Neurolymphatic clearance in neurodegenerative disease: Emerging mechanisms and potential translational strategies

Abstract

Introduction: Neurolymphatic dysfunction has been linked to cognitive decline and implicated in the pathogenesis of neurodegenerative disorders such as Alzheimer's Disease (AD) and Parkinson's Disease (PD). Despite its growing recognition, the potential role of pharmacological or surgical neurolymphatic modulation remains poorly understood.

Objectives: This review summarizes current evidence on the neurolymphatic system's anatomy, physiology and its involvement in neurodegenerative diseases. It also examines emerging pharmacological and lymphatic reconstructive techniques.

Methods: A comprehensive literature search was conducted in PubMed, yielding 187 studies related to the neurolymphatic system. Studies were screened for the following topics: (1) Anatomy and physiology of the neurolymphatic system, (2) The association between neurolymphatic dysfunction and neurodegenerative diseases, (3) Pharmacological and (4) Microsurgical neurolymphatic modulation.

Results: Current evidence suggests that the neurolymphatic system facilitates drainage of interstitial and cerebrospinal fluid to the deep cervical lymph nodes. Preclinical models suggest that enhancing their clearance may promote the clearance of neurotoxic proteins and potentially improve cognitive function.

Conclusions: Scientific evidence on neurolymphatic modulation in neurodegenerative diseases is scarce. Both pharmacological and microsurgical modulatory techniques remain experimental approaches for neurodegenerative diseases, with a significant potential to improve patients' quality of life. However, further research is warranted to establish their safety, feasibility, and efficacy. The current knowledge gaps underscore the need for a detailed mapping of the neurolymphatic pathways, preclinical evaluation, and translational interdisciplinary trials.

Keywords: Glymphatic system; Meningeal lymphatic vessels; Microsurgery; Neurodegenerative Diseases; Neurolymphatic system; Neuromodulation.

Figure 1

Anatomical pathways of the neurolymphatic system (green). Interstitial fluid is transported along perivascular routes toward the skull base and ultimately into the deep cervical lymph nodes. Cerebrospinal fluid drains via three principal routes: (1) arachnoid villi and granulations into the dural venous sinuses, (2) perineural spaces along the olfactory nerves through the cribriform plate into nasal lymphatics, and (3) meningeal lymphatic vessels located dorsally along the superior sagittal sinus and basally along the petrosquamosal and sigmoid sinuses.

Figure 2

Currently hypothesized translational strategies for neurolymphatic modulation. Lymphovenous anastomosis (LVA) and vascularized lymph node transfer (VLNT) to the neck are believed to enhance lymphatic flow. Pharmacologic agents such as VEGF-C, oxytocin, and vitamin D may further modulate meningeal lymphatic activity.