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
- Hansson O, Janelidze S, Hall S, Magdalinou N, Lees AJ, Andreasson U, Norgren N, Linder J, Forsgren L, Constantinescu R, Zetterberg H, Blennow K, Swedish BioFINDER study. Blood-based NfL: A biomarker for differential diagnosis of parkinsonian disorder. Neurology. 2017 Feb 8; PubMed.
- Alves G, Bonanni L. Neurofilament light: A heavyweight diagnostic biomarker in neurodegenerative parkinsonism?. Neurology. 2017 Mar 7;88(10):922-923. Epub 2017 Feb 8 PubMed.