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April 27, 2020

White Matter Degeneration—A Treatable Target?

Author Affiliations
  • 1Department of Anatomy and Cell Biology, Western University, London, Ontario, Canada
  • 2Deparment of Clinical Neurological Sciences, Western University, London, Ontario, Canada
JAMA Neurol. 2020;77(7):793-794. doi:10.1001/jamaneurol.2020.0814

The World Health Organization predicts that by 2050, one-fifth of the world’s population will be older than 60 years, with roughly 115 million individuals affected by dementia.1 These numbers do not account for the additional 16% to 20% of elderly individuals who are estimated to experience mild cognitive impairment, which can begin years before clinical presentation.2 Despite this large public health concern, interventional strategies are limited, and timely identification of prodromal disease states requires improvement. To date, most therapies aim to protect or preserve at-risk neurons, and there are very few therapies that target the brain’s white matter, which makes up half of the brain and may be a critical site of prodromal disease.

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    4 Comments for this article
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    A Coordinated Approach to Find New Treatments
    Andrew Lockhart, PhD | Pharmaceutical Research
    The authors flag an important area of research, which in comparison to other dementia-related mechanisms, receives limited attention despite the devastating impact of cerebrovascular disease (CVD) on patients and their families.

    It is important that efforts to tackle this disease are coordinated across academic/ medical centres of excellence and pharmaceutical companies to ensure robust target identification and the efficient development of therapies (1,2).

    The feasibility of relatively small clinical trials in dementia patients with CVD that incorporate enrichment strategies and biomarkers has been demonstrated (3) and should not be a limiting factor in the evaluation and development of
    new treatments.

    REFERENCES

    1. Wren et al. "Mechanisms of vascular disease in dementia: what does industry want to know?." Clinical science 131.9 (2017): 799-802.
    2. Horsburgh et al. "Small vessels, dementia and chronic diseases–molecular mechanisms and pathophysiology." Clinical science 132.8 (2018): 851-868.
    3. Maher-Edwards et al. "A 24-week study to evaluate the effect of rilapladib on cognition and cerebrospinal fluid biomarkers of Alzheimer's disease." Alzheimer's & Dementia: Translational Research & Clinical Interventions 1.2 (2015): 131-140.
    CONFLICT OF INTEREST: Hold stocks in GSK from previous employment.
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    White Matter Degeneration
    Charles brill, MD, retied | Thomas Jefferson University Hospital
    You didn't mention not smoking, which saves money in addition to being good for vascular and pulmonary health.
    CONFLICT OF INTEREST: None Reported
    Wallerian Degeneration is a Specific Therapeutic Target in White Matter Degeneration
    Ciaran Hill, FRCS PhD | University College London
    The authors highlight white matter pathology as an important and sometimes forgotten aspect of neurological pathology. They mention in their text box "Axonal health is maintained by ...nutrient transport from the neuronal cell body" but do not refer to Wallerian degeneration by name. I would strongly encourage any interested readers not to overlook this important cell-autonomous, neuron-specific, axonal death pathway. Wallerian degeneration has a well-characterised molecular pathway that can be subjected to pharmacological and genetic manipulation (1). Wallerian degeneration occurs in both the central and peripheral nervous systems and its role in neurological disease is an exciting and rapidly expanding field of research.

    REFERENCE

    1. Coleman, M.P., Höke, A. Programmed axon degeneration: from mouse to mechanism to medicine. Nat Rev Neurosci 21, 183–196 (2020). https://doi.org/10.1038/s41583-020-0269-3
    CONFLICT OF INTEREST: None Reported
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    Alcohol as an Etiology
    David Peters, D.O. | Michigan State University
    There are a multitude of etiologies for this. However don’t sidestep the most ubiquitous and culturally encouraged: alcohol. See eg https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513685/.
    CONFLICT OF INTEREST: None Reported
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