Bypassing the Blood-Central Nervous System (CNS) Barrier: A Dual-Axis Framework for Amyotrophic Lateral Sclerosis (ALS) Utilizing Glymphatic-Lymphatic Clearance and In Situ Chaperone Synthesis
Year: 2026
Type: review
Abstract: Amyotrophic lateral sclerosis (ALS) is characterized by prion-like propagation of misfolded TAR DNA-binding protein 43 (TDP-43) and superoxide dismutase 1 (SOD1) across motor neuron pools. Because any circulating pharmacological agent must cross the blood-brain and blood-spinal cord barriers (BBB and BSCB), this review proposes active craniospinal tensioning (ACT) as a mechanical, non-pharmacological route to disease modification that acts on cerebrospinal fluid (CSF) and venous pressure dynamics rather than requiring penetration of these barriers. ACT is proposed to engage a single Monro-Kellie/Queckenstedt pressure continuity through two concurrent mechanisms: suboccipital venous occlusion-rebound, hypothesized to transiently raise and release craniospinal CSF pressure via venous compression and thereby accelerate venous-side glymphatic efflux; and dural pull-recoil, hypothesized to generate a reciprocal CSF pressure gradient via spinal elongation, agitating perivascular CSF directly while inducing a coupled venous pressure gradient. Because both mechanisms act concurrently on a shared venous-side target, the combined maneuver is proposed to be more potent than either delivered alone, as in prior work on pelvis-stabilized axial spinal traction (PSAST), which lacks the occlusion-rebound component. A secondary, hypothesis-generating micro-biochemical axis, cerebral venous preconditioning (CVPC), proposes that the same occlusion-rebound cycle produces capillary/venule wall strain sufficient to activate heat shock factor 1 (HSF-1) across the neurovascular unit, independent of oxygen tension, with a possible but uncharacterized contribution from hypoxia-inducible factor 1-alpha (HIF-1α). The two routes are non-exclusive, with the macro-fluidic axis alone proposed as sufficient. This framework is entirely theoretical, requires preclinical and clinical validation, and is intended as a template for related proteinopathy-driven neurodegenerative diseases, including Parkinson's disease, Huntington's disease, spinocerebellar ataxia, and fatal familial insomnia, addressed in forthcoming work.
Source: Cureus
Author: Huan-Wei Chen
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7214605191