I am yet to request serum neurofilament light protein (NfL) in my practice. I am not sure yet why I should, but until now I confess I really haven’t looked for a reason to do so. I however know that some MSologists now tick it, along with other blood tests, when they investigate people they suspect may have multiple sclerosis (MS). NfL are proteins that are released by damaged neurones. Should I be requesting NfL in my clinical practice? I sniffed around to find the case for testing serum NfL, and below is what I found.
Many studies have looked at the value of NfL in MS. One such very well-planned study that addresses many of my questions is that by Guili Disanto and colleagues, published in the journal Annals of Neurology in 2017. In the paper, titled Serum Neurofilament light: a biomarker of neuronal damage in multiple sclerosis, the authors studied >380 people with MS and >150 healthy controls, and report four important findings.
The levels of NfL in serum strongly correlate with the levels in cerebrospinal fluid (CSF) of people with MS.
People with more active and more severe MS had higher levels of NfL.
People with MS on disease modifying treatment (DMT) had lower NfL levels than those who were not on treatment.
In people with MS who had their serum NfL tested serially over time, the level of NfL predicted those who will develop frequent relapses or progressive MS.
The authors concluded, with enough justification I think, that serum NfL is a “sensitive and clinically meaningful blood biomarker to monitor tissue damage and the effects of therapies in MS“.
As for long term outcome, the 10 year follow up study by Alok Bahn and colleagues, published in the Multiple Sclerosis Journal in 2018, is most informative. In their paper titled Neurofilaments and 10-year follow-up in multiple sclerosis, the authors noted that “CSF levels of NfL at the time of diagnosis seems to be an early predictive biomarker of long-term clinical outcome and conversion from RRMS to SPMS”. Further support for the long term prognostic value of serum NfL comes from a paper published in 2018 in the journal Brain titled Serum neurofilament as a predictor of disease worsening and brain and spinal cord atrophy in multiple sclerosis. The authors, Christian Barro and colleagues, studied more than 250 people with MS and concluded that “the higher the serum neurofilament light chain percentile level, the more pronounced was future brain and cervical spinal volume loss“.
Neurologists are always cautious when making a diagnosis of Parkinson’s disease (PD). This shouldn’t be the case because PD is not difficult to recognise-at least not most of the time. For one, PD has classical clinical signs- the trio of resting tremor, slow movements (bradykinesia), and stiffness (rigidity). For another, it is asymmetrical, starting and remaining worse on one side of the body.
All these features are however vague in the early stages of PD. To make matters worse, there are many other diseases that mimic PD. These include multiple system atrophy (MSA), progressive supranuclear palsy (PSP), Lewy body disease (LBD), corticobasal degeneration (CBD), and even SWEDDS (if it exists at all!). And always lurking in the shadows, waiting to catch the neurologist out, are dystonic tremor and essential tremor.
These PD mimics challenge and intrigue neurologists in equal measure. They contribute to the delayed and missed diagnosis of PD in 20% of cases. Are there shortcuts out there to improve our diagnostic accuracy? A simple test perhaps? Maybe some biomarker? Here are 6 budding contestants.
1. Dopamine transporter (DAT) scans
DAT scans are now in general, even if not universal, use. They help to distinguish PD from conditions such as essential tremor or drug-induced Parkinsonism. DAT scans are however expensive, and they do not distinguish PD from many of its other mimics such as MSA, PSP, (you know the roll call). There are indications that DAT scans may be normal in cases of PD. We therefore clearly need better, cheaper (and newer!) PD biomarkers than DAT scans.
2. Cerebrospinal fluid (CSF) biomarkers
Perhaps the answer is in a spinal tap or lumbar puncture (LP). A lumbar puncture is a simple but dreaded test. It is however useful for giving us access to the cerebrospinal fluid (CSF) that bathes the brain and spinal cord. Analysis of the CSF often gives the game away in many neurological disorders. It is not surprising therefore that researchers looked at a panel of nine CSF biomarkersthat may identify PD. The paper, published in the JNNP, suggests that there may be biomarker roles for neurofilament light chain (NFL), soluble amyloid precursor protein (sAPP), and α-synuclein (of course). CSF α-synuclein is the focus of another paper in BioMedCentral whichreports that one form, oligomeric α-synuclein, is theone to watch out for.
Another set of CSF biomarkers is related to blood vessel formation (angiogenesis). I came across this in a paper in Neurology titled Increased CSF biomarkers of angiogenesis in Parkinson disease. The authors are referring to vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 and VEGFR-2. Others are placental growth factor (PlGF), angiopoietin 2 (Ang2), and interleukin-8. Enough to keep researchers busy for a while.
3. Peripheral blood biomarkers
Even the most compliant patient would prefer to have a blood test rather than a spinal tap. Thankfully there are some blood-based biomarkers in the offing. One set are called α-synuclein blood transcripts (SNCA transcripts). The authors of an article published in the journal Brain report that SNCA transcripts are consistently reduced in the blood of people with early PD. The accompanying editorial however cautions on the utility of these SNCA transcripts because low levels are also seen in some people who do not have PD. The true value of SNCA transcripts may lie in their ability to predict cognitive decline, but how many people really want to know that?
Other potential blood based biomarkers mentioned are uric acid and epidermal growth factor (EGF).
4. Retinal optical coherence tomography (OCT)
Even better than blood and spinal fluid biomarkers would be something totally painless. And to the rescue comes retinal optical coherence tomography (OCT). OCT uses light waves to take pictures of the retina. This allows measurement of the size of different parts of the retina; the area of interest in PD is called the foveal pit. A paper in Movement Disorders reports that OCT is a sensitive marker of PD. The authors show that the foveal pit in PD has a unique form; it is shallow in the superior-inferior and the nasal-temporal slopes. Perhaps neurologists will soon be running to ophthalmologists, cap-in-hand, to save their blushes.
5. Salivary gland α-synuclein
Back to painful biomarkers I’m afraid, all in aid of clinching an early diagnosis you must understand. This time it’s salivary gland biopsy. Some eager researchers took biopsy samples of the submandibular salivary glands of people with early PD. They then looked for, and found, α-synuclein in about 75% of them. Their paper is published in Movement Disorders titled Peripheral Synucleinopathy in Early Parkinson’s Disease: Submandibular Gland Needle Biopsy Findings. Unfortunately 20% of control subjects without PD also had α-synuclein in their salivary glands. Could these people have pre-manifest PD? We must await larger and longer studies before we start needling away at the salivary glands of the worried-well.
Motor neurone disease (MND) is, to say the least, dreadful. It also doesn’t help that the terminology neurologists use adds to the distress. West of the Atlantic, amyotrophic lateral sclerosis (ALS) means MND but goes eastwards and it is only a subtype of MND. Thankfully, for most Americans at least, there is no confusion; it is simply Lou Gehrigdisease.
MND however remains a conundrum for neurologists who are struggling to solve its puzzling riddles. MND researchers continue to toil and sweat, but their efforts are bearing fruits. Take for example the great strides that established the link between MND and the C9ORF72 gene. What are the promising prospects in the world of MND? Here are some.
Associations: Thiamine deficiency and Diabetes
Should we be on the lookout for thiamine deficiency in patients with MND? This question is prompted by an article in the JNNP which shows an unexpectedly high frequency of laboratory, but not clinical, thiamine deficiency. Titled Thiamine deficiency in amyotrophic lateral sclerosis, the paper reported thiamine deficiency in about 28% of subjects with MND. The authors did not impute any causal association, and there is nothing to suggest that replenishing the thiamine improved outcomes. It is still worth thinking about because people with MND, as the paper emphasised, are at risk of thiamine deficiency.
Will MND ever be a curable disease? A big question, but this is the vision of all the hard-working researchers in this field. What are the prospects for a cure? One group of researchers believe the answer is in preventing misfolding of TDP-43, the protein that plays an important role in MND. They set out their case in an article published in Neurotherapeutics titled TDP-43 Proteinopathy and ALS: Insights into Disease Mechanisms and Therapeutic Targets. And don’t worry, its free access. The bold abstract says it all: “we present the case that preventing the misfolding of TDP-43 and/or enhancing its clearance represents the most important target for effectively treating ALS”. The proof of the pudding….
Diagnostic test: Nerve ultrasound
Making the diagnosis of MND is not always (make that is hardly ever) straightforward. In the early stages, symptoms are vague, and clinical signs are non-specific. MND also has many mimics. One of such mimics is multifocal motor neuropathy (MMN). To distinguish this and other mimics from MND, neurologist rely on a test called nerve conduction study (NCS). Even this however is not always helpful.
Brain magnetic resonance imaging (MRI) is not a test neurologist rely upon to make the diagnosis of MND. Not anymore it seems, going by an article in American Journal of Neuroradiology. The paper is titled A Potential Biomarker in Amyotrophic Lateral Sclerosis. In the article, the authors assessed the amount of iron deposition in the brains of people with MND using the MRI techniques called SWI and DTI. Their findings suggest that the amount of iron in the motor cortex and motor tracts of the brain is a good guide to the presence of MND. If confirmed, this technique will help to reduce the long time it often takes before neurologists confirm their suspicions of MND to patients and their families.
The outcome of MND, poor as it often is, varies quite widely. This is influenced by several factors such as the type of MND, use of the medicine riluzole, and multidisciplinary care. New research suggests that neurofilament light chain (NfL) may be a more sensitive marker of prognosis. This is reported in an article published in Neurology titled Neurofilament light chain: A prognostic biomarker in amyotrophic lateral sclerosis. The authors demonstrated that patients with MND have much higher levels of NfL than those without the disease. Furthermore, subjects with MND who had the highest levels at the onset had a higher mortality hazard ratio. I think I know what that means.
Prognostic scale: ALS-MITOS predictive system
A paper in the JNNP has proposed a new predictive system for MND called ALS-MITOS, reportedly better than the more familiar ALSFRS-R. The report is titled The MITOS system predicts long-term survival in amyotrophic lateral sclerosis. Most practicing neurologists wouldn’t know the difference because they don’t to use such predictive systems. But MND researchers would be licking their lips at the prospect of a better measure of disease progression; it will make it much easier for them to show that their interventions really do work!
There are >100 mutations in the superoxide dismutase 1 (SOD-1), a gene known to cause MND. SOD-1 is an enzyme that binds both copper and zinc, and when defective it results in mutant copper (don’t worry, I’m just finding this out myself). Acting on this hypothesis, researchers came up with a crafty way of delivering normal copper into the central nervous system of mice modelled with SOD-1 MND. Publishing in Neurobiology of Disease, the authors showed how they achieved this with CuATSM, a chemical that contains copper and currently used for PET scans. CuATSM is readily transported into the nervous system, delivering its copper as it does so.
Every recalcitrant disease is today threatened with gene therapy. Considering it has a long list of genetic risk factors, why should MND be any different? Research taking steps in this direction is therefore long overdue. One such step was published in Gene Therapy and is titled Healthy and diseased corticospinal motor neurons are selectively transduced upon direct AAV2-2 injection into the motor cortex.The authors report that they successfully transduced motor nerves of mice models of MND. In doing so they have set the stage for gene therapy in MND. I don’t claim to understand it all, but it sounds very much like they have set the ball rolling. Promising.
No, Will Smith has not developed chronic traumatic encephalopathy (CTE). He is however playing Nigerian-born Bennett Omalu in an upcoming film, Concussion. The Nigerian-born and trained forensic pathologist was the first to report an association between repeated head trauma and the neurodegenerative disease CTE. He relates his story in this interview.
It will be interesting to see the film portrays the great lengths the National Football League (NFL) went to discredit the hero but here is a trailer:
And talking of Nigerian doctors and the movies, Danny Glover will be playing a part in 93 days, a film about the action of a few dedicated doctors to stop the spread of the deadly ebola virus in Nigeria, Africa’s most populated country.