Blood NfL Levels May Distinguish Parkinson's Disease From Atypical Parkinsonian Disorders

Deborah Brauser

February 13, 2017

Testing blood samples for neurofilament light chain (NfL) protein levels may help differentiate Parkinson's disease (PD) from atypical parkinsonian disorders (APDs), new research suggests.

Analysis of more than 500 total participants among three cohorts showed that blood NfL was significantly increased in all subgroups with APD — including those with progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal syndrome (CBS) — compared with healthy volunteers or those with standard PD.

The blood test had a specificity of 90% to 91% in distinguishing between PD and APDs in two of the cohorts and of 80% in the cohort comprising only those with disease duration of 3 years or less.

In addition, "I was somewhat surprised that the diagnostic accuracy of NfL in blood was just as good as when analyzing NfL in cerebrospinal fluid (CSF)," lead author Oskar Hansson, MD, PhD, professor of neurology at Lund University, Sweden, told Medscape Medical News.

Dr Oskar Hansson

Dr Hansson added that although rare, ADPs usually progress much faster than PD and have more disabling symptoms, so providing the correct diagnosis is important for determining a patient's future needs.

"If the blood levels of NfL are increased in a certain patient with parkinsonism, then the results could be interpreted as a 'red flag,'" he said.

However, this type of test "is only one piece of the puzzle," Dr Hansson noted. "The neurological examination, patient history, and brain imaging will still be very important."

The findings were published online February 8 in Neurology.

"Overlapping Symptomatology"

The investigators note that differentiating between PD and APDs "is often difficult due to the overlapping symptomatology, especially during the early stages of the disease course."

Past studies have shown increased CSF concentration of NfL in APDs but not in PD. "However, lumbar puncture is not easily implemented in the primary care setting and may patients feel apprehensive about [it], reducing the clinical usefulness of these findings," they write.

"It's important that patients with parkinsonism are correctly diagnosed," added Dr Hansson. "Most with APD do not respond well to dopamine-targeting medications, and many…need to be handled by a team of movement disorder specialists."

The current study included three prospective cohorts. All three included patients with PD, PSP, CBS, and MSA. Only the Lund cohort and the London cohort also had healthy volunteers, whereas all of the patients in the third cohort had the disease for less than 4 years.

Table 1. Number of Patients by Condition in Each Cohort

Cohort PD MSA PSP CBS Healthy Volunteers
Lund (n = 278) 171 30 19 5 53
London (n = 117) 20 30 29 12 26
Early disease (n = 109) 53 28 22 6 0


"Blood NfL concentration was measured using an ultrasensitive single molecule array (Simoa) method," report the researchers.

In the Lund and London cohorts, blood NfL was significantly correlated with CSF NfL (both, P < .001).

Both cohorts showed that those with any of the APDs had significantly greater levels of blood NfL than did the healthy volunteers (all comparisons, P < .001).

There were also significantly greater levels of blood NfL in patients with any APD vs those with PD in all three cohorts (all comparisons, P ≤ .001). These differences remained significant in both the Lund and London cohorts even after controlling for disease duration.

Interestingly, the London cohort alone showed that blood NfL was significantly greater in the patients with PD compared with the healthy volunteers (P = .01). However, "the levels were far below those observed in patients with APD," note the investigators.

In all three cohorts, blood NfL showed high accuracy in distinguishing PD from APDs.

Table 2. Accuracy in Distinguishing Between PD and APD with Blood NfL

Cohort Area Under Curve (95% Confidence Interval) Specificity (%) Sensitivity (%)
Lund 0.91 (0.87 - 0.95) 91 82
London 0.85 (0.72 - 0.98) 90 80
Early disease 0.81 (0.73 - 0.90) 80 70


The investigators note that the study provides Class III evidence on the discriminatory abilities of blood NfL tests. One of its limitations, though, is that it cannot differentiate between the different types of APDs.

Still, the "easily accessible biomarker of axonal degeneration may improve the diagnostic workup of patients with parkinsonian symptoms in specialized clinics as well in primary care settings," they write.

Larger Studies, New Protocols Needed

James Beck, PhD, vice president of scientific affairs at the Parkinson's Disease Foundation, a division of the Parkinson's Foundation, told Medscape Medical News that this was "an interesting take" on a way to determine parkinsonisms, which can be "notoriously difficult to separate out."

Dr James Beck

"Having a test which might one day be able to do that could be really useful," said Dr Beck, who is also an adjunct professor at the New York University School of Medicine. He was not involved with this research.

"Early on, these disease can look very similar when they present to clinicians. So having something that would be more accurate than just waiting would be a real benefit to this patient population."

When asked if he thought these findings, which were in patients in Sweden and the United Kingdom, might be generalizable to other countries, Dr Beck said, "I think they will be at some point."

He noted that it's still early days, the test needs to be assessed in a larger group, and standardized protocols would be needed "so that it can be done anywhere in the world."

"Diagnostic tests are like baking. You need to be very precise in how you do it so that it can be repeatable from place to place. And that's often been the downfall for many tests such as this," said Dr Beck. "If it's not done consistently, the results can be confusing or even contradictory to each other."

If all of these technical issues are resolved, "I think this could be a useful aid to clinicians," he concluded.

The study was supported by the European Research Council, the Swedish Research Council, the Parkinson Foundation of Sweden, the Swedish Brain Foundation, the Knut and Alice Wallenberg Foundation, the Torsten Soderberg Foundation at the Royal Swedish Academy of Sciences, and the Swedish Federal Government "under the ALF Agreement." Dr Hansson has disclosed no relevant financial relationships. Disclosures for the coauthors are in the paper.

Neurology. Published online February 8, 2016. Full text

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