Biomedical subjects
Publications and source records attributed to Mitsunori Morimatsu.
A 17-year-old boy without a significant past medical history presented with recurrent cluster-like headaches induced by meals for 3 years. Magnetic resonance images showed a pituitary tumor. Just after starting treatment with cabergoline, the headaches resolved completely and the patient has been absolutely free from such headache attacks for 2 years.
Apolipoprotein AI (apoAI), a major component of high-density lipoproteins, is one of the major amyloid fibril proteins and a minor constituent of the senile plaques observed in Alzheimer's disease. We examined colocalization of apoAI in various kinds of systemic amyloidosis in this study. Forty-three of 48 formalin-fixed paraffin-embedded heart specimens with various forms of systemic amyloidosis reacted immunohistochemically with anti-human apoAI antibody. ApoAI was also detected in water-extracted amyloid material by immunoblotting. In addition, we observed colocalization of apoAI and murine amyloid A (AA) amyloidosis in human apoAI transgenic mice. This is the first report of colocalization of apoAI with amyloid deposits in various forms of human systemic amyloidosis and murine AA amyloidosis in human apoAI transgenic mice. ApoAI may not always be a major component of amyloid fibrils, even when it is present in systemic amyloid deposits.
Pseudomigraine with pleocytosis (PMP) is an uncommon disease in Japan. The diagnostic criteria include at least one episode of transient neurological deficit accompanied or followed by migraine-like severe headache, cerebrospinal fluid (CSF) lymphocytosis, and normal neuroimaging. Both the etiology and the pathophysiology of PMP is not yet well defined. We report a 40-year-old man with a PMP-like syndrome. He came to our clinic because of severe throbbing headache and amnesia, and the examination showed CSF lymphocytosis of 23/mm3, a transient decrease of cerebral blood flow in the left thalamus. All the symptoms were completely resolved within 2 months.
Early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH) is an autosomal recessive neurodegenerative disorder characterized by early-onset ataxia, ocular motor apraxia, and hypoalbuminemia. Recently, the causative gene for EAOH, APTX, has been identified. Of the two splicing variants of APTX mRNA, the short and the long forms, long-form APTX mRNA was found to be the major isoform. Aprataxin is mainly located in the nucleus, and, furthermore, the first nuclear localization signal located near the amino terminus of the long-form aprataxin is essential for its nuclear localization. We found, based on the yeast two-hybrid and coimmunoprecipitation experiments, that the long-form but not the short-form aprataxin interacts with XRCC1 (x-ray repair cross-complementing group 1). Interestingly the amino terminus of the long-form aprataxin is homologous with polynucleotidekinase-3'-phosphatase, which has been demonstrated to be involved in base excision repair, a subtype of single-strand DNA break repair, through interaction with XRCC1, DNA polymerase beta, and DNA ligase III. These results strongly support the possibility that aprataxin and XRCC1 constitute a multiprotein complex and are involved in single-strand DNA break repair, and furthermore, that accumulation of unrepaired damaged DNA underlies the pathophysiological mechanisms of EAOH.
Among the diseases causing parkinsonism, drug-induced parkinsonism is important because physicians often use anti-dopaminergic drugs such as benzamides for gastrointestinal disorders. In 28 patients with drug-induced parkinsonism, 13 (47%) showed persistent parkinsonism even 6 months after the cessation of the causative drugs. This means anti-dopaminergic drugs may bring subclinical parkinsonism to the clinical level especially in the elderly. Progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and multiple system atrophy including striatonigral degeneration were recognized in 2003 as specific diseases by the National Health Insurance of Japan. The diagnostic criteria of PSP (the modification of NINDS-SPSP criteria) made by the study group of the Ministry of Health, Welfare and Labour (MHWL) of Japan has demonstrated that their sensitivity was 83% and specificity 97% in "probable PSP". Patients with CBD were surveyed among the main neurologic institutions in Japan using the provisional diagnostic criteria There were 151 patients with "probable CBD" and 13 with "definite CBD". Based on these data, the number of patients with PSP and CBD in 2001 was estimated as 6,400 (5.03 per 100,000) and 2,500 (1.93 per 100,000), respectively, in Japan. Neuroprotective drugs hold hope for the treatment of neurodegenerative diseases. Although many agents were reported to be neuroprotective for Parkinson's disease from in vitro studies, pramipexole, a dopamine agonist, is the only one with good clinical evidence based on neuroimaging. Other dopamine agonists as well as various nerve trophic factors may also have the same effects, though further confirmatory studies are necessary.
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Corticobasal degeneration (CBD) and atypical progressive supranuclear palsy (PSP) were reviewed with special reference to their symptomatology, laboratory examination and differential diagnosis. In our survey of the autopsy cases of CBD in Japan, only about 60% of the pathologically confirmed CBD cases were correctly diagnosed clinically, meaning that atypical (non-classical) clinical forms are common in CBD. Concerning the autopsy cases of PSP in Japan, 75% of the PSP cases had correct clinical diagnosis. In literatures, the clinically atypical CBD includes (1) frontotemporal dementia, also with primary progressive aphasia and frontal lobe dementia as subforms, (2) PSP-like form, and (3) others. The clinically atypical PSP comprises (1) pure akinesia, (2) pure easy falling syndrome (Yuasa), (3) no postural instability, (4) no gaze palsy, (5) asymmetric parkinsonism, (6) no or severe dementia, etc.. PSP with cortical manifestations such as primary progressive aphasia and CBD-like features were also reported. The atypical CBD and PSP probably reflect the distribution of tau pathology different from that in typical forms. Except for the report that phosphorylated tau is increased in CSF in CBD, but not in PSP (Urakami et al), no reliable laboratory data have been available on clinical differentiation between atypical CBD and PSP.
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We report a case of myopathic form of very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency with adolescent onset which presented with recurrent rhabdomyolysis and was diagnosed by immunostain of biopsy muscle. She was an 18-year-old woman who showed recurrent episodes of rhabdomyolysis after exercise since the age of 15. The diagnosis was made by the immunostain using anti-VLCAD antibody and the measurement of acyl-CoA dehydrogenase activity for the biopsy muscle. Her elder sister had also showed recurrent episodes of rhabdomyolysis at least two times. The analysis of genomic DNA on blood samples of the patient and her sister was performed and the same mutations were identified. Hence, these sister were revealed to have VLCAD deficiency. We should keep in mind this disorder for those presenting with recurrent rhabdomyolysis. In addition, as far as we know, this is the first report that a correct diagnosis was obtained by immunostain. Immunostain is probably a useful diagnostic procedure to identify an uncommon myopathy.
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In the central nervous system, stressful conditions can easily cause the oxidation of lipoprotein particles, followed by the oxidative modification of apolipoproteins such as apolipoprotein E (apoE) and the production of free radicals and aldehydes. We have confirmed that oxidized very-low-density lipoprotein (VLDL) inhibits the proliferation, viability and differentiation of neuronal PC12 cells leading to cell death. The cells internalized intact apoE, but did not internalize oxidized apoE. The phosphorylation of stathmin and various mitogen-activated protein (MAP) kinases including extracellular signal-regulated protein kinase (ERK), p38, and c-Jun N-terminal kinase (JNK) was examined in PC12 cells exposed to native and oxidized VLDL, H(2)O(2) (which generates free radicals), and 4-hydroxy-2-nonenal (HNE) (an aldehyde). Oxidized VLDL and H(2)O(2) reduced stathmin phosphorylation while HNE increased it, suggesting that oxidized VLDL and H(2)O(2) stimulated similar signal transduction pathways. Based on the results, free radicals, but not aldehydes may play a major role in the neuronal cell death induced by lipoprotein oxidation. Furthermore, the phosphorylation status of MAP kinases indicated that the activation of the JNK cascade might be required for neuronal cell death.
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We conducted the survey of patients with CBD in 2001 for 29 neurological institutions in Japan which joined Research Group on Neurodenerative Diseases supported by Ministry of Health and Welfare. Provisional diagnostic criteria of CBD were as follows: "probable CBD" means a clinical category including (1) classical form, consisting of progressive limb-kinetic apraxia and akinetic rigidity, predominant on one side, associated with late dementia, (2) quasi-classical form, revealing other corticobasal signs, predominant on one side, associated with late dementia, and (3) non-classical from, showing early aphasia, dementia, behavior disorder, etc., followed by lateralized limb-kinetic apraxia and akinetic rigidity. "Possible CBD" was not made. "Definite CBD" is pathologically confirmed CBD. There were 151 patients with "probable CBD", comprising 121 patients with classical form, 17 with quasi-classical form and 13 with non-classical from, while patients with "definite CBD" were 13. The number of patients with progressive supranuclear palsy (PSP) was also examined. The ratio of the number of patients CBD/PSP was 1/2.6 in clinical cases and 1/2.5 in autopsy cases. Nakashima et al. performed population survey of PSP patients in Yonago city in 1999, demonstrating prevalence of PSP 4.36/100,000. Considering this rate, the prevalence of CBD is assumed as 1.7 and the presumed number of PSP and CBD patients in 1999 in Japan could be 5,500 and 2,100, respectively.