Cognitive decline in prodromal Huntington Disease: implications for clinical trials

Abstract

Controversy exists regarding the feasibility of preventive clinical trials in prodromal Huntington disease (HD). A primary limitation is a lack of outcome measures for persons with the gene mutation who have not yet been diagnosed with HD. Many longitudinal studies of cognitive decline in prodromal HD have not stratified samples based on disease progression, thereby obscuring differences between symptomatic and nonsymptomatic individuals. Prodromal participants from PREDICT-HD were stratified by disease progression into one of three groups: those having a High, Medium, or Low probability of motor manifestation within the next five years. Data from a total of N = 1299 participants with up to 5950 data points were subjected to linear mixed effects regression on 29 longitudinal cognitive variables, controlling for age, education, depression, and gender. Performance of the three prodromal HD groups was characterized by insidious and significant cognitive decline over time. Twenty-one variables from 19 distinct cognitive tasks revealed evidence of a disease progression gradient, meaning that the rate of deterioration varied as a function of progression level, with faster deterioration associated with greater disease progression. Nineteen measures showed significant longitudinal change in the High group, nine showed significant change in the Medium group and four showed significant cognitive decline in the Low group. Results indicate that clinical trials may be conducted in prodromal HD using the outcome measures and methods specified. The findings may help inform interventions in HD as well as other neurodegenerative disorders.

Huntington's Disease: Premotor Phase

“…Even though data on cognitive decline progression in premotor HD patients is contradictory, there have been several studies that have had results similar to those of Paulsen et al [29] with different tools and variables, all pointing to the fact that there is indeed a cognitive decline very early on and prior to the onset of motor symptoms [8,29,30,31]. Moreover, one article presented evidence that these cognitive changes can have a prognostic value, with motor planning/speed and sensory-perceptual processing being the best indicators.…”

Disruption of response inhibition circuits in prodromal Huntington disease

“…Though our cross-sectional analyses suggested some stepwise changes in brain functioning from early to later stages of prHD, this prospect must be validated using longitudinal study designs. Of relevance here is that many cognitive measures are sensitive to changes in prHD in both cross-sectional and longitudinal studies (Paulsen, Smith, & Long, 2013). As such, functional imaging markers of cognitive change may well show longitudinal changes.…”

Egocentric and allocentric visuospatial working memory in premotor Huntington's disease: A double dissociation with caudate and hippocampal volumes

“…HD is an auto-somal dominant inherited disorder caused by an expansion of the trinucleotide repeat cytosine-adenine-guanine (CAG). Individuals with pmHD do not yet exhibit the motor symptoms including chorea, but can exhibit cognitive or psychiatric changes (Epping et al, 2015; Paulsen et al, 2013), including working memory impairments (You et al, 2014). Caudate volume loss is present more than a decade before HD diagnosis and contributes robustly to cognitive impairment, whereas hippocampal volumes are relatively preserved and do not predict cognitive impairment (Aylward et al, 2013, 2004).…”