Increased concentrations of CSF NFL are

Increased concentrations of CSF NFL are not specific to HIV-related brain damage; CSF NFL levels have been shown to be a sensitive indicator of CNS axonal injury in several neurological diseases (Norgren et al., 2003; Constantinescu et al., 2010; Gunnarsson et al., 2011) including various infections (Studahl et al., 2000; Grahn et al., 2013), and, by extrapolation, plasma NFL has the potential to become a valuable marker in a wide range of neurological disease settings. Plasma NFL increased with age in our controls in a pattern similar to that found in the CSF. This age-dependent increase in CSF NFL has been clearly defined in earlier, larger studies (Jessen Krut et al., 2014). The mechanisms underlying the age-dependent increase in CSF NFL have not been established, but these age effects need to be considered when analyzing NFL concentrations, including the effects of treatment in individuals with HIV followed over longer periods of time. NFL is important for maintenance of the axonal caliber and morphological integrity and is expressed predominantly in large-caliber myelinated A-1210477 (Hoffman et al., 1987), but is also present in neurites (axons and dendrites) of CNS neurons in the cerebral and cerebellar cortex, hypothalamus and spinal cord (Trojanowski et al., 1986). Its CSF levels reflect leakage from injured or degenerating neurons, correlate with white-matter lesions and other injuries to subcortical brain regions (Jonsson et al., 2010), and predict severity and survival in several neurodegenerative diseases (Skillback et al., 2014). The robust correlation between plasma and CSF levels of NFL strongly suggests that plasma levels indeed reflect ongoing CNS injury, which is in agreement with a recent study on amyotrophic lateral sclerosis, however using a less sensitive method that does not allow proper quantification in all samples (Lu et al., 2015). However, an increase in plasma NFL without adjacent increase in CSF could theoretically also be a result of peripheral neuronal injury given that NFL is also found in peripheral nervous system neurons (Trojanowski et al., 1986). The magnitude of this effect needs to be evaluated in future studies of patients with the common HIV distal sensory and other neuropathies.
Contributors
Declaration of Interest
Introduction The lack of neuroprotective treatments for acute and chronic brain disorders presents a major challenge to modern medicine. Therapeutic hypothermia is a rare example of a proven neuroprotective intervention — however, it is only practically useful in restricted patient groups (Yenari and Han, 2012; Jacobs et al., 2013; Andrews et al., 2015). Improved mechanistic understanding of neuroprotective hypothermia could reveal novel molecular targets with which to exploit the protective effect of cooling in a wider clinical context. Against this background, a range of experimental systems and studies of hibernating animals have implicated several pathways that might mediate hypothermic neuroprotection (Arendt et al., 2003; Chip et al., 2011; Yenari and Han, 2012; Rzechorzek et al., 2015). A potentially important candidate is microtubule-associated protein tau. Specifically, reversible hyperphosphorylation of tau in hibernating, hypothermic and developing brains – brains which are comparatively resistant to injury – suggests cold-inducible changes in tau might contribute to hypothermic neuroprotection (Mawal-Dewan et al., 1994; Arendt et al., 2003; Planel et al., 2007; Stieler et al., 2011). Interspecies differences in cellular and molecular biology have impeded translation of neuroprotective strategies from pre-clinical models to man. With regard to tau, a potentially significant species difference lies in the developmentally-regulated expression of its multiple isoforms (Janke et al., 1999). The relative abundance of tau isoforms determines tau function in health and disease (Trojanowski and Lee, 1995), therefore this balance might be altered under conditions that influence neuronal survival, such as hypothermia. Whilst there is little evidence of this effect in in vivo models of hypothermic neuroprotection (Stieler et al., 2011), several core human tau isoforms are absent in the adult rodent brain (Janke et al., 1999). These observations provide a strong rationale to explore tau in the context of hypothermic neuroprotection in a physiologically relevant human system.