Document Type


Date of Degree

Spring 2016

Degree Name

PhD (Doctor of Philosophy)

Degree In


First Advisor

Peggy C. Nopoulos


Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a mutation involving an expansion of the CAG trinucleotide repeats in the gene encoding for huntingtin (HTT) protein. The discovery of the disease-causing faulty gene (mutant huntingtin; mHTT) has enabled valid presymptomatic gene assessment for HD with results being categorized as ‘gene-expanded (GE; CAG repeats ≥ 36)' or ‘gene non-expanded (GNE)'. Individuals tested to be gene-expanded are destined to develop HD symptoms and will receive clinical diagnosis at an average age of 40 years when abnormal motor symptoms manifest. Those who are GNE will not develop HD. The availability of genetic testing has also provided a valuable research opportunity to study the pathoetiology of HD in PreHD subjects (those tested to be ‘gene-expanded' but are in the prediagnostic stage of HD). The genetic mutation results in widespread neuronal degeneration preferentially within the striatum. The clinical manifestations of HD include a triad of motor, cognitive and psychiatric symptoms.

Challenging the classical view of HD as a neurodegenerative disease, recent studies have brought about a conceptual shift to include abnormal neurodevelopmental aspects in the etiology of HD1, based on the notion that lifelong HTT gene mutation may compromise HTT's crucial role in normal brain development. The fronto-striatal circuitry has been a main interest in HD research for its profound pathological association with symptom manifestation and marked neuroanatomical change. However, no study to date has investigated the neuropathological alteration of the fronto-striatal circuitry during childhood in mHTT carriers. In line with the proposed new perspective, the overall hypothesis of the current proposal is that the deteriorating effect of mHTT on the fronto-striatal circuits stems from abnormal development of these circuits. Therefore, the main goal of the current study was to enhance our understanding of how mHTT alters the evolving capacity of the fronto-striatal circuitry from a developmental perspective. To this end, the study examined the fronto-striatal circuit structure (using magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI)) and function (using resting state functional MRI and cognitive/behavior tests) in children (6-18 years of age) at risk for HD. Healthy control children with no family history of HD were also evaluated. For research purposes only, children at risk for HD were genotyped and designated as GE or GNE based the result of their genetic testing. While the assessment of the fronto-striatal circuit development focused on anatomical delineations, the tests of the fronto-striatal circuit functionality were carried out separately for the three distinct cognitive, motor and affective loops within the fronto-striatal circuitry. The overall aim of the project was to evaluate the effect of mHTT on subcortical brain structures, white matter connection development and functional integrity of the cognitive, motor and affective loops within the fronto-striatal circuitry in Gene-Expanded (GE) children compared to those of Healthy Control (HC) children and again to those who are Gene Non-Expanded (GNE). Test of the hypothesized mHTT-associated developmental alteration of the fronto-striatal circuitry was addressed in two specific aims:

Specific Aim #1: To observe subcortical gray matter volumes and white matter integrity of the fronto-striatal circuitry in children at risk for HD

Decline in corpus striatal volume as well as aberrant fronto-striatal circuit connectivity has been reported in manifest HD patients and also in preHD adults.2-4 However, there is no experimental evidence of the onset or pattern of the pathophysiological change in the fronto-striatal circuitry. Therefore, volumes of subcortical structures and white matter integrity were measured in order to assess the development of the fronto-striatal circuitry in children at risk for HD.

Specific Aim #2: To assess the functionalities of specific fronto-striatal circuit loops in children at risk for HD

Functional abnormalities of the fronto-striatal circuitry have been observed in HD patients as well as in preHD adults.5 In order to closely examine the mHTT effect on fronto-striatal circuit function, resting state functional connectivity as well as performances on cognitive and behavioral tasks tapping into the functionality of the three fronto-striatal loops were evaluated in children at risk for HD.

It was hypothesized that GE children would have diminished fronto-striatal circuit function. The GE children were predicted to show statistically significant deficits in 1) resting state functional connectivity between specific frontal lobe areas and striatal sub-regions, 2) cognitive control, 3) motoric control and 4) behavior control when compared to healthy controls and children without the HTT CAG expansion.

The current study reports the baseline profile of the fronto-striatal structure and function in children at risk for HD. We have found that children who are on average 30 years ahead of HD diagnosis to have developmental alterations in the brain structure and function directly linked to the effect of mHTT. Brain morphology analysis revealed specific subcortical gray and white matter changes. The changes include disproportionately smaller caudate and putamen volumes and increased radial diffusivity localized to the external capsule which were more evident in males with HTT gene expansion. Fronto-striatal circuit functional assessment revealed a drop in motor functionality (both at rest and active performance) and externalizing behavior problems indicative of compromised inhibition than aggression. Children from HD families but do not have the genetic mutation also showed development aberrations in both brain structure and function when compared to healthy controls. Importantly, the altered structural morphology and functional profile seen in the GNE group differed from that of the GE children, emphasizing the impact of mHTT. The findings from those who share similar household environment but differ in genetic expansion status are important in highlighting the potential interaction of gene-environment effect on the manifestation of mHTT related changes seen in the children with the genetic expansion for HD.

Investigation of subtle but persistent effects of mHTT on normal neural developmental processes may further our understanding of the pathogenesis of HD. Continuous longitudinal comprehensive assessments of the mHTT associated neurophenotype would aid in prognostic scenario estimation and thereby lead to effective clinical decision making to maximize the benefit of early intervention.

Public Abstract

Huntington’s disease (HD) is characterized by uncontrolled movements, and causes cognitive and emotional disturbances. HD is a neurologic disorder caused by a genetic mutation that is inherited in an autosomal dominant fashion, meaning children of a parent with HD have a 50 percent chance of developing this disease. The mutation occurs in a gene that encodes a protein called huntingtin (HTT). Both HTT and the mutated HTT (mHTT), are active throughout development, childhood and adulthood. HTT is known to be important for normal brain development. So if this gene is mutated, then its role in brain development might get compromised, setting the stage for HD.

The discovery of the HD gene marker provided an opportunity to study HD in individuals with mHTT before diagnosis which typically occurs around the age of 40. As a result, mHTT-related changes in the adult aging brain are well documented. Making a change in the observational window, we evaluated brain areas associated with the striatum, which is most affected in HD, in children growing up with mHTT. We found changes in the striatal areas, motor function and behavior in the children who are estimated to be on average 30 years ahead of HD diagnosis. The observed changes were subtle enough that they could be potentially managed by compensatory mechanisms. These findings hold great importance in learning how the disease arises. Moreover, identifying the earliest symptom is essential in determining the optimal time point for intervention to delay or possibly prevent the disease manifestation.


publicabstract, Development, Huntington' Disease


xiii, 92




Copyright 2016 Qyong Lee