Mapping the order and pattern of brain structural MRI changes using change‐point analysis in premanifest Huntington's disease

Wu, Dan; Faria, Andréia V.; Younes, Laurent; Mori, Susumu; Brown, Timothy; Johnson, Hans J.; Paulsen, Jane S.; Ross, Christopher A.; Miller, Michael I.

doi:10.1002/hbm.23713

Cited by 28 publications

(26 citation statements)

References 105 publications

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“…It is likely that the white matter changes in the earlyHD group begin many years prior to diagnosis but are not necessarily detectable in comparisons with non‐CAG expanded individuals. There is robust evidence to suggest that macrostructural white matter changes in the cortex occur prior to those in the gray matter with similar white matter microstructural changes (Paulsen et al, 2010; Tabrizi et al, 2012; Wu et al, 2017). …”

Section: Discussionmentioning

confidence: 99%

Natural biological variation of white matter microstructure is accentuated in Huntington's disease

Gregory

Crawford

Seunarine

et al. 2018

Human Brain Mapping

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Huntington's disease (HD) is a monogenic neurodegenerative disorder caused by a CAG‐repeat expansion in the Huntingtin gene. Presence of this expansion signifies certainty of disease onset, but only partly explains age at which onset occurs. Genome‐wide association studies have shown that naturally occurring genetic variability influences HD pathogenesis and disease onset. Investigating the influence of biological traits in the normal population, such as variability in white matter properties, on HD pathogenesis could provide a complementary approach to understanding disease modification. We have previously shown that while white matter diffusivity patterns in the left sensorimotor network were similar in controls and HD gene‐carriers, they were more extreme in the HD group. We hypothesized that the influence of natural variation in diffusivity on effects of HD pathogenesis on white matter is not limited to the sensorimotor network but extends to cognitive, limbic, and visual networks. Using tractography, we investigated 32 bilateral pathways within HD‐related networks, including motor, cognitive, and limbic, and examined diffusivity metrics using principal components analysis. We identified three independent patterns of diffusivity common to controls and HD gene‐carriers that predicted HD status. The first pattern involved almost all tracts, the second was limited to sensorimotor tracts, and the third encompassed cognitive network tracts. Each diffusivity pattern was associated with network specific performance. The consistency in diffusivity patterns across both groups coupled with their association with disease status and task performance indicates that naturally‐occurring patterns of diffusivity can become accentuated in the presence of the HD gene mutation to influence clinical brain function.

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Section: Discussionmentioning

confidence: 99%

Natural biological variation of white matter microstructure is accentuated in Huntington's disease

Gregory

Crawford

Seunarine

et al. 2018

Human Brain Mapping

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“…Finally, we only assessed associations between caudate and putamen brain structures and dual tasking performance, as these are the principle brain structures affected by the disease and sensitive to early disease changes. It is important to note that other brain structures are also affected, including the cerebellum and brain stem, 40,41 which may also influence dual tasking in HD. 42,43 Additional studies should investigate the role of other subcortical and cortical structures and dual tasking.…”

Section: Study Limitationsmentioning

confidence: 99%

Dual tasking impairments are associated with striatal pathology in Huntington’s disease

Reyes

Pulverenti

et al. 2020

Ann Clin Transl Neurol

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Background Recent findings suggest that individuals with Huntington’s disease (HD) have an impaired capacity to execute cognitive and motor tasks simultaneously, or dual task, which gradually worsens as the disease advances. The onset and neuropathological changes mediating impairments in dual tasking in individuals with HD are unclear. The reliability of dual tasking assessments for individuals with HD is also unclear. Objectives To evaluate differences in dual tasking performance between individuals with HD (presymptomatic and prodromal) and matched controls, to investigate associations between striatal volume and dual tasking performance, and to determine the reliability of dual tasking assessments. Methods Twenty individuals with HD (10 presymptomatic and 10 prodromal) and 20 healthy controls were recruited for the study. Individuals undertook four single and dual task assessments, comprising motor (postural stability or force steadiness) and cognitive (simple or complex mental arithmetic) components, with single and dual tasks performed three times each. Participants also undertook a magnetic resonance imaging assessment. Results Compared to healthy controls, individuals with presymptomatic and prodromal HD displayed significant deficits in dual tasking, particularly cognitive task performance when concurrently undertaking motor tasks (P < 0.05). The observed deficits in dual tasking were associated with reduced volume in caudate and putamen structures (P < 0.05),however, not with clinical measures of disease burden. An analysis of the reliability of dual tasking assessments revealed moderate to high test–retest reliability [ICC: 0.61‐0.99] for individuals with presymptomatic and prodromal HD and healthy controls. Conclusions Individuals with presymptomatic and prodromal HD have significant deficits in dual tasking that are associated with striatal degeneration. Findings also indicate that dual tasking assessments are reliable in individuals presymptomatic and prodromal HD and healthy controls.

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“…Gray matter and motor and cognitive functioning show significant prodromal decline in HD ( 11 , 15 , 25 , 38 – 41 ). Our results first confirmed that variation in these domains relates significantly to CAP, a metric reflecting disease burden and based on CAG mutation and exposure time (age) ( 13 , 42 ).…”

Section: Discussionmentioning

confidence: 99%

Genetics Modulate Gray Matter Variation Beyond Disease Burden in Prodromal Huntington’s Disease

et al. 2018

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Huntington’s disease (HD) is a neurodegenerative disorder caused by an expansion mutation of the cytosine–adenine–guanine (CAG) trinucleotide in the HTT gene. Decline in cognitive and motor functioning during the prodromal phase has been reported, and understanding genetic influences on prodromal disease progression beyond CAG will benefit intervention therapies. From a prodromal HD cohort (N = 715), we extracted gray matter (GM) components through independent component analysis and tested them for associations with cognitive and motor functioning that cannot be accounted for by CAG-induced disease burden (cumulative effects of CAG expansion and age). Furthermore, we examined genetic associations (at the genomic, HD pathway, and candidate region levels) with the GM components that were related to functional decline. After accounting for disease burden, GM in a component containing cuneus, lingual, and middle occipital regions was positively associated with attention and working memory performance, and the effect size was about a tenth of that of disease burden. Prodromal participants with at least one dystonia sign also had significantly lower GM volume in a bilateral inferior parietal component than participants without dystonia, after controlling for the disease burden. Two single-nucleotide polymorphisms (SNPs: rs71358386 in NCOR1 and rs71358386 in ADORA2B) in the HD pathway were significantly associated with GM volume in the cuneus component, with minor alleles being linked to reduced GM volume. Additionally, homozygous minor allele carriers of SNPs in a candidate region of ch15q13.3 had significantly higher GM volume in the inferior parietal component, and one minor allele copy was associated with a total motor score decrease of 0.14 U. Our findings depict an early genetical GM reduction in prodromal HD that occurs irrespective of disease burden and affects regions important for cognitive and motor functioning.

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Mapping the order and pattern of brain structural MRI changes using change‐point analysis in premanifest Huntington's disease

Cited by 28 publications

References 105 publications

Natural biological variation of white matter microstructure is accentuated in Huntington's disease

Natural biological variation of white matter microstructure is accentuated in Huntington's disease

Dual tasking impairments are associated with striatal pathology in Huntington’s disease

Genetics Modulate Gray Matter Variation Beyond Disease Burden in Prodromal Huntington’s Disease

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