Effective Early-Phase Neurological Disease Biomarkers

The main age-related neurological diseases, ALS, Parkinson’s disease, and Alzheimer’s disease have mostly unknown and non-gene etiologies. In addition, by the time they are clinically diagnosed, considerable damage has occurred in the CNS rendering most attempted therapies moot. The only solution to this that I can see is to find a peripheral screen for the emergence of the earliest phases of the disease cascade so that the disease process can be addressed before it has done damage to neurons.
The vision is to make effective diagnosis and treatment available to prospective disease victims long before the clinical phase of the disease.

A proposed target here could be the ‘glymphatic system’ as proposed by researchers M. Nedergaard and S. A. Goldman (‘Glymphatic failure as a final common pathway to dementia’, Science, 2 October, 2020; pp. 50-55) wherein the the brain’s natural/normal ‘waste removal system’ (DNA fragments, proteins, cell components, etc.) slowly fails due to aging (and this being tied to the loss of NREM sleep in over 40 adults, and the associated loss of ‘arterial pulsativity’ * (driven by ‘slow wave’ activity in the NREM stage) which serves as the mechanical force that drives said clearance/removal (the loss of which leads to the build-up of plaques, ‘dead’ proteins, etc. associated with neurodegeneration).

Nedergaard and Goldman also emphasize the key role of dysfunctional microglia cells (occupying the peri-vascular space surrounding the cerebral arteries: AAC, AMC, APC).

The restoration (or artificial stimulation) of this ‘waste clearance’ function/system (ultimately through Cerebral Spinal Fluid excretion) offers a fresh/promising research path.

This phenomenon (or a closely related one) is also called ‘meningeal lymphatic dysfunction’ (basically, ‘poor drainage’) and focuses on the intersection of microglia, lymphatics, and the blood-brain barrier). Here is an additional reference on this topic:

S. Da Mesquita et al; ‘Meningeal lymphatics affect microglia responses and anti-AB; immunotherapy’, Nature, 2021.

@cashaw To briefly address the original poster’s ‘peripheral screen’ proposal, I would suggest development of a diagnostic or assessment tool that can measure/detect the current state of this cerebral drainage system (the ‘biomarker’), the condition of which (its dysfunctional state) appears to be strongly correlated with the development of dementia and neurodegenerative disease.

Thus, if this ‘poor drainage’ (glymphatic clearance’) connection to dementia can be fully validated (and the evidence supporting it is strong), a possible XPrize could be the demonstration of increased clearance AND resulting improvement in cognitive function (or the cessation of cognitive impairment, if dysfunction is advanced).

*loss of arterial pulsativity commonly accompanies cardio-vascular disease
(artherosclerosis, etc.) and also type I diabetes.

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This is a great idea, thank you.

Your welcome. I hope it helps and furthers this topic, which is a critical one for millions of aging adults. thanks for keeping it ‘in focus’.

@cashaw Oh, it just occurred to me that measuring ‘arterial pulsativity’ (basically, a function of the flexibility/plasticity of the artery walls) could be another (more specific) biomarker!

Thanks for posting this discussion, @cashaw! Shall I move this into the Global Visioneering discussions, so we can consider it as a potential topic for our next prize competition?

Yes, Nick, that might be a good idea.

Done! You can now also vote for the topic. Find the vote button next to the discussion title at the top of the thread.

Excellent idea, @cashaw!

I wonder if we should expand the challenge: not just detecting neurological diseases at an early stage, but also demonstrating an effective treatment for them, that can delay the onset of more advanced symptoms.

What do you think?

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@marz62 -
Thanks for the extensive review. I conducted a similar review around a year ago, so I know how exhausting it can be :slight_smile:

This is the plan. If we can detect the onset of disease long before clinical features appear, we may have a hope of stopping the underlying process. Understanding the process, in turn, should lead to therapeutic options that target that early degenerative process.

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No problem. Actually, I routinely read papers of neurodegeneration and neuroscience in general …so, It’s actually a pleasure to distill what I have ‘digested’ cognitively (plus, my niece is working on her PhD focusing on AD mitigation, so, I try to stay up so that I can converse with her).