Atsuo Koto

Evidence for in vivo production of Humanin peptide, a neuroprotective factor against Alzheimer's disease-related insults

An unbiased functional screening with brain cDNA library from an Alzheimers disease (AD) brain identified a novel 24-residue peptide Humanin (HN), which suppresses AD-related neurotoxicity. As the 1567-base cDNA containing the open reading frame (ORF) of HN is 99% identical to mitochondrial 16S ribosomal RNA as well as registered human mRNA, it was elusive whether HN is produced in vivo. Here, we raised anti-HN antibody and found that long cDNAs containing the ORF of HN (HN-ORF) produced the HN peptide in mammalian cells, dependent on the presence of full-length HN-ORF. Immunoblot analysis detected a 3-kDa protein with HN immunoreactivity in the testis and the colon in 3-week-old mice and in the testis in 12-week-old mice. HN immunoreactivity was also detected in an AD brain, but little in normal brains. This study suggests that HN peptide could be produced in vivo, and would provide a novel insight into the pathophysiology of AD.

Cerebrovascular NADPH diaphorase-containing nerve fibers in the rat.

Recently, neuronal nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase has been elucidated to be the nitric oxide synthase (NOS) per se. In order to examine the existence and distribution of cerebrovascular nerve fibers containing these substances, NADPH-diaphorase histochemistry was applied to the cerebral blood vessels and the cranial ganglia known to innervate the cerebral vessels in the rat. Numerous nerve fibers with varicosities forming plexuses were observed in the circle of Willis and its branches. In addition, thick nerve bundles were seen to run along the wall of the internal ethmoidal artery. NADPH-diaphorase reaction was prominent in neurons of the sphenopalatine, otic and internal carotid ganglia. This study demonstrated, for the first time, the NADPH-diaphorase-containing nerve fibers in the cerebral vessels and ganglion cells in the parasympathetic and sensory ganglia known to innervate the cerebral vessels.

Pathologic findings of silent, small hyperintense foci in the basal ganglia and thalamus on MRI

Article abstract We analyzed the pathologic features of silent, small hyperintense foci in the basal ganglia and thalamus on MRI T2-weighted images (T2WI). Eight foci were histologically lacunar infarcts (LI), and 21 were dilated perivascular spaces (DPS). The foci with smooth margins were mostly DPS, whereas those with irregular margins were mostly LI (p = 0.018). Most putaminal foci were DPS, whereas most thalamic foci were LI (p = 0.001). The mean areas of LI and DPS overlapped below 19.6 mm2. The shape and site of hyperintense foci on T2WI are important for differentiating LI from DPS.

Camptocormia in Japanese patients with Parkinson's disease: a multicenter study.

The aim of this work was to investigate the prevalence of camptocormia and the clinical characteristics of patients with camptocormia in a large population of PD patients.

Detrimental Effects of Exogenous Glutamate on Spinal Cord Neurons During Brief Ischemia In Vivo

BACKGROUND Paraplegia remains a serious complication of thoracoabdominal aortic operations. However, despite growing in vitro evidence, it has been difficult to demonstrate glutamate neurotoxicity in vivo because of the reuptake activity that occurs. We hypothesized that glutamate can be toxic to the spinal cord under metabolic stress. METHODS Infrarenal aortic isolation was performed in New Zealand white rabbits. Group A animals (n = 7) then received a segmental infusion of glutamate (50 mmol/L) for 5 minutes. Group B animals (n = 7) received saline as a negative control. Group C animals (n = 6) were pretreated with a segmental infusion of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)-quinoxaline (4 mg/kg), a competitive alpha-amino-3-hydroxy-5-methylisoazole-4-propionic acid/kainate antagonist, followed by the segmental infusion of glutamate (30 mmol/L) for 4 minutes. Group D animals (n = 6) received the vehicle agents only, followed by the same glutamate infusion (30 mmol/L) as in group C as a control for group C. Neurologic status was assessed at 12, 24, and 48 hours after operation and scored using the Tarlov system. RESULTS Group A animals exhibited paraplegia or paraparesis with marked neuronal necrosis. Group B animals recovered fully. Group C animals had better neurologic function than group D animals (p = 0.0039). CONCLUSIONS Exogenous glutamate can have detrimental effects on spinal cord neurons during a brief period of ischemia. This model may be useful for the purpose of assaying a glutamate receptor antagonist in vivo.

Distribution and origins of cerebrovascular NADPH-diaphorase-containing nerve fibers in the rat

Neuronal NADPH-diaphorase has been proved to be nitric oxide synthase itself. In this study, we investigated distribution and origins of NADPH-diaphorase-containing nerve fibers in the cerebral vessels in the rat. Adult male Sprague-Dawley rats were divided into 4 groups. Nasociliary nerves were transected bilaterally in group 1. In group 2, intracranial branches of the sphenopalatine ganglion were transected bilaterally. In group 3, both of these structures were transected. The remaining animals were served as control (group 4). Two weeks after the above procedures, they were perfused with paraformaldehyde and glutaraldehyde. The pial arteries and superior cervical, trigeminal, internal carotid, otic and sphenopalatine ganglia were dissected. All specimens were processed for NADPH-diaphorase histochemistry. Numerous NADPH-diaphorase-containing nerve fibers with varicosities forming plexuses were observed in the circle of Willis and its branches. Relatively thick nerve bundles were noted in the anterior half of the circle of Willis. They are most abundant in the internal ethmoidal artery. Approximately 5% of such fibers in anterior half of the circle of Willis disappeared in group 1, 90% in group 2, and no fibers were seen to remain in group 3. NADPH-diaphorase reaction was positive in the neurons of sphenopalatine, otic trigeminal and internal carotid ganglia. Among these ganglia, the reaction was prominent in sphenopalatine, otic and internal carotid ganglia. In summary: (1) NADPH-diaphorase-containing nerve fibers distribute to the circle of Willis and its branches.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormal insulin secretion in amyotrophic lateral sclerosis

Abstract Plasma glucose and insulin (IRI) values during a 50-g oral glucose tolerance test were measured in patients with amyotrophic lateral sclerosis (ALS). Blood sugar curves were abnormal in 7 out of 18 patients in whom glucose tolerance tests were performed, and mean values of plasma glucose levels at 30, 60 and 120 min after glucose loading in the patients were significantly higher than those in control subjects. All cases with generalized muscle atrophy showed abnormal glucose tolerance except for 2 cases who showed borderline response, while in cases with localized atrophy, all but one borderline case demonstrated normal response. IRI response in patients with ALS was abnormal in 11 out of 14 cases, and the mean value at 30 min after glucose administration in the patients was significantly lower than that in control subjects; it was abnormal even in patients who did not have generalized muscle atrophy and showed normal glucose tolerance. The results suggest that abnormal glucose metabolism in ALS is primarily based on the impairment of pancreatic insulin secretion and that the addition of generalized muscle atrophy to the above factor results in apparently abnormal glucose utilization.

Creutzfeldt-Jakob disease: a case with extensive white matter degeneration and optic atrophy

SummaryA 52-year-old woman is described, whose clinical features were typical of Creutzfeldt-Jakob disease except for the presence of optic atrophy. Serial CT scans showed rapid development of brain atrophy early in the course. Postmortem examination revealed extensive degeneration of the cerebral and cerebellar white matter and of the optic nerves in addition to the classic findings of Creutzfeldt-Jakob disease. It is suggested that both the grey and white matter may undergo a severe destructive process early in the course of the disease, and the possibility is discussed that the white matter involvement is not a result of neuronal loss.ZusammenfassungDie klinischen Symptome einer 52 Jahre alten Frau mit typischer Creutzfeldt-Jakobscher Erkrankung und zusätzlich einer Atrophie des N. opticus werden beschrieben. Serienmäßige CT-Untersuchungen zeigten schon im Frünstadium der Erkrankung eine rasch fortschreitende Hirnatrophie. Autoptisch wurden neben den für die Creutzfeldt-Jakobsche Erkrankung klassischen Befunden eine ausgedehnte Degeneration der zerebralen und zerebellaren weißen Substanz sowie der Sehnerven gefunden. Diese Befunde deuten darauf hin, daß sowohl die graue als auch die weiße Substanz bereits im Frühstadium der Erkrankung schwer zerstört sein können und daß möglicherweise die Beteiligung der weißen Substanz nicht eine Folge neuronaler Schädigung ist.

Localized hypertrophic mononeuropathy involving the femoral nerve

Article abstract The authors report a case of localized hypertrophic mononeuropathy involving the femoral nerve in a 20-year-old woman referred because of progressive weakness and atrophy of the left thigh. MRI showed an enlarged femoral nerve and biopsies of fascicles displayed a concentric pattern of cells resembling an onion bulb. These cells were positive for epithelial membrane antigen immunostaining and had an incomplete basal lamina.

Early‐onset Dementia with Lewy Bodies

The clinical and neuropathological characteristics of an atypical form of dementia with Lewy bodies (DLB) are described. The proband experienced difficulties in her school performance at 13 years of age. Neurological examination revealed cognitive dysfunction, dysarthria, parkinsonism and myoclonus. By age 14 years, the symptoms had worsened markedly and the proband died at age 15 years. On neuropathological examination, the brain was severely atrophic. Numerous intracytoplasmic and intraneuritic Lewy bodies, as well as Lewy neurites, were present throughout the cerebral cortex and subcortical nuclei; vacuolar changes were seen in the upper layers of the neocortex and severe neuronal loss and gliosis were evident in the cerebral cortex and substantia nigra. Lewy bodies and Lewy neurites were strongly immunoreactive for α‐synuclein and ubiquitin. Lewy bodies were composed of filamentous and granular material and isolated filaments were decorated by α‐synuclein antibodies. Immunohistochemistry for tau or β‐amyloid yielded negative results. The etiology of this atypical form of DLB is unknown, since there was no family history and since sequencing of the exonic regions of α‐Synuclein, β‐Synuclein, Synphilin‐1, Parkin, Ubiquitin C‐terminal hydrolase L1 and Neurofilament‐M failed to reveal a pathogenic mutation. This study provides further evidence of the clinical and pathological heterogeneity of DLB.