Mild Cognitive Impairment as an Early Landmark in Huntington's Disease.

Ying Zhang,Jane S Paulsen,Junyi Zhou,Jeffrey D Long,Carissa R Gehl,Kathleen Shannon,Daniel Sewell,Vincent A Magnotta,Hans Johnson

doi:10.3389/fneur.2021.678652

Abstract

As one of the clinical triad in Huntington's disease (HD), cognitive impairment has not been widely accepted as a disease stage indicator in HD literature. This work aims to study cognitive impairment thoroughly for prodromal HD individuals with the data from a 12-year observational study to determine whether Mild Cognitive Impairment (MCI) in HD gene-mutation carriers is a defensible indicator of early disease. Prodromal HD gene-mutation carriers evaluated annually at one of 32 worldwide sites from September 2002 to April 2014 were evaluated for MCI in six cognitive domains. Linear mixed-effects models were used to determine age-, education-, and retest-adjusted cut-off values in cognitive assessment for MCI, and then the concurrent and predictive validity of MCI was assessed. Accelerated failure time (AFT) models were used to determine the timing of MCI (single-, two-, and multiple-domain), and dementia, which was defined as MCI plus functional loss. Seven hundred and sixty-eight prodromal HD participants had completed all six cognitive tasks, had MRI, and underwent longitudinal assessments. Over half (i.e., 54%) of the participants had MCI at study entry, and half of these had single-domain MCI. Compared to participants with intact cognitive performances, prodromal HD with MCI had higher genetic burden, worsened motor impairment, greater brain atrophy, and a higher likelihood of estimated HD onset. Prospective longitudinal study of those without MCI at baseline showed that 48% had MCI in subsequent visits and data visualization suggested that single-domain MCI, two-domain MCI, and dementia represent appropriate cognitive impairment staging for HD gene-mutation carriers. Findings suggest that MCI represents an early landmark of HD and may be a sensitive enrichment variable or endpoint for prodromal clinical trials of disease modifying therapeutics.

Highlights

It is well-known that Huntington’s disease (HD) manifests as a triad of clinical symptoms; its diagnosis continues to rely primarily on the presence of motor impairment [1]
The results will be informative for evaluating the extent to which Mild Cognitive Impairment (MCI) in HD gene-mutation carriers is a defensible indicator of early disease potentially appropriate as an endpoint in preventive trials
The analysis consisted of three steps, the first being the classification of gene-expanded individuals as MCI performed at each visit, the second step was to use MCI status at baseline to predict the timing of HD onset, the third step was to demarcate stages in longitudinal cognitive decline

Summary

Introduction

It is well-known that Huntington’s disease (HD) manifests as a triad of clinical symptoms (motor, cognitive, psychiatric); its diagnosis continues to rely primarily on the presence of motor impairment [1]. Nearly two decades of research in persons with the gene expansion for HD have documented measures of earlier disease, but none are yet accepted as endpoints for preventive clinical trials. Patients with diagnosed or manifest HD are currently undergoing Phases II and III clinical trials for gene silencing using antisense oligonucleotides [6]. Phase I clinical trials targeting somatic expansion have been announced, UniQure is testing a adeno-associated virus (AAV5) vector carrying an artificial micro-RNA tailored to silence the huntingtin gene and several investigators are focusing on the genome-editing technology CRISPR. This work motivates the need for additional endpoints for clinical trials in early HD

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