No abstract

With the potential development of new disease-modifying Alzheimer’s Disease (AD) therapies, simple, widely available screening tests are needed to identify which individuals who are experiencing symptoms of cognitive or behavioral decline should be further evaluated for initiation of treatment. A blood-based test for AD would be a less invasive and less expensive screening tool than the currently approved CSF or amyloid β-PET diagnostic tests. We examined whether plasma phosphorylated tau at residue 181 (pTau181) could differentiate between clinically diagnosed or autopsy confirmed AD and Frontotemporal Lobar Degeneration (FTLD). Plasma pTau181 concentrations were increased by 3.5 fold in AD compared to controls and differentiated AD from both clinically diagnosed (Receiver Operating Characteristic Area Under the Curve [AUC]=0.894) and autopsy confirmed FTLD (AUC=0.878). Plasma pTau181 identified amyloid β-PET positive individuals regardless of clinical diagnosis and correlated with cortical tau protein deposition measured by 18 F-Flortaucipir PET. Plasma pTau181 may be useful to screen for tau pathology associated with AD.

The nuclear protein high-mobility group box 1 (HMGB-1) promotes inflammation in sepsis, but little is known about its role in brain ischemia-induced inflammation. We report that HMGB-1 and its receptors, receptor for advanced glycation end products (RAGE), Toll-like receptor 2 (TLR2), and TLR4, were expressed in normal brain and in cultured neurons, endothelia, and glial cells. During middle cerebral artery occlusion (MCAO), in mice, HMGB-1 immunostaining rapidly disappeared from all cells within the striatal ischemic core from 1 h after onset of occlusion. High-mobility group box 1 translocation from nucleus to cytoplasm was observed within the cortical periinfarct regions 2 h after ischemic reperfusion (2 h MCAO). High-mobility group box 1 predominantly translocated to the cytoplasm or disappeared in cells that colabeled with the neuronal marker NeuN. Furthermore, RAGE was robustly expressed in the periinfarct region after MCAO. Cellular release of HMGB-1 was detected by immunoblotting of cerebrospinal fluid as early as 2 h after ischemic reperfusion (2 h MCAO). High-mobility group box 1 released from neurons, in vitro, after glutamate excitotoxicity, maintained biologic activity and induced glial expression of tumor necrosis factor a (TNFa). Anti-HMGB-1 antibody suppressed TNFa upregulation in astrocytes exposed to conditioned media from glutamate-treated neurons. Moreover, TNFa and the cytokine intercellular adhesion molecule-1 increased in cultured glia and endothelial cells, respectively, after adding recombinant HMGB-1. In conclusion, HMGB-1 is released early after ischemic injury from neurons and may contribute to the initial stages of the inflammatory response.

Background: Rapid and easy clinical assessments for volumes of infarction and perfusion mis-

No abstract

Cerebrospinal fluid (CSF) p-tau181 (tau phosphorylated at threonine 181) is an established biomarker of Alzheimer's disease (AD), reflecting abnormal tau metabolism in the brain. Here we investigate the performance of CSF p-tau217 as a biomarker of AD in comparison to p-tau181. In the Swedish BioFINDER cohort (n = 194), p-tau217 shows stronger correlations with the tau positron emission tomography (PET) tracer [ 18 F]flortaucipir, and more accurately identifies individuals with abnormally increased [ 18 F]flortaucipir retention. Furthermore, longitudinal increases in p-tau217 are higher compared to p-tau181 and better correlate with [ 18 F]flortaucipir uptake. P-tau217 correlates better than p-tau181 with CSF and PET measures of neocortical amyloid-β burden and more accurately distinguishes AD dementia from non-AD neurodegenerative disorders. Higher correlations between p-tau217 and [ 18 F] flortaucipir are corroborated in an independent EXPEDITION3 trial cohort (n = 32). The main results are validated using a different p-tau217 immunoassay. These findings suggest that p-tau217 might be more useful than p-tau181 in the diagnostic work up of AD.

Background and Purpose-Studies suggest statins ameliorate aneurysmal subarachnoid hemorrhage (SAH)-induced cerebral vasospasm and ischemic complications. We tested safety and feasibility of simvastatin 80 mg/d for vasospasm prevention in SAH patients. Methods-Thirty-nine statin-naïve Fisher grade 3 SAH subjects were double-blind randomized to receive simvastatin 80 mg/d (nϭ19) or placebo (nϭ20), stratified by Hunt and Hess grade. Primary end points were death and drug morbidity. Results-Mortality was 3/20 in the placebo and 0/19 in the simvastatin group. Study drug was withdrawn in 1 subject in each treatment group for reversible liver enzyme or creatine phosphokinase elevation. MethodsThirty-nine adults (age Ͼ18) with Fisher grade 3 SAH were included. Subjects were eligible if their ruptured aneurysm(s) were secured and if study drug can be started within 96 hours of aneurysm rupture. Patients at high risk for early mortality (Hunt and Hess grade V, or intracranial pressure Ͼ30 cm H 2 O for Ͼ30 minutes) were excluded. Other exclusion criteria were abnormal baseline serum creatine phosphokinase (CPK), alanine aminotransferase (ALT), or aspartate aminotransferase (AST), prior statin use, and contraindication for statin use. The institutional review board approved this study (ClinicalTrials.gov Identifier: NCT00235963).After informed consent from patient or health-care proxy, subjects were double-blind randomized to receive placebo or simvastatin 80 mg/d (until discharge from neurointensive care unit, or a maximum of 21 days), stratified by Hunt and Hess scores (I-II versus III-IV) to ensure an even distribution of this important outcome predictor. Plasma CPK, ALT and AST were monitored every 7 days. Study drug was stopped on unexplained 3-fold elevation of CPK or ALT/AST on 2 consecutive measurements 24 hours apart.Primary end points of this study were death and incidence of drug morbidity defined as CK/AST/ALT elevation. Secondary outcomes included incidence of transcranial Doppler (TCD), angiographic or clinical vasospasm, vasospasm-related infarcts, clinical outcomes at discharge, and cardiac and infectious morbidities.Angiographic vasospasm was defined as focal or generalized reduction of cerebral arterial caliber on conventional cerebral angiogram confirmed by a neuroradiologist and a neurocritical care physician. TCD vasospasm was defined as any peak systolic middle cerebral artery velocity (PSV MCA ) Ͼ200 cm/s and a Lindegaard ratio of Ͼ3. Clinically, delayed ischemic neurological deficit (DIND) was defined as any 2 or more point fall in modified Glasgow Coma Scale or unaccountable new focal neurological deficit lasting Ն2 hours. Vasospasm-related ischemic infarct was defined as the development of a new lesion consistent with infarction on CT or MRI in the vascular territory of angiographic or TCD vasospasm.All patients received nimodipine and an anticonvulsant, were kept euthermic, euvolemic, and euglycemic, and had daily TCD monitoring per standardized protocols. Patients with abnormal TCD velocities or...

Code availabilityAll code for data cleaning and analysis associated with the current submission is available upon request to the corresponding author and is provided as part of the replication package.