Clinical EEG slowing correlates with delirium severity and predicts poor clinical outcomes.

OBJECTIVE: To determine which findings on routine clinical EEGs correlate with delirium severity across various presentations and to determine whether EEG findings independently predict important clinical outcomes. METHODS: We prospectively studied a cohort of nonintubated inpatients undergoing EEG for evaluation of altered mental status. Patients were assessed for delirium within 1 hour of EEG with the 3-Minute Diagnostic Interview for Confusion Assessment Method (3D-CAM) and 3D-CAM severity score. EEGs were interpreted clinically by neurophysiologists, and reports were reviewed to identify features such as theta or delta slowing and triphasic waves. Generalized linear models were used to quantify associations among EEG findings, delirium, and clinical outcomes, including length of stay, Glasgow Outcome Scale scores, and mortality. RESULTS: We evaluated 200 patients (median age 60 years, IQR 48.5-72 years); 121 (60.5%) met delirium criteria. The EEG finding most strongly associated with delirium presence was a composite of generalized theta or delta slowing (odds ratio 10.3, 95% confidence interval 5.3-20.1). The prevalence of slowing correlated not only with overall delirium severity (R 2 = 0.907) but also with the severity of each feature assessed by CAM-based delirium algorithms. Slowing was common in delirium even with normal arousal. EEG slowing was associated with longer hospitalizations, worse functional outcomes, and increased mortality, even after adjustment for delirium presence or severity. CONCLUSIONS: Generalized slowing on routine clinical EEG strongly correlates with delirium and may be a valuable biomarker for delirium severity. In addition, generalized EEG slowing should trigger elevated concern for the prognosis of patients with altered mental status.

SIRT1 and NAD+ precursors: Therapeutic targets in multiple sclerosis a review.

Neurodegeneration is an important determinant of disability in multiple sclerosis (MS) but while currently approved treatments reduce inflammation, they have not been shown to reduce neurodegeneration. SIRT1, a NAD dependent protein deacetylase, has been implicated in the pathogenesis of neurodegeneration in neurological diseases including MS. We have studied the role of SIRT1 in experimental autoimmune encephalomyelitis (EAE) and found evidence for a neuroprotective role. In this review we summarize the most recent findings from the use of SIRT1 activators and SIRT1 overexpression in transgenic mice. These data support provide a rational for the use of SIRT1 activators in MS.

Mitochondrial transcription factor A regulation of mitochondrial degeneration in experimental diabetic neuropathy.

Oxidative stress-induced mitochondrial dysfunction and mitochondrial DNA (mtDNA) damage in peripheral neurons is considered to be important in the development of diabetic neuropathy. Mitochondrial transcription factor A (TFAM) wraps mtDNA and promotes mtDNA replication and transcription. We studied whether overexpression of TFAM reverses experimental peripheral diabetic neuropathy using TFAM transgenic mice (TFAM Tg) that express human TFAM (hTFAM). Levels of mouse mtDNA and the total TFAM (mouse TFAM + hTFAM) in the dorsal root ganglion (DRG) increased by approximately twofold in the TFAM Tg mice compared with control (WT) mice. WT and TFAM Tg mice were made diabetic by the administration of streptozotocin. Neuropathy end points were motor and sensory nerve conduction velocities, mechanical allodynia, thermal nociception, and intraepidermal nerve fiber density (IENFD). In the DRG neurons, mtDNA copy number and damage to mtDNA were quantified by qPCR, and TFAM levels were measured by Western blot. Mice with 16-wk duration of diabetes developed motor and sensory nerve conduction deficits, behavioral deficits, and intraepidermal nerve fiber loss. All of these changes were mostly prevented in diabetic TFAM Tg mice and were independent of changes in blood parameters. Mice with 16 wk of diabetes had a 40% decrease in mtDNA copy number compared with nondiabetic mice (P < 0.01). Importantly, the mtDNA copy number in diabetic TFAM Tg mice reached the same level as that of WT nondiabetic mice. In comparison, there was upregulation of mtDNA and TFAM in 6-wk diabetic mice, suggesting that TFAM activation could be a therapeutic strategy to treat peripheral neuropathy.