What was once possible only with spinal fluid now looks to be reproducible in blood. As reported online in Neurology on February 8, a sensitive test for neurofilament light chain (NfL) distinguishes Parkinson’s disease (PD) from related parkinsonian disorders. Blood NfL rises significantly in people with multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS), while in PD and controls it creeps up only slightly or not at all, report scientists led by Oskar Hansson, Lund University, Sweden. While not quite ready for the clinic, this test may help in differential diagnoses, Hansson told Alzforum. Scientists believe that NfL, a cytoskeletal protein found in myelinated axons, could be a general marker of white matter neurodegeneration. “If NfL is elevated, it doesn’t necessarily mean a person has an atypical parkinsonian disorder, but it could be red flag that a patient might not have ordinary PD,” he said.

Clinicians find it difficult to distinguish atypical parkinsonian disorders (APD) from PD based on clinical symptoms alone, especially early in disease. Similar motor difficulties can mask different underlying pathologies. This makes disease management challenging, since only PD patients respond to levodopa. Patients with APD tend to decline faster and die sooner than people with PD. “Distinguishing major parkinsonian groups is crucial for best possible treatment and care,” wrote Guido Alves, Stavanger University Hospital, Norway, and Laura Bonanni, University G. d’Annunzio of Chieti-Pescara, Italy, in an accompanying editorial. This is especially true after the first symptoms begin, when doctors are advising patients about clinical trials, treatments, and prognosis.

Scientists have been seeking biomarkers that will tell APD and PD apart. Hansson and others have reported that levels of cerebrospinal fluid (CSF) NfL spike higher in APD than in PD patients and healthy controls (Nov 2012 news; Aug 2015 news). This may reflect the widespread neuronal damage in APDs, which can affect axons in multiple brain regions. In PD, neurodegeneration occurs mostly in the dopaminergic neurons of the substantia nigra.

Researchers have also been testing blood for NfL. A recent study led by Jens Kuhle, University Hospital Basel, Switzerland, and Mathias Jucker, University of Tübingen, reported that an electrochemiluminescence (ECL) immunoassay-based blood test for NfL separated people with PD from APD in 200 banked samples from the Neuro-Biobank Tübingen (Jun 2016 news). In the current study, Hansson, along with other scientists from the Swedish BioFINDER study, adopted a single molecule array assay, or SIMOA. It is 25 times more sensitive, detecting less than 1 picogram NfL per milliliter of fluid (see Apr 2016 news). They tested blood and CSF samples from three separate cohorts—278 patients from Lund, another 117 from London, and 109 Swedish patients whose symptoms had begun no more than three years before. All together, Hansson had samples from 244 people with PD, 88 with MSA, 70 with PSP, 23 with CBS, and 79 healthy controls.In each cohort, the correlations between CSF and blood NfL levels were tight. “They were much better than I would have anticipated,” said Hansson. “It’s a good linear correlation that we haven’t seen with tau and other potential biomarkers.” In all three groups, people with APD consistently had higher levels of NfL in their blood than either controls or people with PD. Blood NfL could distinguish PD from APD in the Lund and London cohorts with a specificity of 90 percent and a sensitivity of 81 percent. Percentages were lower, though still significant, in the early disease cohort, with a specificity and sensitivity of 80 and 70 percent, respectively.

“That they showed the same results in three different cohorts is important,” said Kuhle, who was not involved in the project. “Biomarkers fail frequently because the data are irreproducible,” he said. “NfL is one of the rare candidates [with data] reproduced by several different groups around the world.”

“Overall, blood NfL seems to have the potential to provide a good biomarker to differentiate PD from APD,” wrote Alves and Bonanni. They found the data convincing, also because of the three separate cohorts, one with incipient disease.

However, all scientists interviewed for this article agreed that before it is suitable for routine clinical use, any NfL blood test will need to be standardized to ensure it is consistent and yields the same values when used by different labs. Replication is also needed in another early disease cohort, to be certain differences can be seen early in progression, wrote Brit Mollenhauer, University Medical Center Göttingen, Germany, to Alzforum. On that note, Marcel Verbeek, Radboud University Medical Center, The Netherlands, claimed the lower percentages in the early disease cohort would argue against using NfL for diagnostic purposes early in disease (see full comment below). He suggested follow-up studies to determine the prognostic value of NfL when diagnoses are uncertain.

As the authors acknowledge, NfL in body fluids is common to many disorders that involve extensive axonal damage, so will not be specific for APD. It also cannot differentiate between MSA, CBS, and PSP, as all three had similar upticks in the marker. Regardless, an assessment of blood NfL can enhance a patient’s workup, and alert doctors that an atypical disorder is afoot, Hansson said.—Gwyneth Dickey Zakaib 

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  1. It is an interesting study, describing the first identification of a biochemical marker in blood for a neurological disorder (other than autoimmune or genetic disorders), with a sufficiently high diagnostic accuracy (sensitivity and specificity of blood NfL each more than 80 percent). This is a major step forward in the eventual application of such biomarkers in clinical practice. The nice thing about this study is the major effort in collecting three different cohorts from two different countries. Besides, the findings remain significant in a cohort with a relatively short disease duration. However, it should be noted that both sensitivity and specificity drop to lower levels in this cohort (80 percent or lower), which would argue against the use of this test in diagnosis of early cases (because of too low a diagnostic accuracy).

    However, we have to keep in mind that—as in many similar diagnostic studies—these patients groups are probably biased toward a selection with a clear diagnosis that was made after a number of years of follow-up. In future studies it should be investigated what the prognostic value is for these biomarkers at a time when the clinical diagnosis is still very uncertain. And, how much will this test add to the diagnostic work-up (clinical and neurological investigations, response to medication, MRI) that will be done anyway in such patients; in other words, does the implementation of the analysis of NfL in blood change the decisions of the treating clinician? These are questions that should be answered in follow-up studies.

    A more technical aspect of the study is that quantification of NfL in blood now relies on the availability of specific equipment (Simoa, Quanterix). More widespread implementation of this biomarker assay will be possible when this biomarker test can be developed using other, more frequently used platforms. For the moment, the use of this test will be limited to specialty labs. Moreover, it would be nice to see if the same results can be replicated by others, thereby demonstrating the robustness of the assay across different laboratories.

    On a slightly different topic, it is interesting to see that the PD groups within the London and Lund cohorts (cohorts nos. 1 and 2 in the study) not only differ in disease severity (by 0.6 points on the H&Y score) and four years in disease duration, but most strikingly in the levels of cerebrospinal fluid NfL, which, in the Lund group, are exactly the same in the PD and control groups, but in the London cohort are three times higher (and close to the levels in the atypical parkinsonism groups) than in controls. This makes you wonder, if CSF and blood levels are so well correlated, why in the London group the blood NfL levels are still relatively comparable to the controls. And what might be the reason for this large difference in the two PD groups? It would be interesting to further delineate the characteristics of the PD groups in these two cohorts.

  2. I fully agree that further work is needed, such as evaluating whether the test adds to the diagnostic work-up of uncertain cases of parkinsonism, especially in a setting where the patients are examined by medical doctors who are not specialists in movement disorders. I also agree that it will take time to establish a method of measuring NfL in blood that can be used in a clinical routine setting, and I believe that technical platforms other than the Simoa could also be used in this context. However, the differences between the Lund and the London cohorts when it comes to CSF NfL levels should be interpreted with caution. In the London cohort the NfL levels in CSF (not blood) were only available in five cases with PD (as written in the manuscript, e.g. in the legend of Figure 1 and in the legend of Table 2). Of these five patients with PD, four had completely normal CSF NfL levels (in the same range as the controls), but there was one outlier with a value of more than 7,000 ng/L (which resulted in a huge effect on the mean value of this parameter presented in Table 2). This is the reason we write in the result section about CSF NfL in the London cohort that: "The number of PD cases with available CSF NfL measurements (n = 5) was too low to conduct statistical analysis."

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References

News Citations

  1. Biomarker Progress? Picking the New, Better Measuring the Old
  2. Biomarkers Differentiate Parkinsonian Diseases and Forecast Decline
  3. Blood NfL Looks Good as Progression and Outcome Marker
  4. WANTED: Biomarkers for Drug Trials in Frontotemporal Dementia

Further Reading

Primary Papers

  1. . Blood-based NfL: A biomarker for differential diagnosis of parkinsonian disorder. Neurology. 2017 Feb 8; PubMed.
  2. . Neurofilament light: A heavyweight diagnostic biomarker in neurodegenerative parkinsonism?. Neurology. 2017 Mar 7;88(10):922-923. Epub 2017 Feb 8 PubMed.