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Select Measures in Young Adults with a Premanifest Huntington’s Disease Gene May Guide Early Intervention

Young adults with a premanifest Huntington's disease gene (preHD) showed normal brain function but an increase in sensitive measures of neurodegeneration about 24 years ahead of the expected time of clinical onset, according to a cross-sectional analysis published on June 1 in The Lancet Neurology

The investigators wanted to assess early disease-associated changes and to determine which tests for early preHD are most precise.  

Disease-modifying therapies are being developed in Huntington disease so identifying an optimal timepoint for an intervention could be crucial to their success, the study investigators said. "Our findings suggest that approximately 24 years from predicted onset, when cognitive and neuropsychiatric function appears intact, represents a potentially appropriate time to initiate future disease-modifying therapies," wrote Rachael I Scahill, PhD, of University College in London, and colleagues.

The investigators assessed 67 controls and 64 young adults with preHD in the United Kingdom. Mean age was about 29 years for both groups. They included young adults with preHD and controls matched for sex, education, and age to ensure each cohort had 60 participants or more with imaging data, taking into consideration scan fails. The imaging data were collected through diffusion imaging, volumetric MRI, and multiparametric mapping.

Controls did not have a family history of Huntington's disease or either had a negative genetic test result or had a family history of Huntington's disease. The study cohort underwent a detailed cognitive and neuropsychiatric evaluation.  Using CSF and blood collection, the researchers assessed biofluid markers of neuronal health.

A number of observational studies in preHD have demonstrated slight cognitive, neuropsychiatric, and motor impairments at least 10 to 15 years prior to clinical onset. However, by this point, Huntington's disease pathology has already had an effect on brain structure and shown signs of white matter degeneration and striatal atrophy, the group noted. 

In the current study, the investigators observed no significant evidence of psychiatric or cognitive impairment in preHD participants about 23.6 years out from anticipated onset. Although the preHD study group had slightly smaller putamen volumes, this did not seem to be associated with anticipated years of onset, the researchers wrote. And they observed no differences in brain imaging measures across both cohorts.

However, plasma neurofilament light protein (NfL), cerebrospinal fluid (CSF) YKL-40, and CSF NfL were high in this young adult preHD cohort (p=0.01) compared with controls (p=0.03). CSF NfL occurred more often in participants with closer to expected clinical onset, they added.

"In summary, by identifying a cohort of preHD individuals with no detectable functional impairment but who begin to exhibit subtle elevations in select biological measures of neurodegeneration, we have highlighted a crucial point early in the disease process. Intervening at this stage might offer the prospect of delaying or preventing further neurodegeneration while function is intact, giving gene carriers many more years of life without impairment," the research group wrote.

The researchers said that among the study's limitations, it may have been underpowered to find a correlation between CAG repeat length and age. Another limitation was that although comprehensive, the measures were not exhaustive, and thus, other tests might have demonstrated more sensitivity in preHD.

Disclosures: Scahill reported no disclosures.

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Scahill RI, Zeun P, Osborne-Crowley K, et al. 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; Epub 2020 June 1.