Yet another lethal condition, for which no known treatment exists or is even in the pharma drug pipelines, turns out to be little more than chronic neurodegeneration driven by endotoxin (LPS) and peroxidation byproducts of PUFA such as 4-hydroxy-nonenal (4-HNE). For the record, 4-HNE is well-known to medicine and is already a known biomarker for a wide spectrum of chronic conditions, not just neurodegeneration. In contrast, medicine views (so far) LPS as more of an “innocent” bystander, and refuses to acknowledge that something so simple, yet so pervasive in patients, can explain a host of lethal and untreatable conditions. That may be changing as a few recent studies demonstrated that LPS is a reliable predictive biomarker of AIDS disease course, as well as future mortality from the condition. The study below, now adds ALS to the list of conditions that are likely of inflammatory origin, with systemic inflammation driven predominantly by 4-HNE, LPS and the endotoxin/LPS receptor TLR4.
“…The three biomarkers were chosen for their biological coherence with what is known about ALS pathophysiology. 4-hydroxy-2-nonenal, or 4-HNE, is a toxic product of lipid peroxidation, the chemical assault on cell membranes that follows when dysfunctional mitochondria churn out reactive oxygen species. Lipopolysaccharide binding protein, or LBP, is synthesized and secreted by hepatocytes in the liver as part of the acute phase response, the innate, nonspecific first reaction of the body to immunological stress; it binds bacterial lipopolysaccharide and presents it to immune receptors such as CD14 and Toll-like receptor 4, amplifying inflammatory signaling. Neurofilament light chain, or NfL, is a structural protein released when axons degenerate, and it has already emerged as one of the most scrutinized fluid markers in neurodegeneration. All three were quantified by standard enzyme-linked immunosorbent assays, the kind of procedure routinely available in clinical diagnostic laboratories.”
“…The cross-sectional findings immediately set ALS apart from other neurodegenerative diseases. Rapidly progressing patients, defined as those losing one or more points per month on the revised ALS Functional Rating Scale, showed significantly higher 4-HNE than both healthy controls and slowly progressing patients. LBP was elevated in rapid progressors compared with slow progressors and controls, and even slow progressors had higher LBP than controls. NfL followed a similar pattern, higher in rapid progressors than in slow ones and controls. Crucially, 4-HNE and LBP showed no such elevations in patients with Parkinson’s disease or mild cognitive impairment and Alzheimer’s disease, whereas NfL rose in those conditions as expected. This dissociation suggests that oxidative stress and systemic inflammation are not generic accompaniments of neurodegeneration but are specifically intensified in ALS.”
“…The longitudinal data revealed a compelling divergence in how the three markers behave over time. At diagnosis, NfL showed the largest elevation relative to controls, roughly 3.3-fold, with LBP at about 1.6-fold and 4-HNE at a modest 1.3-fold. Yet from diagnosis to the last available sample, the picture inverted: 4-HNE climbed 177 percent and LBP rose 80 percent, while NfL increased only 27 percent, effectively plateauing. In other words, axonal injury as reflected by NfL is largely front-loaded into the early disease course, whereas lipid peroxidation and systemic inflammation escalate continuously as the disease advances. This temporal architecture helps explain why NfL did not correlate with ALSFRS-R scores in this cohort, since the functional scale kept declining steadily while NfL had already peaked.”
“…The correlation analyses underscored the primacy of the inflammatory and oxidative markers. LBP at diagnosis showed the strongest negative correlation with ALSFRS-R score at diagnosis (r = −0.688) and the strongest correlation with survival from diagnosis to death (r = −0.773), along with the strongest link to progression rate (r = 0.668). 4-HNE tracked closely behind, correlating with survival at r = −0.661 and with progression rate at r = 0.589. NfL, by contrast, correlated only weakly with survival (r = −0.325) and progression rate (r = 0.274). The biomarkers also correlated with one another, moderately so between LBP and 4-HNE and between NfL and 4-HNE, painting a picture of interacting pathways in which oxidative damage, inflammation, and axonal breakdown feed one another. As expected clinically, older age at diagnosis and faster progression each correlated with shorter survival.”
Via: https://haidut.me/?p=3141
