Based on MRI scans, Huntington’s disease patients with major cognitive impairments have reduced gray matter volume and a thinner brain cortex than those without cognitive problems, a study has demonstrated.
Major cognitive decline was not associated with CAG repeat length, age, or education, suggesting additional mechanisms contribute to cognitive decline in these patients.
The study, “Structural brain correlates of dementia in Huntington’s disease,” was published in the journal NeuroImage: Clinical.
A hallmark of Huntington’s disease is the progressive atrophy (shrinkage) in the region of the brain known as the basal ganglia, which is responsible for movement coordination. That shrinkage can be detected up to 15 years before the appearance of motor symptoms.
Recent evidence suggests that Huntington’s also leads to reductions in whole brain volume as well as gray matter volume and thinning of the cortex, the outer layer of the brain that controls thought, behavior and memory. Of note, gray matter is a component of the central nervous system (the brain and spinal cord) consisting of neuronal cell bodies, glial cells and capillaries, among other structures.
Many of these changes underlie cognitive decline and dementia, manifesting as memory and learning difficulties, and problems with judgment, answering questions, and making decisions.
However, it remains unclear how these specific brain atrophy patterns lead to cognitive impairments of different severity in Huntington’s disease.
Researchers based at the Hospital de la Santa Creu i Sant Pau in Spain designed a study using MRI to measure brain structure changes and identify correlations with major cognitive deficits.
The study included 35 symptomatic adults (mean age 51.8 years) that carried more than 38 CAG trinucleotide repeats — the underlying genetic cause of the disease that consists of a series of three DNA building blocks (nucleotides), CAG, in the huntingtin gene (HTT), which is between 10 and 35 repeats in healthy people, but longer in those with Huntington’s.
Also included were 15 age- and education-matched healthy controls (mean age 45.8) who were relatives of the Huntington’s participants.
Patients were classified with or without severe cognitive impairment using the Huntington’s-specific Parkinson’s Disease-Cognitive Rating Scale (PD-CRS), a screening tool for global cognition in people with Huntington’s, in which a PD-CRS cutoff score of 64 or less classified a patient with dementia.
Based on PD-CRS scores, 20 participants were classified without dementia (HD-ND), and 15 in the dementia group (HD-Dem). No differences were found between HD-ND and HD-Dem groups regarding age, gender, education, or CAG repeat length.
The mean total PD-CRS score for the HD-ND group was 84.3, which places them in the range between cognitive normality and mild cognitive deficits.
Compared to controls, patients without dementia showed significantly lower gray matter volume in specific brain regions, including: the bilateral caudate nucleus (voluntary movement); the putamen (movement and learning); the bilateral insula (emotional experience); the bilateral inferior orbital prefrontal cortex (executive function); and other areas involved in processing sensory information and object recognition.
Participants with dementia, compared to controls, found marked gray matter volume differences in the whole basal ganglia and the insular cortex (sensory processing, self-awareness, cognitive function, and social behavior), the frontal cortex (decision-making, memory, social interaction, and motor function), the occipital gyrus (object recognition), and the lingual gyrus (vision processing).
A comparison of HD-ND and HD-Dem found that those with dementia had reduced gray matter volume in the parietal-temporal regions, including the insular cortex, the superior temporal gyrus (sound processing), and the supramarginal gyrus (tactile sensory processing).
Cortical thinning, compared to controls, was found in the frontotemporal (executive functioning) and parieto-occipital regions (planning) in the HD-ND group, while those with dementia had a similar but more significant thinning pattern than those in the HD-ND group.
In the HD-Dem group compared to the HD-ND cohort, cortical thinning predominantly affected frontotemporal and parietal (sensory processing) regions of the left hemisphere and temporo-occipital (spatial awareness) regions of the right hemisphere.
These brain alterations were associated with poorer cognitive performance in tasks that assessed executive and attention domains, as well as memory, language and constructional abilities.
After adjusting for age, education, CAG repeat length, and the Unified Huntington’s Disease Rating Scale-Total motor score (UHDRS-TMS), the lower PD-CRS scores (more dementia) were correlated with lower gray matter volume in areas such as basal ganglia, frontal lobes, temporal lobes, insular cortex, mid cingulate (emotional regulation, sensing, and action interface), and the occipital and parietal lobe.
Like the gray matter volume results, the cortical thinning analysis found some of the same regions strongly associated with poor PD-CRS cognitive performance, with the most significant changes in the posterior-cortical regions, specifically at the fusiform gyrus (recognition) in the temporo-occipital area (cognitive function and voluntary movements).
“Major cognitive impairment in the range of dementia in HD is associated with brain and cognitive alterations exceeding the prototypical frontal-executive deficits commonly recognized in [Huntington’s disease], the researchers wrote. “Critically, major cognitive impairment in this sample was not associated with CAG repeat length, age, or education.”
“This finding could support a possible involvement of additional neuropathological mechanisms aggravating cognitive deterioration in [Huntington’s disease],” they added.
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