RESUMO
Neuronal ceroid lipofuscinoses (Batten disease) are a group of inherited lysosomal storage disorders characterized by progressive neurodegeneration leading to motor and cognitive dysfunction, seizure activity and blindness. The disease can be caused by mutations in 1 of 13 ceroid lipofuscinosis neuronal (CLN) genes. Naturally occurring sheep models of the CLN5 and CLN6 neuronal ceroid lipofuscinoses recapitulate the clinical disease progression and post-mortem pathology of the human disease. We used longitudinal MRI to assess global and regional brain volume changes in CLN5 and CLN6 affected sheep compared to age-matched controls over 18 months. In both models, grey matter volume progressively decreased over time, while cerebrospinal fluid volume increased in affected sheep compared with controls. Total grey matter volume showed a strong positive correlation with clinical scores, while cerebrospinal fluid volume was negatively correlated with clinical scores. Cortical regions in affected animals showed significant atrophy at baseline (5 months of age) and progressively declined over the disease course. Subcortical regions were relatively spared with the exception of the caudate nucleus in CLN5 affected animals that degenerated rapidly at end-stage disease. Our results, which indicate selective vulnerability and provide a timeline of degeneration of specific brain regions in two sheep models of neuronal ceroid lipofuscinoses, will provide a clinically relevant benchmark for assessing therapeutic efficacy in subsequent trials of gene therapy for CLN5 and CLN6 disease.
RESUMO
OBJECTIVE: Many factors can contribute to the reliability and robustness of MRI-derived metrics. In this study, we assessed the reliability and reproducibility of three MRI modalities after an MRI scanner was relocated to a new hospital facility. METHODS: Twenty healthy volunteers (12 females, mean age (standard deviation) â= â41 (11) years, age range [25-66]) completed three MRI sessions. The first session (S1) was one week prior to the 3T GE HDxt scanner relocation. The second (S2) occurred nine weeks after S1 and at the new location; a third session (S3) was acquired 4 weeks after S2. At each session, we acquired structural T1-weighted, pseudo-continuous arterial spin labelled, and diffusion tensor imaging sequences. We used longitudinal processing streams to create 12 summary MRI metrics, including total gray matter (GM), cortical GM, subcortical GM, white matter (WM), and lateral ventricle volume; mean cortical thickness; total surface area; average gray matter perfusion, and average diffusion tensor metrics along principal white matter pathways. We compared mean MRI values and variance at the old scanner location to multiple sessions at the new location using Bayesian multi-level regression models. K-fold cross validation allowed identification of important predictors. Whole-brain analyses were used to investigate any regional differences. Furthermore, we calculated within-subject coefficient of variation (wsCV), intraclass correlation coefficient (ICC), and dice similarity index (SI) of cortical segmentations across scanner relocation and within-site. Additionally, we estimated sample sizes required to robustly detect a 4% difference between two groups across MRI metrics. RESULTS: All global MRI metrics exhibited little mean difference and small variability (bar cortical gray matter perfusion) both across scanner relocation and within-site repeat. T1- and DTI-derived tissue metrics showed â< â|0.3|% mean difference and <1.2% variance across scanner location and <|0.4|% mean difference and <0.8% variance within the new location, with between-site intraclass correlation coefficient (ICC) â> â0.80 and within-subject coefficient of variation (wsCV) â< â1.4%. Mean cortical gray matter perfusion had the highest between-session variability (6.7% [0.3, 16.7], estimate [95% uncertainty interval]), and hence the smallest ICC (0.71 [0.44,0.92]) and largest wsCV (13.4% [5.4, 18.1]). No global metric exhibited evidence of a meaningful mean difference between scanner locations. However, surface area showed evidence of a mean difference within-site repeat (between S2 and S3). Whole-brain analyses revealed no significant areas of difference between scanner relocation or within-site. For all metrics, we found no support for a systematic difference in variance across relocation sites compared to within-site test-retest reliability. Necessary sample sizes to detect a 4% difference between two independent groups varied from a maximum of n â= â362 per group (cortical gray matter perfusion), to total gray matter volume (n â= â114), average fractional anisotropy (n â= â23), total gray matter volume normalized by intracranial volume (n â= â19), and axial diffusivity (n â= â3 per group). CONCLUSION: Cortical gray matter perfusion was the most variable metric investigated (necessitating large sample sizes to identify group differences), with other metrics showing substantially less variability. Scanner relocation appeared to have a negligible effect on variability of the global MRI metrics tested. This manuscript reports within-site test-retest variability to act as a tool for calculating sample size in future investigations. Our results suggest that when all other parameters are held constant (e.g., sequence parameters and MRI processing), the effect of scanner relocation is indistinguishable from within-site variability, but may need to be considered depending on the question being investigated.
