Brain white matter microstructural alterations in children of type I Gaucher disease characterized with diffusion tensor MR imaging

Kang, Huibin; Zhang, Miao; Ouyang, Minhui; Guo, Ruolan; Yu, Qinlin; Peng, Qinmu; Zhang, Yonghong; Duan, Yanlong; Tang, Xiaolu; Mishra, Virendra; Fang, Fang; Li, Wei; Huang, Hao; Peng, Yun

doi:10.1016/j.ejrad.2018.02.014

Cited by 9 publications

(6 citation statements)

References 29 publications

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“… 56 Diffusion tensor imaging in small groups of GD3 and GD1 patients showed decreased fractional anisotropy and increased mean diffusivity primarily in the middle cerebellar peduncles, but also in the superior cerebellar peduncles. 57 A larger study confirmed diffusion tensor imaging abnormalities in these areas and in the posterior thalamus and other white matter regions in 22 patients identified as GD1, 58 despite most having GBA1 mutations typically associated with neuronopathic GD. Taken together, subtle white matter abnormalities that probably underlie functional connectivity disturbances are present in patients with GD3 even in the presence of normal standard brain MRI.…”

Section: Discussionmentioning

confidence: 75%

Venglustat combined with imiglucerase for neurological disease in adults with Gaucher disease type 3: the LEAP trial

Schiffmann

Cox

Dedieu

et al. 2022

Brain

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Gaucher disease type 3 (GD3) is a chronic neuronopathic disorder with wide-ranging effects, including hepatosplenomegaly, anaemia, thrombocytopenia, skeletal disease, and diverse neurological manifestations. Biallelic mutations in GBA1 reduce lysosomal acid β-glucosidase activity, and its substrates, glucosylceramide and glucosylsphingosine, accumulate. Enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) ameliorate systemic features of Gaucher disease, but no therapies are approved for neurological manifestations. Venglustat is an investigational, brain-penetrant, glucosylceramide synthase inhibitor with potential to improve the disease by rebalancing influx of glucosylceramide with impaired lysosomal recycling. The Phase 2, open-label LEAP trial (NCT02843035) evaluated orally administered venglustat 15 mg once daily in combination with maintenance dose of imiglucerase ERT during one year of treatment in eleven adults with GD3. Primary endpoints were venglustat safety and tolerability and change in concentration of glucosylceramide and glucosylsphingosine in CSF from baseline to Week 26 and Week 52. Secondary endpoints included change in plasma concentrations of glucosylceramide and glucosylsphingosine, venglustat pharmacokinetics in plasma and CSF, neurologic function, infiltrative lung disease and systemic disease parameters. Exploratory endpoints included changes in brain volume assessed with volumetric MRI (vMRI) using tensor-based morphometry, and resting functional MRI (fMRI) analysis of regional brain activity and connectivity between resting state networks. Mean (SD) plasma venglustat AUC0-24 on Day 1 was 851 (282) ng•hr/mL; Cmax of 58.1 (26.4) ng/mL was achieved at a median tmax 2.00 hours. After once-daily venglustat, plasma concentrations (4 hours post dose) were higher compared with Day 1, indicating approximately 2-fold accumulation. One participant (Patient 9) had low-to-undetectable venglustat exposure at Weeks 26 and 52. Based on mean plasma and CSF venglustat concentrations (excluding Patient 9), steady state appeared to be reached on or before Week 4. Mean (SD) venglustat concentration at Week 52 was 114 (65.8) ng/mL in plasma and 6.14 (3.44) ng/mL in CSF. After one year of treatment, median (IQR) glucosylceramide decreased 78% (72, 84) in plasma and 81% (77, 83) in CSF; median (IQR) glucosylsphingosine decreased 56% (41, 60) in plasma and 70% (46, 76) in CSF. Ataxia improved slightly in nine patients: mean (SD, range) total modified SARA score decreased from 2.68 (1.54 [0.0 to 5.5]) at baseline to 1.55 (1.88 [0.0 to 5.0]) at Week 52 (mean change: -1.14 [95% CI: -2.06 to -0.21]). Whole brain volume increased slightly in patients with venglustat exposure and biomarker reduction in CSF (306.7 ± 4253.3 mm3) and declined markedly in Patient 9 (-13894.8 mm3). fMRI indicated stronger connectivity at Weeks 26 and 52 relative to baseline between a broadly distributed set of brain regions in patients with venglustat exposure and biomarker reduction but not Patient 9, although neurocognition, assessed by Vineland II, deteriorated in all domains over time, which illustrates disease progression despite the intervention. There were no deaths, serious adverse events or discontinuations. In adults with GD3 receiving imiglucerase, addition of once-daily venglustat showed acceptable safety and tolerability and preliminary evidence of clinical stability with intriguing but intrinsically inconsistent signals in selected biomarkers, which need to be validated and confirmed in future research.

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Section: Discussionmentioning

confidence: 75%

Venglustat combined with imiglucerase for neurological disease in adults with Gaucher disease type 3: the LEAP trial

Schiffmann

Cox

Dedieu

et al. 2022

Brain

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“…The thalamus fiber connection is involved in the emotion regulation system and plays an important role in perception and movement. The PLIC plays a role in stroke and in depression (Karababa et al, 2015 ; Hyett et al, 2018 ; Kang et al, 2018 ). The PTR is an important bridge between the associated thalamus and the visual cortex and with maturity improves the quality of movement and visual function (Aeby et al, 2009 ).…”

Section: Discussionmentioning

confidence: 99%

Analysis of Age-Related White Matter Microstructures Based on Diffusion Tensor Imaging

Ouyang

Cui

Yuan

et al. 2021

Front. Aging Neurosci.

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Population aging has become a serious social problem. Accordingly, many researches are focusing on changes in brains of the elderly. In this study, we used multiple parameters to analyze age-related changes in white matter fibers. A sample cohort of 58 individuals was divided into young and middle-age groups and tract-based spatial statistics (TBSS) were used to analyze the differences in fractional anisotropy (FA), mean diffusion (MD), axial diffusion (AD), and radial diffusion (RD) between the two groups. Deterministic fiber tracking was used to investigate the correlation between fiber number and fiber length with age. The TBSS analysis revealed significant differences in FA, MD, AD, and RD in multiple white matter fibers between the two groups. In the middle-age group FA and AD were lower than in young people, whereas the MD and RD values were higher. Deterministic fiber tracking showed that the fiber length of some fibers correlated positively with age. These fibers were observed in the splenium of corpus callosum (SCC), the posterior limb of internal capsule (PLIC), the right posterior corona radiata (PCR_R), the anterior corona radiata (ACR), the left posterior thalamic radiation (include optic radiation; PTR_L), and the left superior longitudinal fasciculus (SLF_L), among others. The results showed that the SCC, PLIC, PCR_R, ACR, PTR_L, and SLF_L significantly differed between young and middle-age people. Therefore, we believe that these fibers could be used as image markers of age-related white matter changes.

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“…It is not known whether the observed trend toward decreased cognitive functioning on the PedsQL CFS in the pediatric GD1 sample results from illness during an important time of neurodevelopment, mild cognitive effects from chronic GD1, or other factors. Some recent studies have demonstrated non-specific white matter microstructural alterations on neuroimaging 11,12 and altered brain functional networks 13 among pediatric patients with GD1. Neurobiological contributions to cognitive dysfunction cannot be ruled out.…”

Section: Relationship To Disease Severitymentioning

confidence: 99%

“…5,[7][8][9] In addition, individuals with GD1 and carriers of GBA mutations show an increased risk for Parkinson's disease (PD) and related neurodegenerative disorders such as Lewy body disease. 10 Additional work has suggested abnormal microstructural 11,12 as well as functional 13 brain magnetic resonance imaging (MRI) findings in children classified as having GD1. A magnetic resonance spectroscopy study 14 reported neurochemical abnormalities in individuals with GD1 under stable GD therapy.…”

Section: Introductionmentioning

confidence: 99%

Neurocognitive Functioning of Pediatric and Young Adult Patients with Gaucher Disease, Type 1

Alioto

Packman

Gomez

et al. 2022

MRAJ

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This exploratory study aimed to evaluate the cognitive and executive functioning of sixteen pediatric and fifteen young adult (ages 5 through 30) patients with Gaucher disease, Type 1. The neurocognitive functioning of children with Gaucher disease, Type 1 was based on self- and parent-proxy reports while neurocognitive functioning in young adults was based on self-report only. Results showed that pediatric participants with Gaucher disease, Type 1 on self-report demonstrated a trend toward weaker cognitive functioning than healthy children. Parent proxy-reports did not show significantly different cognitive functioning of children with Gaucher disease, Type 1 compared to healthy peers. Young adults with Gaucher disease, Type 1 self-reported no significant differences in cognitive functioning from healthy young adults. No group differences in executive functioning were observed for child or young adult samples. Parent-reported disease severity was not associated with cognitive outcomes among the pediatric or young adult samples. Results suggest possible mild cognitive weaknesses among children with Gaucher disease, Type 1 while cognition in young adults appears relatively well preserved. This is the first independent examination of cognitive functioning among children and young adults with GD1. Additional studies in younger patients with Gaucher disease, Type 1 are needed to identify possible cognitive dysfunction and elucidate underlying mechanisms.

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Brain white matter microstructural alterations in children of type I Gaucher disease characterized with diffusion tensor MR imaging

Cited by 9 publications

References 29 publications

Venglustat combined with imiglucerase for neurological disease in adults with Gaucher disease type 3: the LEAP trial

Venglustat combined with imiglucerase for neurological disease in adults with Gaucher disease type 3: the LEAP trial

Analysis of Age-Related White Matter Microstructures Based on Diffusion Tensor Imaging

Neurocognitive Functioning of Pediatric and Young Adult Patients with Gaucher Disease, Type 1

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