Cerebrospinal fluid neurofilament light chain levels in CLN2 disease patients treated with enzyme replacement therapy normalise after two years on treatment

Classic late infantile neuronal ceroid lipofuscinosis (CLN2 disease) is caused by a deficiency of tripeptidyl-peptidase-1. In 2017, the first CLN2 enzyme replacement therapy (ERT) cerliponase alfa (Brineura) was approved by the FDA and EMA. The CLN2 disease clinical rating scale (CLN2 CRS) was developed to monitor loss of motor function, language and vision as well as frequency of generalised tonic clonic seizures. Using CLN2 CRS in an open label clinical trial it was shown that Brineura slowed down the progression of CLN2 symptoms. Neurofilament light chain (NfL) is a protein highly expressed in myelinated axons. An increase of cerebrospinal fluid (CSF) and blood NfL is found in a variety of neuroinflammatory, neurodegenerative, traumatic, and cerebrovascular diseases. We analysed CSF NfL in CLN2 patients treated with Brineura to establish whether it can be used as a possible biomarker of response to therapy. Newly diagnosed patients had CSF samples collected and analysed at first treatment dose and up to 12 weeks post-treatment to look at acute changes. Patients on a compassionate use programme who were already receiving ERT for approximately 1yr had CSF samples collected and NfL analysed over the following 1.3 years (2.3 years post-initiation of ERT) to look at long-term changes. All newly diagnosed patients we investigated with classical late infantile phenotype had high NfL levels >2000 pg/ml at start of treatment. No significant change was observed in NfL up to 12 weeks post-treatment. After one year of ERT, two out of six patients still had high NfL levels, but all patients showed a continued decrease, and all had low NfL levels after two years on ERT. NfL levels appear to correspond and predict improved clinical status of patients on ERT and could be useful as a biomarker to monitor neurodegeneration and verify disease modification in CLN2 patients on ERT

Serum neurofilament light concentration does not increase following exposure to low velocity football heading

Objectives To investigate if heading frequency and impact biomechanics in a single session influence the concentration of serum neurofilament light (NF-L), a sensitive biomarker for axonal damage, up to 7 days after heading incident at ball velocities reflecting basic training drills. Methods Forty-four males were randomized into either control (n=8), 10 header (n=12), 20 header (n=12) or 40 header (n=12) groups. Linear and angular head accelerations were quantified during heading. Venous blood samples were taken at baseline, 6 hours, 24 hours and 7 days after heading. Serum NF-L was quantified using Quanterix NF-L assay kit on the Simoa HD-1 Platform. Results Serum NF-L did not alter over time (p=0.44) and was not influenced by number of headers [p=0.47; mean(95% CI) concentrations at baseline 6.00 pg/ml (5.00 – 7.00 pg/ml); 6 hours post 6.50 pg/ml (5.70 – 7.29 pg/ml); 24 hours post 6.07 pg/ml (5.14 – 7.01 pg/ml); and 7 days post 6.46 pg/ml (5.45 – 7.46 pg/ml)]. There was no relationship between percentage change in NF-L and summed session linear and angular head accelerations. Conclusion In adult men, heading frequency or impact biomechanics did not affect NF-L response during a single session of headers at ball velocities reflective of basic training tasks