Neurofilaments (NFs) are intermediate filaments that constitute the main structural proteins of the neuronal cytoskeleton, both in the central (CNS) and peripheral (PNS) nervous systems. NFs are found at the neuron cell body, at dendrites and at pre- and post-synaptic areas. They are especially present in axons and abundantly assembled in large myelinated axons.
NFs are involved in the maintenance of cell and axon structure and shape particularly relevant for axonal radial growth, regulation of nerve conduction velocity, interaction with several proteins, axonal distribution of vesicular organelles and axonal transport. NFs are composed of four subunits, light (NFL), medium (NFM) and heavy (NFH) chains plus ?-internexin in CNS and peripherin in PNS. Mutations in these subunits have been found in patients with neurological disorders like Charcot-Marie-Tooth disease (CMT), early-onset Parkinson’s disease (PD), Alzheimer’s disease (AD) and sporadic Amyotrophic Lateral Sclerosis (ALS).
Mutant NF proteins are characterized by defective transport or assembly and NF aggregation or accumulation, causing axonal dysfunction, atrophy, degeneration and decreased conduction velocities. Further, mutations described in genes other than those specifying NF subunits, may interfere with NF transport and assembly in these neurological disorders. Apart from these genetic causes, as NF are characterized by long half-lives, this potentially increases the likelihood to accumulate damage derived from inflammation, oxidative stress, neurodegenerative, vascular or traumatic injuries over time. Small quantities of NFs, particularly NFL that is the most abundant and soluble among NF subunits, are released from axons to the extracellular space in healthy individuals and this release increases normally with age. A more consistent release has been observed upon traumatic brain injury and stroke and in several neurological conditions, characterized by axonal dysfunction and degeneration like CMT, ALS, PD and other parkinsonian disorders, AD, spinal muscular atrophy (SMA), frontotemporal dementia (FTD), multiple system atrophy (MSA), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Huntington’s disease (HD), prion disease, multiple sclerosis (MS), diabetic neuropathy, HIV-associated neurocognitive disorders. Damaged NF subunits, released into the interstitial space, diffuse into the cerebrospinal fluid (CSF) and then to the blood.
While NFL subunits can be measured in CSF by conventional immunoassays, recently newly developed ultra-sensitive technologies have allowed their quantification in peripheral blood. In addition, several studies have demonstrated the close correlation between CSF and blood levels, with a clear vantage over CSF due to the higher feasibility of sampling and to the easier serial measurements for longitudinal and pharmacological studies.
There is an urgent need to identify new blood biomarkers of neurodegenerative pathologies, potentially useful as a screening method in allowing to determine potential risk to develop cognitive decline and/or neurological disorders in healthy individuals. NFL chains cannot be used alone to discriminate between distinct neurodegenerative conditions, as they are a non-specific biomarker of axonal injury. Nevertheless, in combination with specific biomarkers or diagnostic tools, their quantification might be a useful tool to discriminate among certain neurodegenerative disorders hallmarked by clinical overlap but displaying a different degree of large demyelinated axon injury. Further, NFL chains have been revealed to be a promising biomarker as a prognostic factor of survival, useful to monitor and predict the rate of progression and disease activity and to evaluate the therapy response.
We welcome any type of contribution (Original Research manuscripts, Reviews, Perspectives), exploring this theme in any type of CNS and PNS disorders characterized by axonal injury, to provide a comprehensive overview of the importance of NFL measurement in CSF and blood for the diagnosis, prognosis and response to pharmacologic interventions in neurodegenerative conditions. Contributions on the analytical methods currently used in different laboratories and their standardization, particularly focusing on the determination of reference intervals in pathological and health conditions, are also welcome.
Neurofilaments (NFs) are intermediate filaments that constitute the main structural proteins of the neuronal cytoskeleton, both in the central (CNS) and peripheral (PNS) nervous systems. NFs are found at the neuron cell body, at dendrites and at pre- and post-synaptic areas. They are especially present in axons and abundantly assembled in large myelinated axons.
NFs are involved in the maintenance of cell and axon structure and shape particularly relevant for axonal radial growth, regulation of nerve conduction velocity, interaction with several proteins, axonal distribution of vesicular organelles and axonal transport. NFs are composed of four subunits, light (NFL), medium (NFM) and heavy (NFH) chains plus ?-internexin in CNS and peripherin in PNS. Mutations in these subunits have been found in patients with neurological disorders like Charcot-Marie-Tooth disease (CMT), early-onset Parkinson’s disease (PD), Alzheimer’s disease (AD) and sporadic Amyotrophic Lateral Sclerosis (ALS).
Mutant NF proteins are characterized by defective transport or assembly and NF aggregation or accumulation, causing axonal dysfunction, atrophy, degeneration and decreased conduction velocities. Further, mutations described in genes other than those specifying NF subunits, may interfere with NF transport and assembly in these neurological disorders. Apart from these genetic causes, as NF are characterized by long half-lives, this potentially increases the likelihood to accumulate damage derived from inflammation, oxidative stress, neurodegenerative, vascular or traumatic injuries over time. Small quantities of NFs, particularly NFL that is the most abundant and soluble among NF subunits, are released from axons to the extracellular space in healthy individuals and this release increases normally with age. A more consistent release has been observed upon traumatic brain injury and stroke and in several neurological conditions, characterized by axonal dysfunction and degeneration like CMT, ALS, PD and other parkinsonian disorders, AD, spinal muscular atrophy (SMA), frontotemporal dementia (FTD), multiple system atrophy (MSA), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Huntington’s disease (HD), prion disease, multiple sclerosis (MS), diabetic neuropathy, HIV-associated neurocognitive disorders. Damaged NF subunits, released into the interstitial space, diffuse into the cerebrospinal fluid (CSF) and then to the blood.
While NFL subunits can be measured in CSF by conventional immunoassays, recently newly developed ultra-sensitive technologies have allowed their quantification in peripheral blood. In addition, several studies have demonstrated the close correlation between CSF and blood levels, with a clear vantage over CSF due to the higher feasibility of sampling and to the easier serial measurements for longitudinal and pharmacological studies.
There is an urgent need to identify new blood biomarkers of neurodegenerative pathologies, potentially useful as a screening method in allowing to determine potential risk to develop cognitive decline and/or neurological disorders in healthy individuals. NFL chains cannot be used alone to discriminate between distinct neurodegenerative conditions, as they are a non-specific biomarker of axonal injury. Nevertheless, in combination with specific biomarkers or diagnostic tools, their quantification might be a useful tool to discriminate among certain neurodegenerative disorders hallmarked by clinical overlap but displaying a different degree of large demyelinated axon injury. Further, NFL chains have been revealed to be a promising biomarker as a prognostic factor of survival, useful to monitor and predict the rate of progression and disease activity and to evaluate the therapy response.
We welcome any type of contribution (Original Research manuscripts, Reviews, Perspectives), exploring this theme in any type of CNS and PNS disorders characterized by axonal injury, to provide a comprehensive overview of the importance of NFL measurement in CSF and blood for the diagnosis, prognosis and response to pharmacologic interventions in neurodegenerative conditions. Contributions on the analytical methods currently used in different laboratories and their standardization, particularly focusing on the determination of reference intervals in pathological and health conditions, are also welcome.