Topological Alterations of the Structural Brain Connectivity Network in Children with Juvenile Neuronal Ceroid Lipofuscinosis

Abstract

BACKGROUND AND PURPOSE: We used diffusion MR imaging to investigate the structural brain connectivity networks in juvenile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disease of childhood. Although changes in conventional MR imaging are typically not visually apparent in children aged ,10 years, we previously found significant microstructural abnormalities by using diffusion MR imaging. Therefore, we hypothesized that the structural connectivity networks would also be affected in the disease. MATERIALS AND METHODS: We acquired diffusion MR imaging data from 14 children with juvenile neuronal ceroid lipofuscinosis (mean 6 SD age, 9.6 6 3.4 years; 10 boys) and 14 control subjects (mean 6 SD age, 11.2 6 2.3 years; 7 boys). A follow-up MR imaging was performed for 12 of the patients (mean 6 SD age, 11.4 6 3.2 years; 8 boys). We used graph theoretical analysis to investigate the global and local properties of the structural brain connectivity networks reconstructed with constrained spherical deconvolution-based whole-brain probabilistic tractography. RESULTS: We found significantly increased characteristic path length (P = .003) and decreased degree (P = .003), which indicated decreased network integration and centrality in children with juvenile neuronal ceroid lipofuscinosis. The findings were similar for the follow-up MR imaging, and there were no significant differences between the two acquisitions of the patients. In addition, we found that the disease severity correlated negatively (P , .007) with integration, segregation, centrality, and small-worldness of the networks. Moreover, we found significantly (P , .0003) decreased local efficiency in the left supramarginal gyrus and temporal plane, and decreased strength in the right lingual gyrus. CONCLUSIONS: We found significant global and local network alterations in juvenile neuronal ceroid lipofuscinosis that correlated with the disease severity and in areas related to the symptomatology.

Gait phenotype in Batten disease: A marker of disease progression

“…Diffusion-weighted imaging enables investigation of the white matter microstructure [62,63]. Using this technique in CLN3 patients, significant impairment in the white matter microstructure and brain connectivity networks has been demonstrated before the age of 10 years, thus present substantial earlier than can be demonstrated using conventional MRI [64,65]. Using functional studies, both thalamic, nigrostriatal and striatal dysfunction has been reported in CLN3 [67,68], but as the impairments only showed a modest correlation with the extrapyramidal symptoms, it has been suggested that degenerative J o u r n a l P r e -p r o o f changes of other CNS areas may be contributory to the parkinsonian phenotype seen in CLN3 [66,67].…”

Top-down and bottom-up propagation of disease in the neuronal ceroid lipofuscinoses

“…Thirdly, the presence of a non-syndromic retinal disease in patients with certain mutations in CLN3 showing retinal degeneration without additional progression of CLN3 disease (41-43) further supports that the retina seems to be the most vulnerable organ to CLN3 deficiency. Finally, the effects of CLN3 disease are present within parts of the visual system connectome at a very early stage (8) and thinning of the occipital cortex occurs years before cortical atrophy is seen in other parts of the brain (24).…”

“…Thinning of the frontal and parietal cortices occurs later, as do atrophic changes of the brainstem, whereas cerebellar atrophy is seen only around 19 years of age (24). Diffusion-weighted imaging in CLN3 patients revealed significant impairment in the white matter microstructure and brain connectivity networks before the age of ten years, which is substantially earlier than can be demonstrated using conventional MRI (7,8). Functional studies (PET and SPECT) in CLN3 patients between 15-27 years of age demonstrated thalamic, nigrostriatal and striatal dysfunction as well (26,27).…”

“…An alternative approach to understand the NCLs would be to consider them as a group of related neurodegenerative diseases characterized by lipofuscin pathobiology as the core feature, but with two defining characteristics used to distinguish each form: (1) the anatomical site of where disease becomes evident (2) the progressive propagation and distribution of disease related to structural and functional dysconnectivity similar to what is seen in other neurodegenerative diseases such as Parkinson's disease (5,6). So far, investigation of the brain connectome in human NCLs is limited to Juvenile NCL (CLN3), where Roine and coworkers have demonstrated significant global and local network alterations that correlated with the disease severity and in areas related to the symptomatology (7,8). In the present study, we present and discuss the known differences in symptomatology and pathology between the classical CLN1 phenotype caused by complete loss of PPT1 gene function (i.e., the classical infantile form) and the classical juvenile CLN3 phenotype.…”

Neuronal Ceroid Lipofuscinosis: The Multifaceted Approach to the Clinical Issues, an Overview

“…All gray regions of the brain are affected by neuronal death, showing however differential patterns in the topography of neuronal loss, the rate of progression and the secondary involvement of the white matter. Selective neurodegeneration, targeting specific regions and particular cell populations, can be observed during the early stages of the disease, and the patterns of disease evolution can be monitored by neuroimaging studies (136)(137)(138)(139)(140). Whether these features reflect the genetic heterogeneity of the NCL is a matter to be investigated further.…”