Reduction of brain lipid peroxidation by CSF drainage in Alzheimer's disease patients

Abstract

Alzheimer' s disease (AD) is associated with an increase in cerebrospinal fluid (CSF) levels of the isoprostane 8,12iso-iPF2α-VI, a specific marker of in vivo lipid peroxidation. Poor cerebral clearance of end products of oxidative reactions via CSF circulation may contribute to and sustain ongoing stress. CSF drainage via a low-flow ventriculoperitoneal (VP) shunt may improve removal of these products, reducing oxidative stress. We quantified this biomarker in patients with AD undergoing to VP shunt placement at baseline and after one-year period. CSF sampling occurred at baseline and quarterly visits for one year. Levels of this isoprostane were determined simultaneously at the end of the study by gas chromatography negative ion chemical ionization mass spectrometry. Over one-year, CSF 8,12-iso-iPF2α-VI levels consistently decreased versus baseline (51% of initial level), while CSF protein, glucose, cell count and IgG concentrations remained within normal limits. This finding supports the hypothesis that improving CSF drainage enhances extra-cellular clearance of end products of oxidative reactions and lowers brain lipid peroxidation.

Multiplicity of cerebrospinal fluid functions: New challenges in health and disease

“…Evidence continues to accumulate, however, for the importance of CSF flow on cerebral metabolism. Because the CP-CSF supplies micronutrients and peptides to neuronal networks, and removes many catabolites, impeded CSF flow disturbs metabolism in early life [119] as well as in late stages [174]. …”

“…As CSF formation rate dwindles by 50% or more in senescence and disease [3,19], the sink action [33] of slower-flowing CSF is attenuated [9]. The concentration of potentially-toxic peptides and organic metabolites in CSF [174] and brain consequently builds up due to sluggish flow. Less favorable concentration gradients for catabolites diffusing from ISF to ventricular CSF, results in reduced clearance of harmful substances from brain.…”

“…Stabilizing the CSF composition is predicated largely on pharmacological manipulation of the barrier transporters and on restoration of a breached BCSFB or BBB [223-225]. To help manage certain CSF disorders, aberrant concentrations of proteins [226] and catabolites [174] in CSF need to be profiled and categorized for various stages of NPH and AD.…”

“…Excessive metabolite efflux from ISF to ventricles can toxify the CSF. Toxic catabolites in CSF, generated by peroxidative phenomena, increase with age and neurodegeneration [174]. Glycated proteins in CSF are elevated in AD [231].…”

Severe Neurologic Impairment in Mice with Targeted Disruption of the Electrogenic Sodium Bicarbonate Cotransporter NBCe2 (Slc4a5 Gene)

“…Modulating the production and chemistry of CSF is utilized clinically in the treatment of intracranial hypertension, mountain sickness, and seizure disorders (8 -10) and would be of potential value in conditions such as Alzheimer disease (11,12), normal pressure hydrocephalus (13), and aging (14), where the CSF turnover is abnormal leading to a buildup of harmful metabolites (6). The process of CSF transepithelial ion and fluid secretion involves an array of transporters and channels (6,15).…”