Masaaki Matsushita

Enhanced carbonyl stress in a subpopulation of schizophrenia.

CONTEXT Various factors are involved in the pathogenesis of schizophrenia. Accumulation of advanced glycation end products, including pentosidine, results from carbonyl stress, a state featuring an increase in reactive carbonyl compounds (RCOs) and their attendant protein modifications. Vitamin B(6) is known to detoxify RCOs, including advanced glycation end products. Glyoxalase I (GLO1) is one of the enzymes required for the cellular detoxification of RCOs. OBJECTIVES To examine whether plasma levels of pentosidine and serum vitamin B(6) are altered in patients with schizophrenia and to evaluate the functionality of GLO1 variations linked to concomitant carbonyl stress. DESIGN An observational biochemical and genetic analysis study. SETTING Multiple centers in Japan. PARTICIPANTS One hundred six individuals (45 schizophrenic patients and 61 control subjects) were recruited for biochemical measurements. Deep resequencing of GLO1 derived from peripheral blood or postmortem brain tissue was performed in 1761 patients with schizophrenia and 1921 control subjects. MAIN OUTCOME MEASURES Pentosidine and vitamin B(6) concentrations were determined by high-performance liquid chromatographic assay. Protein expression and enzymatic activity were quantified in red blood cells and lymphoblastoid cells using Western blot and spectrophotometric techniques. RESULTS We found that a subpopulation of individuals with schizophrenia exhibit high plasma pentosidine and low serum pyridoxal (vitamin B(6)) levels. We also detected genetic and functional alterations in GLO1. Marked reductions in enzymatic activity were associated with pentosidine accumulation and vitamin B(6) depletion, except in some healthy subjects. Most patients with schizophrenia who carried the genetic defects exhibited high pentosidine and low vitamin B(6) levels in contrast with control subjects with the genetic defects, suggesting the existence of compensatory mechanisms. CONCLUSIONS Our findings suggest that GLO1 deficits and carbonyl stress are linked to the development of a certain subtype of schizophrenia. Elevated plasma pentosidine and concomitant low vitamin B(6) levels could be the most cogent and easily measurable biomarkers in schizophrenia and should be helpful for classifying heterogeneous types of schizophrenia on the basis of their biological causes.

Differentiation of first-episode schizophrenia patients from healthy controls using ROI-based multiple structural brain variables

BACKGROUND Brain morphometric measures from magnetic resonance imaging (MRI) have not been used to discriminate between first-episode patients with schizophrenia and healthy subjects. METHODS Magnetic resonance images were acquired from 34 (17 males, 17 females) first-episode schizophrenia patients and 48 (24 males, 24 females) age- and parental socio-economic status-matched healthy subjects. Twenty-nine regions of interest (ROI) were measured on 1-mm-thick coronal slices from the prefrontal and central parts of the brain. Linear discriminant function analysis was conducted using standardized z scores of the volumes of each ROI. RESULTS Discriminant function analysis with cross-validation procedures revealed that brain anatomical variables correctly classified 75.6% of male subjects and 82.9% of female subjects, respectively. The results of the volumetric comparisons of each ROI between patients and controls were generally consistent with those of the previous literature. CONCLUSIONS To our knowledge, this study provides the first evidence of MRI-based successful classification between first-episode patients with schizophrenia and healthy controls. The potential of these methods for early detection of schizophrenia should be further explored.

Distribution of basal ganglia lesions in diffuse neurofibrillary tangles with calcification: a clinicopathological study of five autopsy cases

Abstract. We investigated five Japanese autopsy cases of diffuse neurofibrillary tangles with calcification (DNTC), both clinically and pathologically, and examined the degree and distribution of the basal ganglia lesions, especially in the amygdala, striatum, pallidum, and substantia nigra. The lesions in the amygdala, striatum, and pallidum were classified into three categories (mild, moderate, and severe). The lesions in the substantia nigra were qualitatively judged, compared with normal controls. Severe dementia was observed in four cases neuropathologically showing pronounced neuronal loss in the cerebral cortex, but one case without neuronal loss in the cerebral cortex showed mild memory disturbance. Extrapyramidal signs were evident in three cases. Obvious neuronal loss in the substantia nigra with the presence of Lewy bodies was noticed in four cases. Basal ganglia lesions in all five cases were uniform: the amygdala showed severe to moderate lesions, the caudate nucleus moderate to slight lesions, and the putamen and pallidum slight lesions to normal. Furthermore, the lesions in the amygdala were more prominent in the basolateral group than in the corticomedial group, inconsistent with those in the amygdala of Alzheimers disease. Moderate lesions were evident in the basolateral group of the amygdala in the case without neuronal loss in the cerebral cortex. In DNTC, the degree and distribution of the basal ganglia lesions, except for nigral lesions, were analogous to those found in Picks disease with Pick bodies. These clinicopathological findings may contribute to the elucidation of the clinicopathological hallmarks in this disorder.

Distribution of cerebral cortical lesions in diffuse neurofibrillary tangles with calcification: a clinicopathological study of four autopsy cases showing prominent parietal lobe involvement

We investigated clinicopathologically four Japanese autopsy cases of diffuse neurofibrillary tangles with calcification (DNTC), which has been believed to be characterized by temporal or temporofrontal circumscribed lobar atrophy, and examined the distribution of their cerebral cortical lesions using hemisphere specimens. The lesions were classified into three categories (slight, moderate, and severe). Severe lesions were present in the temporal lobes and insular gyri of all four cases, consistent with the studies reported to date. In contrast, severe lesions were encountered in the parietal lobe of case 1 and moderate lesions were found in the parietal lobes of cases 2–4. Furthermore, moderate lesions of the precentral gyrus were present in cases 2–4, and moderate lesions of the postcentral gyrus were encountered in all four cases. We postulate that the distribution of cerebral cortical lesions in DNTC is more widespread than previously assumed. Our data also indicate that the unusual clinical signs of DNTC reported by several Japanese researchers, including parietal signs such as apraxia and agnosia, are roughly consistent with the topographic distribution of cerebral cortical lesions in DNTC elucidated in this study.

Parkinson’s disease mimicking senile dementia of the Alzheimer type: a clinicopathological study of four autopsy cases

This report concerns four Japanese autopsy cases of Parkinson’s disease (PD) mimicking senile dementia of the Alzheimer type. Three patients with a clinical diagnosis of senile dementia of the Alzheimer type developed memory disturbance as the initial sign, and a patient with a clinical diagnosis of atypical senile dementia presented with hallucination and delusion as the initial sign. Dementia was evident in all four patients, and slight parkinsonism appeared in the middle to late stages of the disease in two patients. Macroscopical examination of the brain disclosed slight depigmentation of the substantia nigra and pro‐minent depigmentation of the locus ceruleus in all four cases. Histological examination of the four patients showed neuronal loss with astrocytosis and the appearance of Lewy bodies in the substantia nigra, locus ceruleus, and dorsal vagal nucleus. The nucleus basalis of Meynert was involved in three cases, in which this structure was examined. The total Lewy body scores of the four cases were 1 in three cases and 0 in the other, compatible with PD. Massive appearance of senile plaques, consistent with Braak stage C, was found in one case, and the slight appearance of senile plaques, consistent with Braak stage A, was evident in two cases. One case had no evidence of senile plaques. In all four cases, slight neurofibrillary changes were present in the limbic areas, compatible with Braak stages II to III. Based on these clinicopathological findings and a review of the literature, we concluded that PD simulating Alzheimer’s disease without overt parkinsonism rarely exists. Furthermore, we postulate that the clinical features of PD are more widespread than previously believed.

Identification of a male schizophrenic patient carrying a de novo balanced translocation, t(4; 13)(p16.1; q21.31)

Abstract  Herein is reported the case of a male patient with schizophrenia who displayed a de novo balanced translocation between the short arm of chromosome 4 and the long arm of chromosome 13, t(4; 13)(p16.1; q21.31). The 4p16.1 region is where the causative gene (WFS1) for Wolfram syndrome has been mapped. In Wolfram syndrome, approximately 60% of patients suffer from major mental illness. The other breakpoint, chromosome 13q21.31, is another region where previous linkage studies have repeatedly detected linkage to schizophrenia. The documentation of the present case could therefore provide a valuable resource for identifying disease susceptibility genes by localizing the breakpoints.

Alcoholic cerebellar degeneration: A clinicopathological study of six Japanese autopsy cases and proposed potential progression pattern in the cerebellar lesion

Alcoholic cerebellar degeneration (ACD) is one of the most common neurological complications in alcoholics. As far as we know, however, only four Japanese autopsy cases of ACD have been reported, and only limited clinicopathological data on this disease are now available in Japan. The aims of this study were: (i) to examine the clinicopathological correlation of six Japanese autopsy cases of ACD, including three asymptomatic cases; and (ii) to elucidate the pattern of progression of the cerebellar lesion in ACD. All six alcoholics were histopathologically diagnosed as having “pure” ACD without Wernicke’s encephalopathy. The characteristics of the topographical distribution of the cerebellar lesion were as follows. Symptomatic cases (cases 1–3) showed more severe and widespread change than asymptomatic cases (cases 4–6). Even in case 6, which had the mildest lesion, the anterior vermis developed a moderate change (Purkinje cell loss and narrowing of the molecular layer). In cases 4 and 5 with more severe and widespread lesions, the superior and posterior vermis and the adjacent regions of the superior hemisphere, including the anterior lobe and simple lobule, were involved. In all symptomatic cases, the anterior superior hemisphere had severe lesions involving the granular cell layer. In contrast to asymptomatic cases, all symptomatic cases also had severe to moderate lesions in the anterior inferior hemisphere. In cases 1 and 2 with the most severe lesions, the moderate to severe changes were distributed in the posterior and inferior portions of both the vermis and hemisphere. These findings suggest that in ACD, severe lesions successively develop: (i) in the anterior superior vermis; (ii) anterior superior hemisphere; (iii) anterior inferior hemisphere; and (iv) anterior inferior vermis. In addition, cerebellar symptoms may frequently occur if the anterior superior hemisphere and anterior inferior hemisphere, in addition to the anterior superior vermis, are involved.

Analysis of psychogeriatric patients in the psychiatric emergency system

Background:  To date, there have been few studies about elderly psychiatric patients using psychiatric emergency services. In the present study, we analyze data from the Tokyo metropolitan psychiatric emergency system and the Tokyo Metropolitan Matsuzawa Hospital to examine the clinical features and social factors of elderly psychiatric patients hospitalized in psychiatric emergency units.

Early diagnosis of Alzheimer's type dementia with special reference to the clinicopathology of mild cognitive impairment

A considerable number of patients with Alzheimer‐type pathology begin with various types of psychiatric symptoms. In discussing mild cognitive impairment (MCI) and Alzheimer‐type dementia (ATD), psychiatric symptoms other than memory impairment must be considered. There is no obvious neuropathological boundary that distinguishes dementia from non‐dementia. In fact, although Alzheimer‐type pathology of MCI corresponds mainly to Braaks stage I or II, it has a wide range extending from Braaks stage I to V or VI. Difference in compensatory ability and environmental factors among individuals seem to affect the mental state more extensively than previously thought. MCI manifests most frequently in Braaks stage I and II (transentorhinal stage) and its Alzheimer‐type pathology is almost confined to the hippocampal region. Although the degree and distribution of senile plaques vary in each patient, the cerebral isocortex is virtually free from degeneration. There is discrepancy between the corresponding neuropathology and hypo‐metabolism in the posterior cingulated cortex (PCC), which is regarded as an important finding for the early diagnosis of ATD. In PCC, hypo‐metabolism seems to precede that morphological change especially in its premorbid or early period of ATD. The state of MCI could also occur in other diseases causing dementia, among which tangle‐only dementia is particularly notable. The characteristic of tangle‐only dementia is the gradually progressive, persistent pathological memory impairment with relative preservation of personality and cognitive function. These characteristics meet the criteria for MCI. Thus, tangle‐only dementia should be taken into account in patients who exhibit MCI but do not progress to the development of dementia over a prolonged period.