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NFL AS A HIGHLY RELEVANT BIOMARKER IN AD AND OTHER NEUROLOGICAL DISEASES

Updated: Mar 17



What is neurofilament-light chain (NfL)?


Neurofilaments, the larger group to which NfL belongs, are structural components of neuronal cytoskeleton that are abundant in large myelinated axons. They have several biological functions, including stability and growth of axons, conduction properties, stability of mitochondria and maintaining the structure and function of dendritic spines as well as a role in regulating glutamatergic and dopaminergic neurotransmission at the synaptic level.

As a consequence of axonal damage or degeneration, they are released into the cerebrospinal fluid through the axonal plasma membrane. They leak into the extracellular fluid and hence into the CSF, penetrate into the blood, and thus behaving in general as a relatively non-specific marker of neuroaxonal pathology.

There is a good chance you have never heard of neurofilament-light chain outside the context of neurodegenerative diseases, and chances are that will remain so. Google ‘neurofilament light chain’, and apart from a Wikipedia page explaining what it is exactly, the first twenty results you get are related to its quality as a biomarker in a wide range of neurological disorders: Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), multiple sclerosis (MS), stroke, Huntington's disease, …


Neurofilament Light (NfL) is a neuronal protein highly expressed in large calibre myelinated axons. Its levels increase in cerebrospinal fluid (CSF) and blood proportionally to the degree of axonal damage in a variety of neurological disorders, including inflammatory, neurodegenerative, traumatic and cerebrovascular diseases. It is encoded by the NEFL gene, can be measured with immunoassays in cerebrospinal fluid and plasma, and used as a biomarker reflecting axonal damage in a wide variety of neurological disorders.


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NfL in the serum increases with age.



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NfL levels in the CSF and blood are altered in CNS diseases. As they correlate with disease characteristics, and are a quantitative measure of ongoing axonal injury, they can be used to monitor disease progression and, ideally, for evaluating patients’ response to treatments.



Neurofilament-light chain as a diagnostic and treatment-predictive biomarker in neurological disorders


NfL in the CSF – cerebrospinal fluid - is increased in a wide range of neurological disorders, and highest in ALS. They are unspecific to the type of neurologic disease, but are quite good identifiers of disease progression and drug effect. In purely neurodegenerative diseases, NfL could serve as both a prognostic marker of decline but also an efficacy biomarker of experimental therapies.

Simply put, the more levels of NfL go down with treatment, the more it becomes likely that the disease is being treated and the patient is improving, without saying anything on what the underlying mechanism of action is. And there is a clear link with increased NfL in neurodegenerative diseases, demyelinating conditions and inflammatory CNS.

If you look into monitoring of treatment response, it can have value in maybe any neurodegenerative disease. […] In the dementia trials, it's being used in almost every trial that's currently set up.”


In AD, the levels of NfL in CSF are increased years before symptoms of the disease appear.



Link – min. 31 and further:

Dr. Larry Friedhoff, the developer of donepezil, quoted in this regard, in 2019:

A single assessment of this biomarker at a single time could be used to assess drug efficacy. […] Regulators, as I mentioned, have required two of these clinical noisy endpoints. For approval in mild cognitive impairment, there's now a change in the regulation, so that it's possible that a biomarker could be used in place of one of the noisy clinical endpoints. So if that is extended to the treatment of Alzheimer's disease as well, then that would be a lifting of a significant part of the extra clinical statistical burden for the approval of AD products. And why is this important? Because biomarkers for the rate of clinical decline could be in my opinion a game-changer in drug development. Effects could be potentially seen in short studies. Filament light chain seems, from what I can read, to change relatively quickly in response to drug effects and diseases other than Alzheimer's. [… ] They may be less noisy than these clinical endpoints we've been stuck with for many years and biomarkers for the rate of clinical decline could facilitate recruitment of patients who are declining rapidly, even if there the clinical endpoints aren't changing rapidly. We know we might be able to say: ‘well, they're losing neuronal function rapidly, we just don't see it in signs and symptoms yet.’ And of course, the faster the placebo group declines, the easier it is to see a treatment effect from an active drug. And this could lead to shorter, smaller, less expensive studies.



In AD, NfL changes in blood appear to precede the first clinical manifestations of AD by about 16 years, and a peak in the rate of increase of blood NfL has been observed near with the onset of symptoms, thus suggesting that NfL marks onset and intensity of neurodegeneration in AD. Therefore, finding a noninvasive prognostic biomarker and testing potential early treatment options to prevent Alzheimer disease prior to the onset of symptoms is of great importance. CSF NfL might be a measure of both amyloid-dependent and independent neuronal loss, which is particularly relevant if considering the contribution of different proteinopathies, vascular disease and neuroinflammation (the so-called mixed pathology) in AD pathophysiology. Higher levels of NfL, regardless of what type was collected, were generally associated with decreased cognitive performance. NfL was related to the domains of attention, memory, visuospatial, language, information processing, and executive functions. Still in AD, increased levels of NfL were seen as indicative of white matter lesions and hence NfL could serve as a biomarker of white matter integrity (white matter being essentially myelinated axons, whereas grey matter is essentially composed of neurons – cfr ‘Alzheimer’s disease should be approached as white matter disease, not gray’).


In MCI, a cognitively healthy individuals with higher CSF NfL values have a threefold higher risk of mild cognitive impairment (MCI) over a median follow-up of 3.8 years. CSF t-tau, phosphorylated tau (p-tau) and neurogranin were not found to have a similar potential as predictors of MCI.

It was shown that CSF-NfL levels were higher in a AD dementia group as well as in a stable mild cognitive impairment (MCI) group, and in a progressive MCI group compared to a healthy control group.


In MS, blood NfL concentrations could identify acute and chronic neuronal damage, increasing NfL can predict disease worsening and brain & spinal cord atrophy, and decrease in NfL correlates with positive response to treatment. Serum NfL can predict long term clinical outcomes in this disease, with serum NfL cutoff of 7.62 pg/mL having been identified as possible discriminator of future disease progression. Higher levels of NfL were associated with decreased cognition; specifically, poorer performance on measures of working memory, executive function information processing speed, verbal fluency, attentional control, and verbal, episodic and semantic memory. Reductions of NfL have been reported for most treatments for relapsing MS, which are in line with the perceived hierarchy of treatment efficacies, with the greatest reductions seen following the most intensive treatments. Largest reductions in plasma levels were seen following alemtuzumab (48%), and the smallest reduction for teriflunomide (7%), with the other agents falling in the middle. One study showed a significant reduction of 51% in CSF NfL levels after 12-24 months of treatment with mitoxantrone in 35 patients with MS.


In ALS, the elevation of NfL levels in cerebrospinal fluid (CSF) exceeds that observed in most other neurological diseases, where it also correlates with disease progression and can provide prognostic information. Due to the rapid degeneration of motor neurons, cells with large myelinated axons containing a great amount of neurofilaments, CSF NFL levels are more than sevenfold increased in ALS in comparison with neurologically healthy controls. NFL is also associated with survival according to nearly all studies conducted on CSf, serum and and plasma.

In PD, the relationship with cognition is less clear, but increased levels of NfL did predict a reduction in motor progression.


In Frontotemporal Dementia, on 28 July 2020, Alector reported a 29% reduction of NfL in its AL001 Phase 1b and Phase 2 open-label study over 28 weeks (7 months). On 29 July 2021, in its Phase 2 study at 12 months, it reported a 47% clinical slowing of progression and a change from 7.3 to 6.5 in NfL in CSF.



Neurofilament-light chain reporting in Alzheimer’s disease trials


This is the reporting made by different companies in the Alzheimer’s disease biotech realm.


Company

Reported reduction in neurofilament-light chain

INmune Bio (XPro)

12 weeks: -84%

Cassava Sciences (simufilam)

28 days: -28% (50mg) / -34% (100 mg) / 6 months: -55%

Annovis Bio (Bantenerutap)

-6% in AD / -10% in PD. Timeframe not mentioned.

Anavex Life Sciences (AVXL 2-73)

/ (not reported / not retrieved)

Biogen (aducanumab)

(not reported / not retrieved)

Biogen (lecanemab)

Noticeable difference in decline compared to placebo, percentage not mentioned

Roche (gantenerumab)

Slowed increased of 1.7% compared to 3.9% in placebo

Roche (solanezumab)

No benefit.



Conclusion


NfL can be seen as both a diagnostic as well as a treatment-predictive measure in an array of neurodegenerative diseases.

Increased levels of NfL can indicate disease in AD before symptoms onset. NfL reduction after treatment could be predictive of treatment response.



Further pictures and links are included here:


INmune Bio:


Cassava Sciences:




Annovis Bio:



Biogen (lecanemab)



Roche (gantenerumab and solanezumab): link


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