Diagnostic Impact of Cerebrospinal Fluid Biomarkers in Atypical Dementias in Canada.

BACKGROUND: In Canada, standard dementia workup consists of clinical, neurological, and cognitive evaluation, as well as structural brain imaging. For atypical dementia presentations, additional FDG-PET brain imaging is recommended. Cerebrospinal fluid (CSF) biomarkers have recently been proposed as the gold standard for in vivo detection of Alzheimer's disease (AD) pathophysiology (NIA-AA research framework, 2018). As clinical implementation of CSF assessment is still limited in Canada, the present study assessed its impact on diagnostic accuracy in atypical neurodegenerative disorders in the clinical practice. METHODS: This retrospective clinical chart review included patients with cognitive complaints who underwent lumbar puncture (LP) in addition to the standard diagnostic workup. CSF analysis determined the presence of biological AD based on reduced amyloid-ß42-to-total-tau index (ATI) and increased phosphorylated-tau (p-tau) levels. CSF-based diagnoses were compared to standard workup and FDG-PET-based diagnoses. RESULTS: A total of 28 patients with atypical dementia presentations were included in the present study after evaluation for cognitive complaints at a specialized dementia clinic between November 2017 and July 2019. CSF analysis changed or better specified the initial clinical diagnosis in 43.0% of cases (alternative diagnosis revealed in 25% and excluded in 18%). In patients with additional FDG-PET imaging (n = 23), FDG-PET and CSF-based diagnosis did not correspond in 35% of patients, even though FDG-PET appeared to increase diagnostic accuracy compared to the initial clinical diagnosis. CONCLUSION: CSF biomarkers improved diagnostic accuracy in atypical cognitively-impaired patients beyond standard workup and FDG-PET imaging. These results support CSF analysis implementation for atypical dementias in Canada, in addition to the standard diagnostic workup.

nor-BNI Antagonism of Kappa Opioid Agonist-Induced Reinstatement of Ethanol-Seeking Behavior.

Recent work suggests that the dynorphin (DYN)/kappa opioid receptor (KOR) system may be a key mediator in the behavioral effects of alcohol. The objective of the present study was to examine the ability of the KOR antagonist norbinaltorphimine (nor-BNI) to attenuate relapse to ethanol seeking due to priming injections of the KOR agonist U50,488 at time points consistent with KOR selectivity. Male Wistar rats were trained to self-administer a 10% ethanol solution, and then responding was extinguished. Following extinction, rats were injected with U50,488 (0.1-10 mg/kg, i.p.) or saline and were tested for the reinstatement of ethanol seeking. Next, the ability of the nonselective opioid receptor antagonist naltrexone (0 or 3.0 mg/kg, s.c.) and nor-BNI (0 or 20.0 mg/kg, i.p.) to block U50,488-induced reinstatement was examined. Priming injections U50,488 reinstated responding on the previously ethanol-associated lever. Pretreatment with naltrexone reduced the reinstatement of ethanol-seeking behavior. nor-BNI also attenuated KOR agonist-induced reinstatement, but to a lesser extent than naltrexone, when injected 24 hours prior to injections of U50,488, a time point that is consistent with KOR selectivity. While these results suggest that activation of KORs is a key mechanism in the regulation of ethanol-seeking behavior, U50,488-induced reinstatement may not be fully selective for KORs.