Higher CSF sTNFR1-related proteins associate with better prognosis in very early Alzheimer’s disease

Hu, William T.; Öztürk, Tuğba; Kollhoff, Alexander L.; Wharton, Whitney; Howell, J. Christina; Weiner, Michael W.; Aisen, Paul S.; Petersen, Ronald C.; Jack, Clifford R.; Jagust, William J.; Trojanowki, John Q.; Toga, Arthur W.; Beckett, Laurel A.; Green, Robert C.; Saykin, Andrew J.; Morris, John C.; Perrin, Richard J.; Shaw, Leslie M.; Kachaturian, Zaven; Carrillo, Maria; Potter, William Z.; Barnes, Lisa L.; Bernard, Marie A.; González, Héctor Alfredo Baptista; Ho, Carole; Hsiao, John K.; Masliah, Eliezer; Masterman, Donna; Okonkwo, Ozioma C.; Ryan, Laurie; Silverberg, Nina; Fleisher, Adam; Montine, Tom; Kaye, Jeffrey; Silbert, Lisa C.; Schneider, Lon S.; Pawluczyk, Sonia; Becerra, Mauricio; Brewer, James B.; Heidebrink, Judith L.; Knopman, David S.; Villanueva‐Meyer, Javier; Doody, Rachelle S.; Kass, Joseph S.; Stern, Yaakov; Honig, Lawrence S.; Mintz, Akiva; Ances, Beau M.; Mintun, Mark A.; Geldmacher, David S.; Love, Marissa Natelson; Grossman, Hillel; Goldstein, Martin; Shah, Raj C.; Lamar, Melissa; Duara, Ranjan; Greig‐Custo, Maria T.; Albert, Marilyn; Onyike, Chiadi U.; Smith, Amanda; Sadowski, Martin; Wısnıewskı, Thomas; Shulman, Melanie; Doraiswamy, P. Murali; Petrella, Jeffrey R.; James, Olga; Karlawish, Jason; Wolk, David A.; Smith, Charles D.; Jicha, Gregory A.; Khouli, Riham El; López, Oscar L.; Porsteinsson, Anton P.; Thai, Gaby; Pierce, Aimee; Kelley, Brendan J.; Nguyen, Trung; Womack, Kyle; Levey, Aĺlan I.; Lah, James J.; Burns, Jeffrey M.; Swerdlow, Russell H.; Brooks, William M.; Silverman, Daniel; Kremen, Sarah; Graff‐Radford, Neill R.; Farlow, Martin R.; Dyck, Christopher H. van; Mecca, Adam P.; Chertkow, Howard; Vaitekunis, Susan; Black, Sandra E.; Stefanović, Bojana; Heyn, Chinthaka; Hsiung, Ging‐Yuek Robin; Sossi, Vesna; Finger, Elizabeth; Pasternak, Stephen; Rachinsky, Irina; Grant, Ian; Rogalskı, Emily; Mesulam, Marek Marsel; Pomara, Nunzio; Hernando, Raymundo; Sarrael, Antero; Rosen, Howard J.; Miller, Bruce L.; Perry, David C.; Turner, Raymond Scott; Sperling, Reisa A.; Johnson, Keith A.; Marshall, Gad A.; Yesavage, Jerome A.; Taylor, Joy L.; Chao, Steven; Belden, Christine M.; Atri, Alireza; Spann, Bryan M.; Killiany, Ronald; Stern, Robert; Mez, Jesse; Obisesan, Thomas O.; Ntekim, Oyonumo; Lerner, Alan J.; Ogrocki, Paula; Tatsuoka, Curtis; Fletcher, Evan; Maillard, Pauline; Olichney, John; DeCarli, Charles; Bates, Vernice; Capote, Horacio; Borrie, Michael; Lee, T.-Y.; Bartha, Rob; Johnson, Sterling C.; Asthana, Sanjay; Carlsson, Cynthia M.; Perrin, Allison; Scharre, Douglas W.; Kataki, Maria; Tarawneh, Rawan; Hart, David; Zimmerman, Earl A.; Celmins, Dzintra; Miller, Delwyn D.; Koleva, Hristina; Shim, Hyungsub; Williamson, Jeff D.; Craft, Suzanne; Cleveland, Jo; Ott, Brian R.; Drake, Jonathan; Tremont, Geoffrey; Sabbagh, Marwan N.; Ritter, Aaron; Mintzer, Jacobo; Masdeu, Joseph C.; Shi, Jiong; Newhouse, Paul; Potkin, Steven G.; Salloway, Stephen; Malloy, Paul; Correia, Stephen; Kittur, Smita; Pearlson, Godfrey D.; Blank, Karen; Flashman, Laura A.; Seltzer, Marc; Lee, Athena; Relkin, Norman; Chiang, Gloria

doi:10.1038/s41467-021-24220-7

Cited by 26 publications

(22 citation statements)

References 49 publications

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“…In a different context, the involvement of mtDNA signaling in pathogenesis of Alzheimer's disease (AD) is also currently under discussion, as several reports of mitochondrial dysfunction and also the dysfunction of Pink1/Parkin, excessive ROS production are reported in association with AD (Witte et al, 2009;Ye et al, 2015). However, a direct contribution of mtDNA in pathogenesis of AD was not proven yet, the inflammatory component, showing induction of the inflammasome, cytokines and NF-ΚB might hint a correlation of mtDNA accumulation in AD (Heneka et al, 2013;Ahmed et al, 2017;Hu et al, 2021).…”

Section: Discussion and Perspectivesmentioning

confidence: 99%

Role of Mitochondrial Nucleic Acid Sensing Pathways in Health and Patho-Physiology

Chowdhury

Witte

Aich

2022

Front. Cell Dev. Biol.

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Mitochondria, in symbiosis with the host cell, carry out a wide variety of functions from generating energy, regulating the metabolic processes, cell death to inflammation. The most prominent function of mitochondria relies on the oxidative phosphorylation (OXPHOS) system. OXPHOS heavily influences the mitochondrial-nuclear communication through a plethora of interconnected signaling pathways. Additionally, owing to the bacterial ancestry, mitochondria also harbor a large number of Damage Associated Molecular Patterns (DAMPs). These molecules relay the information about the state of the mitochondrial health and dysfunction to the innate immune system. Consequently, depending on the intracellular or extracellular nature of detection, different inflammatory pathways are elicited. One group of DAMPs, the mitochondrial nucleic acids, hijack the antiviral DNA or RNA sensing mechanisms such as the cGAS/STING and RIG-1/MAVS pathways. A pro-inflammatory response is invoked by these signals predominantly through type I interferon (T1-IFN) cytokines. This affects a wide range of organ systems which exhibit clinical presentations of auto-immune disorders. Interestingly, tumor cells too, have devised ingenious ways to use the mitochondrial DNA mediated cGAS-STING-IRF3 response to promote neoplastic transformations and develop tumor micro-environments. Thus, mitochondrial nucleic acid-sensing pathways are fundamental in understanding the source and nature of disease initiation and development. Apart from the pathological interest, recent studies also attempt to delineate the structural considerations for the release of nucleic acids across the mitochondrial membranes. Hence, this review presents a comprehensive overview of the different aspects of mitochondrial nucleic acid-sensing. It attempts to summarize the nature of the molecular patterns involved, their release and recognition in the cytoplasm and signaling. Finally, a major emphasis is given to elaborate the resulting patho-physiologies.

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Section: Discussion and Perspectivesmentioning

confidence: 99%

Role of Mitochondrial Nucleic Acid Sensing Pathways in Health and Patho-Physiology

Chowdhury

Witte

Aich

2022

Front. Cell Dev. Biol.

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“…Diniz et al found that a high serum sTNFR1 level was associated with a higher risk of progression from mild cognitive impairment (MCI) to AD [ 25 ]. Hu et al showed that higher levels of proteins related to sTNFR1 were associated with a reduced risk of conversion to dementia and that these sTNFR1-related inflammatory proteins provided prognostic information independent of established Alzheimer’s markers [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Combination of Serum and Plasma Biomarkers Could Improve Prediction Performance for Alzheimer’s Disease

Zhang

Petersen

Johnson

et al. 2022

Genes

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Alzheimer’s disease (AD) can be predicted either by serum or plasma biomarkers, and a combination may increase predictive power, but due to the high complexity of machine learning, it may also incur overfitting problems. In this paper, we investigated whether combining serum and plasma biomarkers with feature selection could improve prediction performance for AD. 150 D patients and 150 normal controls (NCs) were enrolled for a serum test, and 100 patients and 100 NCs were enrolled for the plasma test. Among these, 79 ADs and 65 NCs had serum and plasma samples in common. A 10 times repeated 5-fold cross-validation model and a feature selection method were used to overcome the overfitting problem when serum and plasma biomarkers were combined. First, we tested to see if simply adding serum and plasma biomarkers improved prediction performance but also caused overfitting. Then we employed a feature selection algorithm we developed to overcome the overfitting problem. Lastly, we tested the prediction performance in a 10 times repeated 5-fold cross validation model for training and testing sets. We found that the combined biomarkers improved AD prediction but also caused overfitting. A further feature selection based on the combination of serum and plasma biomarkers solved the problem and produced an even higher prediction performance than either serum or plasma biomarkers on their own. The combined feature-selected serum–plasma biomarkers may have critical implications for understanding the pathophysiology of AD and for developing preventative treatments.

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“…Soluble forms of the amyloid precursor protein sAPPα and sAPPβ were also measured in the Luminex 200 platform (Immuno-Biological Laboratories, Minneapolis, MN) due to their implication in ALS [23,24]. All assays were performed using manufacturers' protocols with the exception that 100 mL of CSF was used in the inflammatory protein assays, and these assays have been used extensively in the Hu Lab to characterize neurodegenerative, inflammatory, and other biological processes in aging, Alzheimer's disease (AD), multiple sclerosis (MS), HIV-associated neurocognitive dysfunctions, and COVID-19-related neurological dysfunctions with high accuracy and precision [22,[25][26][27][28].…”

Section: Methodsmentioning

confidence: 99%

CSF IL-8 Associated with Response to Gene Therapy in a Case Series of Spinal Muscular Atrophy

et al. 2023

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Gene therapies have greatly changed the outlook in spinal muscular atrophy (SMA), and this disorder provides a rare opportunity to study longitudinal biomarker changes correlated with reduced disease burden and improved clinical outcomes. Recent work suggests clinical response to correlate with declining cerebrospinal fluid (CSF) levels of the neurodegenerative marker neurofilament light chain (NfL) in children receiving serial anti-sense oligonucleotide therapy. However, change in CSF NfL levels is no longer a practical biomarker as more children undergo single-dose gene replacement therapy. Here we leverage serial CSF samples (median of 4 per child) collected in 13 children with SMA undergoing anti-sense oligonucleotide therapy to characterize the longitudinal profiles of NfL as well as inflammatory and neuronal proteins. In contrast to neurodegeneration in adults, we found NfL levels to first decrease following initiation of treatment but then increase upon further treatment and improved motor functions. We then examined additional CSF inflammatory and neuronal markers for linear association with motor function during SMA treatment. We identified longitudinal IL-8 levels to inversely correlate with motor functions determined by clinical examination (F(1, 47) = 12.903, p = 0.001) or electromyography in the abductor pollicis brevis muscle (p = 0.064). In keeping with this, lower baseline IL-8 levels were associated with better longitudinal outcomes, even though this difference diminished over 2 years in the younger group. We thus propose CSF IL-8 as a biomarker for baseline function and short-term treatment response in SMA, and a candidate biomarker for future treatment trials in other neurodegenerative disorders.

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Higher CSF sTNFR1-related proteins associate with better prognosis in very early Alzheimer’s disease

Cited by 26 publications

References 49 publications

Role of Mitochondrial Nucleic Acid Sensing Pathways in Health and Patho-Physiology

Role of Mitochondrial Nucleic Acid Sensing Pathways in Health and Patho-Physiology

Combination of Serum and Plasma Biomarkers Could Improve Prediction Performance for Alzheimer’s Disease

CSF IL-8 Associated with Response to Gene Therapy in a Case Series of Spinal Muscular Atrophy

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