In ALS, the diagnosis can take up to 12 months. To identify patients more quickly, clinicians are hoping to identify biomarkers that can help them diagnose the disease.
One emerging biomarker, phosphorylated neurofilament heavy chain (pNfH), accumulates in ALS and may therefore be helpful in identifying patients with the disease (Brettschneider et al., 2006; Ganesalingam et al., 2013). But this buildup, which likely occurs due to motor neuron damage, could be a more general sign of neurodegenerative disease (Gajdusek, 1985).
Now, clinicians from Belgium make the case for the use of pNfH to differentially diagnose ALS– ruling out diseases that share similar symptoms. The results add to growing evidence that the measurement of these proteins may help confirm diagnosis of the disease (Steinacker et al. 2016). The study provided the basis for a lively discussion among ALS experts at the satellite meeting of the European Network for the Cure of ALS (ENCALS) in Dublin in December.
Neurologist Philip Van Damme of the University of Leuven presented the results of his latest study, in which he compared cerebrospinal fluid samples from 152 patients with clinically confirmed ALS to those from 214 non-ALS controls with neurologic disease. Crucially, the study group included 18 people whose condition looked very similar to ALS, but wasn’t. “In daily clinical practice we don’t really need a marker to distinguish ALS from other neurologic diseases, except the disease mimics,” Van Damme explained, because in most cases of true ALS, the diagnosis is straightforward based on symptoms. The mimics included cases of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and primary progressive multiple sclerosis (PPMS).
The researchers measured levels of key components of axonal neurofilaments: neurofilament light chain (NfL), neurofilament heavy chain (NfH) and phosphorylated NfH (pNfH). pNfH was higher in true ALS than in controls, including diseases that resembled ALS, with limited overlap. The test accurately identified 92% of non-ALS cases. Values for neither NfH nor NfL were as useful for distinguishing ALS from disease mimics.
The results suggest that pNfH levels may be helpful in identifying patients with ALS. The assay is currently being developed by Iron Horse Diagnostics in Phoenix, Arizona (see July 2016 news).
“Our results validate the diagnostic performance of pNfH in a real-world diagnostic setting,” Van Damme concluded.
pNfH: A prediction tool?
Key questions remain. Could pNfH be used to predict when patients could present with a familial form of the disease? Van Damme’s team tested asymptomatic individuals at risk for ALS, carrying C9orf72 repeat expansions. However, measures of pNfH were no higher than controls, leaving open the question of whether the assay could help predict the timing of disease onset.
Another key question is whether the levels of pNfH reflect the disease state, which could serve as an indicator of effective therapy. The scientists analyzed longitudinal samples from a subset of patients, but did not find a strong correlation of pNfH values with disease progression. Instead, pNfH levels in individual patients tended to be stable over time.
Importantly, however, the researchers noticed that pNfH levels appeared to be higher in fast progressors suggesting this assay may be helpful in the prognosis of ALS. The results add to growing evidence that measuring levels of certain components of neurofilaments in the blood and cerebrospinal fluid might be valuable in clinical trials for stratifying patients by likely progression rate (Boylan et al., 2013; Lu et al., 2015; Lu et al., 2015).
Some neurologists, however, remain skeptical based on Van Damme’s results that pNfH can be used to speed up the diagnosis of ALS. The reason says University of Miami neurologist Michael Benatar is that the patients with diseases that appeared similar to ALS were identified in advance. “In the clinic, the overwhelming majority of patients will have ALS,” said Michael Benatar of the University of Miami. “We won’t know the test’s actual utility until we try it in a longitudinal study in patients for whom we are truly uncertain about the diagnosis.”
Neurologist Martin Turner of the University of Oxford in England agreed: “We should pilot a multicenter international study on disease mimics with true uncertainty,” he said.
Measurements of pNfH levels may have their greatest utility in clinical trials, suggested Turner, where they could stratify patients based on their likely progression rate. If researchers find that a change in pNfH levels corresponds to a clinically meaningful change in function or survival in response to treatment, it could also potentially serve as an early sign of efficacy, enabling shorter trials. For that to come about, however, pNfH will first need to be used as an exploratory measure in clinical trials, according to Turner, and those trials will need to be successful—altogether a tall order.
Finally, there is a limit to the ability of pNfH, or any diagnostic test, to reduce the 12 month diagnostic delay so common in ALS said Turner. That’s because patients often ignore or deny their early symptoms, or visit other specialists such as orthopedists, taking up valuable time before they arrive at the neurologist’s office.
“I fully agree,” Van Damme said. “We don’t yet know if it will allow us to make a diagnosis earlier.”
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