Monitoring Huntington's disease progression through preclinical and early stages

Abstract

Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder that typically begins in middle adulthood. The neurodegenerative process that underlies HD, however, likely begins many years before clinical diagnosis. Since genetic testing can identify individuals that will develop HD during this preclinical period, clinical trials aiming to slow disease progression will likely focus on this phase of the illness in an effort to delay disease onset. How to best measure the efficacy of potential disease-modifying therapies in preclinical HD remains a complex challenge. This article will review the clinical and imaging measures that have been assessed as potential markers of disease progression in preclinical and early symptomatic HD.

Figure 1. Relationship between estimated years to diagnosis of Huntington’s disease and various other measures in presymptomatic gene carriers

On each plot, the solid line represents the predicted mean response and broken lines represent the 95% CIs for the mean. Reproduced from [12] with permission from BMJ Publishing Group Ltd.

Figure 2. Progressive decline of total functional capacity at varying points in the course of clinically manifest Huntington’s disease

Bars represent the confidence intervals of the mean annual rates of decline. TFC: Total functional capacity. Reproduced with permission from [21].

Figure 3. MRI volumetric changes in preclinical and early symptomatic Huntington’s disease

Statistical parametric maps showing regions in which (A) gray matter and (B) white matter atrophy rates in the presymptomatic (pre-HD-A and pre-HD-B groups) and early symptomatic (HD1 and HD2 groups) HD patients were significantly different from the healthy control group (family-wise error at p < 0.05 level). HD: Huntington’s disease. Reproduced from [26] © 2011 with permission from Elsevier.

Figure 4. The Huntington’s disease-related metabolic pattern

(A) This pattern was identified by network analysis of baseline [¹⁸F]fluorodeoxyglucose PET scans from 12 presymptomatic Huntington’s disease (HD) gene carriers and 12 age-matched healthy volunteer subjects. The pattern was characterized by metabolic decreases in the striatum and cingulate cortex associated with relative increases in the ventral thalamus, motor cortex and occipital lobe. Subject scores for this pattern discriminated the preclinical HD (pHD) subjects from the controls (p < 0.01). The display represents voxels that contribute significantly to the network at p < 0.005. Voxels with positive region weights (metabolic increases) are color coded from red to yellow; those with negative region weights (metabolic decreases) are color coded from blue to purple. (B) Mean HD-related metabolic pattern activity in the pHD group (squares) at baseline, and at the 1.5 and 4 year follow-up visits. Mean network activity is represented separately for the four pHD subjects (triangles) who subsequently developed symptoms, and for the eight remaining pHD subjects (circles) who had not phenoconverted by the third time point. Mean HD-related metabolic pattern activity is abnormally elevated at all time points, although a significant decline (p < 0.05) in pattern expression was evident between 1.5 and 4 years. The broken and dotted lines represent the mean ± standard deviation for the 12 healthy control subjects. (C) The pHD subjects demonstrated an elevation of thalamic metabolism at baseline (p < 0.05), which was more pronounced in the subgroup who did not phenoconvert during the follow-up period (circles). Elevated thalamic metabolism persisted in these nonconverters. Although elevations in thalamic metabolism were also present in the baseline scans of those subjects who subsequently phenoconverted (triangles), this local metabolic response declined to subnormal levels over time in this subgroup. The broken and dotted lines represent the mean ± standard error for the 12 healthy control subjects. (A & C) Reproduced from [7] with permission from Oxford University Press.

Figure 5. The Huntington’s disease symptom-related metabolic pattern

(A) This pattern was identified by network analysis of [¹⁸F]fluorodeoxyglucose PET scans from the ten original preclinical Huntington’s disease subjects who returned for follow-up at 4 years, including four subjects who had phenoconverted by this time point and six others who remained presymptomatic. This candidate pattern was characterized by metabolic increases in primary motor and premotor regions associated with relative decreases in the ventral thalamus. The display represents voxels that contribute significantly to the network at p < 0.01. Voxels with positive region weights (metabolic increases) are color coded from red to yellow; those with negative region weights (metabolic decreases) are color coded from blue to purple. (B) Subject scores for this pattern were elevated in the four subjects who had phenoconverted by 4 years (triangles). Elevations in network activity were also present in the baseline and 1.5-year scans of these subjects. By contrast, network values for the remaining nonphenoconverters (circles) were in the normal range at all three time points. Squares represent the mean of all preclinical Huntington’s disease subjects at the three time points. The broken and dotted lines represent the mean ± standard deviation for the 12 healthy control subjects.