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Background: The last few years have seen major advances in blood biomarkers for Alzheimer's Disease (AD) with the development of ultrasensitive immunoassays, promising to transform how we diagnose, prognose, and track progression of neurodegenerative dementias., Methods: We evaluated a panel of four novel ultrasensitive electrochemiluminescence (ECL) immunoassays against presumed CNS derived proteins of interest in AD in plasma [phosphorylated-Tau181 (pTau181), total Tau (tTau), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP)]. Two sets of banked plasma samples from the Massachusetts Alzheimer's Disease Research Center's longitudinal cohort study were examined: A longitudinal prognostic sample ( n = 85) consisting of individuals with mild cognitive impairment (MCI) and 4 years of follow-up and a cross-sectional sample ( n = 238) consisting of individuals with AD, other neurodegenerative diseases (OND), and normal cognition (CN)., Results: Participants with MCI who progressed to dementia due to probable AD during follow-up had higher baseline plasma concentrations of pTau181, NfL, and GFAP compared to non-progressors. The best prognostic discrimination was observed with pTau181 (AUC = 0.83, 1.7-fold increase) and GFAP (AUC = 0.83, 1.6-fold increase). Participants with autopsy- and/or biomarker verified AD had higher plasma levels of pTau181, tTau and GFAP compared to CN and OND, while NfL was elevated in AD and further increased in OND. The best diagnostic discrimination was observed with pTau181 (AD vs CN: AUC = 0.90, 2-fold increase; AD vs. OND: AUC = 0.84, 1.5-fold increase) but tTau, NfL, and GFAP also showed good discrimination between AD and CN (AUC = 0.81-0.85; 1.5-2.2 fold increase)., Conclusions: These new ultrasensitive ECL plasma assays for pTau181, tTau, NfL, and GFAP demonstrated diagnostic utility for detection of AD. Moreover, the absolute baseline plasma levels of pTau181 and GFAP reflect cognitive decline over the next 4 years, providing prognostic information that may have utility in both clinical practice and clinical trial populations., Competing Interests: PK, CC, GS, MS, and SA are named as co-inventors on a US patent application related to neurological biomarker assays that is jointly held by Massachusetts General Hospital and Meso Scale Diagnostics. KJ has served as paid consultant for Bayer, GE Healthcare, Janssen Alzheimer's Immunotherapy, Siemens Medical Solutions, Genzyme, Novartis, Biogen, Roche, ISIS Pharma, AZTherapy, GEHC, Lundberg, and Abbvie. He is a site coinvestigator for Eli Lilly/Avid, Pfizer, Janssen Immunotherapy, and Navidea. He has spoken at symposia sponsored by Janssen Alzheimer's Immunotherapy, and Pfizer. BD has received consulting fees from Acadia, Alector, Arkuda, Biogen, Denali, Eisai, Lilly, Merck, Novartis, Takeda, and Wave Lifesciences, royalties from Cambridge University Press, Elsevier, and Oxford University Press, and research grant support from NIH, Alzheimer's Association, and the Alzheimer's Drug Discovery Foundation. He has been advising for Merck, Wave LifeSciences, Arkuda, Axovant, and Alector. TG-I has received funding from NIH, MassCATS, and Cure Alzhimer's Fund, and served on the Eli Lilly DSMB. DB has received funding from NIA, NINDS, and NIMH, has obtained compensation for serving on the Editorial Board of Belvoir Communications; and is on the Advisory Board of the National Cell Repository for Alzheimer's Disease and the Risk Evaluation Education for Dementia (AGREED) study. BH has received funding from NIH, has served on an Advisory Board for Biogen, and he and/or his family has stock options in Novartis and Dewpoint. AA, PB, CC, GS, and MS are paid employees of Meso Scale Diagnostics, LLC. SA has received honoraria and/or travel expenses for lectures from Abbvie, Biogen, and Eisai, and has served on scientific advisory boards of Corte, has received consulting fees from Abbvie, Boyle Shaughnessy Law, Cognito Therapeutics, Eisai, EIP Pharma, M3 Biotech, Orthogonal Neuroscience, and Risen Pharmaceutical Technology Co., Ltd., and has received research grant support from NIH, Alzheimer's Association, Alzheimer's Drug Discovery Foundation, Challenger Foundation, John Sperling Foundation, Abbvie, Amylyx, Athira Pharma, Chromadex, EIP Pharma, Janssen Pharmaceuticals, Novartis, SEER Biosciences, and vTv Therapeutics, and has served on an MSDB and/or Advisory Board for Allyx Therapeutics, Bob's Last Marathon, Cassava, Cortexyme, Sage Therapeutics, and vTv Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kivisäkk, Carlyle, Sweeney, Trombetta, LaCasse, El-Mufti, Tuncali, Chibnik, Das, Scherzer, Johnson, Dickerson, Gomez-Isla, Blacker, Oakley, Frosch, Hyman, Aghvanyan, Bathala, Campbell, Sigal, Stengelin and Arnold.)

Background: COVID-19 has resulted in significant morbidity and mortality worldwide. Lateral flow assays can detect anti-Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) antibodies to monitor transmission. However, standardized evaluation of their accuracy and tools to aid in interpreting results are needed., Methods: We evaluated 20 IgG and IgM assays selected from available tests in April 2020. We evaluated the assays' performance using 56 pre-pandemic negative and 56 SARS-CoV-2-positive plasma samples, collected 10-40 days after symptom onset, confirmed by a molecular test and analyzed by an ultra-sensitive immunoassay. Finally, we developed a user-friendly web app to extrapolate the positive predictive values based on their accuracy and local prevalence., Results: Combined IgG + IgM sensitivities ranged from 33.9 to 94.6%, while combined specificities ranged from 92.6 to 100%. The highest sensitivities were detected in Lumiquick for IgG (98.2%), BioHit for both IgM (96.4%), and combined IgG + IgM sensitivity (94.6%). Furthermore, 11 LFAs and 8 LFAs showed perfect specificity for IgG and IgM, respectively, with 15 LFAs showing perfect combined IgG + IgM specificity. Lumiquick had the lowest estimated limit-of-detection (LOD) (0.1 μg/mL), followed by a similar LOD of 1.5 μg/mL for CareHealth, Cellex, KHB, and Vivachek., Conclusion: We provide a public resource of the accuracy of select lateral flow assays with potential for home testing. The cost-effectiveness, scalable manufacturing process, and suitability for self-testing makes LFAs an attractive option for monitoring disease prevalence and assessing vaccine responsiveness. Our web tool provides an easy-to-use interface to demonstrate the impact of prevalence and test accuracy on the positive predictive values.

Investigators are increasingly interested in using microglial depletion to study the role of microglia under pathologic conditions. Liposome-encapsulated clodronate is commonly used to eliminate macrophage populations because it causes functionally irreversible inhibition and apoptosis once phagocytized by macrophages. Recent studies have shown that microglia can be depleted in disease models by injecting clodronate liposomes into the brain parenchyma. However, it is unclear whether intracerebral administration of clodronate liposomes is a practical method of eliminating microglia under physiologic conditions or whether microglial depletion induces damage to other brain cells. In this study, injecting 1 μL of clodronate liposomes (7 μg/μL) into the striatum of mice caused ablation of microglia at 1 day that persisted for 3 days. Microglia reappeared in the boundary regions of microglia elimination after 5 days. Importantly, we observed an increase in proinflammatory cytokine levels and an increase in neural/glial antigen 2 and glial fibrillary acidic protein expression in the perilesional region. In contrast, expression levels of myelin basic protein, microtubule-associated protein 2, and postsynaptic protein-95 decreased in the periphery of regions where microglia were depleted. Moreover, clodronate liposome administration decreased the density and integrity of blood vessels in the perilesional regions. In cultured primary neurons, clodronate liposome exposure also attenuated ATP synthesis. Together, these findings suggest that intracerebral administration of clodronate liposomes into brain parenchyma can deplete microglia, but can also damage other brain cells and blood vessel integrity.