Prospective Quantification of CSF Biomarkers in Antibody-Mediated Encephalitis

Objectives:To determine whether neuronal and neuroaxonal injury, neuroinflammation and synaptic dysfunction associate with clinical course and outcomes in antibody-mediated encephalitis (AME), we measured biomarkers of these processes in CSF from patients presenting with AME and cognitively normal individuals.Methods:Biomarkers of neuronal (total-tau, VILIP-1) and neuroaxonal damage (neurofilament light chain [NfL]), inflammation (YKL-40) and synaptic function (neurogranin, SNAP-25) were measured in CSF obtained from 45 patients at the time of diagnosis of NMDA receptor (n=34) or LGI1/CASPR-2 (n=11) AME, and 39 age- and sex-similar cognitively normal individuals. The association between biomarkers and modified Rankin Scores were evaluated in a subset (n=20) of longitudinally followed patients.Results:Biomarkers of neuroaxonal injury (NfL) and neuroinflammation (YKL-40) were elevated in AME cases at presentation, while markers of neuronal injury and synaptic function were stable (total-tau) or decreased (VILIP-1, SNAP-25, neurogranin). The log-transformed ratio of YKL-40/SNAP-25 optimally discriminated cases from cognitively normal individuals (AUC=0.99; 95%CI: 0.97, >0.99). Younger age (ρ=-0.56; p=0.01), lower VILIP-1 (ρ=-0.60; p<0.01) and SNAP-25 (ρ=-0.54; p=0.01), and higher log10(YKL-40/SNAP-25) [(ρ=0.48; p=0.04] associated with greater disease severity (higher modified Rankin Score) in prospectively followed patients. Higher YKL-40 (ρ=0.60; p=0.02) and neurogranin (ρ=0.55; p=0.03) at presentation were associated with higher modified Rankin Scores 12-months following hospital discharge.Conclusions:CSF biomarkers suggest that neuronal integrity is acutely maintained in AME patients, despite neuroaxonal compromise. Low-levels of biomarkers of synaptic function may reflect antibody-mediated internalization of cell-surface receptors, and may represent an acute correlate of antibody-mediated synaptic dysfunction, with the potential to inform disease severity and outcomes.

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Effects of simufilam on cerebrospinal fluid biomarkers in Alzheimer’s disease: A randomized clinical trial

10.21203/rs.3.rs-249858/v1 ◽

2021 ◽

Author(s):

Hoau-Yan Wang ◽

Zhe Pei ◽

Kuo-Chieh Lee ◽

Yaneicy Gonzalez Rojas ◽

Tamara Doehner ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Spatial Working Memory ◽

Csf Biomarkers ◽

Filamin A ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Total Tau ◽

Primary Endpoints ◽

Csf Levels

Abstract BACKGROUND Simufilam is a first-in-class drug candidate targeting altered filamin A, a proteopathy in Alzheimer’s disease. The primary objective of this Phase 2 clinical trial was to evaluate the effects of simufilam on cerebrospinal fluid (CSF) biomarkers in Alzheimer’s disease patients. A secondary objective was to assess cognitive enhancement. METHODS In a randomized, placebo-controlled trial conducted across 9 clinical sites in the US, 64 mild-to-moderate Alzheimer’s disease patients were randomized to simufilam 50 or 100 mg b.i.d. or placebo for 28 days. Clinical diagnosis was confirmed by CSF total tau/amyloid-beta1 − 42 (Aβ42) > 0.28. Co-primary endpoints were changes in CSF Aβ42, total tau, phospho-tau (P-tau181), neurogranin, neurofilament light chain, and YKL-40. Secondary endpoints included additional CSF biomarkers assessing neuroinflammation and blood brain barrier integrity, and tests of episodic and spatial working memory. RESULTS Adjusting for multiplicity of the six co-primary endpoints (p < 0.008 versus placebo required for significance), simufilam 50 and 100 mg significantly reduced CSF levels of total tau, hyperphosphorylated tau (P-tau181), neurogranin, neurofilament light chain and YKL-40. Simufilam 50 mg significantly increased CSF levels of Aβ42. On secondary CSF biomarker endpoints, both doses of simufilam significantly reduced IL-6, soluble TREM2 (triggering receptor expressed on myeloid cells-2), HMGB1 (high mobility group box-1), albumin and immunoglobulin G. All but one patient improved from baseline across biomarkers. Simufilam 50 and 100 mg showed effect sizes versus placebo (0.23–0.46) in change from baseline in episodic memory and spatial working memory. Episodic memory improvements correlated most strongly with decreases in P-tau181 (R2 = 0.48). Simufilam was safe and well tolerated. Target engagement was demonstrated by filamin A linkages to nicotinic acetylcholine receptor subtype α7 (α7nAChR) and toll-like receptor 4 (TLR4) in lymphocytes. CONCLUSIONS Simufilam was safe and well tolerated and significantly improved eleven CSF biomarkers in patients with Alzheimer’s disease, implying biological evidence of disease modification. Simufilam will be further evaluated in large, definitive clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT04079803.

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Neurofilament Levels Are Reflecting the Loss of Presynaptic Dopamine Receptors in Movement Disorders

Frontiers in Neuroscience ◽

10.3389/fnins.2021.690013 ◽

2021 ◽

Vol 15 ◽

Author(s):

Elena Diekämper ◽

Britta Brix ◽

Winfried Stöcker ◽

Stefan Vielhaber ◽

Imke Galazky ◽

...

Keyword(s):

Dopamine Transporter ◽

Strong Correlation ◽

Corticobasal Degeneration ◽

Alpha Synuclein ◽

Csf Biomarkers ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Total Tau ◽

Nucleus Caudatus ◽

Z Scores

Aims: Neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain (pNfH) are biomarkers for neuroaxonal damage. We assessed whether NfL and other biomarker levels in the CSF are correlated to the loss of presynaptic dopamine transporters in neurons as detected with dopamine transporter SPECT (DaTscan).Methods: We retrospectively identified 47 patients (17 Alzheimer’s dementia, 10 idiopathic Parkinson’s disease, 7 Lewy body dementia, 13 progressive supranuclear palsy or corticobasal degeneration) who received a DaTscan and a lumbar puncture. DaTscan imaging was performed according to current guidelines, and z-scores indicating the decrease in uptake were software based calculated for the nucleus caudatus and putamen. The CSF biomarkers progranulin, total-tau, alpha-synuclein, NfL, and pNfH were correlated with the z-scores.Results: DaTscan results in AD patients did not correlate with any biomarker. Subsuming every movement disorder with nigrostriatal neurodegeneration resulted in a strong correlation between putamen/nucleus caudatus and NfL (nucleus caudatus right p < 0.01, putamen right p < 0.05, left p < 0.05) and between pNfH and putamen (right p < 0.05; left p < 0.042). Subdividing in disease cohorts did not reveal significant correlations. Progranulin, alpha-synuclein, and total-tau did not correlate with DaTscan results.Conclusion: We show a strong correlation of NfL and pNfH with pathological changes in presynaptic dopamine transporter density in the putamen concomitant to nigrostriatal degeneration. This correlation might explain the reported correlation of impaired motor functions in PD and NfL as seen before, despite the pathological heterogeneity of these diseases.

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Cognitively Normal APOE ε4 Carriers Have Specific Elevation of CSF SNAP-25

10.21203/rs.3.rs-122858/v1 ◽

2020 ◽

Author(s):

Omar Hameed Butt ◽

Justin M Long ◽

Rachel L. Henson ◽

Elizabeth Herries ◽

Courtney L. Sutphen ◽

...

Keyword(s):

Alzheimer Disease ◽

Genetic Risk ◽

Carrier Status ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Cognitively Normal ◽

Disease Research ◽

Total Tau ◽

T Tau ◽

Phosphorylated Tau 181

Abstract Background: Cerebrospinal fluid (CSF) synaptosomal-associated protein 25 (SNAP-25) and neurogranin are recently described biomarkers for synaptic integrity that are known to be elevated in the CSF of symptomatic Alzheimer disease (AD). Their relationship with Apolipoprotein E (APOE) ε4 carrier status, the major genetic risk factor for AD, remains unclear.Methods: In this study, CSF SNAP-25 and neurogranin were compared in cognitively normal APOE ε4 carriers and non-carriers (n=274, mean age 65.0 ± 9.0 years, 39% APOE ε4 carriers, 58% female) enrolled at the Knight Alzheimer Disease Research Center, and in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database.Results: SNAP-25, a biomarker of pre-synaptic integrity, was specifically elevated in APOE ε4 carriers versus non-carriers (5.95 ± 1.72 pg/ml, 4.44 ± 1.40 pg/ml, p <0.0001), even after adjusting for age, sex, years of education, and amyloid status (p <0.0001). In contrast, CSF neurogranin, a biomarker of post-synaptic integrity, did not vary by APOE ε4 status. Further, CSF total tau (t-tau), phosphorylated-tau-181 (ptau181), and neurofilament light chain (NfL) also did not vary by APOE ε4 status. Similar results were observed in the ADNI cohort. Conclusion: Our findings suggest APOE ε4 carriers have both amyloid-related and amyloid-independent presynaptic disruption as reflected by elevated CSF SNAP-25 levels. In contrast, post-synaptic disruption as reflected by elevations in CSF neurogranin is related to amyloid status.

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Unraveling Pathophysiological Mechanisms of Parkinson’s Disease: Contribution of CSF Biomarkers

Biomarker Insights ◽

10.1177/1177271920964077 ◽

2020 ◽

Vol 15 ◽

pp. 117727192096407

Author(s):

Lucia Farotti ◽

Federico Paolini Paoletti ◽

Simone Simoni ◽

Lucilla Parnetti

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Clinical History ◽

Substantial Contribution ◽

Csf Biomarkers ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Disease Modifying Drugs ◽

Precise Diagnosis ◽

And Oxidative Stress

Diagnosis of Parkinson’s disease (PD) relies on clinical history and physical examination, but misdiagnosis is common in early stages. Identification of biomarkers for PD may allow for early and more precise diagnosis and provide information about prognosis. Developments in analytical chemistry allow for the detection of a large number of molecules in cerebrospinal fluid (CSF), which are known to be associated with the pathogenesis of PD. Given the pathophysiology of PD, CSF α-synuclein species have the strongest rationale for use, also providing encouraging preliminary results in terms of early diagnosis. In the field of classical Alzheimer’s disease (AD) biomarkers, low CSF Aβ42 levels have shown a robust prognostic value in terms of development of cognitive impairment. Other CSF biomarkers including lysosomal enzymes, neurofilament light chain, markers of neuroinflammation and oxidative stress, although promising, have not proved to be reliable for diagnostic and prognostic purposes yet. Overall, the implementation of CSF biomarkers may give a substantial contribution to the optimal use of disease-modifying drugs.

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Inflammation-related plasma and CSF biomarkers for multiple sclerosis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1912839117 ◽

2020 ◽

Vol 117 (23) ◽

pp. 12952-12960 ◽

Cited By ~ 6

Author(s):

Jesse Huang ◽

Mohsen Khademi ◽

Lars Fugger ◽

Örjan Lindhe ◽

Lenka Novakova ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Neurological Diseases ◽

Area Under The Curve ◽

Csf Biomarkers ◽

Healthy Controls ◽

Protein Biomarkers ◽

Neurofilament Light Chain ◽

Diagnostic Efficacy ◽

Neurofilament Light

Effective biomarkers for multiple sclerosis diagnosis, assessment of prognosis, and treatment responses, in particular those measurable in blood, are largely lacking. We have investigated a broad set of protein biomarkers in cerebrospinal fluid (CSF) and plasma using a highly sensitive proteomic immunoassay. Cases from two independent cohorts were compared with healthy controls and patients with other neurological diseases. We identified and replicated 10 cerebrospinal fluid proteins including IL-12B, CD5, MIP-1a, and CXCL9 which had a combined diagnostic efficacy similar to immunoglobulin G (IgG) index and neurofilament light chain (area under the curve [AUC] = 0.95). Two plasma proteins, OSM and HGF, were also associated with multiple sclerosis in comparison to healthy controls. Sensitivity and specificity of combined CSF and plasma markers for multiple sclerosis were 85.7% and 73.5%, respectively. In the discovery cohort, eotaxin-1 (CCL11) was associated with disease duration particularly in patients who had secondary progressive disease (PCSF< 4 × 10−5,Pplasma< 4 × 10−5), and plasma CCL20 was associated with disease severity (P= 4 × 10−5), although both require further validation. Treatment with natalizumab and fingolimod showed different compartmental changes in protein levels of CSF and peripheral blood, respectively, including many disease-associated markers (e.g., IL12B, CD5) showing potential application for both diagnosing disease and monitoring treatment efficacy. We report a number of multiple sclerosis biomarkers in CSF and plasma for early disease detection and potential indicators for disease activity. Of particular importance is the set of markers discovered in blood, where validated biomarkers are lacking.

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Cerebrospinal fluid levels of chitinase 3-like 1 and neurofilament light chain predict multiple sclerosis development and disability after optic neuritis

Multiple Sclerosis Journal ◽

10.1177/1352458515574148 ◽

2015 ◽

Vol 21 (14) ◽

pp. 1761-1770 ◽

Cited By ~ 60

Author(s):

S Modvig ◽

M Degn ◽

H Roed ◽

TL Sørensen ◽

HBW Larsson ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Optic Neuritis ◽

Light Chain ◽

Oligoclonal Bands ◽

Enzyme Linked Immunosorbent Assay ◽

Csf Biomarkers ◽

Neurofilament Light Chain ◽

Neurofilament Light

Background: Cerebrospinal fluid (CSF) biomarkers have been suggested to predict multiple sclerosis (MS) after clinically isolated syndromes, but studies investigating long-term prognosis are needed. Objective: To assess the predictive ability of CSF biomarkers with regard to MS development and long-term disability after optic neuritis (ON). Methods: Eighty-six patients with ON as a first demyelinating event were included retrospectively. Magnetic resonance imaging (MRI), CSF leukocytes, immunoglobulin G index and oligoclonal bands were registered. CSF levels of chitinase-3-like-1, osteopontin, neurofilament light-chain, myelin basic protein, CCL2, CXCL10, CXCL13 and matrix metalloproteinase-9 were measured by enzyme-linked immunosorbent assay. Patients were followed up after 13.6 (range 9.6–19.4) years and 81.4% were examined, including Expanded Disability Status Scale and MS functional composite evaluation. 18.6% were interviewed by phone. Cox regression, multiple regression and Spearman correlation analyses were used. Results: Forty-six (53.5%) developed clinically definite MS (CDMS) during follow-up. In a multivariate model MRI ( p=0.0001), chitinase 3-like 1 ( p=0.0033) and age ( p=0.0194) combined predicted CDMS best. Neurofilament light-chain predicted long-term disability by the multiple sclerosis severity scale ( p=0.0111) and nine-hole-peg-test ( p=0.0202). Chitinase-3-like-1 predicted long-term cognitive impairment by the paced auditory serial addition test ( p=0.0150). Conclusion: Neurofilament light-chain and chitinase-3-like-1 were significant predictors of long-term physical and cognitive disability. Furthermore, chitinase-3-like-1 predicted CDMS development. Thus, these molecules hold promise as clinically valuable biomarkers after ON as a first demyelinating event.

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Association of Plasma Neurofilament Light Chain with Neocortical Amyloid-β Load and Cognitive Performance in Cognitively Normal Elderly Participants

Journal of Alzheimer s Disease ◽

10.3233/jad-180025 ◽

2018 ◽

Vol 63 (2) ◽

pp. 479-487 ◽

Cited By ~ 19

Author(s):

Pratishtha Chatterjee ◽

Kathryn Goozee ◽

Hamid R. Sohrabi ◽

Kaikai Shen ◽

Tejal Shah ◽

...

Keyword(s):

Cognitive Performance ◽

Light Chain ◽

Amyloid Β ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Cognitively Normal

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Immunity and amyloid beta, total tau and neurofilament light chain: Findings from a community‐based cohort study

Alzheimer s & Dementia ◽

10.1002/alz.12212 ◽

2020 ◽

Author(s):

Lana Fani ◽

Shahzad Ahmad ◽

M. Kamran Ikram ◽

Mohsen Ghanbari ◽

M. Arfan Ikram

Keyword(s):

Cohort Study ◽

Amyloid Beta ◽

Light Chain ◽

Community Based ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Total Tau

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In the blood: biomarkers for amyloid pathology and neurodegeneration in Alzheimer’s disease

Brain Communications ◽

10.1093/braincomms/fcaa054 ◽

2020 ◽

Vol 2 (1) ◽

Cited By ~ 2

Author(s):

Jamie Toombs ◽

Henrik Zetterberg

Keyword(s):

Light Chain ◽

Amyloid Β ◽

Population Based ◽

Blood Biomarkers ◽

Neurofilament Light Chain ◽

Population Based Study ◽

Neurofilament Light ◽

Total Tau ◽

Amyloid Pathology ◽

Relationship Of

This scientific commentary refers to ‘Plasma total-tau, neurofilament light chain and amyloid-β levels and risk of dementia: a population-based study’ by de Wolf et al. (https://doi.org/10.1093/brain/awaa054), and ‘Relationship of amyloid-b1–42 in blood and brain amyloid: Ginkgo Evaluation of Memory Study’ by Lopez et al. (https://doi.org/10.1093/braincomms/fcz038), two papers that illustrate these latest developments.

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