated in tau inclusions.

An N-terminal fragment of ProSAAS (a granin-like neuroendocrine peptide precursor) is associated with tau inclusions in Pick's disease.

The deposition of aggregated tau in cytoplasmic inclusions is one of the common neuropathological features in various dementing neurodegenerative disorders. At present, it remains unclear whether tau inclusions exert neurotoxicity or they are simply the consequence of neurodegeneration. In our approach for the analysis of the composition of tau inclusions, we detected the intense binding of anti-diacylglycerol kinase-zeta (DGK-zeta) antibodies to Pick bodies (PBs), which represent tau inclusions in Picks disease. The polyclonal antibodies were found to cross-react with a 21-kDa protein, but not with tau or ubiquitin, on Western blots of normal human brain extracts. Analysis of the 21-kDa protein by two-dimensional-gel electrophoresis and mass-spectrometry revealed that the protein is an N-terminal fragment of proSAAS (a human granin-like neuroendocrine peptide precursor). Our results suggest that sequestration of the N-terminal fragment of proSAAS in intracellular PBs may cause a functional disturbance of neurons in Picks disease.

Comparison of entorhinal cortex atrophy between early‐onset and late‐onset Alzheimer's disease using the VSRAD, a specific and sensitive voxel‐based morphometry

The most characteristic symptom of Alzheimers disease (AD) is episodic memory impairment, which is closely associated with atrophy of the entorhinal cortex. Meanwhile, atypical symptoms are more frequent in early‐onset AD than in late‐onset AD, suggesting that the former subtype has less atrophy in the entorhinal cortex. Therefore, we investigated whether the degree of atrophy in the entorhinal cortex is different between the two subtypes of AD using the voxel‐based specific regional analysis system for AD (VSRAD) targeting this region.

Application of the VSRAD, a Specific and Sensitive Voxel-Based Morphometry, to Comparison of Entorhinal Cortex Atrophy between Dementia with Lewy Bodies and Alzheimer’s Disease

Background: Previous studies using magnetic resonance imaging (MRI) showed that dementia with Lewy bodies (DLB) had less atrophy in some medial temporal structures than Alzheimer’s disease (AD). However, very few studies have focused on the entorhinal cortex, which is closely related to episodic memory. We compared the degree of entorhinal cortex atrophy between the two types of dementia using the voxel-based specific regional analysis system for AD (VSRAD) targeting this region. Methods: The subjects consisted of 60 patients with DLB and 210 patients with AD. The degree of entorhinal cortex atrophy was quantified by application of the VSRAD to MRI data, and a Z score >2 was defined as significant atrophy. Results: The DLB group had significantly lower Z scores than the AD group (mean ± SD: 2.25 ± 1.10 vs. 2.85 ± 1.33, p < 0.01). The analysis of covariance with possible confounding factors as covariates also showed that Z scores were significantly lower in the DLB group than in the AD group (p < 0.01). The proportion of patients with atrophy was significantly lower in the DLB group than in the AD group (53 vs. 72%, p < 0.01). Conclusions: The present study using the VSRAD suggests that DLB shows less atrophy in the entorhinal cortex than AD.

Successful treatment by paroxetine of delusional disorder, somatic type, accompanied by severe secondary depression.

The case of a 42-year-old woman with delusional disorder, somatic type (DDST), with infestation delusion and delusions of body odor and halitosis accompanied by severe secondary depression is presented. These somatic delusions and depressive symptoms responded favorably to treatment with paroxetine 10 to 30 mg/d. Hypoperfusion in the left temporal and parietal lobes observed when she had marked clinical symptoms was improved at near recovery. The present report suggests that paroxetine is effective and a reasonable drug for DDST with secondary depression. It also supports previous observations that DDST is associated with hypoperfusion in the temporal and parietal lobes.