Reduction rate of body mass index predicts prognosis for survival in amyotrophic lateral sclerosis: a multicenter study in Japan.

Malnutrition in the early stage has been reported as an independent predictor of survival in amyotrophic lateral sclerosis (ALS). We analyzed retrospectively the effect of variation of body mass index (BMI) on survival in ALS patients. In total, 77 consecutive ALS patients were enrolled from nine hospitals in Japan. Reduction rate of BMI was calculated from BMI before the disease onset and at the time of the first visit to each hospital. We analyzed the correlation between BMI reduction rate and total disease duration. Results showed that the median BMI reduction rate was 2.5 per year (interquartile range 1.3-3.8). The BMI reduction rate was significantly correlated with survival length (p <0.0001). There was also a significant difference in survival between ALS patients with a BMI reduction rate ≥ and < 2.5 (Kaplan-Meier survival analysis and the log-rank test, p < 0.0001; hazard ratio by the Cox model, 2.9816). In conclusion, faster reduction of BMI at the initial stage before the first visit to hospital predicts shorter survival length also in Japanese ALS patients.

Creutzfeldt-Jakob disease with the M232R mutation in the prion protein gene in two cases showing different disease courses: a clinicopathological study.

We report two autopsy cases of Creutzfeldt-Jakob disease (CJD) with the M232R mutation of the prion protein (PrP) gene that exhibited different clinicopathological features (age at death, 64/54 years; disease duration, 13/26 months). Both cases showed myoclonus, hyperintensity on diffusion-weighted MRI, and increased 14-3-3 protein in the cerebrospinal fluid. The initial sign in each case was memory disturbance and abnormal pharyngeal sensation, respectively. In the first case, the disease progressed rapidly with akinetic mutism developing 6 months after onset, while it occurred 23 months after onset in the second case. Pathologically, both cases had severe neuronal loss with gliosis and spongiform change in the cerebral cortex, basal ganglia, and cerebellum. PrP deposition was the diffuse synaptic type in the first case, but the second case had both diffuse synaptic and perivacuolar types. PrP(sc) immunoblotting revealed a type 1 band pattern in the first case, but both types 1 and 2 in the second case. Based on these findings, together with the results in previous CJD cases with M232R, we noted the possibility that the presence of type 2 PrP(sc) may be associated with both morphological features of PrP deposition and slow disease progression in this genetic prion disease.

Increased expression and activation of cytosolic phospholipase A2 in the spinal cord of patients with sporadic amyotrophic lateral sclerosis.

Compelling evidence identifies a link between cytotoxic effects of cytosolic phospholipase A2 (cPLA2) activity and neuron death in cell cultures. cPLA2 catalyzes the hydrolysis of membrane phospholipids to produce and release arachidonate, leading to plasma membrane injury, inflammatory response and subsequent cell death. To assess a role for cPLA2 in the pathomechanism of amyotrophic lateral sclerosis (ALS), we performed immunohistochemical, immunoblot, and densitometric analyses of cPLA2 and its active form phosphorylated at S505 (p-cPLA2) on spinal cords obtained at autopsy from ten sporadic ALS patients and ten age-matched controls. On sections, immunoreactivities for cPLA2 and p-cPLA2 were distinct and localized in almost all of the motor neurons, reactive astrocytes, and activated microglia in the ALS cases, while immunoreactivities were only weak or not at all observed in neurons and glia in the control cases. On immunoblots, both the cPLA2/ß-actin density ratio and the p-cPLA2/cPLA2 density ratio were significantly increased in the ALS group compared to the control group. There was no significant link between the densitometric data and the clinical phenotypes, age at death or disease duration of the ALS patients. These results provide in vivo evidence for increased expression and activation of cPLA2 in motor neurons, reactive astrocytes, and activated microglia in ALS, suggesting occurrence of arachidonate cascade-induced motor neuron death via cell-autonomous and/or non-cell-autonomous mechanisms.

Persistent cleavage and nuclear translocation of apoptosis-inducing factor in motor neurons in the spinal cord of sporadic amyotrophic lateral sclerosis patients.

Mounting evidence suggests that glutamate excitotoxicity induces both enzymatic cleavage and nuclear translocation of apoptosis-inducing factor (AIF), which is involved in apoptosis-like programed cell death characterized by nuclear condensation without appearance of apoptotic bodies. Given the lack of apoptotic bodies in motor neurons in the spinal cord of patients with amyotrophic lateral sclerosis (ALS), the aim of the present study was to determine the role for AIF in this disease. We investigated the expression of AIF in spinal cords obtained at autopsy from ten sporadic ALS patients and ten age-matched, control subjects, using morphological and quantitative techniques. Immunohistochemical analysis showed that AIF immunoreactivity was localized in the nucleus as well as the cytoplasm of a subset of affected motor neurons and reactive astrocytes in the ALS cases, while it was restricted to the cytoplasm of these cells in the control cases. Immunoblot analysis disclosed immunoreactivity for cleaved AIF in both cytoplasmic and nuclear protein extracts at a 57-kDa mobility. Densitometric analysis revealed significant increases in the cytoplasmic cleaved AIF/cytoplasmic ß-actin ratio and the nuclear cleaved AIF/nuclear histone H1 ratio in the ALS group compared with the control group. There was no significant link between the cytoplasmic and nuclear cleaved AIF levels in the ALS spinal cords and the clinical features such as phenotypes, age at death, and disease duration. Our results provide evidence for persistent cleavage and nuclear translocation of AIF in ALS spinal cord, suggesting implications for the AIF-mediated motor neuron death in this disease.

Activation of signal transducer and activator of transcription-3 in the spinal cord of sporadic amyotrophic lateral sclerosis patients.

BACKGROUND: Neuroinflammation has been implicated in the pathomechanism of amyotrophic lateral sclerosis (ALS). It is known that signal transducer and activator of transcription-3 (STAT3) is a proinflammatory transcription factor. However, it remains to be determined whether STAT3 is involved in ALS. OBJECTIVE: To test the hypothesis that STAT3 may be upregulated, activated, or both in the spinal cord of ALS patients. METHODS: We performed immunohistochemical, immunoblot and densitometric analyses of total STAT3 (t-STAT3) or phosphorylated active form of STAT3 (p-STAT3) in spinal cords obtained at autopsy from 10 sporadic ALS patients and 10 age-matched control subjects. RESULTS: On sections, p-STAT3 immunoreactivity was localized in the nucleus as well as the cytoplasm of almost all activated microglia in the ALS cases, while it was detectable in a few resting microglia in the control cases. On blots, densitometric p-STAT3 levels in nuclear protein extracts significantly increased in the ALS group compared with the control group, although there was no significant difference in densitometric t-STAT3 levels in cytosolic protein extracts between the two groups. Additionally, there was no significant relationship between the nuclear p-STAT3 levels in the ALS cases and the clinical phenotypes, age at death, or disease duration. CONCLUSION: The present results suggest that persistent activation and nuclear translocation but not upregulation of STAT3 occurs in ALS spinal cord microglia, which may regulate inflammatory activity.

Coexistence of Creutzfeldt-Jakob disease, Lewy body disease, and Alzheimer's disease pathology: an autopsy case showing typical clinical features of Creutzfeldt-Jakob disease.

We report here an autopsy case of sporadic Creutzfeldt-Jakob disease (CJD) without hereditary burden and with a clinical course typical of sporadic CJD. A 77-year old man developed memory disturbance, followed by gait disturbance and myoclonus. He died of bronchopneumonia 5 months after the disease onset. Post-mortem examination revealed neuronal loss, astrocytosis, and patchy spongiosis in the cerebral cortex and lenticular nuclei. Synaptic-type deposits of prion protein were present in the cerebral cortex. Additionally, Lewy bodies were observed in the cerebral cortex and substantia nigra. Furthermore, senile plaques compatible with definite Alzheimer's disease according to Consortium to Establish a Registry for Alzheimer's disease criteria and neurofibrillary changes of the limbic system consistent with Braak stage IV were found. Based on a review of the published literature, this autopsy case is very rare, and we suppose that the incidence of CJD accompanied by Lewy body disease and Alzheimer's disease is very low.

Two different clinical phenotypes of Creutzfeldt-Jakob disease with a M232R substitution.

OBJECTIVE: To describe the clinical features of Creutzfeldt-Jakob disease with a substitution of arginine for methionine (M232R substitution) at codon 232 (CJD232) of the prion protein gene (PRNP). PATIENTS AND METHODS: We evaluated the clinical and laboratory features of 20 CJD232 patients: age of onset, initial symptoms, duration until becoming akinetic and mute, duration until occurrence of periodic sharp and wave complexes on EEG (PSWC), MRI findings, and the presence of CSF 14-3-3 protein. Immunohistochemically, prion protein (PrP) deposition was studied. RESULTS: None of the patients had a family history of CJD. We recognized two clinical phenotypes: a rapidly progressive type (rapidtype) and a slowly progressive type (slow-type). Out of 20 patients, 15 became akinetic and mute, demonstrated myoclonus, and showed PSWC within a mean duration of 3.1, 2.4, and 2.8 months, respectively (rapid-type). Five showed slowly progressive clinical courses (slow-type). Five became akinetic and mute and four demonstrated myoclonus within a mean duration of 20.6 and 15.3 months, respectively, which were significantly longer than those in the rapid-type. Only one demonstrated PSWC 13 months after the onset. Diffuse synaptic-type deposition was demonstrated in four rapidtype patients, and perivacuolar and diffuse synaptic-type deposition in two, and diffuse synaptic-type deposition in one slow-type patient. Three of 50 suspected but non-CJD patients had the M232R substitution. CONCLUSIONS: Patients with CJD232 had no family history like patients with sCJD, and showed two different clinical phenotypes in spite of having the same PRNP genotype. More studies are needed to determine whether M232R substitution causes the disease and influences the disease progression.

Protein-bound crotonaldehyde accumulates in the spinal cord of superoxide dismutase-1 mutation-associated familial amyotrophic lateral sclerosis and its transgenic mouse model.

Growing evidence documents oxidative stress involvement in ALS. We previously demonstrated accumulation of a protein-bound form of the highly toxic lipid peroxidation product crotonaldehyde (CRA) in the spinal cord of sporadic ALS patients. In the present study, to the determine the role for CRA in the disease processes of superoxide dismutase-1 (SOD1) mutation-associated familial ALS (FALS), we performed immunohistochemical and semi-quantitative cell count analyses of protein-bound CRA (P-CRA) in the spinal cord of SOD1-mutated FALS and its transgenic mouse model. Immunohistochemical analysis revealed increased P-CRA immunoreactivity in the spinal cord of the FALS patients and the transgenic mice compared to their respective controls. In the FALS patients, P-CRA immunoreactivity was localized in almost all of the chromatolytic motor neurons, neurofilamentous conglomerates, spheroids, cordlike swollen axons, reactive astrocytes and microglia, and the surrounding neuropil in the affected areas represented by the anterior horns. In the transgenic mice, P-CRA immunoreactivity was localized in only a few ventral horn glia in the presymptomatic stage, in almost all of the vacuolated motor neurons and cordlike swollen axons and some of the ventral horn reactive astrocytes and microglia in the onset stage, and in many of the ventral horn reactive astrocytes and microglia in the advanced stage. Cell count analysis on mouse spinal cord sections disclosed a statistically significant increase in the density of P-CRA-immunoreactive glia in the ventral horns of the young to old G93A mice compared to the age-matched control mice. The present results indicate that enhanced CRA formation occurs in motor neurons and reactive glia in the spinal cord of SOD1-mutated FALS and its transgenic mouse model as well as sporadic ALS, sug- gesting implications for CRA in the pathomechanism common to these forms of ALS.

Rapidly progressed acquired immunodeficiency syndrome dementia complex as an initial manifestation.

We report a patient with acquired immunodeficiency syndrome dementia complex (ADC) that presented human immunodeficiency virus infection as an initial manifestation. A 34-year-old man developed disturbance of consciousness and severe abulia over 3 months. The CD4 lymphocyte count was 7.9/microl, while human immunodeficiency virus RNA in blood amounted to 4.2 x 10(4) copies/ml. T2-weighted magnetic resonance imaging showed diffusely high signal intensity in the deep white matter of both cerebral hemispheres. On the 20th hospital day, the patient died of sepsis caused by methicillin-resistant Staphylococcus aureus. Autopsy findings in the brain included increased glial cells and multinucleated giant cells in cerebral white matter and subcortical gray matter. These features were compatible with ADC.

Oxidative stress and metal content in blood and cerebrospinal fluid of amyotrophic lateral sclerosis patients with and without a Cu, Zn-superoxide dismutase mutation.

Hydroxyl radical, ascorbate free radical, superoxide dismutase (SOD) activities, Cu,Zn-SOD protein, Mn-SOD protein, 8-hydroxy-2' -deoxyguanosine (8-OHdG) and metals were compared in red blood cells (RBC), plasma and/or cerebrospinal fluid (CSF) between patients with sporadic amyotrophic lateral sclerosis (SALS), familial ALS (FALS) showing the Leu126Ser mutation in the Cu, Zn-SOD gene and controls. In patients with FALS or SALS, concentrations of hydroxyl radical in blood and ascorbate free radical and 8-OHdG in CSF were higher than control group values, while SOD activities in RBC and CSF were lower. In contrast, Cu, Zn-SOD protein concentrations in RBC were low only in FALS patients. Concentrations of Cu in CSF of SALS patients were higher than in controls. Thus, the pathogenesis of increased oxidative stress differs between SALS patients and FALS patients with a mutant Leu126Ser SOD1 gene.

Influence of repetitive transcranial magnetic stimulation on disease severity and oxidative stress markers in the cerebrospinal fluid of patients with spinocerebellar degeneration.

Ataxia severity, cerebellar hemispheric blood flow (CHBF), ascorbate free radical (AFR), superoxide dismutase protein, superoxide scavenging activity, and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in cerebrospinal fluid (CSF) were compared before and after an 8-week course of repetitive transcranial magnetic stimulation (rTMS) in 20 patients with spinocerebellar degenerations (SCD). SCD patients showed higher AFR, 8-OHdG, and superoxide scavenging activity than 19 controls. In SCD patients, AFR and ataxia severity declined, and CHBF increased after rTMS. As the SCD patients showed negative correlations between ataxia severity and CHBF or superoxide scavenging activity, the therapeutic mechanism of rTMS may involve decreased oxidative stress and increased CHBF.

Selective colocalization of transglutaminase-like activity in ubiquitinated intranuclear inclusions of hereditary dentatorubral-pallidoluysian atrophy.

To investigate the role of transglutaminase (TG) in the pathophysiology of dentatorubral-pallidoluysian atrophy (DRPLA), the distributions of ubiquitin-positive neuronal intranuclear inclusions (Ub-NII) and TG activity were studied in three patients with DRPLA and four disease controls. In the cerebellar granule cells of DRPLA, 2.5-4.9% of neurons had Ub-NII, and 7.5-9.8% of them were TG positive. In the frontal cortex; however, the ratio of neurons with Ub-NII was relatively low compared with those in the cerebellar cortex, and no Ub-NII was TG positive. There was no distinct difference in the ratio of neurons with Ub-NII and their TG positivity between the cases with homozygous or heterozygous DRPLA patients. The selective and good colocalization of Ub-NII and TG in the cerebellar granule cells may reveal a role of TG in the neurodegenerative process in DRPLA.

Thyroid function in nurses: the influence of povidone-iodine hand washing and gargling.

The effect of povidone-iodine (PVP-I) hand washing and gargling on thyroid function was assessed. In 16 nurses using PVP-I products and 16 control subjects, serum inorganic iodine levels and thyroid functions were investigated. The status of PVP-I use was also surveyed in the nurses. Clinical symptoms considered to be attributable to thyroid dysfunctions were seen in none of the subjects, nor was a goiter observed in any of the subjects. In nurses, serum inorganic iodine levels were slightly increased as compared to those in the control subjects, although the difference was not significant. The iodine incorporated during working hours of nurses appears to be attributable to gargling rather than to hand washing. The long-term use of PVP-I for gargling should be avoided by (1) people with a high risk of developing thyroid dysfunction due to the excessive intake of iodine, (2) pregnant women and (3) breast-feeding mothers.