Browsing by Author "Johnson, Erik C. B."

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    A protein panel in cerebrospinal fluid for diagnostic and predictive assessment of alzheimer’s disease
    (American Association for the Advancement of Science, 2023) Haque, Rafi; Watson, Caroline M.; Liu, Jiaqi; Carter, E. Kathleen; Duong, Duc M.; Lah, James J.; Wingo, Aliza P.; Roberts, Blaine R.; Johnson, Erik C. B.; Saykin, Andrew J.; Shaw, Leslie M.; Seyfried, Nicholas T.; Wingo, Thomas S.; Levey, Allan I.; Radiology and Imaging Sciences, School of Medicine
    Alzheimer's disease (AD) is a neurodegenerative disease with heterogenous pathophysiological changes that develop years before the onset of clinical symptoms. These preclinical changes have generated considerable interest in identifying markers for the pathophysiological mechanisms linked to AD and AD-related disorders (ADRD). On the basis of our prior work integrating cerebrospinal fluid (CSF) and brain proteome networks, we developed a reliable and high-throughput mass spectrometry-selected reaction monitoring assay that targets 48 key proteins altered in CSF. To test the diagnostic utility of these proteins and compare them with existing AD biomarkers, CSF collected at baseline visits was assayed from 706 participants recruited from the Alzheimer's Disease Neuroimaging Initiative. We found that the targeted CSF panel of 48 proteins (CSF 48 panel) performed at least as well as existing AD CSF biomarkers (Aβ42, tTau, and pTau181) for predicting clinical diagnosis, FDG PET, hippocampal volume, and measures of cognitive and dementia severity. In addition, for each of those outcomes, the CSF 48 panel plus the existing AD CSF biomarkers significantly improved diagnostic performance. Furthermore, the CSF 48 panel plus existing AD CSF biomarkers significantly improved predictions for changes in FDG PET, hippocampal volume, and measures of cognitive decline and dementia severity compared with either measure alone. A potential reason for these improvements is that the CSF 48 panel reflects a range of altered biology observed in AD/ADRD. In conclusion, we show that the CSF 48 panel complements existing AD CSF biomarkers to improve diagnosis and predict future cognitive decline and dementia severity.
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    Proteomics of brain, CSF, and plasma identifies molecular signatures for distinguishing sporadic and genetic Alzheimer's disease
    (American Association for the Advancement of Science, 2023) Sung, Yun Ju; Yang, Chengran; Norton, Joanne; Johnson, Matt; Fagan, Anne; Bateman, Randall J.; Perrin, Richard J.; Morris, John C.; Farlow, Martin R.; Chhatwal, Jasmeer P.; Schofield, Peter R.; Chui, Helena; Wang, Fengxian; Novotny, Brenna; Eteleeb, Abdallah; Karch, Celeste; Schindler, Suzanne E.; Rhinn, Herve; Johnson, Erik C. B.; Oh, Hamilton Se-Hwee; Rutledge, Jarod Evert; Dammer, Eric B.; Seyfried, Nicholas T.; Wyss-Coray, Tony; Harari, Oscar; Cruchaga, Carlos; Neurology, School of Medicine
    Proteomic studies for Alzheimer's disease (AD) are instrumental in identifying AD pathways but often focus on single tissues and sporadic AD cases. Here, we present a proteomic study analyzing 1305 proteins in brain tissue, cerebrospinal fluid (CSF), and plasma from patients with sporadic AD, TREM2 risk variant carriers, patients with autosomal dominant AD (ADAD), and healthy individuals. We identified 8 brain, 40 CSF, and 9 plasma proteins that were altered in individuals with sporadic AD, and we replicated these findings in several external datasets. We identified a proteomic signature that differentiated TREM2 variant carriers from both individuals with sporadic AD and healthy individuals. The proteins associated with sporadic AD were also altered in patients with ADAD, but with a greater effect size. Brain-derived proteins associated with ADAD were also replicated in additional CSF samples. Enrichment analyses highlighted several pathways, including those implicated in AD (calcineurin and Apo E), Parkinson's disease (α-synuclein and LRRK2), and innate immune responses (SHC1, ERK-1, and SPP1). Our findings suggest that combined proteomics across brain tissue, CSF, and plasma can be used to identify markers for sporadic and genetically defined AD.