MULTIMODAL MRI IN HD

A multimodal MRI approach to Huntington Disease to disclose a marker of onset and evolution in presymptomatic mutation carriers

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 Obiettivo del progetto (Objective)

'Huntington’s disease (HD) is a neurodegenerative familial disease encoded by a CAG expansion mutation in the gene that encodes the protein huntingtin (htt). The abnormal function of mutated htt causes a progressive brain degeneration which in turn causes a sequence of motor, behavioral and cognitive impairment up to dementia. Even though a genetic test allows preclinical diagnosis many years before the clinical onset, there is no effective therapy to stop the disease to date. For that reason, the identification of biomarkers of brain changes, and cognitive/behavioural premorbid profile at presymptomatic stages of the disease may represent an effective strategy to monitor the progression of the pathological process and to assess the potential efficacy of preventive treatments since before the appearance of clinical manifestations.

Neuropathological studies have described cerebral changes since the early stages of the disease mainly in the striatum, but also in other subcortical nuclei and cortical areas. MRI measures conversely are sensitive to the cerebral changes occurring since presymptomatic stages of the disease. Due the complexity of the changes affecting cerebral tissue in HD (i.e. loss of neurons, htt inclusions, reactive gliosis and iron accumulation); the use of a multimodal MRI protocol providing correlated measures sensitive to different characteristics of brain tissue is expected to be introduced in the clinical practice to monitor the complexity of the pathology. All things considered, the current application aims at 1) testing multiple imaging and cognitive/behavioural markers in presymptomatic stages of the disease to evaluate their efficacy to detect disease onset and disease-stage; 2) exploring the relationships between cerebral impairment and behavioural disturbances trying to identify clinical phenotypes; 3) evaluating the influence of the CAG repeat length on cerebral impairment'

Introduzione (Teaser)

Slowing down the process of neurodegeneration is desirable to improve the life of affected individuals and their families. For testing neuroprotective drugs, innovative monitoring tools and biomarkers associated with different disease stages are needed.

Descrizione progetto (Article)

Huntington's disease (HD) is an inherited disorder characterised by progressive degeneration of brain cells, and is caused by a mutation in the gene that encodes the protein huntingtin (htt). This leads to impairment of movement and cognitive disability, and may also reach psychiatric dimensions. Although genetic testing can predict disease onset long before it develops, currently there is no cure.

For most efficient disease management and monitoring of preventive treatments, HD biomarkers are urgently required. With this in mind, the EU-funded MULTIMODAL MRI IN HD project set out to develop tools for measuring signs of disease pathology. The idea was to devise methods for evaluating neural change over time, especially before symptoms arise.

In this context, scientists developed a magnetic resonance imaging (MRI) protocol and combined it with advanced imaging analysis. They looked at iron distribution in the brain of pre-symptomatic and early-stage HD patients, discovering that, even before symptoms emerge, there is a progressive iron increase and volume loss in basal ganglia. Interestingly, these features were strongly associated with the type of mutation. This led scientists to conclude that iron accumulation may be linked with the observed toxicity underlying HD.

Furthermore, HD patients exhibited structural brain impairment in the form of grey matter loss in all the cortical and sub-cortical areas. Brain damage seems to inflict more peripheral nodes first, indicating that rehabilitation may be a viable intervention.

Emerging treatments for neurodegenerative diseases come in the shape of iron chelators and antioxidants. The findings of the MULTIMODAL MRI IN HD study not only support the rationale of such modalities, they also underscore the importance of assessing iron levels and tissue integrity. Combined with relaxometry, MRI and grey/white matter measures could prove useful for monitoring the onset and progression of HD.