Elevated CSF neurofilament proteins predict brain atrophy: A 15-year follow-up study.
Petzold A, Steenwijk MD, Eikelenboom JM, Wattjes MP, Uitdehaag BM.
BACKGROUND: Body fluid and structural imaging biomarkers give information on neurodegeneration. The relationship over time is not known in multiple sclerosis.
OBJECTIVE: To investigate the temporal relationship of elevated cerebrospinal fluid (CSF) neurofilament (Nf) protein levels, a biomarker for axonal loss, with magnetic resonance imaging (MRI) atrophy measures.
METHODS: In patients with multiple sclerosis, CSF Nf heavy chain (NfH) phosphoform levels were quantified at baseline and dichotomised into ‘normal’ and ‘high’. Atrophy was assessed by MRI at baseline and 15-year follow-up using SIENAX and FreeSurfer software.
RESULTS: High baseline CSF NfHSMI35 levels predicted pronounced atrophy at 15-year follow-up (odds ratio (OR): 36, p < 0.01), in the absence of baseline brain atrophy (OR: 28, p < 0.05), for the averaged MRI normalised brain volume (1.44 L vs 1.33 L, p < 0.05), normalised grey matter volume (0.77 L vs 0.69 L, p < 0.01) and putamen (12.7 mL vs 10.7 mL, p < 0.05). Region-specific calculations including the spinal cord showed that a power of >80% is reached with 14-50 patients.
CONCLUSION: These data suggest that high CSF NfH levels are an early predictor of later brain and spinal cord atrophy using structural imaging biomarkers and can be investigated in reasonably sized patient cohorts.
This is an area of research that our group understand well; so much so, that we have translated this piece of work into our clinics. Our patients now undergo lumbar punctures at diagnosis to evaluate their risk of short-term and long-term disease progression based on neurofilament levels. Prof G often talks about the adoption curve, comprising of the innovators (the first group to use a product – the more risk oriented), followed by early adopters, and eventually the laggards (the very conservative). This concept is very pertinent to what we’re doing currently and we hope to revolutionize the way MS is managed in real-life terms with this test. This is the beginning of personalized medicine.
Axel Petzold as early as 2005 demonstrated that baseline CSF neurofilament heavy chain levels (NfH, a marker of axonal damage) could predict irreversible disease progression at 3 years (Petzold A et al. Axonal damage accumulates in the progressive phase of multiple sclerosis: Three year follow up study.J Neurol Neurosurg Psychiatry 2005; 76:206–211). Here, the group extend their 3-year follow-up data and test whether high baseline CSF NfH predicts more severe brain volume loss after 15 years? The short answer to this is a ‘YES’! The Odds ratio (which is the risk of a particular outcome if a certain factor is present) of this happening is 36. To give you an idea of the importance of this statement, the odds ratio of low vitamin D predicting the development of MS is ~2.
Another piece of interesting information also arises from this work, which is that their 3 year study did not show this association with brain volume loss; the association only emerges at 15 years, indicating a serious lag to when axonal injury is manifest on MRI (see Fig below). Very annoying if your intention is to design a clinical trial using brain atrophy as the primary outcome measure!
levels. Elevated neurofilament levels precede global brain atrophy on MRI.