Background:Alzheimer’s disease (AD) is currently incurable and a majority of investigational drugs have failed clinical trials. One explanation for this failure may be the invalidity of hypotheses focus-ing on amyloid to explain AD pathogenesis. Recently, hypotheses which are centered on synaptic and met-abolic dysfunction are increasingly implicated in AD.Objective:Evaluate AD hypotheses by comparing neurotransmitter and metabolite marker concentrations in normal versus AD CSF.Methods:Meta-analysis allows for statistical comparison of pooled, existing cerebrospinal fluid (CSF) marker data extracted from multiple publications, to obtain a more reliable estimate of concentrations. This method also provides a unique opportunity to rapidly validate AD hypotheses using the resulting CSF con-centration data. Hubmed, Pubmed and Google Scholar were comprehensively searched for published Eng-lish articles, without date restrictions, for the keywords “AD”, “CSF”, and “human” plus markers selected for synaptic and metabolic pathways. Synaptic markers were acetylcholine, gamma-aminobutyric acid (GABA), glutamine, and glycine. Metabolic markers were glutathione, glucose, lactate, pyruvate, and 8 other amino acids. Only studies that measured markers in AD and controls (Ctl), provided means, standard er-rors/deviation, and subject numbers were included. Data were extracted by six authors and reviewed by two others for accuracy. Data were pooled using ratio of means (RoM of AD/Ctl) and random effects meta-analysis using Cochrane Collaboration’s Review Manager software.Results:Of the 435 identified publications, after exclusion and removal of duplicates, 35 articles were in-cluded comprising a total of 605 AD patients and 585 controls. The following markers of synaptic and met-abolic pathways were significantly changed in AD/controls: acetylcholine (RoM 0.36, 95% CI 0.24-0.53, p<0.00001), GABA (0.74, 0.58-0.94, p<0.01), pyruvate (0.48, 0.24-0.94, p=0.03), glutathione (1.11, 1.01-1.21, p=0.03), alanine (1.10, 0.98-1.23, p=0.09), and lower levels of significance for lactate (1.2, 1.00-1.47, p=0.05). Of note, CSF glucose and glutamate levels in AD were not significantly different than that of the controls.Conclusion:This study provides proof of concept for the use of meta-analysis validation of AD hypothe-ses, specifically via robust evidence for the cholinergic hypothesis of AD. Our data disagree with the other synaptic hypotheses of glutamate excitotoxicity and GABAergic resistance to neurodegeneration, given ob-served unchanged glutamate levels and decreased GABA levels. With regards to metabolic hypotheses, the data supported upregulation of anaerobic glycolysis, pentose phosphate pathway (glutathione), and anaple-rosis of the tricarboxylic acid cycle using glutamate. Future applications of meta-analysis indicate the pos-sibility of further in silico evaluation and generation of novel hypotheses in the AD field.
Introduction : In small vessel disease (SVD)‐related acute ischemic stroke (AIS), no specific acute treatment exists. We propose an acute treatment protocol for patients with fluctuating exam secondary to salvageable micropenumbra in high risk SVD‐related AIS. Methods : Inclusion criteria included acute SVD‐related stroke with NIHSS fluctuation ≥ 2 previously described as a sensitive indicator of neurological deterioration in SVD ischemic stroke. Patients with large vessel atheroma secondarily causing stroke were excluded. Treatment protocol consisted of albumin IV, eptifibatide IV, magnesium sulfate IV, cilostazol PO, normoglycemia, normothermia, aggressive fluid resuscitation, and targeted blood pressure parameters in a neurocritical care setting. Protocol was prospectively initiated in August 2020 at onset of exam fluctuation and continued until plateau NIHSS was reached. Retrospective data for subjects from January 2017 to July 2020 was collected for historical controls. Primary outcomes measures included safety and early efficacy end points. Efficacy was measured by change from maximum NIHSS to plateau NIHSS (NIHSS‐diff). Wilcoxon rank‐sum test was used to evaluate significant difference of NIHSS‐diff in both groups. Social Science Statistics was used for data analysis. Results : From January 2017 ‐ May 2021, out of 7,146 AIS patients, 30 met selection criteria. From August 2020 to May 2021, consecutive subjects received treatment protocol (n = 15, baseline NIHSS 4.93, 95% CI [3.3572, 6.5028]). They were compared with historical controls (n = 15, baseline NIHSS 5.87, 95% CI [2.9407, 8.7993]). There was no significant difference in baseline characteristics (p = 1; U = 112 at p<0.05; z‐score 0). In the SVD group, no subjects had adverse events leading to early termination. Early efficacy as suggested by NIHSS‐diff between groups was statistically significant (p = 0.00228; U = 38.5; z‐score 3.04864; 80% power at p<0.05). Conclusions : To our knowledge, this is the first systematic demonstration of safety and early efficacy of multimodal intervention for acute SVD‐related ischemic stroke. Larger randomized trials using concurrent controls are required to corroborate our findings.
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