Browsing by Subject "Neurofilament proteins"

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    Assessment of Blood Biomarker Profile After Acute Concussion During Combative Training Among US Military Cadets
    (JAMA, 2021-02) Giza, Christopher C.; McCrea, Michael; Huber, Daniel; Cameron, Kenneth L.; Houston, Megan N.; Jackson, Jonathan C.; McGinty, Gerald; Pasquina, Paul; Broglio, Steven P.; Brooks, Alison; DiFiori, John; Duma, Stefan; Harezlak, Jaroslaw; Goldman, Joshua; Guskiewicz, Kevin; McAllister, Thomas W.; McArthur, David; Meier, Timothy B.; Mihalik, Jason P.; Nelson, Lindsay D.; Rowson, Steven; Gill, Jessica; Foroud, Tatiana; Katz, Barry; Saykin, Andrew; Campbell, Darren E.; Svoboda, Steven; Psychiatry, School of Medicine
    Importance: Validation of protein biomarkers for concussion diagnosis and management in military combative training is important, as these injuries occur outside of traditional health care settings and are generally difficult to diagnose. Objective: To investigate acute blood protein levels in military cadets after combative training-associated concussions. Design, setting, and participants: This multicenter prospective case-control study was part of a larger cohort study conducted by the National Collegiate Athletic Association and the US Department of Defense Concussion Assessment Research and Education (CARE) Consortium from February 20, 2015, to May 31, 2018. The study was performed among cadets from 2 CARE Consortium Advanced Research Core sites: the US Military Academy at West Point and the US Air Force Academy. Cadets who incurred concussions during combative training (concussion group) were compared with cadets who participated in the same combative training exercises but did not incur concussions (contact-control group). Clinical measures and blood sample collection occurred at baseline, the acute postinjury point (<6 hours), the 24- to 48-hour postinjury point, the asymptomatic postinjury point (defined as the point at which the cadet reported being asymptomatic and began the return-to-activity protocol), and 7 days after return to activity. Biomarker levels and estimated mean differences in biomarker levels were natural log (ln) transformed to decrease the skewness of their distributions. Data were collected from August 1, 2016, to May 31, 2018, and analyses were conducted from March 1, 2019, to January 14, 2020. Exposure: Concussion incurred during combative training. Main outcomes and measures: Proteins examined included glial fibrillary acidic protein, ubiquitin C-terminal hydrolase-L1, neurofilament light chain, and tau. Quantification was conducted using a multiplex assay (Simoa; Quanterix Corp). Clinical measures included the Sport Concussion Assessment Tool-Third Edition symptom severity evaluation, the Standardized Assessment of Concussion, the Balance Error Scoring System, and the 18-item Brief Symptom Inventory. Results: Among 103 military service academy cadets, 67 cadets incurred concussions during combative training, and 36 matched cadets who engaged in the same training exercises did not incur concussions. The mean (SD) age of cadets in the concussion group was 18.6 (1.3) years, and 40 cadets (59.7%) were male. The mean (SD) age of matched cadets in the contact-control group was 19.5 (1.3) years, and 25 cadets (69.4%) were male. Compared with cadets in the contact-control group, those in the concussion group had significant increases in glial fibrillary acidic protein (mean difference in ln values, 0.34; 95% CI, 0.18-0.50; P < .001) and ubiquitin C-terminal hydrolase-L1 (mean difference in ln values, 0.97; 95% CI, 0.44-1.50; P < .001) levels at the acute postinjury point. The glial fibrillary acidic protein level remained high in the concussion group compared with the contact-control group at the 24- to 48-hour postinjury point (mean difference in ln values, 0.22; 95% CI, 0.06-0.38; P = .007) and the asymptomatic postinjury point (mean difference in ln values, 0.21; 95% CI, 0.05-0.36; P = .01). The area under the curve for all biomarkers combined, which was used to differentiate cadets in the concussion and contact-control groups, was 0.80 (95% CI, 0.68-0.93; P < .001) at the acute postinjury point. Conclusions and relevance: This study's findings indicate that blood biomarkers have potential for use as research tools to better understand the pathobiological changes associated with concussion and to assist with injury identification and recovery from combative training-associated concussions among military service academy cadets. These results extend the previous findings of studies of collegiate athletes with sport-associated concussions.
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    Comparative neurofilament light chain trajectories in CSF and plasma in autosomal dominant Alzheimer's disease
    (Springer Nature, 2024-11-18) Hofmann, Anna; Häsler, Lisa M.; Lambert, Marius; Kaeser, Stephan A.; Gräber-Sultan, Susanne; Obermüller, Ulrike; Kuder-Buletta, Elke; la Fougere, Christian; Laske, Christoph; Vöglein, Jonathan; Levin, Johannes; Fox, Nick C.; Ryan, Natalie S.; Zetterberg, Henrik; Llibre-Guerra, Jorge J.; Perrin, Richard J.; Ibanez, Laura; Schofield, Peter R.; Brooks, William S.; Day, Gregory S.; Farlow, Martin R.; Allegri, Ricardo F.; Mendez, Patricio Chrem; Ikeuchi, Takeshi; Kasuga, Kensaku; Lee, Jae-Hong; Roh, Jee Hoon; Mori, Hiroshi; Lopera, Francisco; Bateman, Randall J.; McDade, Eric; Gordon, Brian A.; Chhatwal, Jasmeer P.; Jucker, Mathias; Schultz, Stephanie A.; Dominantly Inherited Alzheimer Network; Pathology and Laboratory Medicine, School of Medicine
    Disease-modifying therapies for Alzheimer's disease (AD) are likely to be most beneficial when initiated in the presymptomatic phase. To track the benefit of such interventions, fluid biomarkers are of great importance, with neurofilament light chain protein (NfL) showing promise for monitoring neurodegeneration and predicting cognitive outcomes. Here, we update and complement previous findings from the Dominantly Inherited Alzheimer Network Observational Study by using matched cross-sectional and longitudinal cerebrospinal fluid (CSF) and plasma samples from 567 individuals, allowing timely comparative analyses of CSF and blood trajectories across the entire disease spectrum. CSF and plasma trajectories were similar at presymptomatic stages, discriminating mutation carriers from non-carrier controls 10-20 years before the estimated onset of clinical symptoms, depending on the statistical model used. However, after symptom onset the rate of change in CSF NfL continued to increase steadily, whereas the rate of change in plasma NfL leveled off. Both plasma and CSF NfL changes were associated with grey-matter atrophy, but not with Aβ-PET changes, supporting a temporal decoupling of Aβ deposition and neurodegeneration. These observations support NfL in both CSF and blood as an early marker of neurodegeneration but suggest that NfL measured in the CSF may be better suited for monitoring clinical trial outcomes in symptomatic AD patients.
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    Compartmentalization of cerebrospinal fluid inflammation across the spectrum of untreated HIV-1 infection, central nervous system injury and viral suppression
    (Public Library of Science, 2021-05-13) Gisslen, Magnus; Keating, Sheila M.; Spudich, Serena; Arechiga, Victor; Stephenson, Sophie; Zetterberg, Henrik; Di Germanio, Clara; Blennow, Kaj; Fuchs, Dietmar; Hagberg, Lars; Norris, Philip J.; Peterson, Julia; Shacklett, Barbara L.; Yiannoutsos, Constantin T.; Price, Richard W.; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health
    Objective: To characterize the evolution of central nervous system (CNS) inflammation in HIV-1 infection applying a panel of cerebrospinal fluid (CSF) inflammatory biomarkers to grouped subjects representing a broad spectrum of systemic HIV-1 immune suppression, CNS injury and viral control. Methods: This is a cross-sectional analysis of archived CSF and blood samples, assessing concentrations of 10 functionally diverse soluble inflammatory biomarkers by immunoassays in 143 HIV-1-infected subjects divided into 8 groups: untreated primary HIV-1 infection (PHI); four untreated groups defined by their blood CD4+ T lymphocyte counts; untreated patients presenting with subacute HIV-associated dementia (HAD); antiretroviral-treated subjects with ≥1 years of plasma viral suppression; and untreated elite controllers. Twenty HIV-1-uninfected controls were included for comparison. Background biomarkers included blood CD4+ and CD8+ T lymphocytes, CSF and blood HIV-1 RNA, CSF white blood cell (WBC) count, CSF/blood albumin ratio, CSF neurofilament light chain (NfL), and CSF t-tau. Findings: HIV-1 infection was associated with a broad compartmentalized CSF inflammatory response that developed early in its course and changed with systemic disease progression, development of neurological injury, and viral suppression. CSF inflammation in untreated individuals without overt HAD exhibited at least two overall patterns of inflammation as blood CD4+ T lymphocytes decreased: one that peaked at 200-350 blood CD4+ T cells/μL and associated with lymphocytic CSF inflammation and HIV-1 RNA concentrations; and a second that steadily increased through the full range of CD4+ T cell decline and associated with macrophage responses and increasing CNS injury. Subacute HAD was distinguished by a third inflammatory profile with increased blood-brain barrier permeability and robust combined lymphocytic and macrophage CSF inflammation. Suppression of CSF and blood HIV-1 infections by antiretroviral treatment and elite viral control were associated with reduced CSF inflammation, though not fully to levels found in HIV-1 seronegative controls.
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    Downstream Biomarker Effects of Gantenerumab or Solanezumab in Dominantly Inherited Alzheimer Disease: The DIAN-TU-001 Randomized Clinical Trial
    (American Medical Association, 2024) Wagemann, Olivia; Liu, Haiyan; Wang, Guoqiao; Shi, Xinyu; Bittner, Tobias; Scelsi, Marzia A.; Farlow, Martin R.; Clifford, David B.; Supnet-Bell, Charlene; Santacruz, Anna M.; Aschenbrenner, Andrew J.; Hassenstab, Jason J.; Benzinger, Tammie L. S.; Gordon, Brian A.; Coalier, Kelley A.; Cruchaga, Carlos; Ibanez, Laura; Perrin, Richard J.; Xiong, Chengjie; Li, Yan; Morris, John C.; Lah, James J.; Berman, Sarah B.; Roberson, Erik D.; van Dyck, Christopher H.; Galasko, Douglas; Gauthier, Serge; Hsiung, Ging-Yuek R.; Brooks, William S.; Pariente, Jérémie; Mummery, Catherine J.; Day, Gregory S.; Ringman, John M.; Mendez, Patricio Chrem; St. George-Hyslop, Peter; Fox, Nick C.; Suzuki, Kazushi; Okhravi, Hamid R.; Chhatwal, Jasmeer; Levin, Johannes; Jucker, Mathias; Sims, John R.; Holdridge, Karen C.; Proctor, Nicholas K.; Yaari, Roy; Andersen, Scott W.; Mancini, Michele; Llibre-Guerra, Jorge; Bateman, Randall J.; McDade, Eric; Dominantly Inherited Alzheimer Network–Trials Unit; Neurology, School of Medicine
    Importance: Effects of antiamyloid agents, targeting either fibrillar or soluble monomeric amyloid peptides, on downstream biomarkers in cerebrospinal fluid (CSF) and plasma are largely unknown in dominantly inherited Alzheimer disease (DIAD). Objective: To investigate longitudinal biomarker changes of synaptic dysfunction, neuroinflammation, and neurodegeneration in individuals with DIAD who are receiving antiamyloid treatment. Design, setting, and participants: From 2012 to 2019, the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU-001) study, a double-blind, placebo-controlled, randomized clinical trial, investigated gantenerumab and solanezumab in DIAD. Carriers of gene variants were assigned 3:1 to either drug or placebo. The present analysis was conducted from April to June 2023. DIAN-TU-001 spans 25 study sites in 7 countries. Biofluids and neuroimaging from carriers of DIAD gene variants in the gantenerumab, solanezumab, and placebo groups were analyzed. Interventions: In 2016, initial dosing of gantenerumab, 225 mg (subcutaneously every 4 weeks) was increased every 8 weeks up to 1200 mg. In 2017, initial dosing of solanezumab, 400 mg (intravenously every 4 weeks) was increased up to 1600 mg every 4 weeks. Main outcomes and measures: Longitudinal changes in CSF levels of neurogranin, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase 3-like 1 protein (YKL-40), glial fibrillary acidic protein (GFAP), neurofilament light protein (NfL), and plasma levels of GFAP and NfL. Results: Of 236 eligible participants screened, 43 were excluded. A total of 142 participants (mean [SD] age, 44 [10] years; 72 female [51%]) were included in the study (gantenerumab, 52 [37%]; solanezumab, 50 [35%]; placebo, 40 [28%]). Relative to placebo, gantenerumab significantly reduced CSF neurogranin level at year 4 (mean [SD] β = -242.43 [48.04] pg/mL; P < .001); reduced plasma GFAP level at year 1 (mean [SD] β = -0.02 [0.01] ng/mL; P = .02), year 2 (mean [SD] β = -0.03 [0.01] ng/mL; P = .002), and year 4 (mean [SD] β = -0.06 [0.02] ng/mL; P < .001); and increased CSF sTREM2 level at year 2 (mean [SD] β = 1.12 [0.43] ng/mL; P = .01) and year 4 (mean [SD] β = 1.06 [0.52] ng/mL; P = .04). Solanezumab significantly increased CSF NfL (log) at year 4 (mean [SD] β = 0.14 [0.06]; P = .02). Correlation analysis for rates of change found stronger correlations between CSF markers and fluid markers with Pittsburgh compound B positron emission tomography for solanezumab and placebo. Conclusions and relevance: This randomized clinical trial supports the importance of fibrillar amyloid reduction in multiple AD-related processes of neuroinflammation and neurodegeneration in CSF and plasma in DIAD. Additional studies of antiaggregated amyloid therapies in sporadic AD and DIAD are needed to determine the utility of nonamyloid biomarkers in determining disease modification.
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    Plasma Neurofilament Light for Prediction of Disease Progression in Familial Frontotemporal Lobar Degeneration
    (American Academy of Neurology, 2021-05-04) Rojas, Julio C.; Wang, Ping; Staffaroni, Adam M.; Heller, Carolin; Cobigo, Yann; Wolf, Amy; Goh, Sheng-Yang M.; Ljubenkov, Peter A.; Heuer, Hilary W.; Fong, Jamie C.; Taylor, Joanne B.; Veras, Eliseo; Song, Linan; Jeromin, Andreas; Hanlon, David; Yu, Lili; Khinikar, Arvind; Sivasankaran, Rajeev; Kieloch, Agnieszka; Valentin, Marie-Anne; Karydas, Anna M.; Mitic, Laura L.; Pearlman, Rodney; Kornak, John; Kramer, Joel H.; Miller, Bruce L.; Kantarci, Kejal; Knopman, David S.; Graff-Radford, Neill; Petrucelli, Leonard; Rademakers, Rosa; Irwin, David J.; Grossman, Murray; Ramos, Eliana Marisa; Coppola, Giovanni; Mendez, Mario F.; Bordelon, Yvette; Dickerson, Bradford C.; Ghoshal, Nupur; Huey, Edward D.; Mackenzie, Ian R.; Appleby, Brian S.; Domoto-Reilly, Kimiko; Hsiung, Ging-Yuek R.; Toga, Arthur W.; Weintraub, Sandra; Kaufer, Daniel I.; Kerwin, Diana; Litvan, Irene; Onyike, Chiadikaobi U.; Pantelyat, Alexander; Roberson, Erik D.; Tartaglia, Maria C.; Foroud, Tatiana; Chen, Weiping; Czerkowicz, Julie; Graham, Danielle L.; van Swieten, John C.; Borroni, Barbara; Sanchez-Valle, Raquel; Moreno, Fermin; Laforce, Robert; Graff, Caroline; Synofzik, Matthis; Galimberti, Daniela; Rowe, James B.; James B., Mario; Finger, Elizabeth; Vandenberghe, Rik; de Mendonça, Alexandre; Tagliavini, Fabrizio; Santana, Isabel; Ducharme, Simon; Butler, Chris R.; Gerhard, Alexander; Levin, Johannes; Danek, Adrian; Otto, Markus; Sorbi, Sandro; Cash, David M.; Convery, Rhian S.; Bocchetta, Martina; Foiani, Martha; Greaves, Caroline V.; Peakman, Georgia; Russell, Lucy; Swift, Imogen; Todd, Emily; Rohrer, Jonathan D.; Boeve, Bradley F.; Rosen, Howard J.; Boxer, Adam L.; Neurology, School of Medicine
    Objective: We tested the hypothesis that plasma neurofilament light chain (NfL) identifies asymptomatic carriers of familial frontotemporal lobar degeneration (FTLD)-causing mutations at risk of disease progression. Methods: Baseline plasma NfL concentrations were measured with single-molecule array in original (n = 277) and validation (n = 297) cohorts. C9orf72, GRN, and MAPT mutation carriers and noncarriers from the same families were classified by disease severity (asymptomatic, prodromal, and full phenotype) using the CDR Dementia Staging Instrument plus behavior and language domains from the National Alzheimer's Disease Coordinating Center FTLD module (CDR+NACC-FTLD). Linear mixed-effect models related NfL to clinical variables. Results: In both cohorts, baseline NfL was higher in asymptomatic mutation carriers who showed phenoconversion or disease progression compared to nonprogressors (original: 11.4 ± 7 pg/mL vs 6.7 ± 5 pg/mL, p = 0.002; validation: 14.1 ± 12 pg/mL vs 8.7 ± 6 pg/mL, p = 0.035). Plasma NfL discriminated symptomatic from asymptomatic mutation carriers or those with prodromal disease (original cutoff: 13.6 pg/mL, 87.5% sensitivity, 82.7% specificity; validation cutoff: 19.8 pg/mL, 87.4% sensitivity, 84.3% specificity). Higher baseline NfL correlated with worse longitudinal CDR+NACC-FTLD sum of boxes scores, neuropsychological function, and atrophy, regardless of genotype or disease severity, including asymptomatic mutation carriers. Conclusions: Plasma NfL identifies asymptomatic carriers of FTLD-causing mutations at short-term risk of disease progression and is a potential tool to select participants for prevention clinical trials. Trial registration information: ClinicalTrials.gov Identifier: NCT02372773 and NCT02365922. Classification of evidence: This study provides Class I evidence that in carriers of FTLD-causing mutations, elevation of plasma NfL predicts short-term risk of clinical progression.