Neuroanatomical basis of paroxysmal sympathetic hyperactivity: a diffusion tensor imaging analysis.

PRIMARY OBJECTIVE: Paroxysmal sympathetic hyperactivity (PSH) is observed in a sub-set of patients with moderate-to-severe traumatic brain injury (TBI). The neuroanatomical basis of PSH is poorly understood. It is hypothesized that PSH is linked to changes in connectivity within the central autonomic network. RESEARCH DESIGN: Retrospective analysis in a sub-set of patients from a multi-centre, prospective cohort study Methods and procedures: Adult patients who were <3 weeks after severe TBI were enrolled and screened for PSH using a standard definition. Patients underwent multimodal MRI, which included quantitative diffusion tensor imaging. MAIN OUTCOMES AND RESULTS: Principal component analysis (PCA) was used to resolve the set of tracts into components. Ability to predict PSH was evaluated via area under the receiver operating characteristic (AUROC) and tree-based classification analyses. Among 102 enrolled patients, 16 met criteria for PSH. The first principle component was significantly associated (p = 0.024, AUROC = 0.867) with PSH status even after controlling for age and admission GCS. In a classification tree analysis, age, GCS and decreased FA in the splenium of the corpus callosum and in the right posterior limb of the internal capsule discriminated PSH vs no PSH with an AUROC of 0.933. CONCLUSIONS: Disconnection involving the posterior corpus callosum and of the posterior limb of the internal capsule may play a role in the pathogenesis or expression of PSH.

Carbamoylation correlates of cyanate neuropathy and cyanide poisoning: relevance to the biomarkers of cassava cyanogenesis and motor system toxicity.

We sought to elucidate the protein carbamoylation patterns associated with cyanate neuropathy relative to cyanide poisoning. We hypothesized that under a diet deficient in sulfur amino acids (SAA), the carbamoylation pattern associated with cyanide poisoning is similar to that of cyanate neuropathy. Male rats (6-8 weeks old) were fed a diet with all amino acids (AAA) or 75%-deficiency in SAA and treated with 2.5 mg/kg/body weight (bw) NaCN, or 50 mg/kg/bw NaOCN, or 1 µl/g/bw saline, for up to 6 weeks. Albumin and spinal cord proteins were analyzed using liquid chromatography mass spectrometry (LC-MS/MS). Only NaOCN induced motor deficits with significant levels of carbamoylation. At Day 14, we found a diet-treatment interaction effect on albumin carbamoylation (p = 0.07). At Day 28, no effect was attributed to diet (p = 0.71). Mean number of NaCN-carbamoylated sites on albumin was 47.4% higher relative to vehicle (95% CI:16.7-86.4%). Only NaOCN carbamoylated spinal cord proteins, prominently, under SAA-restricted diet. Proteins targets included myelin basic and proteolipid proteins, neurofilament light and glial fibrillary acidic proteins, and 2', 3' cyclic-nucleotide 3'-phosphodiesterase. Under SAA deficiency, chronic but not acute cyanide toxicity may share biomarkers and pathogenetic similarities with cyanate neuropathy. Prevention of carbamoylation may protect against the neuropathic effects of cyanate.

Does the cycad genotoxin MAM implicated in Guam ALS-PDC induce disease-relevant changes in mouse brain that includes olfaction?

Western Pacific amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC), a prototypical neurodegenerative disease (tauopathy) affecting distinct genetic groups with common exposure to neurotoxic chemicals in cycad seed, has many features of Parkinson's and Alzheimer's diseases (AD), including early olfactory dysfunction. Guam ALS-PDC incidence correlates with cycad flour content of cycasin and its aglycone methylazoxymethanol (MAM), which produces persistent DNA damage (O(6)-methylguanine) in the brains of mice lacking O(6)-methylguanine methyltransferase (Mgmt(-/-)). We described in Mgmt(-/-)mice up to 7 days post-MAM treatment that brain DNA damage was linked to brain gene expression changes found in human neurological disease, cancer, and skin and hair development. This addendum reports 6 months post-MAM treatment- related brain transcriptional changes as well as elevated mitogen activated protein kinases and increased caspase-3 activity, both of which are involved in tau aggregation and neurofibrillary tangle formation typical of ALS-PDC and AD, plus transcriptional changes in olfactory receptors. Does cycasin act as a "slow (geno)toxin" in ALS-PDC?