Neurofilament markers for ALS correlate with extent of upper and lower motor neuron disease

Poesen, Koen; Schaepdryver, Maxim De; Stubendorff, Beatrice; Gille, Benjamin; Muckova, Petra; Wendler, Sindy; Prell, Tino; Ringer, Thomas; Rhode, Heidrun; Stevens, Olivier; Claeys, Kristl G.; Couwelier, Goedele; D’Hondt, Ann; Lamaire, Nikita; Tilkin, Petra; Reijen, Dimphna Van; Gourmaud, Sarah; Fedtke, Nadin; Heiling, Bianka; Rumpel, M; Rödiger, Annekathrin; Gunkel, A.; Witte, Otto W.; Paquet, Claire; Vandenberghe, Rik; Großkreutz, Julian; Damme, Philip Van

doi:10.1212/wnl.0000000000004029

Cited by 203 publications

(264 citation statements)

References 17 publications

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“…Finally, as for the power of pNfH to discriminate between ALS and HC, our results are in line with previous reports about pNfH quantifications in the serum and CSF of ALS patient using the same ELISA kit [14] or other quantification methods [6]. …”

Section: Discussionsupporting

confidence: 91%

“…Correlations between neurofilaments and clinical parameters such as diagnostic latency and disease progression have been already been noted in previous studies in ALS [5, 6, 13, 14, 20]. We found that serum and CSF pNfH correlated significantly with progression rate at diagnosis and at the last observation, total ALSFRS-R score, and modified Rankin scale score at the last observation (albeit not at diagnosis).…”

Section: Discussionsupporting

confidence: 86%

“…In previous studies comparing the performance status of neurofilaments’ isoforms, pNfH has been proven to be a more specific and sensitive biomarker for ALS when measured in cerebrospinal fluid (CSF) [6] and serum [5]. Neurofilaments are major axonal cytoskeleton proteins which contribute to maintenance of the diameter of large myelinated axons and the integrity of nerve conduction [7].…”

Section: Introductionmentioning

confidence: 99%

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Cerebrospinal Fluid Neurofilaments May Discriminate Upper Motor Neuron Syndromes: A Pilot Study

et al. 2018

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Background: Patients presenting with upper motor neuron (UMN) signs may widely diverge in prognosis, ranging from amyotrophic lateral sclerosis (ALS) to primary lateral sclerosis (PLS) and hereditary spastic paraplegia (hSP). Neurofilaments are emerging as potential diagnostic and prognostic biomarkers for ALS, but the diagnosis of UMN syndromes still relies mostly on clinical long-term observation and on familiarity or genetic confirmation. Objectives: To test whether phosphorylated neurofilament heavy chain (pNfH) may discriminate different UMN syndromes at diagnosis and to test their prognostic role among these diseases. Methods: We measured the cerebrospinal fluid (CSF) and serum pNfH of 30 patients presenting with UMN signs and diagnosed with ALS, hSP, and PLS, plus 9 healthy controls (HC). Results: ALS patients had higher levels of pNfH in CSF and serum compared to HC (p < 0.001 and p < 0.001 in CSF and serum, respectively) and PLS (p = 0.015 and p = 0.038) and hSP (p = 0.003 and p = 0.001) patients. PLS and hSP patients had similar CSF and serum pNfH concentrations, but a higher CSF pNfH concentration, compared to HC (p = 0.002 and p = 0.003 for PLS and hSP, respectively). Receiver operating characteristic curves for discriminating ALS from PLS and hSP showed an area under the curve of 0.79 for CSF and 0.81 for serum. In multivariable survival analysis including relevant clinical factors CSF pNfH represented the strongest variable predicting survival (HR 40.43; 95% CI 3.49–467.79, p = 0.003) independently of clinical group. Conclusions: Despite some statistical instability of the results due to limitations in sample size, our study supports the role of CSF pNfH as a prognostic biomarker for motor neuron diseases presenting with UMN signs. A potential power to discriminate between ALS and other UMN syndromes at presentation, and between all of the examined MND and HC, has been detected for both CSF and serum pNfH.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

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Cerebrospinal Fluid Neurofilaments May Discriminate Upper Motor Neuron Syndromes: A Pilot Study

et al. 2018

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“…Previous studies on ALS patients reported stable NfL levels, but showed an increase over time for a subset of patients with a rapid disease progression 17, 42, 43. Serum NfL levels have also been shown to progressively increase in sporadic PPA patients 44.…”

Section: Discussionmentioning

confidence: 96%

Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

Meeter

Gendron

Sias

et al. 2018

Ann Clin Transl Neurol

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ObjectiveTo evaluate poly(GP), a dipeptide repeat protein, and neurofilament light chain (NfL) as biomarkers in presymptomatic C9orf72 repeat expansion carriers and patients with C9orf72‐associated frontotemporal dementia. Additionally, to investigate the relationship of poly(GP) with indicators of neurodegeneration as measured by NfL and grey matter volume.MethodsWe measured poly(GP) and NfL levels in cerebrospinal fluid (CSF) from 25 presymptomatic C9orf72 expansion carriers, 64 symptomatic expansion carriers with dementia, and 12 noncarriers. We explored associations with grey matter volumes using region of interest and voxel‐wise analyses.ResultsPoly(GP) was present in C9orf72 expansion carriers and absent in noncarriers (specificity 100%, sensitivity 97%). Presymptomatic carriers had lower poly(GP) levels than symptomatic carriers. NfL levels were higher in symptomatic carriers than in presymptomatic carriers and healthy noncarriers. NfL was highest in patients with concomitant motor neuron disease, and correlated with disease severity and survival. Associations between poly(GP) levels and small grey matter regions emerged but did not survive multiple comparison correction, while higher NfL levels were associated with atrophy in frontotemporoparietal cortices and the thalamus.InterpretationThis study of C9orf72 expansion carriers reveals that: (1) poly(GP) levels discriminate presymptomatic and symptomatic expansion carriers from noncarriers, but are not associated with indicators of neurodegeneration; and (2) NfL levels are associated with grey matter atrophy, disease severity, and shorter survival. Together, poly(GP) and NfL show promise as complementary biomarkers for clinical trials for C9orf72‐associated frontotemporal dementia, with poly(GP) as a potential marker for target engagement and NfL as a marker of disease activity and progression.

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“…While some authors have reported an association between CSF NFs and the number of body segments showing upper and lower motor neuron involvement42 or a correlation between CSF NFL and MRI measures of degeneration of the corticospinal tract,43 our results support the view that NF levels reflect the rate of motor neuron degeneration, that is, the biological aggressiveness of the disease (and therefore the rate of clinical deterioration), rather than its anatomical extent (and the clinical stage),5 being already high in patients with recent onset of symptoms and not differing between El Escorial diagnostic categories 11. This is also in agreement with stability of serum NFL over time,18 which seems to reflect the linear progression of clinical deterioration in ALS 44.…”

Section: Discussionmentioning

confidence: 97%

Neurofilament light chain in serum for the diagnosis of amyotrophic lateral sclerosis

Verde¹,

Steinacker

Weishaupt

et al. 2018

J Neurol Neurosurg Psychiatry

216

179

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ObjectiveTo determine the diagnostic and prognostic performance of serum neurofilament light chain (NFL) in amyotrophic lateral sclerosis (ALS).MethodsThis single-centre, prospective, longitudinal study included the following patients: 124 patients with ALS; 50 patients without neurodegenerative diseases; 44 patients with conditions included in the differential diagnosis of ALS (disease controls); 65 patients with other neurodegenerative diseases (20 with frontotemporal dementia, 20 with Alzheimer’s disease, 19 with Parkinson’s disease, 6 with Creutzfeldt-Jakob disease (CJD)). Serum NFL levels were measured using the ultrasensitive single molecule array (Simoa) technology.ResultsSerum NFL levels were higher in ALS in comparison to all other categories except for CJD. A cut-off level of 62 pg/mL discriminated between ALS and all other conditions with 85.5% sensitivity (95% CI 78% to 91.2%) and 81.8% specificity (95% CI 74.9% to 87.4%). Among patients with ALS, serum NFL correlated positively with disease progression rate (rs=0.336, 95% CI 0.14 to 0.506, p=0.0008), and higher levels were associated with shorter survival (p=0.0054). Serum NFL did not differ among patients in different ALS pathological stages as evaluated by diffusion-tensor imaging, and in single patients NFL levels were stable over time.ConclusionsSerum NFL is increased in ALS in comparison to other conditions and can serve as diagnostic and prognostic biomarker. We established a cut-off level for the diagnosis of ALS.

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Neurofilament markers for ALS correlate with extent of upper and lower motor neuron disease

Abstract: This study provides Class II evidence that elevated concentrations of CSF pNfH and NfL can accurately identify patients with ALS.

Cited by 203 publications

References 17 publications

Cerebrospinal Fluid Neurofilaments May Discriminate Upper Motor Neuron Syndromes: A Pilot Study

Cerebrospinal Fluid Neurofilaments May Discriminate Upper Motor Neuron Syndromes: A Pilot Study

Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

Neurofilament light chain in serum for the diagnosis of amyotrophic lateral sclerosis

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