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Group differences in main white matter tracts. Average group maps of the FA values, neurite density index (NDI) values, and orientation dispersion index (ODI) values (all ranging from 0.2-0.8) in transversal slices covering the majority of the brain from superior to inferior. Superimposed are the mean FA skeleton (green) and the statistical group differences (red: controls > patients; blue: patients > controls). Presented results are TFCE-corrected and thresholded at a corrected alpha-level of 0.05. For display purposes, the results are thickened by filling it out into the local tracts (as implemented in TBSS). Note that left is right in these maps
Source publication
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 beha...
Contexts in source publication
Context 1
... the left columns of Fig. 1, mean FA maps are shown. Superimposed are the significant group differences, observed across the majority of the WM tracts, except for the cerebellar tracts. In the middle columns of Fig. 1, the group differences in NDI are shown. Visual comparison shows these changes overlap with FA changes, but are more localized. NDI changes were found mainly bilateral and located mostly in the anterior part of the brain. In Fig. 2, the group differences are overlaid on colour maps, aiding in the localization of the tracts (using the atlas of Wakana et al 2003). On the right-sided columns of Fig. 1, group differences in ODI are displayed, overlaid on mean ODI maps and the skeleton. Again, ODI changes overlap FA, but are more specifically localized. Dispersion changes were mainly located on the left, middle parts of the brain (see Fig. 2 for tract localisation) and showed minimal overlap with the NDI changes. To examine the cerebellum irrespective of the skeleton, ROIs were manually drawn based on the group averaged FA map: two in bilateral middle cerebellar peduncles (one more anterior, one more posterior). No group differences were found in FA, NDI or ODI (all p > ...
Context 2
... the left columns of Fig. 1, mean FA maps are shown. Superimposed are the significant group differences, observed across the majority of the WM tracts, except for the cerebellar tracts. In the middle columns of Fig. 1, the group differences in NDI are shown. Visual comparison shows these changes overlap with FA changes, but are more localized. NDI changes were found mainly bilateral and located mostly in the anterior part of the brain. In Fig. 2, the group differences are overlaid on colour maps, aiding in the localization of the tracts (using the atlas of Wakana et al 2003). On the right-sided columns of Fig. 1, group differences in ODI are displayed, overlaid on mean ODI maps and the skeleton. Again, ODI changes overlap FA, but are more specifically localized. Dispersion changes were mainly located on the left, middle parts of the brain (see Fig. 2 for tract localisation) and showed minimal overlap with the NDI changes. To examine the cerebellum irrespective of the skeleton, ROIs were manually drawn based on the group averaged FA map: two in bilateral middle cerebellar peduncles (one more anterior, one more posterior). No group differences were found in FA, NDI or ODI (all p > ...
Context 3
... the left columns of Fig. 1, mean FA maps are shown. Superimposed are the significant group differences, observed across the majority of the WM tracts, except for the cerebellar tracts. In the middle columns of Fig. 1, the group differences in NDI are shown. Visual comparison shows these changes overlap with FA changes, but are more localized. NDI changes were found mainly bilateral and located mostly in the anterior part of the brain. In Fig. 2, the group differences are overlaid on colour maps, aiding in the localization of the tracts (using the atlas of Wakana et al 2003). On the right-sided columns of Fig. 1, group differences in ODI are displayed, overlaid on mean ODI maps and the skeleton. Again, ODI changes overlap FA, but are more specifically localized. Dispersion changes were mainly located on the left, middle parts of the brain (see Fig. 2 for tract localisation) and showed minimal overlap with the NDI changes. To examine the cerebellum irrespective of the skeleton, ROIs were manually drawn based on the group averaged FA map: two in bilateral middle cerebellar peduncles (one more anterior, one more posterior). No group differences were found in FA, NDI or ODI (all p > ...
Citations
... 56 CG is considered a secondary congenital disorder of glycosylation (CDG), and CG patients can have altered transferrin mobility in diagnostic tests because the transferrin protein is improperly glycosylated. 43,49,59 Disrupted glycosylation is an attractive mechanism of disease pathology because CG patients display irregular white matter, 41,[60][61][62][63][64][65][66][67][68][69][70] which is rich in galactose-bearing lipids. Indeed, approximately 25% of myelin's lipid content is made up of the cerebroside galactosylceramide (GalCer; $20%) and its 3-O sulfated derivatives (sulfatides; $5%), 71 which are necessary for the stability and maintenance of myelin. ...
... 75 Cerebrosides are necessary for the structural integrity and maintenance of myelin. [72][73][74] Since myelin-rich white matter is disrupted in CG patients 41,[60][61][62][63][64][65][66][67][68][69][70] and an autopsied brain from a CG patient had reduced GalCer, 42 we hypothesized that the most myelin-enriched cerebroside, GalCer 24:1, and its sulfated derivative, sulfatide 24:1, may be impacted in the GALT-deficient mouse brain. ...
Classic galactosemia (CG) arises from loss‐of‐function mutations in the Galt gene, which codes for the enzyme galactose‐1‐phosphate uridylyltransferase (GALT), a central component in galactose metabolism. The neonatal fatality associated with CG can be prevented by galactose dietary restriction, but for decades it has been known that limiting galactose intake is not a cure and patients often have lasting complications. Even on a low‐galactose diet, GALT's substrate galactose‐1‐phosphate (Gal1P) is elevated and one hypothesis is that elevated Gal1P is a driver of pathology. Here we show that Gal1P levels were elevated above wildtype (WT) in Galt mutant mice, while mice doubly mutant for Galt and the gene encoding galactokinase 1 (Galk1) had normal Gal1P levels. This indicates that GALK1 is necessary for the elevated Gal1P in CG. Another hypothesis to explain the pathology is that an inability to metabolize galactose leads to diminished or disrupted galactosylation of proteins or lipids. Our studies reveal that levels of a subset of cerebrosides—galactosylceramide 24:1, sulfatide 24:1, and glucosylceramide 24:1—were modestly decreased compared to WT. In contrast, gangliosides were unaltered. The observed reduction in these 24:1 cerebrosides may be relevant to the clinical pathology of CG, since the cerebroside galactosylceramide is an important structural component of myelin, the 24:1 species is the most abundant in myelin, and irregularities in white matter, of which myelin is a constituent, have been observed in patients with CG. Therefore, impaired cerebroside production may be a contributing factor to the brain damage that is a common clinical feature of the human disease.
... We chose the STG/SMG as one of many relevant language areas. In previous work, we reported differences in the functional connectivity between IFG and STG in CG patients compared to healthy controls 26 It is therefore reasonable to assume that stimulation of IFG would also have an effect on language processing. The same might hold true for all regions within the dual route language network as described in Matchin and Hickok. ...
Patients with classic galactosemia (CG), an inborn error of galactose metabolism, suffer from impairments in cognition, including language processing. Potential causes are atypical brain oscillations. Recent electroencephalogram (EEG) showed differences in the P300 event‐related‐potential (ERP) and alterations in the alpha/theta‐range during speech planning. This study investigated whether transcranial alternating current stimulation (tACS) at theta‐frequency compared to sham can cause a normalization of the ERP post stimulation and improves language performance. Eleven CG patients and fourteen healthy controls participated in two tACS‐sessions (theta 6.5 Hz/sham). They were engaged in an active language task, describing animated scenes at three moments, that is, pre/during/post stimulation. Pre and post stimulation, behavior (naming accuracy, voice‐onset‐times; VOT) and mean‐amplitudes of ERP were compared, by means of a P300 time‐window analysis and cluster‐based‐permutation testing during speech planning. The results showed that theta stimulation, not sham, significantly reduced naming error‐percentage in patients, not in controls. Theta did not systematically speed up naming beyond a general learning effect, which was larger for the patients. The EEG analysis revealed a significant pre‐post stimulation effect (P300/late positivity), in patients and during theta stimulation only. In conclusion, theta‐tACS improved accuracy in language performance in CG patients compared to controls and altered the P300 and late positive ERP‐amplitude, suggesting a lasting effect on neural oscillation and behavior.
... In particular, neuroimaging studies observed altered myelination, scattered white matter abnormalities, cerebral and cerebellar atrophy. [5][6][7] With regard to cognitive functioning, attentional, memory and expressive language impairments have been reported. Whereas receptive language seems to not be affected in CG, patients experience difficulties in articulation, but also in syntactic planning during speech production. ...
... Differences in resting state connectivity and in white matter structure have been reported, suggesting altered information processing. 7,11 With regard to speech production, a similar network of brain regions was observed to be active both in CG patients and healthy controls; however, additional regions (i.e., inferior frontal gyrus and superior temporal gyrus) were active in patients, highlighting the potential recruitment of additional neural resources to compensate for network deficits. 12 Moreover, an event-related potential (ERP) study pointed to differences in amplitude of the P300 component in CG patients and controls, 8 interpreted as patients recruiting additional syntactic planning resources. ...
... Recruiting more resources might be a compensatory mechanism within a language network with compromised connectivity. 7,11 The increased power in multiple frequency bands might reflect the engagement of larger populations of neurons. This interpretation is in line with findings of our previous fMRI study. ...
Classical galactosaemia (CG) is a hereditary disease in galactose metabolism that despite dietary treatment is characterized by a wide range of cognitive deficits, among which is language production. CG brain functioning has been studied with several neuroimaging techniques, which revealed both structural and functional atypicalities. In the present study, for the first time, we compared the oscillatory dynamics, especially the power spectrum and time–frequency representations (TFR), in the electroencephalography (EEG) of CG patients and healthy controls while they were performing a language production task. Twenty‐one CG patients and 19 healthy controls described animated scenes, either in full sentences or in words, indicating two levels of complexity in syntactic planning. Based on previous work on the P300 event related potential (ERP) and its relation with theta frequency, we hypothesized that the oscillatory activity of patients and controls would differ in theta power and TFR. With regard to behavior, reaction times showed that patients are slower, reflecting the language deficit. In the power spectrum, we observed significant higher power in patients in delta (1–3 Hz), theta (4–7 Hz), beta (15–30 Hz) and gamma (30–70 Hz) frequencies, but not in alpha (8–12 Hz), suggesting an atypical oscillatory profile. The time‐frequency analysis revealed significantly weaker event‐related theta synchronization (ERS) and alpha desynchronization (ERD) in patients in the sentence condition. The data support the hypothesis that CG language difficulties relate to theta–alpha brain oscillations.
... In contrast, we found no apparent structural correlates of cerebellar symptoms (Fig. 1b). Previous studies have described similar radiological findings and variable cerebellar changes, possibly due to alterations in myelination [11,12]. ...
Introduction: Identifying the underlying etiology of nonfamilial adult-onset progressive cerebellar ataxia is often challenging because neurologists must consider almost all nongenetic and genetic causes of ataxia. Case Presentation: A 39-year-old woman was hospitalized for progressive ataxia with pyramidal and cognitive dysfunction after a right arm shaking and coordination problem deteriorated progressively over 1.5 years. The patient's medical history included amenorrhea, cataracts, developmental delays, consanguinity of the parents, motor coordination issues, and diarrhea and vomiting in infancy. An important finding that enabled us to solve the diagnostic conundrum was the elevated CDT levels in the lack of alcohol-related symptoms, which also occur in untreated carbohydrate metabolism disorders, sometimes with ataxia as a leading symptom. The decreased erythrocyte galactose-1-phosphate uridyltransferase (GALT) enzyme activity and the elevated erythrocyte galactose-1-phosphate (Gal-1P) concentration led to the final diagnosis of galactosemia, a rare metabolic disorder. The patient's condition stayed stable with strict adherence to lactose-free and galactose-restricted diets, regular physiotherapy, and speech therapy, despite attempts to control the crippling tremor. Conclusion: This case highlights the importance of considering rare diseases based on unexplained clinical and laboratory findings. Newborn screening does not change the long-term complications of early-treated classical galactosemia. A small percentage of these patients develop ataxia tremor syndrome.
... In the case of oxidative stress related to CG, it is known that it implicates cell death due to electrolyte excess and enzyme activity loss, such as Na + ,K + -ATPase, which may related to neuron depletion, leading to the cognitive damage and the executive function loss in this disease. However, the magnetic resonance imaging studies there are not shown correlation between brain area's inactivity and lower IQ in CG patients (Gitzelmann and Steinmann 1984;Lebea and Pretorius 2005;Lai et al. 2009;Zhang et al. 2010;Timmers et al. 2015;Welsink-Karssies et al. 2020;Haskovic et al. 2020;Rossi-Espagnet et al. 2021;Budni et al. 2021). ...
Classic galactosemia is a rare inborn error of metabolism that affects the metabolism of galactose, a sugar derived from milk and derivates. Classic galactosemia is caused by variants of the GALT gene, which lead to absent or misfolded forms of the ubiquitously present galactose-1-phosphate uridylyltransferase enzyme (GALT) driving galactose metabolites to accumulate, damaging cells from neurons to hepatocytes. The disease has different prevalence around the world due to different allele frequencies among populations and its symptoms range from cognitive and psychomotor impairment to hepatic, ophthalmological, and bone structural damage. The practice of newborn screening still varies among countries, dairy restriction treatment is a consensus despite advances in preclinical treatment strategies. Recent clinical studies in Duarte variant suggest dairy restriction could be reconsidered in these cases. Despite noteworthy advances in the classic galactosemia understanding, preclinical trials are still crucial to fully understand the pathophysiology of the disease and help propose new treatments. This review aims to report a comprehensive analysis of past studies and state of art research on galactosemia screening, its clinical and preclinical trials, and treatments with the goal of shedding light on this complex and multisystemic innate error of the metabolism.
... Another limitation is that standardized MRI scans were not included in this study. However, abnormal cerebral white matter signal intensity, white matter hyperintensities, cerebral atrophy, and cerebellar atrophy have repeatedly been described in patients with CG with the underlying molecular mechanisms remaining elusive [19,21,67,[72][73][74]. ...
It remains unresolved whether central nervous system involvement in treated classical galactosemia (CG) is a progressive neurodegenerative process. This study aimed to investigate retinal neuroaxonal degeneration in CG as a surrogate of brain pathology. Global peripapillary retinal nerve fibre layer (GpRNFL) and combined ganglion cell and inner plexiform layer (GCIPL) were analysed in 11 CG patients and 60 controls (HC) using spectral–domain optical coherence tomography. Visual acuity (VA) and low-contrast VA (LCVA) were acquired to test visual function. GpRNFL and GCIPL did not differ between CG and HC (p > 0.05). However, in CG, there was an effect of intellectual outcome on GCIPL (p = 0.036), and GpRNFL and GCIPL correlated with neurological rating scale scores (p < 0.05). A single-case follow-up analysis showed GpRNFL (0.53–0.83%) and GCIPL (0.52–0.85%) annual decrease beyond the normal aging effect. VA and LCVA were reduced in CG with intellectual disability (p = 0.009/0.006), likely due to impaired visual perception. These findings support that CG is not a neurodegenerative disease, but that brain damage is more likely to occur early in brain development. To clarify a minor neurodegenerative component in the brain pathology of CG, we propose multicenter cross-sectional and longitudinal studies using retinal imaging.
... Regarding the brain, the extent of early damage is less clear. Since myelination -which is affected in galactosemia -continues until adulthood, the window of opportunity for treatment might be wider 51 . ...
Messenger RNA (mRNA) has emerged as a novel therapeutic approach for inborn errors of metabolism. Classic galactosemia (CG) is an inborn error of galactose metabolism caused by a severe deficiency of galactose‐1‐phosphate:uridylyltransferase (GALT) activity leading to neonatal illness and chronic impairments affecting the brain and female gonads. In this proof of concept study, we used our zebrafish model for CG to evaluate the potential of human GALT mRNA (hGALT mRNA) packaged in two different lipid nanoparticles to restore GALT expression and activity at early stages of development. Both, one cell‐stage and intravenous single‐dose injections resulted in hGALT protein expression and enzyme activity in the CG zebrafish (galt knockout) at 5 days post fertilization (dpf). Moreover, the levels of galactose‐1‐phosphate (Gal‐1‐P) and galactonate, metabolites that accumulate because of the deficiency, showed a decreasing trend. LNP‐packaged mRNA was effectively translated and processed in the CG zebrafish without signs of toxicity. This study shows that mRNA therapy restores GALT protein and enzyme activity in the CG zebrafish model, and that the zebrafish is a suitable system to test this approach. Further studies are warranted to assess whether repeated injections safely mitigate the chronic impairments of this disease.
... As mentioned above, mice in which dystroglycans are selectively removed from Schwann cells have incomplete myelin (axonal structures) and villi and may develop neuropathy [4]. There are reports that ODI increases with decreases in nerve cell density [66,67]. Irregular axon composition leads to an increase in the ODI value in white matter regions. ...
Background
Dystrophin strengthens muscle cells; however, in muscular dystrophy, dystrophin is deficient due to an abnormal sugar chain. This abnormality occurs in skeletal muscle and in brain tissue.
Objective
This study aimed to non-invasively analyze the neural organization of the brain in muscular dystrophy. We used a mouse model of muscular dystrophy to study whether changes in brain structure and neurodegeneration following dystrophin deficiency can be assessed by 7T magnetic resonance imaging.
Methods
C57BL/10-mdx (X chromosome-linked muscular dystrophy) mice were used as the dystrophic mouse model and healthy mice were used as controls. Ventricular enlargement is one of the most common brain malformations in dystrophin-deficient patients. Therefore, we examined whether ventricular enlargement was observed in C57BL/10-mdx using transverse-relaxation weighted images. Brain parenchyma analysis was performed using diffusion MRI with diffusion tensor images and neurite orientation dispersion and density imaging. Parenchymal degeneration was assessed in terms of directional diffusion, nerve fiber diffusion, and dendritic scattering density.
Results
For the volume of brain ventricles analyzed by T2WI, the average size was 1.5 times larger in mdx mice compared to control mice. In the brain parenchyma, a significant difference (p < 0.05) was observed in parameters indicating disturbances in the direction of nerve fibers and dendritic scattering density in the white matter region.
Conclusion
Our results show that changes in brain structure due to dystrophin deficiency can be assessed in detail without tissue destruction by combining diffusion tensor images and neurite orientation dispersion and density imaging analyses.
... A small sample-sized first NODDI study reported decreased NDI and increased ODI in the normal-appearing WM of MS patients (49). Higher ODI indicates fiber coherence loss and can possibly be explained by an increase in compensative axonal sprouting or branching (50). Regarding NDI, a decrease in MS is expected due to the demyelinating, inflammatory and neuro-axonal pathology of the disease (2). ...
Motor skills are frequently impaired in multiple sclerosis (MS) patients following grey and white matter damage with cortical excitability abnormalities. We applied advanced diffusion imaging with 3T magnetic resonance tomography for neurite orientation dispersion and density imaging (NODDI), as well as diffusion tensor imaging (DTI) in 50 MS patients and 49 age-matched healthy controls to quantify microstructural integrity of the motor system. To assess excitability, we determined resting motor thresholds using non-invasive transcranial magnetic stimulation. As measures of cognitive-motor performance, we conducted neuropsychological assessments including the Nine-Hole Peg Test, Trail Making Test part A and B (TMT-A and TMT-B) and the Symbol Digit Modalities Test (SDMT). Patients were evaluated clinically including assessments with the Expanded Disability Status Scale. A hierarchical regression model revealed that lower neurite density index (NDI) in primary motor cortex, suggestive for axonal loss in the grey matter, predicted higher motor thresholds, i.e. reduced excitability in MS patients (p = .009, adjusted r² = 0.117). Furthermore, lower NDI was indicative of decreased cognitive-motor performance (p = .007, adjusted r² = .142 for TMT-A; p = .009, adjusted r² = .129 for TMT-B; p = .006, adjusted r² = .142 for SDMT). Motor WM tracts of patients were characterized by overlapping clusters of lowered NDI (p <.05, Cohen’s d = 0.367) and DTI-based fractional anisotropy (FA) (p <.05, Cohen’s d = 0.300), with NDI exclusively detecting a higher amount of abnormally appearing voxels. Further, orientation dispersion index of motor tracts was increased in patients compared to controls, suggesting a decreased fiber coherence (p <.05, Cohen’s d = 0.232). This study establishes a link between microstructural characteristics and excitability of neural tissue, as well as cognitive-motor performance in multiple sclerosis. We further demonstrate that the NODDI parameters neurite density index and orientation dispersion index detect a larger amount of abnormally appearing voxels in patients compared to healthy controls, as opposed to the classical DTI parameter FA. Our work outlines the potential for microstructure imaging using advanced biophysical models to forecast excitability alterations in neuroinflammation.
... By contrast multi-shell acquisition protocols combined with biophysically plausible models have been shown to provide more specific estimates of the microstructural properties of white matter tissue (Lerch et al., 2017). One such approach is Neurite Orientation Dispersion and Density Imaging (NODDI; Zhang et al., 2012), which has been previously used to provide detailed accounts of white matter changes associated with development, ageing and several neurological disorders (e.g., Kodiweera et al., 2016;Kunz et al., 2014;Billiet et al., 2015;Chang et al., 2015;Adluru et al., 2014;Billiet et al., 2014;Winston et al., 2014;Timmers et al., 2015;Veldsman et al., 2020). NODDI-derived parameters, intra-cellular volume fraction (ICVF) and the orientation dispersion index (ODI), respectively measure neurite packing density and dispersion of neurites/axons (an estimate of fiber coherence). ...
Exposure to enriched environments (EE) throughout a lifetime, providing so called reserve, protects against cognitive decline in later years. It has been hypothesised that high levels of alertness necessitated by EE might strengthen the right fronto-parietal networks (FPN) to facilitate this neurocognitive resilience. We have previously shown that EE offset age-related deficits in selective attention by preserving grey matter within right fronto-parietal regions. Here, using neurite orientation dispersion and density imaging (NODDI), we examined the relationship between EE, microstructural properties of fronto-parietal white matter association pathways (three branches of the superior longitudinal fasciculus, SLF), structural brain health (atrophy), and attention (alertness, orienting and executive control) in a group of older adults. We show that EE is associated with a lower orientation dispersion index (ODI) within the right SLF1 which in turn mediates the relationship between EE and alertness, as well as grey- and white-matter atrophy. This suggests that EE may induce white matter plasticity (and prevent age-related dispersion of axons) within the right FPN to facilitate the preservation of neurocognitive health in later years.
