Researchers studying Alzheimer’s disease often focus on the death of neurons in gray-matter regions of the brain, but large white-matter tracts also deteriorate. According to a study in the November 2 JAMA Neurology, debris from these communication highways may serve as a marker of AD progression. Researchers led by Kaj Blennow and Henrik Zetterberg at the University of Gothenburg in Mölndal, Sweden, reported that cerebrospinal fluid levels of neurofilament light chain (NFL), a component of large-caliber axons, correlated with cognitive decline and disease progression in people with preclinical AD. However, CSF NFL concentrations overlapped significantly among people with mild cognitive impairment and AD. The researchers propose using NFL not as a diagnostic marker, but rather as a gauge of disease severity and perhaps as an indicator of age-related comorbidities among patients.
Large-caliber multi-axonal fibers are bolstered by a cytoskeleton made up of heavy, medium, and light neurofilament chains. Rises in CSF NFL correlate with white-matter lesions in multiple neurodegenerative diseases. A recent study from Zetterberg’s group reported that NFL levels differed among various types of dementias: People with frontotemporal dementia, vascular dementia, or with a mixed diagnosis of both AD and vascular dementia had more of the light chain in the CSF than did people with AD alone. It also distinguishes people with parkinsonism who have dementia from those with pure PD (see Aug 2015 news). Regardless of the disease, NFL correlated with more severe cognitive impairment and shortened survival (see Skillbäck et al., 2014).
For the current study, Zetterberg and colleagues teased apart the relationship between NFL and the clinical deterioration in AD. They studied CSF NFL and other biomarkers from 400 participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. At baseline, the participants were cognitively normal, or had mild cognitive impairment (MCI) or probable AD. ADNI tracked them for two years with cognitive and behavioral tests, classifying people with MCI as progressive MCI (pMCI) if they developed AD, or stable MCI (sMCI) if they did not. Zetterberg found that NFL concentration increased with age, and did not correlate with ApoE genotype.
On average, baseline NFL levels were higher in the sMCI, pMCI, and AD groups than in the cognitively normal group. People with AD and pMCI had slightly more CSF NFL than did those in the sMCI group. NFL concentration also rose along with two established markers of neurodegeneration—total CSF tau and p-tau. NFL concentrations went up slightly as CSF Aβ42 went down. However, there was no difference in CSF NFL concentrations between people who had more than and those who had less than 192 pg Aβ42 per milliliter of CSF, an established cutoff for amyloid positivity in the brain. This indicated that NFL levels in the CSR do not strongly associated with amyloid burden.
Zetterberg also considered cognition and brain atrophy. In the AD group, higher NFL tracked with poorer scores on the mini mental state exam (MMSE) and ADAS-Cog. White-matter changes and losses in hippocampal volume seen on MRI scans worsened with increasing concentrations of NFL as well.
To further explore these relationships, the researchers compared the decline of several parameters across NFL quartiles. People in the highest NFL quartiles tended to develop worse outcomes in MMSE scores, whole brain volume, ventricular volume, and white-matter change over the two-year follow up period.
The findings add clinical meaning to previous observations that NFL is elevated in people with AD, Zetterberg told Alzforum. While not likely useful as a diagnostic marker due to overlap between clinical groups, high CSF NFL likely indicated more severe disease, he said. The findings also point to the importance of high-caliber axon destruction in the progression of AD.
That NFL did not correlate with amyloid positivity (as measured by CSF Aβ42) suggests that axon degeneration is not tightly linked with amyloid pathology, Zetterberg said. Rather, elevated NFL concentrations could reflect severe age-related comorbidities such as neurovascular dysfunction and hypoxia, which can harm oligodendrocytes that lay down myelin and support white-matter tracts, for example. Those comorbidities might contribute to cognitive decline beyond that caused by AD pathology. In line with this idea, a previous study reported no correlation between CSF NFL and cognitive decline in younger AD patients, who likely had fewer age-related comorbidities (see Scherling et al., 2014). Zetterberg plans to further tease apart the NFL/amyloid relationship by examining people with early onset AD, who lack age-related comorbidities. Zetterberg said that if NFL turns out to be a strong marker of comorbidities, it could be used to select people with “pure AD” for clinical trials aimed at amyloid.
It is unclear whether NFL concentrations rise due to AD-specific processes or just due to the wider process of neurodegeneration, commented Bradley MacIntosh of the Sunnybrook Research Institute in Toronto. “It is very encouraging however that this study brings white matter into the AD mix,” he added.
Despite the potential lack of connection with amyloid, Anders Fjell of the University of Oslo in Norway commented that NFL could still be useful as a marker. “Prediction of cognitive decline and atrophy from baseline CSF NFL levels clearly adds important information to our understanding of the causes of decline,” he wrote. “Whether NFL levels also can improve prediction beyond the established biomarkers of tau will be an important next question.”—Jessica Shugart
- Skillbäck T, Farahmand B, Bartlett JW, Rosén C, Mattsson N, Nägga K, Kilander L, Religa D, Wimo A, Winblad B, Rosengren L, Schott JM, Blennow K, Eriksdotter M, Zetterberg H. CSF neurofilament light differs in neurodegenerative diseases and predicts severity and survival. Neurology. 2014 Nov 18;83(21):1945-53. Epub 2014 Oct 22 PubMed.
- Scherling CS, Hall T, Berisha F, Klepac K, Karydas A, Coppola G, Kramer JH, Rabinovici G, Ahlijanian M, Miller BL, Seeley W, Grinberg LT, Rosen H, Meredith J Jr, Boxer AL. Cerebrospinal fluid neurofilament concentration reflects disease severity in frontotemporal degeneration. Ann Neurol. 2014 Jan;75(1):116-26. Epub 2014 Jan 2 PubMed.
- Zetterberg H, Skillbäck T, Mattsson N, Trojanowski JQ, Portelius E, Shaw LM, Weiner MW, Blennow K, Alzheimer’s Disease Neuroimaging Initiative. Association of Cerebrospinal Fluid Neurofilament Light Concentration With Alzheimer Disease Progression. JAMA Neurol. 2016 Jan 1;73(1):60-7. PubMed.