Blood-based biomarkers of inflammation in amyotrophic lateral sclerosis

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease in which many processes are detected including (neuro)inflammation. Many drugs have been tested for ALS in clinical trials but most have failed to reach their primary endpoints. The development and inclusion of different types of biomarkers in diagnosis and clinical trials can assist in determining target engagement of a drug, in distinguishing between ALS and other diseases, and in predicting disease progression rate, drug responsiveness, or an adverse event. Ideally, among other characteristics, a biomarker in ALS correlates highly with a disease process in the central nervous system or with disease progression and is conveniently obtained in a peripheral tissue. Here, we describe the state of biomarkers of inflammation in ALS by focusing on peripherally detectable and cellular responses from blood cells, and provide new (combinatorial) directions for exploration that are now feasible due to technological advancements.

Inflammatory checkpoints in amyotrophic lateral sclerosis: From biomarkers to therapeutic targets

“…A recent study found that a decrease in the compound muscle action potential (CMAP) amplitude in the phrenic nerve was associated with increased IL-6 levels in ALS ( 46 ). In corroboration with previous studies, it also reported that changes in peripheral blood PaO 2 affected fluctuations in IL-6 levels in the serum and CSF of ALS ( 47 ). Therefore, the level of IL-6 reflects the severity of respiratory function involvement in patients with ALS to some extent ( 46 , 47 ).…”

“…In corroboration with previous studies, it also reported that changes in peripheral blood PaO 2 affected fluctuations in IL-6 levels in the serum and CSF of ALS ( 47 ). Therefore, the level of IL-6 reflects the severity of respiratory function involvement in patients with ALS to some extent ( 46 , 47 ). Simultaneously, Sun et al.…”

“…Further analysis of the prognostic value of various chemokines revealed that the levels of CCL2, CCL3, CCL4, CCL11, CXCL8, and CXCL10 in the blood correlated with ALSFRS-R score and DPR. CCL4 and CXCL10 levels positively correlated with ALSFRS-R score and negatively correlated with DPR, and CCL3 and CCL11 levels were negatively correlated with survival time ( 11 , 31 , 47 , 51 , 67 ). However, other studies have reported that CCL11 can play a neuroprotective role in ALS and was positively correlated with survival time ( 55 ).…”

Therapeutic Treatment of Superoxide Dismutase 1 (G93A) Amyotrophic Lateral Sclerosis Model Mice with Medical Ozone Decelerates Trigeminal Motor Neuron Degeneration, Attenuates Microglial Proliferation, and Preserves Monocyte Levels in Mesenteric Lymph Nodes

“…For example, immune cell-deficient SOD1 G93A mice progressed faster to the end stage compared to their immune-competent littermates [ 45 , 46 ], and a passive transfer of T cells (T eff and T reg ) to SOD1 G93A mice was able to delay loss of motor function and extended survival [ 47 ]. Furthermore, reductions as well as elevations in a range of immune cell subpopulations have been shown for blood from ALS patients (recently reviewed by [ 48 ]). In our study, we found that, on a gross cellular level, lymphocyte and granulocyte populations did not show disease- or treatment-related changes or adaptations.…”

Therapeutic interventions of Amyotrophic Lateral Sclerosis (ALS)

“…• Elevated metalloproteinase-9 (MMP-9) [2] • Increased levels of MMP-2 [3,4] • The loss of motor neurons is the primary neuropathological hallmark of ALS [20] • Mutations in SOD1 [28] • Elevated Extracellular matrix metalloproteinase inducer (EMMPRIN) [3] • Decrease in the expression of human leukocyte antigen by ALS monocytes [21] • Mutations in tardbp (TDP-43) [29][30][31] • Elevated level of Inflammation Markers, like MCP-1, TNFa, IL-6, IL-7, Eotaxin, GM-CSF, OX40, etc. [5][6][7][8][9] • An increase in the amount of natural killer T lymphocytes [22] • Binding of mutant C9orf72 to trimethylated histones was detected in ALS mononuclear cells [32] • Hypermetabolism, and hyperlipidemia [10][11][12] • High neutrophil-to-lymphocyte ratio [23] • Mutations in FUS gene [33][34][35][36] • High concentrations of lead in blood and in the CSF [13][14][15] • Decrease in the number of regulatory T cells [21,22] • Vesicle-associated membrane proteinassociated protein B (VAPB) [37] • Low level of type I procollagen [16][17][18][19].…”