Neurogenerative Diseases - 25

the disease. Additionally, both NfL and pNfH equally
discriminated ALS from controls with high positive
predictive values (PPVs).16
In a large-scale, two-center study, the diagnostic
utility and PPVs of CSF NfL and pNfH in ALS with
mimics compared with controls was confirmed. In
this study, pNfH was found to be more specific in
ALS with significantly higher diagnostic sensitivity
and specificity with a better negative predictive
value compared with NfL, which is increased in
other diseases such as FTD.15 This observation was
later confirmed in a cohort of Asian ALS patients.18
Furthermore, Nf levels were significantly lower
in ALS patients with slower disease progression
and longer survival. Both pNfH and NfL increased
proportionally with the number of regions with
involvement of both upper and lower motoneurons.
The site of onset did not affect Nf levels.15

Figure 1: Scatter dot plots showing the levels of neurogranin trunc P75
(a) or BACE1 (b) in CSF in the different diagnostic groups: MCI, AD, and
cognitively healthy participants (CTRL). The median levels are presented
as a line in each dot plot. The bars represent the interquartile range.
Statistically significant differences between the groups are presented on
the graphs by **p < 0.01 (adapted from De Vos et al.3)

frontotemporal dementia (FTD).12,13 Additionally,
they are extensively studied as potential diagnostic
biomarkers for amyotrophic lateral sclerosis (ALS),
as the diagnosis of this MND currently requires
the description of upper and lower motoneuron
dysfunction, thus resulting in a delay of approximately
one year from symptom onset to diagnosis.13-16 With
a median survival of three years following symptom
onset, an early diagnosis would allow rapid initiation
of treatment and enrollment of patients into clinical
trials.17

Nfs are produced in neurons, and the concentrations
are approximately 10-fold lower in blood than in
CSF.13 With the availability of a highly sensitive
ELISA, commercialized by EUROIMMUN AG, De
Schaepdryver and colleagues compared the
performance characteristics of pNfH in CSF and
serum of ALS patients. pNfH concentrations in CSF
and serum correlated well, especially in ALS patients,
and both levels diagnostically differentiated ALS
patients from controls. Both CSF and serum pNfH
levels correlated with the disease progression rate.17

In a large prospective study, Steinacker and
colleagues compared the levels of CSF
neurofilament light chain (NfL) and phosphorylated
neurofilament heavy chain (pNfH), T-tau, and
P-tau in ALS patients with mimics versus a control
cohort with other neurological diseases. Both Nf
levels were significantly higher in the ALS cohort
compared with controls, without any difference
in P-tau and T-tau levels, suggesting a differential
release of neuronal proteins such as Nfs and tau in
neurodegenerative processes. Even though Nf levels
were considerably elevated in some ALS-mimicking
disorders compared to controls, the diagnostic
accuracy in ALS was significant. Furthermore, no
difference in Nf levels was observed in different ALS
subtypes as well as familial and sporadic forms of

A major challenge in the early diagnosis of ALS is
the delay between symptom onset and accurate
diagnosis, as the established clinical criteria has
not been met. It is also, in part, due to the lack of
availability of early-stage CSF samples from ALS
patients. Therefore, evaluating pNfH in serum is a
more promising tool to study the prediagnostic
period of ALS and to potentially reduce the diagnostic
delay. In a follow-up study, De Schaepdryver and

25
Neurogenerative Diseases

Table of Contents for the Digital Edition of Neurogenerative Diseases
