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Page 2 of 3 Paraskervas et al. Neuroimmunol Neuroinflammation 2018;5:17 I http://dx.doi.org/10.20517/2347-8659.2018.18

DIAGNOSIS
The various peptides and proteins involved in neurodegenerative diseases are secreted/released in the
extracellular space and finally in the cerebrospinal fluid (CSF) by various mechanisms and some of them can
be measured. Tau protein, either total or phosphorylated (phospho-tau) and beta amyloid peptide with 42
or 40 amino acids (Aβ , Aβ ) can be reliably measured in the CSF, and currently, are recognized as helpful
40
42
in the diagnosis of Alzheimer’s disease (inclusion) or its discrimination from other types of dementia,
[7]
[8,9]
including the FTLDs (exclusion of AD) . Thus, the CSF biochemical profile of AD is well recognized
(increased tau and phospho-tau, decreased Aβ ). In synucleinopathies, α-Syn is an emerging biomarker for
42
Parkinson’s disease, Dementia with Lewy Bodies and Multiple System Atrophy. A lot of studies have been
conducted, while others are on their way towards better characterization of α-Syn isoforms, antibodies used
to recognize different epitopes and elimination of confounding factors interfering with preanalytical and
analytical aspects, all with the purpose of establishing α-Syn as a reliable biomarker in these disorders .
[10]
On the other hand, the biochemical profile of TDP-43 proteinopathies has only recently begun to be explored
and data are scarce and conflicting. Recently, however, CSF TDP-43 (either alone or in combination with
other markers such as tau) has emerged as a candidate biomarker of ALS and FTLD and its levels are increased
in both conditions [11,12] . Extensive investigation in order to determine and optimize its diagnostic potential is
currently under way. Given the heterogeneity of proteinopathies, especially in FTLD (TDP-43 proteinopathies
vs. tauopathies and others) and even within the TDP-43 proteinopathy in both ALS and FTLD (types A, B,
C and D), correcting CSF diagnosis may, additionally, prove helpful in the correct classification of patients
[13]
in clinical trials .

TREATMENT
Current treatments approved for ALS have modest effects and for FTLD are only symptomatic. The lack of
success of pharmacological trials in such patient populations may be due to clinical trials being performed
either too late in the course of the disease, with too short duration, inclusion of heterogeneous groups of
patients, or insufficient knowledge about the specific clinical features and/or pathogenesis. The various steps
in TDP-43 distribution, cytoplasmic accumulation, phosphorylation, ubiquitination, aggregation, autophagy,
[13]
degradation, exosome secretion and toxicity may all be hypothetical targets of therapeutic interventions
and some of them are currently tested in vitro and in animal models, including improved degradation,
reduced neurotoxicity and antibodies against TDP-43 .
[6]

In conclusion, mechanisms of TDP-43 abnormal accumulation and toxicity, extensively reviewed by Dong
and Chen in addition to measurement of CSF TDP-43 levels as a diagnostic tool, are currently hot topics
[6]
relevant to the majority of ALS and roughly half of FTLD patients.

DECLARATIONS
Authors’ contributions
Concept and definition of intellectual content: Paraskervas GP, Bourbouli M, Zaganas I, Kapaki E
Literature search: Paraskervas GP, Bourbouli M
Manuscript preparation: Paraskervas GP, Bourbouli M, Kapaki E
Manuscript editing and manuscript review: Paraskervas GP, Bourbouli M, Zaganas I, Kapaki E

Financial support and sponsorship
None.

Conflicts of interest
There are no conflicts of interest.