Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT06351735 |
| Other study ID # |
2024-0336 |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
August 1, 2024 |
| Est. completion date |
August 1, 2027 |
Study information
| Verified date |
May 2024 |
| Source |
Second Affiliated Hospital, School of Medicine, Zhejiang University |
| Contact |
Yuanjian Fang, Dr |
| Phone |
86-18768109541 |
| Email |
sandman0506[@]foxmail.com |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, affects motor
neurons, causing progressive muscle atrophy and weakness. Current treatments are ineffective,
with most patients dying within 3-5 years of diagnosis. The disease's exact cause is unclear,
but factors such as oxidative stress and protein abnormalities are implicated. Abnormal
protein deposits and neurotoxic factors in the brain and spinal cord contribute to ALS
pathology. Recent research on the brain's glymphatic-lymphatic system suggests impaired waste
clearance may exacerbate ALS. Restoring drainage connections between cervical lymphatic
vessels and veins could potentially alleviate neurodegenerative disease progression.
Description:
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the
simultaneous involvement of upper and lower motor neurons, leading to progressive muscle
atrophy and weakness in patients. Advanced stages of the disease manifest as symptoms such as
swallowing difficulties and respiratory problems. Currently, effective treatments for ALS are
lacking, and most patients succumb to the disease within 3 to 5 years of onset. Therefore,
there is an urgent need to explore new therapeutic approaches. Although the exact
pathogenesis of ALS remains unclear, various mechanisms including oxidative stress, glutamate
toxicity, mitochondrial dysfunction, endoplasmic reticulum stress, and protein misfolding are
thought to contribute to its development. Pathological findings indicate the presence of
abnormal protein deposits, including phosphorylated TDP-43 (Transactive response DNA-binding
protein 43 kDa), superoxide dismutase 1 (SOD1), and dysfunctional ribosomal proteins, in the
brains and spinal cords of ALS patients. Additionally, elevated levels of neurotoxic factors
in the cerebrospinal fluid, such as inflammatory cytokines and reactive oxygen species, have
been implicated in the pathogenesis of ALS. Therefore, clearance of abnormal proteins and
neurotoxic factors from the brain and spinal cord may have potential therapeutic implications
for delaying or preventing neurodegeneration and associated clinical disabilities in ALS
patients.
Recently, the discovery of the brain "glymphatic-lymphatic" system has updated our
understanding of cerebrospinal fluid circulation. Similar to the peripheral lymphatic
circulation, there exists an interstitial fluid circulation system in the brain parenchyma.
Studies have revealed that cerebrospinal fluid in the brain parenchyma enters the
perivascular spaces surrounding arteries through aquaporin-4 channels on astrocytes and then
flows directionally into the perivascular spaces surrounding veins, facilitating waste
clearance and nutrient transport in the brain. This phenomenon is known as the glymphatic
system. Furthermore, abundant lymphatic vessels have been found adjacent to the dural venous
sinuses, participating in cerebrospinal fluid drainage and ultimately draining into the
cervical lymph nodes. In animal models of Alzheimer's disease (AD) and Parkinson's disease
(PD), impairment of the glymphatic-lymphatic drainage function has been associated with the
accumulation of disease-related proteins such as amyloid beta (Aβ), Tau, and alpha-synuclein,
and ligating the cervical lymph nodes has been shown to exacerbate disease progression.
Clinical studies using magnetic resonance imaging have confirmed the decline in
glymphatic-lymphatic system function in patients with AD and PD. Although research on the
role and mechanism of the glymphatic-lymphatic drainage system in the occurrence and
development of ALS is lacking, magnetic resonance imaging has revealed a significant
reduction in glymphatic system function in ALS patients compared to healthy individuals,
suggesting an important role of the glymphatic-lymphatic drainage system in the pathogenesis
of ALS.
As the final destination of glymphatic-lymphatic cerebrospinal fluid drainage, the cervical
lymph nodes play a crucial role in the entire cerebrospinal fluid circulation. With aging,
infection, and chronic inflammation, the function of the cervical lymph nodes gradually
declines, leading to increased cerebrospinal fluid circulation reflux pressure. Furthermore,
the production of large amounts of neurotoxic substances during the progression of AD, PD,
and ALS further impairs the function of the cervical lymph nodes, resulting in abnormal
accumulation of toxic substances in the brain and disease progression. We speculate that
establishing drainage connections between the cervical lymphatic vessels and veins will
reduce cerebrospinal fluid circulation pressure in brain tissues, accelerate interstitial
fluid reflux, and alleviate the accumulation of metabolic waste, thereby slowing the
progression of neurodegenerative diseases.
