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000282590 1001_ $$aSteffke, Christina$$b0
000282590 245__ $$aTargeted Proteomics upon Treatment with Tofersen Identifies Novel Response Markers for Superoxide Dismutase 1-Linked Amyotrophic Lateral Sclerosis.
000282590 260__ $$aHoboken, NJ$$bWiley-Blackwell$$c2025
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000282590 520__ $$aTofersen is the first effective and approved therapy for superoxide dismutase 1 (SOD1)-associated amyotrophic lateral sclerosis (ALS [SOD1-ALS]). Following treatment with tofersen, neurofilament levels in patients' cerebrospinal fluid (CSF) and serum seem to respond earlier than clinical parameters. This evidence prompted us to hypothesize that this novel treatment could provide an opportunity to identify additional biomarkers responsive to therapy in SOD1-ALS.We investigated a panel of 120 neural, glial, and inflammatory markers in CSF and serum samples longitudinally collected from a total of 28 SOD1-ALS patients at baseline, and after 3, 6 and 12 months of treatment with tofersen, followed by validation with conventional methodology.We identified a set of proteins, including neurofilament light chain, neurofilament heavy chain, amyloid-beta 1-40 and amyloid-beta 1-42, neuropeptide Y (NPY), and ubiquitin C-terminal hydrolase L1 (UCHL1), whose CSF levels both differed between SOD1-ALS and the control group, and were responsive to tofersen at 3 and 6 months after treatment initiation. Another group of markers, including the neuropentraxin (NPTX) family members NPTX1, NPTX2 and NPTXR, did not separate untreated SOD1-ALS from controls, but was responsive to tofersen. At 12 months on tofersen the levels of neurofilament light chain, neurofilament heavy chain, NPTX1, NPTX2, and NPTXR remained reduced compared with baseline, and correlated with the clinical response to tofersen. Consistent with increasing CSF pleocytosis and intrathecal immunoglobulin production, inflammatory markers were significantly increased after 12 months of treatment.Our results highlight a complex, time-dependent differential response of CSF biomarkers to tofersen treatment, and may pave the way for developing a panel of responsive proteins to make biomarker endpoints more robust in clinical trials for SOD1-ALS and beyond. ANN NEUROL 2025;98:1318-1334.
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000282590 650_7 $$0EC 1.15.1.1$$2NLM Chemicals$$aSuperoxide Dismutase-1
000282590 650_7 $$2NLM Chemicals$$aBiomarkers
000282590 650_7 $$2NLM Chemicals$$aSOD1 protein, human
000282590 650_7 $$2NLM Chemicals$$aNeurofilament Proteins
000282590 650_7 $$2NLM Chemicals$$aneurofilament protein L
000282590 650_2 $$2MeSH$$aHumans
000282590 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: drug therapy
000282590 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: cerebrospinal fluid
000282590 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: genetics
000282590 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: blood
000282590 650_2 $$2MeSH$$aMale
000282590 650_2 $$2MeSH$$aFemale
000282590 650_2 $$2MeSH$$aMiddle Aged
000282590 650_2 $$2MeSH$$aProteomics: methods
000282590 650_2 $$2MeSH$$aSuperoxide Dismutase-1: genetics
000282590 650_2 $$2MeSH$$aBiomarkers: cerebrospinal fluid
000282590 650_2 $$2MeSH$$aBiomarkers: blood
000282590 650_2 $$2MeSH$$aAged
000282590 650_2 $$2MeSH$$aAdult
000282590 650_2 $$2MeSH$$aNeurofilament Proteins: cerebrospinal fluid
000282590 650_2 $$2MeSH$$aLongitudinal Studies
000282590 7001_ $$aBaskar, Karthik$$b1
000282590 7001_ $$aBachhuber, Franziska$$b2
000282590 7001_ $$aWiesenfarth, Maximilian$$b3
000282590 7001_ $$0P:(DE-2719)9001951$$aDorst, Johannes$$b4$$udzne
000282590 7001_ $$0P:(DE-2719)9002279$$aSchuster, Joachim$$b5$$udzne
000282590 7001_ $$00000-0002-8183-8133$$aSchöberl, Florian$$b6
000282590 7001_ $$aReilich, Peter$$b7
000282590 7001_ $$00000-0002-2172-7386$$aRegensburger, Martin$$b8
000282590 7001_ $$aGerman, Alexander$$b9
000282590 7001_ $$0P:(DE-2719)2811849$$aGünther, René$$b10$$udzne
000282590 7001_ $$aVidovic, Maximilian$$b11
000282590 7001_ $$aPetri, Susanne$$b12
000282590 7001_ $$aMeyer, Thomas$$b13
000282590 7001_ $$00000-0002-3631-3450$$aHagenacker, Tim$$b14
000282590 7001_ $$00000-0001-9525-1424$$aGrosskreutz, Julian$$b15
000282590 7001_ $$aWeyen, Ute$$b16
000282590 7001_ $$0P:(DE-2719)9001116$$aWeydt, Patrick$$b17
000282590 7001_ $$aHaarmeier, Thomas$$b18
000282590 7001_ $$0P:(DE-2719)2812561$$aLingor, Paul$$b19
000282590 7001_ $$aWolf, Joachim$$b20
000282590 7001_ $$0P:(DE-2719)2811732$$aHermann, Andreas$$b21
000282590 7001_ $$0P:(DE-2719)2380559$$aPrudlo, Johannes$$b22
000282590 7001_ $$aGünther, Kornelia$$b23
000282590 7001_ $$aKnehr, Antje$$b24
000282590 7001_ $$aElmas, Zeynep$$b25
000282590 7001_ $$aUzelac, Zeljko$$b26
000282590 7001_ $$0P:(DE-2719)9001976$$aWitzel, Simon$$b27
000282590 7001_ $$0P:(DE-2719)9001522$$aRuf, Wolfgang Philipp$$b28$$udzne
000282590 7001_ $$0P:(DE-2719)9001054$$aFreischmidt, Axel$$b29
000282590 7001_ $$aHo, Ritchie$$b30
000282590 7001_ $$0P:(DE-2719)2812633$$aLudolph, Albert C$$b31$$udzne
000282590 7001_ $$0P:(DE-2719)9000455$$aWeishaupt, Jochen H$$b32
000282590 7001_ $$0P:(DE-2719)9002007$$aTumani, Hayrettin$$b33$$udzne
000282590 7001_ $$0P:(DE-2719)9001560$$aOeckl, Patrick$$b34
000282590 7001_ $$0P:(DE-2719)9002137$$aBrenner, David$$b35$$eLast author
000282590 7001_ $$0P:(DE-2719)9001873$$aCatanese, Alberto$$b36$$eLast author
000282590 773__ $$0PERI:(DE-600)2037912-2$$a10.1002/ana.70025$$gVol. 98, no. 6, p. 1318 - 1334$$n6$$p1318 - 1334$$tAnnals of neurology$$v98$$x0364-5134$$y2025
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