Researchers have shown that an imaging model can detect microstructural abnormalities in the brain associated with Huntington's disease, potentially offering a new method for monitoring disease progression and evaluating new treatments.
Their study, appearing previously as a Reviewed Preprint in eLife and published today as the final Version of Record, is described by eLife's editors as fundamental. It reports the novel use of the Soma and Neurite Density Imaging (SANDI) model to study tissue abnormalities that occur in the basal ganglia of Huntington's disease patients – a region of the brain that controls movements, habits, and learning.
Huntington's disease is an inherited neurodegenerative disorder characterised by a progressive loss of cognitive and motor functions due to deterioration (atrophy) within the basal ganglia. While there are currently no disease-modifying therapies, several clinical trials are in progress, meaning there is a demand for sensitive, non-invasive imaging biomarkers to help evaluate the effects of novel treatments.
MRI scans that measure the volume of whole-brain structures are widely used in clinical trials, but they are unable to show the underlying neuropathological tissue changes that lead to atrophy within the striatum, which acts as the signal processing hub for the basal ganglia system. SANDI – a diffusion MRI model that analyses how water molecules move inside cells to estimate their size and density – could help overcome this challenge.
"We wanted to test how SANDI performs in characterising Huntington's disease-related abnormalities in the basal ganglia and thalami, and examine associations between SANDI indices, volumetric measurements, and motor performance," explains senior author Claudia Metzler-Baddeley, Reader in Cognitive Neuroscience at the Cardiff University Brain Research Imaging Centre (CUBRIC), Cardiff, UK. "We chose the thalami as control regions based on how neurodegeneration progresses in Huntington's disease – that is, beginning with early loss of medium spiny neurons in the striatum before extending to the thalamus and other neighbouring structures. This is the first time, to our knowledge, that SANDI has been applied in Huntington's disease, an approach with potential translatability to other neurodegenerative diseases."
The work was led by first author Vasileios Ioakeimidis, who was a Postdoctoral Researcher at CUBRIC at the time of the study and is now based at the Danish Research Centre for Magnetic Resonance (DRCMR), Amager and Hvidovre Hospital, Copenhagen, Denmark.
Ioakeimidis and colleagues fit the SANDI model to diffusion data from 56 people with Huntington's disease and 57 healthy volunteers who were all scanned using the same MRI system at CUBRIC. Participants with Huntington's disease completed motor tasks, including quick and paced finger tapping, allowing the researchers to compare brain imaging measurements with movement performance. The team then used the data they gathered to analyse correlations between SANDI indices, motor performance, and volumetric measures.
The SANDI measures revealed differences between the two study groups in the estimated density and size of the soma – the rounded 'body' of cells. In people with Huntington's disease, estimates of soma density were lower while estimates of soma size and space between cells were higher than in healthy volunteers – a pattern matching the neuron loss and glial reaction that has been observed in post-mortem brain tissue. Together with age, these SANDI estimates explained up to 63% of the striatum's shrinkage in Huntington's disease and were linked to poorer performance on the motor tasks. As the team expected, they saw no such changes in the thalamus.
Together, the findings suggest that SANDI can provide useful information complementary to volumetric measures, and could be feasible for measuring the effects of disease-modifying therapies in clinical trials. Further studies are now needed to determine if SANDI can track disease progression more sensitively than established imaging biomarkers. Additionally, the model will need to be implemented across standard MRI systems found in hospitals.
"SANDI shows significant promise for tracking Huntington's disease and testing whether new therapies protect brain cells, and could also be applied to more common neurodegenerative conditions such as Alzheimer's and Parkinson's disease," Metzler-Baddeley concludes. "Before that can happen, our findings need to be confirmed in larger, long-term studies, and we hope our work will provide a useful framework for those studies."
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