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

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.

scholarly journals Diagnostic Accuracy of Prion Disease Biomarkers in Iatrogenic Creutzfeldt-Jakob Disease

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 290
Author(s):  
Franc Llorens ◽  
Anna Villar-Piqué ◽  
Peter Hermann ◽  
Matthias Schmitz ◽  
Olga Calero ◽  
...  
Keyword(s):  
Prion Diseases ◽  
Relevant Information ◽  
Alpha Synuclein ◽  
Diagnostic Tools ◽  
Historical Period ◽  
Csf Biomarkers ◽  
Past Infection ◽  
Neurofilament Light ◽  
Total Tau ◽  
Jakob Disease

Human prion diseases are classified into sporadic, genetic, and acquired forms. Within this last group, iatrogenic Creutzfeldt–Jakob disease (iCJD) is caused by human-to-human transmission through surgical and medical procedures. After reaching an incidence peak in the 1990s, it is believed that the iCJD historical period is probably coming to an end, thanks to lessons learnt from past infection sources that promoted new prion prevention and decontamination protocols. At this point, we sought to characterise the biomarker profile of iCJD and compare it to that of sporadic CJD (sCJD) for determining the value of available diagnostic tools in promptly recognising iCJD cases. To that end, we collected 23 iCJD samples from seven national CJD surveillance centres and analysed the electroencephalogram and neuroimaging data together with a panel of seven CSF biomarkers: 14-3-3, total tau, phosphorylated/total tau ratio, alpha-synuclein, neurofilament light, YKL-40, and real-time quaking induced conversion of prion protein. Using the cut-off values established for sCJD, we found the sensitivities of these biomarkers for iCJD to be similar to those described for sCJD. Given the limited relevant information on this issue to date, the present study validates the use of current sCJD biomarkers for the diagnosis of future iCJD cases.

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

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.

Prospective Quantification of CSF Biomarkers in Antibody-Mediated Encephalitis

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000011937
Author(s):  
Gregory Scott Day ◽  
Melanie Y Yarbrough ◽  
Peter MD Körtvelyessy ◽  
Harald Prüss ◽  
Robert C Bucelli ◽  
...  
Keyword(s):  
Disease Severity ◽  
Synaptic Function ◽  
Synaptic Dysfunction ◽  
Csf Biomarkers ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Cognitively Normal ◽  
Surface Receptors ◽  
Total Tau ◽  
Normal Individuals

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.

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

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.

scholarly journals Inflammation-related plasma and CSF biomarkers for multiple sclerosis

2020 ◽  
Vol 117 (23) ◽  
pp. 12952-12960 ◽  
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.

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

2015 ◽  
Vol 21 (14) ◽  
pp. 1761-1770 ◽  
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.

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

2020 ◽  
Vol 2 (1) ◽  
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.

Can CSF biomarkers predict future MS disease activity and severity?

2020 ◽  
Vol 26 (5) ◽  
pp. 582-590 ◽  
Author(s):  
Roberta Magliozzi ◽  
Anne H Cross
Keyword(s):  
Early Report ◽  
Severe Disease ◽  
Prognostic Significance ◽  
Oligoclonal Bands ◽  
Csf Biomarkers ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Baseline Serum ◽  
Brain Volume Loss ◽  
Worse Prognosis

Multiple sclerosis (MS) is a heterogeneous disease. With several disease modifying treatments of different mechanisms of action in use now and in development, it is important to identify reliable biomarkers to identify those higher risk MS patients in whom stronger but riskier treatments might be used, as well as to identify those for whom safer treatments of lower efficacy would be sufficient. Here we review cerebrospinal fluid (CSF) and blood biomarkers that show promise for differentiating people with MS who are at risk for severe disease and disability from those with more benign disease. We reviewed published literature for studies reporting biomarkers with predictive value in MS. Most studies of MS CSF found the presence of oligoclonal bands (both IgG and IgM), high IgG index and high levels of kappa light chains to each be associated with worse prognosis. Neurofilament light chain (NfL) and two markers of glial activation, glial fibrillary acidic protein (GFAP) and YKL-40, were higher in CSF of people with subsequent clinical progression or imaging evidence for neurodegeneration. Few reports have been made yet on the prognostic significance of blood NfL, but in one early report baseline, serum NfL (sNfL) predicted subsequent brain volume loss.

scholarly journals CSF neurofilament light concentration is increased in presymptomatic CHMP2B mutation carriers

Neurology ◽  
2017 ◽  
Vol 90 (2) ◽  
pp. e157-e163 ◽  
Author(s):  
Nina Rostgaard ◽  
Peter Roos ◽  
Erik Portelius ◽  
Kaj Blennow ◽  
Henrik Zetterberg ◽  
...  
Keyword(s):  
Continuous Process ◽  
Csf Biomarkers ◽  
Neurofilament Light Chain ◽  
Cross Sectional ◽  
Neurofilament Light ◽  
Preclinical Phase ◽  
Mutation Carriers ◽  
Amyloid Aβ ◽  
Multiplexed Immunoassay ◽  
T Tau

ObjectiveA rare cause of familial frontotemporal dementia (FTD) is a mutation in the CHMP2B gene on chromosome 3 (FTD-3), described in a Danish family. Here we examine whether CSF biomarkers change in the preclinical phase of the disease.MethodsIn this cross-sectional explorative study, we analyzed CSF samples from 16 mutation carriers and 14 noncarriers from the Danish FTD-3 family. CSF biomarkers included total tau (t-tau) and neurofilament light chain (NfL) as a marker for neurodegeneration, phosphorylated tau (p-tau) as a marker for tau pathology, β-amyloid (Aβ) 38, 40, and 42 (Aβ38, Aβ40, and Aβ42) to monitor Aβ metabolism, and YKL-40 as a marker of neuroinflammation. Aβ isoform concentrations were measured using a multiplexed immunoassay; t-tau, p-tau, NfL, and YKL-40 concentrations were measured using sandwich ELISAs.ResultsCSF NfL concentration was significantly increased in mutation carriers vs noncarriers. Further, CSF NfL concentration was significantly higher in symptomatic mutation carriers compared to presymptomatic carriers, and also significantly higher in presymptomatic carriers compared to noncarriers. No differences in t-tau and p-tau and YKL-40 concentrations between controls and mutation carriers were observed. CSF concentrations of the Aβ peptides Aβ38 and Aβ40 but not Aβ42 were significantly lower in mutation carriers compared to noncarriers.ConclusionsIncreased NfL levels in presymptomatic individuals and in symptomatic patients with FTD-3 indicate a continuous process of neurodegeneration from the presymptomatic to symptomatic state. Although not specific for FTD-3 pathology, our data suggest that CSF NfL could serve as a valuable biomarker to detect onset of neurodegeneration in FTD-3 mutation carriers.

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