Biological markers of cognition in prodromal Huntington's disease: a review

Abstract

Huntington's disease (HD), an autosomal-dominant genetic disorder, has historically been viewed as a degenerative movement disorder but it also includes psychiatric symptoms and progressive cognitive decline. There has been a lack of consensus in the literature about whether or not cognitive signs can be detected in carriers before clinical (motor) onset of the disease, i.e., prodromal HD. However, recently validated mathematical formulas to estimate age of clinical onset, refined over the past 5-7 years, have allowed researchers to overcome the methodological limitation of treating all prodromal carriers as a homogenous high-risk group (i.e., whether they may be 2 or 15 years from diagnosis). Here we review 23 articles on the HD prodrome, all of which related cognition to a biological marker of disease burden (i.e., genetic load, neuroimaging). All studies found at least one cognitive domain was associated with disease burden in prodromal HD participants. There was greater variability in both the detection and cognitive domain affected in those farther from onset (or those with less pathology) while most studies reliably found declines in visuomotor performance and working memory in those closer to onset. These findings indicate that cognitive signs can be reliably detected in the HD prodrome when comparing cognition to additional disease markers, however, there continues to be significant variability on cognitive findings among large and methodologically rigorous studies. This may reflect true heterogeneity in the prodromal HD phenotype which must be further explored by analyzing intra-individual variance, determining demographic risk factors associated with decline/protection, and examining if particular HD families exhibit distinct cognitive profiles. These and additional future directions are discussed.