Brain structure in juvenile-onset Huntington disease

Abstract

ObjectiveTo assess brain morphometry in a sample of patients with juvenile-onset Huntington disease (JOHD) and several mouse models of Huntington disease (HD) that likely represent the human JOHD phenotype.MethodsDespite sharing the mutation in the Huntingtin gene, adult-onset HD characteristically presents as a hyperkinetic motor disorder, while JOHD typically presents as a hypokinetic motor disease. The University of Iowa Kids-JHD program enrolls individuals 5 to 25 years of age who have already received the clinical diagnosis. A total of 19 children with juvenile HD (JHD) (mean CAG = 72) were studied. Patients with JHD were compared to healthy controls (n = 234) using a cross-sectional study design. Volumetric data from structural MRI was compared between groups. In addition, we used the same procedure to evaluate brain morphology of R6/2, zQ175, HdhQ250 HD mice models.ResultsParticipants with JHD had substantially reduced intracranial volumes. After controlling for the small intracranial volume size, the volumes of subcortical regions (caudate, putamen, globus pallidus, and thalamus) and of cortical white matter were significantly decreased in patients with JHD. However, the cerebellum was proportionately enlarged in the JHD sample. The cerebral cortex was largely unaffected. Likewise, HD mice had a lower volume of striatum and a higher volume of cerebellum, mirroring the human MRI results.ConclusionsThe primary pathology of JOHD extends beyond changes in the striatal volume. Brain morphology in both mice and human patients with JHD shows proportional cerebellar enlargement. This pattern of brain changes may explain the unique picture of hypokinetic motor symptoms in JHD, which is not seen in the hyperkinetic chorea-like phenotype of adult-onset HD.

Single-nucleus RNA-seq identifies Huntington disease astrocyte states

“…1a). A recent report suggests that in juvenile HD the cerebral cortex is largely unchanged compared with controls [52]. We next performed differential gene expression analysis from bulk RNAseq specimens, and identified 3165 downregulated genes and 1835 upregulated genes at a Benjamini-Hochberg adjusted false discovery rate of 0.05 ( Fig.…”

Orbitrap mass spectrometry for monitoring the ganglioside pattern in human cerebellum development and aging

“…In the past few years, advanced studies conducted using modern genetic and neuroimaging methods, such as functional magnetic resonance imaging (fMRI) have indicated that human cerebellum also sustains autonomic, limbic, and cognitive functions, including language and thinking; hence, this brain region was lately associated with the occurrence and development of autism . On the basis of the data collected by genetic testing and/or using MRI methods, other reports also relate cerebellar dysfunctions to Alzheimer disease (AD), attention‐deficit/hyperactivity disorder, Huntington disease, hereditary ataxia, and Parkinson disease (PD) . In the case of PD, it was considered that the pathological changes in the cerebellum might be induced by dopaminergic degeneration, which may account for some clinical symptoms specific to this neurodegenerative disorder, while in the case of AD, it recently discovered a unique motif of the cerebellar cortex associated to the disease …”

Developmental origins of cortical hyperexcitability in Huntington's disease: Review and new observations

“…Although neurodegenerative changes have long been recognized to underlie HD motor symptoms, several clinical and experimental studies have suggested that aberrant cortical development may also play an important role in the manifestation of HD symptoms (Godin et al, ; Paulsen et al, ; Tereshchenko et al, ). In this review, we discuss why we think that faulty cortical development is at the root of some HD functional alterations, in particular cortical hyperexcitability.…”

“…Notably, smaller intracranial volumes in prodromal HD patients indicate that mHTT can cause abnormal brain development (Nopoulos, Aylward, Ross, Mills, & Langbehn, ). Interestingly, smaller intracranial volumes can be associated with cerebellar enlargement, which could explain hypokinesia in JHD (Tereshchenko et al, ). Thus, HD therapies have to take into account that the goal is not only to prevent neurodegeneration in a susceptible brain but also to correct aberrant development.…”