In a comprehensive meta-analysis, scientists led by Claire Bridel, VU University Medical Center, Amsterdam, compared levels of neurofilament light in the cerebrospinal fluid of healthy controls and patients covering a spectrum of neurological disorders. In the June 17 JAMA Neurology, they report that while NfL levels are elevated in most neurodegenerative diseases, they are particularly high in frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and the cognitive impairment that accompanies infection with HIV. The findings suggest CSF NfL could aid in the differential diagnosis of these and other disorders.
- Meta-analysis compares CSF NfL across 32 neurological disorders.
- The highest levels occur in FTD, ALS, HIV infection, and HD.
- NfL may distinguish FTD from other dementias, and PD from other parkinsonisms.
“It’s a landmark study on the potential diagnostic use of neurofilament light,” said co-author Marcel Verbeek, Radboud University, Nijmegen, The Netherlands. This systematic review brings all the data from individual case-control studies of NfL in disparate diseases together in one place, putting them in a bigger context, he said.
First author Bridel and colleagues searched PubMed for “cerebrospinal fluid” and “neurofilament light,” limiting their search to publications between 2006 and 2016. They included studies in healthy control groups, people with cognitive complaints, and patients with psychiatric diseases that affect the central nervous system. To minimize variability due to different NfL assays, they analyzed only the studies that used a commercially available ELISA assay from Uman Diagnostics. Forty-seven studies met all these criteria. The authors obtained the individual level data from each, making sure to glean information on the age, sex, and diagnosis of each individual, as well as the treatment status where applicable.
In the end, they reanalyzed raw data from 10,012 people, comprising 32 diagnostic categories. These included inflammatory diseases of the CNS, parkinsonian disorders, dementias, and predementia states.
Across diagnoses, CSF NfL was higher than in healthy controls. This was especially true for impairment in HIV (iHIV), FTD/amyotrophic lateral sclerosis, ALS itself, and Huntington’s disease, with levels averaging 21-, 10.5-, 7.6-, and 5.8-fold higher, respectively, than in controls (see image below). By comparison, AD and PD NfL levels were 1.86 and 1.08 higher than controls, respectively. The study confirmed that NfL is elevated across the board, and because values overlap among diseases, it has little value as a specific marker for any of them.
NfL Spectrum. A comparison of CSF NfL levels (log transformed) for healthy controls (top), all the way to iHIV (bottom). Average FTD levels are higher than in AD. Dots represent outliers. [Courtesy of Bridel et al., 2019.]
What about differential diagnosis? Because the average NfL levels were so much higher in FTD, it could be used to differentiate it from Alzheimer’s, vascular dementia, and dementia with Lewy bodies (DLB), the authors wrote. Yolande Pijnenburg, also at VUMC, said that in its early stages FTD can be hard to distinguish clinically from other disorders as well, such as bipolar disorder and depression, and NfL could help. “It has been a struggle to find a suitable biomarker for FTD, probably due to the multiple underlying pathologies of this disease,” she wrote.
In Parkinson’s disease (PD), PD dementia (PDD), and DLB, NfL levels overlapped, but they were all significantly below those seen in multiple system atrophy (MSA), corticobasal syndrome (CBS), or progressive supranuclear palsy (PSP), suggesting that CSF NfL could help differentiate PD from these atypical parkinsonian disorders. Historically, this has been difficult to do, especially at early stages of PD.
As has been reported before, Bridel and colleagues found that CSF NfL rose with age in healthy controls (see image below). This could reflect age-related neuron loss, ongoing preclinical neurodegenerative disease, or reduced CSF clearance with age, said senior author Charlotte Teunissen, VUMC. The authors found NfL rose in people with most dementias as they aged as well, with the exception of FTD and ALS. In contrast, NfL levels held steady as patients with neuroinflammatory disorders got older, and even decreased with age in untreated relapsing-remitting multiple sclerosis (uRRMS). Perhaps early and massive tissue loss in aggressive neurodegenerative or neuroinflammatory disorders masks age-related effects, suggested Teunissen. In other words, fewer neurons are around in later years to degenerate and contribute to the pool of NfL in the CSF.
Lifetime Changes. As healthy controls age, NfL rises in the CSF (black line). The same happens in most dementias except FTD (left) and in some parkinsonian disorders ones (right). [Courtesy of Bridel et al., 2019 JAMA Neurol.]
If CSF NfL does prove useful as a differential diagnostic marker, then plasma NfL might also. Previous studies have suggested a high concordance between the two (Jun 2016 news; Apr 2016 conference news). More recently, researchers led by Michelle Mielke, Mayo Clinic, Rochester, Minnesota, reported how changes in NfL over time tracked with other markers of neurodegeneration among 79 normal older adults taking part in the Mayo Clinic Study of Aging. An increase in both CSF and plasma NfL over 15 to 30 months correlated with increased amyloid PET and worse global cognition and attention. The findings, published in the June 10 Neurology, are in line with both DIAN and ADNI cohort studies (Jan 2019 news; May 2019 news). Stephanie Schultz, a graduate student in the lab of Tammie Benzinger at Washington University in St. Louis, said the Mayo data will help translate the value of NfL to more heterogeneous populations. Their community-based study does not exclude people who have vascular problems or other comorbidities, she noted.—Gwyneth Dickey Zakaib
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