Abstract

Background: Ataxia Telangiectasia (A-T) is an inherited multisystem disorder with cerebellar neurodegeneration. The relationships between imaging metrics of cerebellar health and neurological function across childhood in A-T are unknown, but may be important for determining timing and impact of therapeutic interventions. Purpose: To WA the hypothesis that abnormalities of cerebellar structure, physiology and cellular health occur in childhood A-T and correlate with neurological disability, we performed multiparametric cerebellar MRI and establish associations with disease status in childhood A-T. Methods: Prospective cross-sectional observational study. 22 young people (9 females / 13 males, age 6.6-17.8 years) with A-T and 24 matched healthy controls underwent 3-Tesla MRI with volumetric, diffusion and proton spectroscopic acquisitions. Participants with A-T underwent structured neurological assessment, and expression / activity of ataxia-telangiectasia mutated (ATM) kinase were recorded. Results: Ataxia-telangiectasia participants had cerebellar volume loss (fractional total cerebellar volume: 5.3% vs 8.7%, P 0.0005, fractional 4th ventricular volumes: 0.19% vs 0.13%, P 0.0005), that progressed with age (fractional cerebellar volumes, r = -0.66, P = 0.001), different from the control group (t = -4.88, P 0.0005). The relationship between cerebellar volume and age was similar for A-T participants with absent ATM kinase production and those producing non-functioning ATM kinase. Markers of cerebellar white matter injury were elevated in ataxia-telangiectasia vs controls (apparent diffusion coefficient 0.89 x 10(-3) mm(2) s(-1) vs 0.69 x 10(-3) mm(2) s(-1), p 0.0005) and correlated (age-corrected) with neurometabolite ratios indicating impaired neuronal viability (N-acetylaspartate:creatine r = -0.70, P 0.001); gliosis (inositol:creatine r = 0.50, P = 0.018; combined glutamine/glutamate:creatine r = -0.55, P = 0.008) and increased myelin turnover (choline:creatine r = 0.68, P 0.001). Fractional 4th ventricular volume was the only variable retained in the regression model predicting neurological function (adjusted r(2) = 0.29, P = 0.015). Conclusions: Quantitative MRI demonstrates cerebellar abnormalities in children with A-T, providing non-invasive measures of progressive cerebellar injury and markers reflecting neurological status. These MRI metrics may be of value in determining timing and impact of interventions aimed at altering the natural history of A-T.