Evaluating Precision and Responsiveness of MRI-derived Brain Volumetric and Clinical Outcome Measures in CLN3 Disease
- 1HJF and NIBIB, NIH
Abstract
Background and ObjectiveFor their acceptance as endpoints in clinical trials, biomarkers and clinical outcome assessment (COA) measures should show reliability by being reproducible (precise) and responsive to change. We evaluated precision and responsiveness of MRI-derived brain volume metrics and various COAs in ceroid-lipofuscinosis, neuronal-3 (CLN3) disease.
MethodsThis longitudinal observational study (NCT03307304) included 44 individuals with CLN3-related disease (ages 0.5-29.1 years, 48% female). Brain volumetric measures were computed using SynthSeg-v2.0 from T1-weighted 3D MPRAGE images acquired at 3T (Median [Q1, Q3] total MRI follow-up duration from baseline: 2.04 [0.00, 3.69] years). Compartmental tissue volumes were normalized to a model-adjusted total intracranial volume and scaled to the tissue-specific volume fraction expected in healthy adolescent brains to extract measures of brain atrophy. COAs included the Vineland Adaptive Behavior Scales, verbal IQ, and the Unified Batten Disease Rating Scale (UBDRS). Analysis of linear mixed-effects models included only CLN3 participants with syndromic presentation, having three or more visits per measurement to estimate slope, its relative standard error (RSE), and the minimum inter-visit interval (Tmin) for statistically significant progression for each participant. Tmin to detect progression in 75% of the population (Tmin,75%) was computed for each metric.
ResultsAmong brain volumetric measures, brain parenchyma volume (BPV) and gray matter volume (GMV) were the most precise and responsive metrics. BPV showed an overall intra-individual decline with age of -1.32%/year (95% CI: -1.64% to -0.99%), low RSE of 12.5%, and short Tmin,75% of 0.85 years (95% CI: 0.47-1.24). Amongst COAs, the UBDRS Clinical Global Impression (CGI) score was the most precise and responsive with an overall intra-individual increase of 1.26 units/year (95% CI: 1.03-1.49), RSE of 24.10%, and Tmin,75% of 2.56 years (95% CI: 1.73-3.46), though with lower precision (RSE higher) and lower responsiveness (Tmin,75% longer) than BPV.
DiscussionMRI-derived metrics, in particular BPV and GMV, detected change in brain atrophy with high precision and responsiveness suggesting that they would be informative for evaluating potential neuroprotective therapies in CLN3 disease. These findings support incorporating MRI-derived volumetric measurements alongside clinical assessments in future clinical trials in CLN3.
Related
- Association Between Disability and Longitudinal Brain Volumetric Measures Across the Peri-Pregnancy Period in Women with Multiple Sclerosis: A Pilot Study
- Precision fluid therapy in sepsis: fluid responsiveness vs. fluid tolerance.
- Tumour extrinsic neutrophil regulation in mesothelioma correlates with responsiveness to AXL and PD1 inhibition in MIST3, a phase IIA clinical trial
- Dynamic Immune Responsiveness in Breast Cancer: Tumor Microenvironment Plasticity, Therapeutic Timing, and Clinical Translation
- Evaluating 5-Item Short Forms of Youth Depression Measures
BibTeX
@misc{hafiz2026evaluating,
title = {{Evaluating Precision and Responsiveness of MRI-derived Brain Volumetric and Clinical Outcome Measures in CLN3 Disease}},
author = {R. Hafiz and C. Farmer and L. Joseph and A. Soldatos and A. Nayak and A. E. Thurm and A. N. Dang Do and C. Pierpaoli},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.29.26363931},
url = {https://www.medrxiv.org/content/10.64898/2026.09.29.26363931v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Evaluating Precision and Responsiveness of MRI-derived Brain Volumetric and Clinical Outcome Measures in CLN3 Disease
AU - R. Hafiz
AU - C. Farmer
AU - L. Joseph
AU - A. Soldatos
AU - A. Nayak
AU - A. E. Thurm
AU - A. N. Dang Do
AU - C. Pierpaoli
PY - 2026
DA - 2026/09/29
PB - medRxiv
DO - 10.64898/2026.09.29.26363931
UR - https://www.medrxiv.org/content/10.64898/2026.09.29.26363931v1
AB - Background and ObjectiveFor their acceptance as endpoints in clinical trials, biomarkers and clinical outcome assessment (COA) measures should show reliability by being reproducible (precise) and responsive to change. We evaluated precision and responsiveness of MRI-derived brain volume metrics and various COAs in ceroid-lipofuscinosis, neuronal-3 (CLN3) disease. MethodsThis longitudinal observational study (NCT03307304) included 44 individuals with CLN3-related disease (ages 0.5-29.1 years, 48% female). Brain volumetric measures were computed using SynthSeg-v2.0 from T1-weighted 3D MPRAGE images acquired at 3T (Median [Q1, Q3] total MRI follow-up duration from baseline: 2.04 [0.00, 3.69] years). Compartmental tissue volumes were normalized to a model-adjusted total intracranial volume and scaled to the tissue-specific volume fraction expected in healthy adolescent brains to extract measures of brain atrophy. COAs included the Vineland Adaptive Behavior Scales, verbal IQ, and the Unified Batten Disease Rating Scale (UBDRS). Analysis of linear mixed-effects models included only CLN3 participants with syndromic presentation, having three or more visits per measurement to estimate slope, its relative standard error (RSE), and the minimum inter-visit interval (Tmin) for statistically significant progression for each participant. Tmin to detect progression in 75% of the population (Tmin,75%) was computed for each metric. ResultsAmong brain volumetric measures, brain parenchyma volume (BPV) and gray matter volume (GMV) were the most precise and responsive metrics. BPV showed an overall intra-individual decline with age of -1.32%/year (95% CI: -1.64% to -0.99%), low RSE of 12.5%, and short Tmin,75% of 0.85 years (95% CI: 0.47-1.24). Amongst COAs, the UBDRS Clinical Global Impression (CGI) score was the most precise and responsive with an overall intra-individual increase of 1.26 units/year (95% CI: 1.03-1.49), RSE of 24.10%, and Tmin,75% of 2.56 years (95% CI: 1.73-3.46), though with lower precision (RSE higher) and lower responsiveness (Tmin,75% longer) than BPV. DiscussionMRI-derived metrics, in particular BPV and GMV, detected change in brain atrophy with high precision and responsiveness suggesting that they would be informative for evaluating potential neuroprotective therapies in CLN3 disease. These findings support incorporating MRI-derived volumetric measurements alongside clinical assessments in future clinical trials in CLN3.
ER -