Clinical and Biomarker Changes in Premanifest Huntington Disease Show Trial Feasibility: A Decade of the PREDICT-HD Study

Abstract

There is growing consensus that intervention and treatment of Huntington disease (HD) should occur at the earliest stage possible. Various early-intervention methods for this fatal neurodegenerative disease have been identified, but preventive clinical trials for HD are limited by a lack of knowledge of the natural history of the disease and a dearth of appropriate outcome measures. Objectives of the current study are to document the natural history of premanifest HD progression in the largest cohort ever studied and to develop a battery of imaging and clinical markers of premanifest HD progression that can be used as outcome measures in preventive clinical trials. Neurobiological predictors of Huntington’s disease is a 32-site, international, observational study of premanifest HD, with annual examination of 1013 participants with premanifest HD and 301 gene-expansion negative controls between 2001 and 2012. Findings document 39 variables representing imaging, motor, cognitive, functional, and psychiatric domains, showing different rates of decline between premanifest HD and controls. Required sample size and models of premanifest HD are presented to inform future design of clinical and preclinical research. Preventive clinical trials in premanifest HD with participants who have a medium or high probability of motor onset are calculated to be as resource-effective as those conducted in diagnosed HD and could interrupt disease 7–12 years earlier. Methods and measures for preventive clinical trials in premanifest HD more than a dozen years from motor onset are also feasible. These findings represent the most thorough documentation of a clinical battery for experimental therapeutics in stages of premanifest HD, the time period for which effective intervention may provide the most positive possible outcome for patients and their families affected by this devastating disease.

Neurotrophin receptor p75NTR mediates Huntington’s disease–associated synaptic and memory dysfunction

“…Decades of research have long established that cognitive function declines in the premanifest and early stages of HD (62)(63)(64). Although several studies point to the contribution of other brain structures such as the hippocampus to learning and memory defiwith our hypothesis, KI mutant mice showed a significant increase in hippocampal RhoA activity compared with either WT, p75 +/-, or KI:p75 +/-mice ( Figure 10A).…”

Sex‐specific effects of the Huntington gene on normal neurodevelopment

“…This is also supported by an HD animal model study that showed an inverse relationship between striatal volume and cortical thickness, indicating that thickening may be compensatory (Lerch et al, 2008). The volume of the caudate and putamen has been shown to be the most powerful biomarker for prediction of motor signs of the disease (Paulsen et al, 2014). Although the cerebellum is not commonly reported as being structurally abnormal in pre-HD subjects, a recent report documented abnormal cortico-cerebellar connectivity in patients with early-manifest HD (Wolf et al, 2015).…”

Selective expression of mutant huntingtin during development recapitulates characteristic features of Huntington’s disease

“…Although the role of these diverse developmental defects for HD pathogenesis remains undefined, they have the potential to impair the integrity of striatal and cortical neuronal homeostasis and function through multiple inductive interactions. Indeed, these changes may provide an explanation for studies, including the Neurobiological Predictors of Huntington's Disease (PREDICT-HD) and TRACK-HD studies, showing electrophysiological abnormalities, discrete brain structural as well as volumetric changes, and cognitive and motor deficits occurring long before disease onset (3)(4)(5)(6)(7)(8). We therefore propose that selective exposure to mutant Htt (mHtt) during neural development can recapitulate characteristic features of HD.…”