. Huntington's disease alters human neurodevelopment. Science. 2020 Jul 16; PubMed.

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  1. These data are very interesting. There has been debate in the Huntington’s disease field regarding the existence of a neurodevelopmental deficit. Evidence is accruing that this may be the case based on differentiating HD IPSc systems, mouse development, and now these studies of early human development.

    We recently found that HD gene carriers ~24 years before predicted disease onset had essentially completely normal brains, including normal cortico-striatal connectivity on advanced neuroimaging, apart from a slightly smaller striatum, which we hypothesized resulted in selective vulnerability of the striatum to subsequent neurodegeneration in HD (Scahill et al., 2020). 

    Importantly, our HD gene carriers performed as well as matched controls on a range of stringent cognitive and motor assessments. Our unpublished functional imaging data in this cohort suggests compensation occurs in these HD gene carriers.

    Therefore, despite these neurodevelopmental deficits, they develop normally and function at a high level into adulthood, but there is a tipping point when gradual neurodegeneration occurs. This all suggests that we need to treat as early as possible with disease-modifying therapies to enable us to delay or prevent symptom onset, and it means that there is still great potential for therapies to potentially prevent the neurodegeneration occurring if we treat early enough. We need to understand more about the very earliest manifestations of neurodegeneration and then intervene at the optimal stage.

    References:

    . Biological and clinical characteristics of gene carriers far from predicted onset in the Huntington's disease Young Adult Study (HD-YAS): a cross-sectional analysis. Lancet Neurol. 2020 Jun;19(6):502-512. Epub 2020 May 26 PubMed.

    View all comments by Sarah Tabrizi
  2. This is an interesting paper. In other single-gene neurodegenerative diseases, from prion to Alzheimer’s, there have been suggestions of potential neurodevelopmental influences, but this study takes an interesting approach to addressing this through the assessment of fetal tissue.

    Our understanding of familial AD has changed over recent decades with very extensive evidence to support a long preclinical period. That period extends over 20 years or so, with progressive accumulation of molecular pathology being followed by neurodegenerative, functional, and cognitive changes—all of which are insidious in onset and relentlessly progressive before diagnosis.

    Evidence of neurodevelopmental effects does raise questions about just how early treatments need to be started in order to be effective, or, as the authors put it, to be "sufficient to forestall symptom progression.” However, in my view, the fact that carriers of mutations for Alzheimer’s disease function to a high level into adulthood, and in fact are effectively indistinguishable from their noncarrier siblings until quite close to symptom onset or clinical diagnosis, means that there is still great potential for therapies to have a transformative impact even at this stage. There is the potential for disease modification to be effective "secondary prevention" and to maintain “normal” cognitive function. We need those therapies.

    View all comments by Nick Fox
  3. This elegant study extends the previous notion that neurodegenerative disorders are preceded by a long, clinically silent phase of at least several decades that might perhaps even start very early in life. Unsurprisingly, several aspects of mHTT mirror familial Alzheimer’s disease bearing PSEN1 mutations, e.g., PSEN1 E280A.

    For example, both disorders present at least five main common features: (i) accumulation of intracellular protein HTT and sAPPβ fragments, (ii) impairment of endosome secretion and recycling in HD and endosome intoxication by sAPPβ fragments, (iii) alterations in neuronal progenitor proliferation, (iv) mHTT and APP fragments (including Aβ42) alter early stages of brain development in human HD and AD; and (v) children show probably compensatory functional mechanisms which mask apparent abnormality in those individuals bearing mHTT and PSEN1 E280A.

    Therefore, it is reasonable to think that treatment for both HD and FAD should start very early in life. I support the view that a developmental component in both progressive neurodegenerative disorders is now unquestionable. We anticipate that this sort of study might stimulate new therapeutic design for HD and FAD patients.

    View all comments by Marlene Jimenez-Del-Rio

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