White matter microstructure pathology in classic galactosemia revealed by neurite orientation dispersion and density imaging

Abstract

White matter abnormalities have been observed in patients with classic galactosemia, an inborn error of galactose metabolism. However, magnetic resonance imaging (MRI) data collected in the past were generally qualitative in nature. Our objective was to investigate white matter microstructure pathology and examine correlations with outcome and behaviour in this disease, by using multi-shell diffusion weighted imaging. In addition to standard diffusion tensor imaging (DTI), neurite orientation dispersion and density imaging (NODDI) was used to estimate density and orientation dispersion of neurites in a group of eight patients (aged 16–21 years) and eight healthy controls (aged 15–20 years). Extensive white matter abnormalities were found: neurite density index (NDI) was lower in the patient group in bilateral anterior areas, and orientation dispersion index (ODI) was increased mainly in the left hemisphere. These specific regional profiles are in agreement with the cognitive profile observed in galactosemia, showing higher order cognitive impairments, and language and motor impairments, respectively. Less favourable white matter properties correlated positively with age and age at onset of diet, and negatively with behavioural outcome (e.g. visual working memory). To conclude, this study provides evidence of white matter pathology regarding density and dispersion of neurites in these patients. The results are discussed in light of suggested pathophysiological mechanisms.

Affected functional networks associated with sentence production in classic galactosemia

“…The ERP wave morphology was similar for controls and patients, but specific differences -including increased ERP amplitudes during time windows associated with lexical and syntactic planning -were identified . The described white matter abnormalities in this disease (Nelson et al, 1992;Timmers et al, 2015), may be related to the observed functional network patterns, as it was found that white matter abnormalities showed specific regional profiles and furthermore correlations with outcome (Timmers et al, 2015). However, further studies are warranted to link the electrophysiological and functional imaging data specifically to data on structural abnormalities in the brain.…”

“…Further, the conditions and examples of responses are described. Previous brain studies in classic galactosemia have shown structural abnormalities, such as diffuse white matter abnormalities and cortical atrophy (Crome, 1962;Haberland et al, 1971;Hughes et al, 2009;Krabbi et al, 2011;Nelson et al, 1992;Ng et al, 1989;Timmers et al, 2015;Wang et al, 2001). In a functional study (Dubroff et al, 2008), widespread baseline decreases in cortical glucose metabolism were found (e.g., in the superior temporal gyrus and cerebellum) in addition to some increases in glucose metabolism.…”

Assessing Microstructural Substrates of White Matter Abnormalities: A Comparative Study Using DTI and NODDI

“…Data on eight patients with an inherited metabolic disease (classic galactosemia; see [20]) [16–21 years of age] and eight healthy controls [15–20 years of age] were acquired on a 3-T Siemens Trio whole body scanner (Siemens Medical System, Erlangen, Germany), using a 32-channel head coil. The DWI data were obtained using a double-refocused single-shot spin echo EPI sequence.…”

“…In this disease, WM pathology has mainly been described in terms of diffuse signal hyperintensities on T2-weighted images [27] and has been linked at least partly to myelin abnormalities, caused by deficient galactosylation of galactocerebrosides (important building stones of myelin) [28]. The interpretation of the results in the context of the disease is published elsewhere [20]. Here, more specifically, we compared group differences using the DTI-derived (FA, RD, AD, MD) and NODDI-derived (NDI, ODI) markers and evaluated the extent to which the markers identified coinciding and unique differences in the results.…”

Age effects and sex differences in human brain white matter of young to middle-aged adults: A DTI, NODDI, and q-space study

“…Thus, NODDI indices are potentially less ambiguous than DTI in the interpretation of diffusion-weighted microstructural characterization with increased specificity in clinical studies of the human brain. The NODDI model has been applied in studies of white matter changes in aging relative studies (Kunz et al 2014, Billiet et al 2015, Chang et al 2015, Nazeri et al 2015), and other neurologic disorders (Adluru et al 2014, Billiet et al 2014, Winston et al 2014, Timmers et al 2015). …”