Authors: Winston, Charisse N. | Goetzl, Edward J. | Baker, Laura D. | Vitiello, Michael V. | Rissman, Robert A.
Article Type: Research Article
Abstract: Age-related changes in cognition are linked to decreased expression of somatotropins, GHRH and IGF-1. Mild cognitive impairment (MCI) and Alzheimer’s disease (AD) are heterogeneous conditions. The loss of GHRH signaling in the brain may be mechanistically involved in AD pathogenesis. The consequent need to identify AD at an early and perhaps more treatable stage has fueled research into blood-based, exosome biomarkers. Plasma exosomes from participants enrolled in a randomized, double-blind, placebo-controlled 20-week trial of GHRH administration, were isolated, precipitated, and enriched by immuno-absorption with anti-L1CAM antibody (neural adhesion protein) from adults with MCI and age-matched, cognitively normal controls (CNC). Extracted …protein cargo from neuronally-derived exosomes (NDEs) were assessed by ELISAs for protein levels implicated in AD neuropathology and for synaptic proteins altered by AD. Plasma NDE concentrations of Aβ1-42 were significantly increased while plasma NDE concentrations of NRGN, synaptophysin, synaptotagmin, and synaptopodin were significantly decreased in patients with MCI, independent of GHRH treatment. Plasma NDE concentrations of ptau-S396 and GAP43 were not affected by cognitive status (CNC versus MCI) or by GHRH treatment. Aβ1-42 , neurogranin (NRGN), synaptophysin, synaptotagmin, and synaptopodin demonstrated the highest diagnostic accuracy for distinguishing between CNC and MCI patients, while synaptophysin and synaptotagmin demonstrated moderate accuracy in distinguishing between placebo-treated and GHRH-treated, MCI patients. Show more
Keywords: Amyloid, biomarker, GHRH, growth hormone, mild cognitive impairment, neuronal exosomes, synapse, tau
DOI: 10.3233/JAD-180302
Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 971-981, 2018
Authors: Winston, Charisse N. | Aulston, Brent | Rockenstein, Edward M. | Adame, Anthony | Prikhodko, Olga | Dave, Kishan N. | Mishra, Priyanka | Rissman, Robert A. | Yuan, Shauna H.
Article Type: Research Article
Abstract: Progressive accumulation of aggregation-prone proteins, amyloid-β (Aβ ) and hyperphosphorylated tau (p-tau), are the defining hallmarks of Alzheimer’s disease (AD). The mechanisms by which Aβ and p-tau are transmitted throughout the diseased brain are not yet completely understood. Interest in exosome research has grown dramatically over the past few years, specifically due to their potential role as biomarkers for staging of neurodegenerative diseases, including AD. Despite their diagnostic utility, the pathogenic potential of exosomes has yet to be fully elucidated. In this study, we use a series of recombinant tau antibodies to characterize a new model of human tau in …vivo. Exosome suspensions derived from neuronally-differentiated, human induced pluripotent stem cells that express the repeat domain of tau P301L and V337M mutations (NiPSCEs) were injected into the wild-type mouse brain and pathological changes were characterized by immunostaining at one- (1 m) and two-month (2 m) post-injection. We found that tau inclusions were present throughout the brain at 2 m post-injection, which were detectable using antibodies raised against full-length tau (K9JA) and misfolded tau (MC1). Furthermore, we found that phosphorylated tau immunoreactivity was elevated 1 m post-injection, which was surprisingly normalized after 2 m. Finally, we observed extensive degeneration of neuronal dendrites in both ipsilateral and contralateral hippocampi in NiPSCE treated mice. In summary, we demonstrate that exosomes are sufficient to cause long-distance propagation of tau pathology and neurodegeneration in vivo . These novel findings support an active role of exosomes in AD pathogenesis. Show more
Keywords: Alzheimer’s disease, exosomes, induced pluripotent stem cells, tau propagation
DOI: 10.3233/JAD-180776
Citation: Journal of Alzheimer's Disease, vol. 67, no. 2, pp. 541-553, 2019
Authors: Alvarez, X. Anton | Winston, Charisse N. | Barlow, James W. | Sarsoza, Floyd M. | Alvarez, Irene | Aleixandre, Manuel | Linares, Carlos | García-Fantini, Manuel | Kastberger, Birgit | Winter, Stefan | Rissman, Robert A.
Article Type: Research Article
Abstract: Background: Plasma neuronal-derived extracellular vesicles (NDEV) contain proteins of pathological, diagnostic, and therapeutic relevance. Objective: We investigated the associations of six plasma NDEV markers with Alzheimer’s disease (AD) severity, cognition and functioning, and changes in these biomarkers after Cerebrolysin®, donepezil, and a combination therapy in AD. Methods: Plasma NDEV levels of Aβ42 , total tau, P-T181-tau, P-S393-tau, neurogranin, and REST were determined in: 1) 116 mild to advanced AD patients and in 20 control subjects; 2) 110 AD patients treated with Cerebrolysin®, donepezil, or combination therapy in a randomized clinical trial (RCT). Samples for NDEV determinations were obtained at baseline …in the NDEV study and at baseline and study endpoint in the RCT. Cognition and functioning were assessed at the same time points. Results: NDEV levels of Aβ42 , total tau, P-T181-tau, and P-S393-tau were higher and those of neurogranin and REST were lower in mild-to-moderate AD than in controls (p < 0.05 to p < 0.001). NDEV total tau, neurogranin, and REST increased with AD severity (p < 0.05 to p < 0.001). NDEV Aβ42 and P-T181-tau correlated negatively with serum BDNF (p < 0.05), and total-tau levels were associated to plasma TNF-α (p < 0.01) and cognitive impairment (p < 0.05). Combination therapy reduced NDEV Aβ42 with respect to monotherapies (p < 0.05); and NDEV total tau, P-T181-tau, and P-S396-tau were decreased in Cerebrolysin-treated patients compared to those on donepezil monotherapy (p < 0.05). Conclusion: The present results demonstrate the utility of NDEV determinations of pathologic and synaptic proteins as effective AD biomarkers, as markers of AD severity, and as potential tools for monitoring the effects of anti-AD drugs. Show more
Keywords: Aβ42, Alzheimer disease, Cerebrolysin®, combination therapy, donepezil, plasma neuronal-derived extracellular vesicles, tau
DOI: 10.3233/JAD-220575
Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 705-717, 2022
Authors: Winston, Charisse N. | Langford, Oliver | Levin, Natalie | Raman, Rema | Yarasheski, Kevin | West, Tim | Abdel-Latif, Sara | Donohue, Michael | Nakamura, Akinori | Toba, Kenji | Masters, Colin L. | Doecke, James | Sperling, Reisa A. | Aisen, Paul S. | Rissman, Robert A.
Article Type: Research Article
Abstract: Background: Participant eligibility for the A4 Study was determined by amyloid PET imaging. Given the disadvantages of amyloid PET imaging in accessibility and cost, blood-based biomarkers may serve as a sufficient biomarker and more cost-effective screening tool for patient enrollment into preclinical AD trials. Objective: To determine if a blood-based screening test can adequately identify amyloid burden in participants screened into a preclinical AD trial. Methods: In this cross-sectional study, 224 participants from the A4 Study received an amyloid PET scan (18 Florbetapir) within 90 days of blood sample collection. Blood samples from all study participants were processed within 2 h …after phlebotomy. Plasma amyloid measures were quantified by Shimazdu and C2 N Diagnostics using mass spectrometry-based platforms. A corresponding subset of blood samples (n = 100) was processed within 24 h after phlebotomy and analyzed by C2 N. Results: Plasma Aβ42 /Aβ40 demonstrated the highest association for Aβ accumulation in the brain with an AUC 0.76 (95%CI = 0.69, 0.82) at C2 N and 0.80 (95%CI = 0.75, 0.86) at Shimadzu. Blood samples processed to plasma within 2 h after phlebotomy provided a better prediction of amyloid PET status than blood samples processed within 24 h (AUC 0.80 versus 0.64; p < 0.001). Age, sex, and APOE ɛ4 carrier status did not the diagnostic performance of plasma Aβ42 /Aβ40 to predict amyloid PET positivity in A4 Study participants. Conclusion: Plasma Aβ42 /Aβ40 may serve as a potential biomarker for predicting elevated amyloid in the brain. Utilizing blood testing over PET imaging may improve screening efficiency into clinical trials. Show more
Keywords: A4, Alzheimer’s disease, amyloid-β, biomarkers, clinical trial, mass spectrometry, PET
DOI: 10.3233/JAD-221118
Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 95-107, 2023