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Cerebrospinal fluid phosphorylated neurofilament heavy chain and chitotriosidase in primary lateral sclerosis
  1. Federico Verde1,2,
  2. Gloria Zaina1,2,
  3. Caterina Bodio3,
  4. Maria Orietta Borghi3,4,
  5. Davide Soranna5,
  6. Silvia Peverelli1,
  7. Nicola Ticozzi1,2,
  8. Claudia Morelli1,
  9. Alberto Doretti1,
  10. Stefano Messina1,
  11. Luca Maderna1,
  12. Claudia Colombrita1,
  13. Valentina Gumina1,
  14. Cinzia Tiloca1,
  15. Pier Luigi Meroni3,4,
  16. Antonella Zambon5,6,
  17. Antonia Ratti1,7,
  18. Vincenzo Silani1,2
  1. 1 Department of Neurology - Stroke Unit and Laboratory of Neuroscience, Istituto Auxologico Italiano, IRCCS, Milan, Italy
  2. 2 Department of Pathophysiology and Transplantation, 'Dino Ferrari' Center, Università degli Studi di Milano, Milan, Italy
  3. 3 Laboratory of Immuno-rheumatology, Istituto Auxologico Italiano, IRCCS, Milan, Italy
  4. 4 Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
  5. 5 Biostatistics Unit, Istituto Auxologico Italiano, IRCCS, Milan, Italy
  6. 6 Department of Statistics and Quantitative Methods, University of Milan–Bicocca, Milan, Italy
  7. 7 Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy
  1. Correspondence to Dr Federico Verde, Department of Neurology - Stroke Unit and Laboratory of Neuroscience, Istituto Auxologico Italiano, IRCCS, Milan 20149, Italy; fdrc.verde{at}

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Primary lateral sclerosis (PLS) is a rare degenerative disease of upper motor neurons (UMNs) manifesting with progressive spasticity. Disease progression is definitely slower than in amyotrophic lateral sclerosis (ALS). Clinical distinction between PLS and ALS can be challenging, as the UMN-dominant form of ALS may sometimes not manifest lower motor neuron (LMN) signs for a long time after symptom onset.1 Therefore, traditional PLS diagnostic criteria allowed diagnosis only after 3 or 4 years of documented absence of LMN signs,2 which poses a psychological burden on patients, hinders correct clinical management and prevents enrolment in clinical trials. In order to overcome these issues, new diagnostic criteria have been recently formulated, shortening the time required for a diagnosis of probable PLS to 2 years.1

Diagnostic uncertainties in PLS are complicated by the lack of specific neurochemical biomarkers. Whereas cerebrospinal fluid (CSF) neurofilament levels are clearly increased in ALS, making them a well-established ALS biomarker reflecting axonal degeneration, few studies reported lower increases in PLS3; a similar pattern was observed for the putative ALS microglial biomarker chitotriosidase (Chit1).4 Here we measured phosphorylated neurofilament heavy chain (pNFH) and Chit1 in the CSF of patients with PLS, ALS and non-neurodegenerative neurological conditions, focusing on the ability of each biomarker to distinguish PLS from controls and from ALS.

Patients and methods


In this retrospective study we included those 10 patients (5 men, 5 women) from our consecutive PLS series (n=52) whose CSF was stored in our biobank. They all fulfilled—at the time of sampling or on later evaluations—the recently published diagnostic criteria for definite (n=9) or probable (n=1) PLS.1 Patients with ALS and neurological controls (NCs) were selected randomly from our biobank to form two cohorts with sex and age distributions similar to PLS. Patients with ALS (n=28; 16 men, 12 women) fulfilled …

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  • Contributors All authors made substantial contributions to study conception and design and/or acquisition of data and/or analysis and interpretation of data. All authors gave final approval of the version to be submitted and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Conception and design of the study: FV, VS. Sample collection, phenotyping and data management: FV, GZ, SP, NT, CM, AD, SM, LM, CC, VG, CT, VS. Study management and coordination: FV, VS. Statistical methods and analysis: DS, AZ, FV. Laboratory analyses: GZ, CB, MOB, SP. Interpretation of results: FV, GZ, CB, MOB, DS, SP, NT, CM, CC, PLM, AZ, AR, VS. Manuscript writing (first draft): FV. Critical revision of the manuscript: FV, GZ, CB, MOB, DS, SP, NT, CM, AD, SM, LM, CC, VG, CT, PLM, AZ, AR, VS.

  • Funding The work was financially supported by the Italian Ministry of Health (grant RF-2013–02355764, C9GenALSPhen).

  • Competing interests VS is in the Editorial Board of Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, European Neurology, American Journal of Neurodegenerative Disease, and Frontiers in Neurology, and received compensation for consulting services and/or speaking activities from AveXis, Cytokinetics, Italfarmaco and Zambon.

  • Patient consent for publication Not required.

  • Ethics approval The study was approved by the Ethics Committee of Istituto Auxologico Italiano, IRCCS (ID: 2020_05_19_07). Patients provided written informed consent for the study.

  • Provenance and peer review Not commissioned; externally peer reviewed.