Survival and respiratory decline are not related to homozygous SMN2 deletions in ALS patients

The presence of the SMN2 deletion in 124 patients with ALS was investigated. Eleven patients had the homozygous deletion of SMN2 (8.8%) in comparison with 20 of 200 (10%) of the healthy control population. No significant differences in sex, age at onset, initial symptoms, form of inheritance, decline in ventilatory function, or survival time were found between patients with and without the deletion. The hypothesis that SMN2 is a prognostic factor in sporadic or familial ALS was not confirmed in this study.     

CT abnormalities and altered methotrexate clearance in children with CNS leukemia

Seventeen children with CNS leukemia treated with chemotherapy and 5 children treated with both cranial radiation (CRT) and chemotherapy were evaluated. Eighty-eight percent of patients treated with chemotherapy alone had CT abnormalities, and all treated with CRT and chemotherapy had abnormal CT. The severity of CT abnormality paralleled intraventricular methotrexate levels and clinical signs of leukoencephalopathy. Children who receive chemotherapy for CNS leukemia, even without cranial irradiation, are more likely to have leukoencephalopathy than children without CNS leukemia. Moreover, patients with CNS leukemia may have abnormalities of CSF clearance of intraventricularly administered drugs.     

Serum cytokine levels are altered in patients with West syndrome.

The objective of this study is to explore the neuroimmunomodulator effect of interleukin (IL)-2, tumor necrosis factor (TNF)-alpha and interferon (IFN)-alpha in West syndrome (WS). Twenty-three cases of WS (13 males and 10 females, aged 4-14 months old) who first visited and consisted from 10 cryptogenic and 13 symptomatic, were enrolled in this study. Double-antibody sandwich enzyme-linked immunosorbent assay was used to measure serum IL-2, TNF-alpha and IFN-alpha levels in 23 patients with WS and the data were compared to those of 15 healthy infants who were matched with regard to age and sex. Levels of all three cytokines were significantly higher in both cryptogenic and symptomatic WS groups than the control group. Serum IL-2 levels in symptomatic WS were significantly higher than that in cryptogenic WS. There was a positive correlation between IL-2 and TNF-alpha in both cryptogenic and symptomatic WS groups. The immune systems of patients with WS are in an activated state. An imbalance in cytokine levels may be involved in the immunopathology of WS.     

Interest of a computerized ALS database in the diagnosis and follow-up of patients with ALS

The aim of the study is to present a computerized database of the Neurology department of Limoges University Hospital and the main results obtained from data of 340 patients suffering from amyotrophic lateral sclerosis (ALS), diagnosed between 1984 and 1997. It is a user friendly and can be accessed by all neurologists at any level of computer knowledge. This database is modular (6 modules) and flexible according to need. The software used, Access 7, is an open relation database, which allows export of data to statistical or other compatible software. One of the reasons, which led to the elaboration of this database was to develop a means of collecting data in an analyzable manner for therapeutic trials. During these trials, a great number of data can be collected during each clinic visit for the evaluation of the degree of impairment, disability, and handicap. We present part of the data from the patients followed, some of whom were treated with riluzole, the current reference molecule for ALS.     

Survival in transgenic ALS mice does not vary with CNS glutathione peroxidase activity

OBJECTIVE: Transgenic mice that overexpress a human gene encoding mutant cytosolic superoxide dismutase (SOD1) develop a progressive motor neuron loss that resembles human ALS. Why mutant SOD1 initiates motor neuron death is unknown. One hypothesis proposes that the mutant molecule has enhanced peroxidase activity, reducing hydrogen peroxide (H2O2) to form toxic hydroxyl adducts on critical targets. To test this hypothesis, the authors generated transgenic ALS mice with altered levels of glutathione peroxidase (GSHPx), the major soluble enzyme that detoxifies H2O2. METHODS: SOD1(G93A) ALS mice were bred with mice bearing a murine GSHPx transgene that have a four-fold elevation in brain GSHPx levels and with mice having targeted inactivation of the GSHPx gene and reduced brain GSHPx activity. RESULTS: Survival was not prolonged in ALS mice with elevated brain GSHPx activity (p = 0.09). ALS mice with decreased GSHPx brain activity (20% of normal) showed no acceleration of the disease course (p = 0.89). The age at disease onset in the ALS mice was unaffected by brain GSHPx activity. CONCLUSION: The level of GSHPx activity in the CNS of transgenic ALS mice does not play a critical role in the development of motor neuron disease.     

Astrogliopathy and oligodendrogliopathy are early events in CNS demyelination

We examined the phenotypic composition of cells and the underlying mechanisms of demyelination following injection of lipopolysaccharide (LPS) into the corpus callosum of rats. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay showed fragmented DNA, which co‐localized with oligodendrocytes in areas of demyelination following intracerebral injection with LPS. Immunostaining showed the presence of caspase 3 in cells which expressed the oligodendrocyte markers, suggesting activation of the apoptotic pathway. Commensurate reduction in glial fibrillary acid protein (GFAP)+/ gap junction protein connexin43+ (Cx43) cells, was also seen in the corpus callosum prior to histochemical evidence of demyelination. Expression of mRNA for proinflammatory cytokines was maximal 3 day postinjection, at a time when the numbers of TUNEL positive cells in the corpus callosum were declining and the total number of CD68+ cells peaked at day 14 postinjection. Our studies suggest that death of oligodendrocytes is an early event in LPS model of demyelination. We believe that the innate immune model of oligodendrocyte death will be useful in the development of neuroprotective agents capable of rescuing oligodendrocytes from apoptosis. GLIA 2013;61:1261–1273     

Assessment of dysarthria and dysphagia in ALS patients

Swallowing and speech disorders are the dramatic consequences of bulbar and pseudo-bulbar syndrome in ALS. Evaluation is necessary to guide speech therapy and to measure the effects of treatment. This article revues the different examinations used to assess bulbar and pseudobulbar involvement in an ALS patient: oromotor assessment, evaluation of the functions with self assessment, perceptive and objective evaluation of speech disorders, fiberoptic endoscopic evaluation of dysphagia (FEES) and videofluoroscopy.     

Mitochondrial DNA deletion mutation levels are elevated in ALS brains

This study was performed to explore the potential role of mitochondrial DNA mutations in the neurodegenerative process in amyotrophic lateral sclerosis (ALS). Using a semi-quantitative assay, a common mitochondrial DNA deletion mutation (mt DNA4977) was assayed in brain tissue obtained from six sporadic ALS patients and compared to four controls. In each brain, levels of this mutation were measured in a brain region affected by neurodegeneration, the motor cortex (Brodmann area 4), and compared to the temporal cortex (Brodmann area 17). In the ALS but not control brains, levels of mt DNA4977 were an average of more than 30-fold (range 15-250) higher in Brodmann area 4. These results support and extend those of previous studies implying that mitochondria may participate in the neurodegenerative process in ALS.     

Increasing trend of ALS in France and elsewhere: are the changes real?

We analyzed 9,005 deaths from amyotrophic lateral sclerosis recorded in France between the years 1968 and 1982. The overall adjusted mortality rates were 1.45/100,000 for men and 0.90/100,000 for women. We found excess male mortality in every age group. Age-specific mortality rates increased with age until 65-74 years and then declined in the older population. There was no meaningful regional pattern. We found a substantial increase in ALS mortality over time: the adjusted rates (per 100,000) in the period 1968 to 1971 were 1.11 for men and 0.63 for women. In the period 1979 to 1982, the corresponding figures were 1.92 and 1.12. The increase was mainly due to persons over 55 years of age and affected mostly the women during the first part of the study (1968 to 1978). In the recent years, increase appeared similar in both sexes. The temporal trends are consistent across studies in different countries.     

Glycosaminoglycan levels and proteoglycan expression are altered in the hippocampus of patients with mesial temporal lobe epilepsy

Extracellular matrix proteoglycans (PGs) and glycosaminoglycans (GAGs) play a crucial role in cell differentiation and synaptogenesis by modulating neurite outgrowth. The chondroitin sulfate (CS)-rich PG, the receptor protein tyrosine phosphatase zeta/beta (RPTP zeta/beta), has been related to neural morphogenesis and axon guidance. Hippocampal sclerosis is the most frequent pathologic finding in patients with intractable mesial temporal lobe epilepsy (MTLE), which is associated with neuron loss, reactive gliosis, and mossy fiber sprouting. In the present study, we investigated the concentration of CS, heparan sulfate (HS) and hyaluronic acid (HA) in the hippocampus and temporal neocortex as well as RPTP zeta/beta expression in the hippocampus of patients with MTLE. Compared to autopsy control tissue, epileptic hippocampi showed a significantly increased concentration of CS (224%; p=0.0109) and HA (146%; p=0.039). HS was instead similar to control values. No differences were found in the concentration of CS, HS, or HA in the temporal neocortex of epileptic patients when compared to control values. In contrast, RPTP zeta/beta immunoreactivity was induced in astrocytes of the inner molecular layer of the dentate gyrus of the sclerotic hippocampus. Because matrix compounds have been associated with tissue injury and repair, the present findings suggest that changes in PGs and GAGs might be related to damage-induced gliosis and neuronal reorganization in the hippocampus of MTLE patients.