Neurofilament Light Chain as Prognostic Biomarker in ALS

March 12, 2017 - als

A retrospective, longitudinal investigate of patients with opposite clinical subtypes of ALS supports a value of neurofilament light sequence (NfL) as a biomarker for illness progression. In a work, published Mar 6 in JAMA Neurology, Gianni Sorarù and colleagues during a University of Padua in Padova, Italy, fact a clever association between cerebrospinal liquid NfL and quick course or shorter presence in a organisation of 94 patients. NfL fared reduction good as a justification marker. The researchers found poignant overlie in NfL levels among patients with ALS, frontotemporal insanity (FTD), and other motor neuronopathies.

 “This investigate supports prior commentary that NfL is towering in ALS and FTD, and provides plain information on NfL in opposite forms of ALS,” pronounced Lucie Bruijn of a ALS Association, Washington, D.C. “Perhaps many important, a work confirms that NfL could be an critical apparatus for specifying quick and delayed progressors. For that reason, it could be a good stratifying magnitude in clinical trials,” Bruijn said. She combined that a investigate adds some critical sum about NfL, including display that levels are not influenced by sex or age. 

When axons tumble apart, they recover neurofilament protein, that scientists are posterior as a biomarker for neurodegeneration in many diseases. Researchers initial reported a remarkable betterment of NfL in a cerebrospinal liquid (CSF) of patients with amyotrophic parallel sclerosis dual decades ago (Rosengren et al., 1996). Subsequent work determined that high CSF or blood levels of NfL tracked with poorer augury and shorter presence (see Jun 2015 news; Weydt et al., 2016; Steinacker et al., 2016). 

To ask either NfL competence be diagnostically useful, initial author Alexandra Gaiani and colleagues analyzed CSF collected from 176 patients in Padua between 2010 and 2016. The organisation enclosed a 94 patients diagnosed with ALS, 20 with FTD, 18 with engine neuropathies, and 44 controls. Each CSF representation was performed between 6 months and dual years after illness conflict and stored. All were analyzed for NfL in 2016.  

As expected, a ALS organisation had significantly aloft CSF NfL than a other engine neuropathies or a control group. The FTD patients had middle levels. NfL in ALS and FTD had formerly usually been complicated separately, Sorarù told Alzforum.

The researchers serve divided a ALS patients into customary ALS (58 subjects), beat arm or beat leg syndrome (11 patients), on-going robust atrophy (PMA, 9), on-going bulbar palsy (PBP, 9), and top engine neuron widespread ALS (UMND, 7). The top NfL levels occurred in patients with normal ALS and in variants compared with top engine neuron lapse (progressive bulbar palsy and top engine neuron widespread ALS). Only medium elevations accompanied a clinically milder forms (flail arm or beat leg syndrome and on-going robust atrophy), that engage especially reduce motor neurons.

Those formula harken behind to a strange 1996 news in that researchers already remarkable a disproportion in neurofilament in top and reduce engine neuron forms of a illness (see also Brettschneider et al., 2012). More recently, freeing tensor imaging, that measures a firmness of vast axons, has directly related plunge of top engine neurons in a corticospinal tract to a arise in NfL in ALS (Menke et al., 2015). 

What about prognosis? The researchers followed patients for adult to 80 months after their lumbar puncture. In agreement with prior findings, NfL thoroughness in a CSF inversely correlated with speed of illness course as good as with altogether survival, even after adjusting for sex, age, ALS subtype, and disease duration.

UMND ALS presented a one disproportion to a rule. Although it is amiable and slow-progressing, patients with this form had CSF NfL as high as customary ALS. The authors speculated this reflects a primarily top corticospinal tract relapse in UMND ALS.

Could NfL be useful for diagnosis? Based on their numbers, a authors advise NfL on a possess can heed ALS from controls with scarcely 90 percent attraction and specificity. However, a pen can't heed ALS from FTD or other engine neuron illness with such certainty.  

“I’m reduction assured about a justification partial of their study, though we cruise a justification that correlates NfL to presence is unequivocally strong,” pronounced Merit Cudkowicz, Harvard Medical School.  “Because they looked during a larger farrago of engine neuron diseases and mimics, they have some-more energy to uncover a widespread of neurofilament values, and a strength as a good premonitory marker.” Cudkowicz forked out that in cases of reduce engine neuron involvement, clinicians don’t know if patients will stay that approach or rise exemplary ALS. “A reduce NfL value during a commencement is a good premonitory sign,” she said.

The parsimonious couple to course means that NfL could assistance clinicians name subjects for clinical trials. “If we take all comers, we get outrageous variability in how people progress, and afterwards we need vast representation sizes to see any effects,” remarkable Cudkowicz. That’s a large plea for a field, she added. “If NfL could assistance to collect a organisation of people who are surpassing faster, afterwards we competence be means to investigate smaller groups,” she said.

 “The investigate is unequivocally clever and well-conducted,” pronounced Henrik Zetterberg, University of Gothenberg, Sweden. By replicating prior studies, it creates a box for NfL in ALS even stronger, he said.

The latest growth in a field, a unequivocally supportive blood exam for NfL formed on singular proton array analysis, should enhance a strech of a exam to many some-more people, and concede for easier, repeat, longitudinal analysis, remarkable Zetterberg (see Feb 2017 news).—Pat McCaffrey

Pat McCaffrey is a author formed in Newton, Massachusetts.

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  1. This is a good acknowledgment of progressing impending studies of neurofilaments in engine neuron diseases (Lu et al., 2015; Steinacker et al. 2016). The dimensions of a light sequence in CSF is mostly a bit wily since of test variations. We could observe this in a turn robin on neurofilaments (Oeckl et al., 2016). Therefore, in a clinical slight we use both neurofilament light sequence and phosphorylated complicated chain. For ALS and other engine neuron diseases, such as primary parallel sclerosis (PLS), this competence not make a large disproportion (see Steinacker et al. 2016). However, it allows a approach acknowledgment of a peculiarity of a measurements. Interestingly, for primary on-going aphasias (PPA), one can subtype specific differences in neurofilament light sequence and phosphorylated complicated sequence measurements (Steinacker et al., 2017).

    References:

    .
    Neurofilament light chain: A premonitory biomarker in amyotrophic parallel sclerosis.
    Neurology. 2015 Jun 2;84(22):2247-57. Epub 2015 May 1
    PubMed.

    .
    Neurofilaments in a diagnosis of motoneuron diseases: a impending investigate on 455 patients.
    J Neurol Neurosurg Psychiatry. 2016 Jan;87(1):12-20. Epub 2015 Aug 21
    PubMed.

    .
    Multicenter validation of CSF neurofilaments as justification biomarkers for ALS.
    Amyotroph Lateral Scler Frontotemporal Degener. 2016 Jul-Aug;17(5-6):404-13. Epub 2016 Apr 11
    PubMed.

    .
    Neurofilament as a blood pen for diagnosis and monitoring of primary on-going aphasias.
    Neurology. 2017 Mar 7;88(10):961-969. Epub 2017 Feb 8
    PubMed.

  2. This is a good acknowledgment of a 1996 Rosengren et al. investigate that reported that patients with amyotrophic parallel sclerosis and other neurodegenerative diseases have increasing levels of neurofilament protein in CSF.

    In agreement with that paper, Gaiani and colleagues also found aloft NfL levels in ALS subtypes with top engine neuron impasse as compared with reduce engine neuron disease. Thus, this paper serve supports a use of CSF biomarkers in a research of patients in clinical neurology.

    Interestingly, for this specific biomarker, technical developments have given a probability to accurately investigate NfL also in blood samples (Gisslén et al., 2015), with plasma levels display a parsimonious association with CSF levels (Gisslén et al., 2015; Kuhle et al., 2016). 

    The initial studies uncover increasing blood levels of NfL in both ALS (Gaiottino et al., 2013) and FTD (Rohrer et al., 2016), identical to a commentary in CSF in a Gaiani study.

    References:

    .
    Patients with amyotrophic parallel sclerosis and other neurodegenerative diseases have increasing levels of neurofilament protein in CSF.
    J Neurochem. 1996 Nov;67(5):2013-8.
    PubMed.

    .
    Plasma Concentration of a Neurofilament Light Protein (NFL) is a Biomarker of CNS Injury in HIV Infection: A Cross-Sectional Study.
    EBioMedicine. 2016 Jan;3:135-40. Epub 2015 Nov 22
    PubMed.

    .
    Comparison of 3 methodical platforms for quantification of a neurofilament light sequence in blood samples: ELISA, electrochemiluminescence immunoassay and Simoa.
    Clin Chem Lab Med. 2016 Oct 1;54(10):1655-61.
    PubMed.

    .
    Increased neurofilament light sequence blood levels in neurodegenerative neurological diseases.
    PLoS One. 2013;8(9):e75091.
    PubMed.

    .
    Serum neurofilament light sequence protein is a magnitude of illness power in frontotemporal dementia.
    Neurology. 2016 Sep 27;87(13):1329-36. Epub 2016 Aug 31
    PubMed.

  3. This investigate adds serve weight to CSF NfL as a heading premonitory biomarker in ALS. The prolongation of a research to cruise clinical top and reduce engine neuron involvement, informal phenotypes, and a clinical illness theatre is interesting, and a correlations seem expected to mostly simulate a underlying rate of illness course in each sub-group.

    CSF NfL should now be a customary partial of all destiny healing trials, to know a practicality and opening in this landscape, compared to customary incapacity measures. A slight justification purpose for CSF NfL is still uncertain. It is not a biomarker specific to ALS, and loyal impersonate disorders are comparatively odd for a gifted ALS neurologist, for whom clinical story and hearing are still a many accurate. Blood-based NfL test growth is also anticipated, that would mislay a poignant unsentimental separator to wider implementation.

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News Citations

  1. Blood Marker May Predict ALS Progression 4 Jun 2015
  2. Touchdown for NfL: Blood Test Tells Parkinson’s from Related Disorders 10 Feb 2017

Paper Citations

  1. .
    Patients with amyotrophic parallel sclerosis and other neurodegenerative diseases have increasing levels of neurofilament protein in CSF.
    J Neurochem. 1996 Nov;67(5):2013-8.
    PubMed.
  2. .
    Neurofilament levels as biomarkers in asymptomatic and symptomatic patrimonial amyotrophic parallel sclerosis.
    Ann Neurol. 2016 Jan;79(1):152-8. Epub 2015 Dec 17
    PubMed.
  3. .
    Neurofilaments in a diagnosis of motoneuron diseases: a impending investigate on 455 patients.
    J Neurol Neurosurg Psychiatry. 2016 Jan;87(1):12-20. Epub 2015 Aug 21
    PubMed.
  4. .
    Axonal repairs markers in cerebrospinal liquid are increasing in ALS.
    Neurology. 2006 Mar 28;66(6):852-6.
    PubMed.
  5. .
    CSF neurofilament light sequence reflects corticospinal tract lapse in ALS.
    Ann Clin Transl Neurol. 2015 Jul;2(7):748-55. Epub 2015 May 25
    PubMed.

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