Identifying neuroaxonal damage and quantifying the intensity of this process is a critical step in patient care because it may support diagnosis and help estimate the prognosis of neurological conditions. In addition, it is essential for the evaluation of drug candidates with disease-modifying potential. Neurofilament light protein (NfL) is an abundant cytoskeletal protein exclusively expressed by central and peripheral neurons. Elevated levels of NfL in cerebrospinal fluid (CSF) were first reported in neurodegenerative conditions more than 20 years ago,¹ sparking interest in the potential of this neuron-specific protein as a biomarker. Since then, elevated levels of NfL in CSF (cNfL) have been described in a number of neurological and psychiatric conditions. The magnitude of the increase in inflammatory, degenerative, infectious, ischemic, and traumatic neurological conditions, as well as in psychiatric disorders, varies between conditions and studies. To date, cNfL levels have not been compared systematically between neurological disorders, and patient numbers in individual studies are often low. A positive association between cNfL and age has been reported in healthy controls (HC)² but was not systematically investigated in neurological conditions and may alter the performance of this biomarker across age categories. Together, these questions limit clinical implementation of cNfL. To compare cNfL levels between diagnoses, assess the association of age and sex with these variables, and evaluate the potential of cNfL level as a diagnostic biomarker, we performed a systematic review and meta-analysis on individual data collected from studies reporting cNfL levels in diseases and controls.

Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by both neurological and systemic abnormalities. We examined the peripheral immune system and found widespread evidence of innate immune activation detectable in plasma throughout the course of HD. Interleukin 6 levels were increased in HD gene carriers with a mean of 16 years before the predicted onset of clinical symptoms. To our knowledge, this is the earliest plasma abnormality identified in HD. Monocytes from HD subjects expressed mutant huntingtin and were pathologically hyperactive in response to stimulation, suggesting that the mutant protein triggers a cell-autonomous immune activation. A similar pattern was seen in macrophages and microglia from HD mouse models, and the cerebrospinal fluid and striatum of HD patients exhibited abnormal immune activation, suggesting that immune dysfunction plays a role in brain pathology. Collectively, our data suggest parallel central nervous system and peripheral pathogenic pathways of immune activation in HD.

Huntington’s disease is an autosomal-dominant neurodegenerative disease caused by CAG trinucleotide repeat expansion in HTT, resulting in a mutant huntingtin protein. IONIS-HTT_Rx (hereafter, HTT_Rx) is an antisense oligonucleotide designed to inhibit HTT messenger RNA and thereby reduce concentrations of mutant huntingtin.