Brain-Specific Cytoskeletal Damage Markers in Cerebrospinal Fluid: Is There a Common Pattern between Amyotrophic Lateral Sclerosis and Primary Progressive Multiple Sclerosis?

Abstract

Many neurodegenerative disorders share a common pathophysiological pathway involving axonal degeneration despite different etiological triggers. Analysis of cytoskeletal markers such as neurofilaments, protein tau and tubulin in cerebrospinal fluid (CSF) may be a useful approach to detect the process of axonal damage and its severity during disease course. In this article, we review the published literature regarding brain-specific CSF markers for cytoskeletal damage in primary progressive multiple sclerosis and amyotrophic lateral sclerosis in order to evaluate their utility as a biomarker for disease progression in conjunction with imaging and histological markers which might also be useful in other neurodegenerative diseases associated with affection of the upper motor neurons. A long-term benefit of such an approach could be facilitating early diagnostic and prognostic tools and assessment of treatment efficacy of disease modifying drugs.

Keywords: amyotrophic lateral sclerosis (ALS); biomarker; neurofilaments; primary progressive multiple sclerosis (PPMS); tau; tubulin.

Figure 1

Main pathophysiological processes involved in Amyotrophic lateral sclerosis (ALS) and primary progressive multiple sclerosis (PPMS). ALS is characterized by accumulation of intracellular cytoplasmic aggregations (TDP-43, fused in sarcoma (FUS) and superoxide dismutase (SOD)) in the motor neurons. Glial cells play an important role in the pathophysiology through different pathways: defective astrocytic glutamate (GLU) uptake through excitatory amino acid transport (EAAT)-2 receptors resulting in glutamate excitotoxicity, defective lactate uptake by the oligodendrocytes through monocarboxylate transporter (MCT)-1 receptors and neurotoxic factors release from the microglial cells. Inflammatory cells like dendritic cells play a role through release of inflammatory mediators like interferon-γ (IFN-γ), reactive oxygen species (ROS) and nitric oxide (NO). In PPMS, however, the axonal loss is mediated by different mechanisms like macrophage and T-cell induced tissue damage, antibodies mediated damage of the myelin sheath and oligodendrocytes, hypoxic tissue injury and primary oligodendrocyte’s susceptibility. Both diseases result in axonal damage with increased levels of different markers in the cerebrospinal fluid (CSF) (total Tau-protein (t-Tau), phosphorylated Tau-protein (p-Tau), neurofilaments, actin and tubulin) and characteristic changes in magnetic resonance imaging (MRI) like brain atrophy and reduction of fractional anisotropy (FA).

Figure 2

Dynamics of CSF-biomarkers in ALS. The long preclinical stage characterized by cellular changes like cytoplasmic vacuoles, mitochondrial changes and synaptic loss because of genetic predisposition (first hit) in addition to environmental factors and oxidative stress (other hits) would be associated with no or minimal cellular death and, thus, no or low level of marker in the CSF. In the presymptomatic stage, where extensive cell death and axonal damage takes place, there would be a massive release of CSF markers for neurodegeneration. The symptoms will appear when the damage exceeds the functional capacity of the CNS. In the symptomatic stage, the CSF levels of neurodegeneration markers do not show significant changes which can be explained by reduced volume of neuroaxonal structures. Less sensitive markers for axonal death like t-Tau will be even normal.

Figure 3

Dynamics of changes in the CSF and MRI-parameters of neurodegeneration over the course of the ALS. In different longitudinal imaging studies, the Fractional Anisotropy (FA) was relatively stable, but different between patients with fast (FP-ALS) and slow (SP-ALS) progressive ALS. The same studies showed progressive atrophy of the cortical grey matter and spinal cord in the symptomatic stages. This suggests that the major damage of corticospinal tract occurs in the presymptomatic stage of the disease. Accordingly, the rate of changes in FA and neurofilaments (NF) in the CSF would be greater in the presymptomatic stage rather than after appearance of the symptoms.

Figure 4

Dynamics of CSF and MRI-parameters of neurodegeneration over the course of the multiple sclerosis (MS). The imaging studies revealed accelerated whole brain, spinal cord and cortical gray matter atrophy in the progressive phase of MS when compared to relapsing remitting multiple sclerosis (RRMS) and clinically isolated syndrome (CIS). Similarly, decrease in cord FA was higher in PPMS compared to RRMS. According to these results, similar changes in the levels of neurofilaments could be postulated.