Abstract Details

Title Normative Brain Atrophy Modeling Incorporating Intracranial Volume Improves Pre-clinical Detection of Dementia Risk

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) P1 - Poster Session 1 (8:00 AM-9:00 AM)

Poster/Presentation
Number 13-002

Objective To develop and validate a lifespan model of brain volume that integrates estimated total intracranial volume (eTIV) to improve sensitivity for early, preclinical brain atrophy associated with cognitive decline and dementia risk.

Background Age-related brain atrophy reflects both developmental and degenerative influences, with considerable inter-individual variability driven by head size and sex. Because eTIV reflects an individual’s maximum brain size, modeling it alongside age may enhance detection of deviations from expected atrophy trajectories. We hypothesized that accounting for eTIV would yield more precise normative metrics and improve prediction of cognitive decline and dementia conversion.

Design/Methods MRI data from 80 public datasets (n=21,977; median age 55 years [range 4–100]; 58% female) were modeled using P-spline GAMLSS, stratified by sex and adjusted for age and eTIV. Normative Quantile Residuals (QR; z-score equivalent) were derived for brain volume. In the ADNI cohort (n=2,407; 52.3% female; 7,759 MRI sessions; mean 3.2 per subject), Cox regression and bootstrapped logistic models assessed whether QR predicted conversion from cognitively normal (CN) to MCI or AD.

Results Head size moderated age-related atrophy rate (χ² > 38, p<10^-7), faster in larger-eTIV individuals. Among 535 ADNI participants, 365 converted to MCI/AD (267 MCI, 98 AD) and 170 remained CN. Median time-to-conversion was 0.51 years (IQR 0.47–0.96); non-converters had 4.05 years follow-up. Each 1-SD decrease in QR corresponded to a 10% higher conversion hazard (HR=0.90, 95% CI 0.87–0.93, p<10^-8). QR model outperformed conventional normalization (C-index 0.688 vs. 0.603; ΔC=0.084, 95% CI 0.068–0.099, p<10^-5) and achieved AUC=0.731 (95% CI 0.706–0.754), sensitivity=0.68, specificity=0.79. QR most strongly correlated with language (r=0.42, P<0.001) and visuospatial abilities (r=0.30, P=0.016).

Conclusions

Integrating intracranial volume into normative modeling refines individualized brain aging estimates, enhances cognitive and prognostic sensitivity, and identifies subtle, pre-clinical deviations predictive of dementia within two to three years, supporting its utility for early pathological detection and clinical trial applications.

Authors/Disclosures
Jonadab Dos Santos Silva, MD, PhD PRESENTER	Dr. Dos Santos Silva has nothing to disclose.
Francesco La Rosa, PhD	Dr. La Rosa has nothing to disclose.
Emma Dereskewicz	Ms. Dereskewicz has nothing to disclose.
Julia Galasso	Ms. Galasso has nothing to disclose.
Robin Graney, Research Coordinator	Ms. Graney has nothing to disclose.
Cesar Garcia	Mr. Garcia has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pareto.
Sarah Levy, PhD (Icahn School of Medicine at Mount Sinai)	Dr. Levy has nothing to disclose.
James F. Sumowski (Icahn School of Medicine At Mount Sinai)	Mr. Sumowski has nothing to disclose.
Erin S. Beck, MD (Icahn School of Medicine at Mount Sinai)	Dr. Beck has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EMD Serono. An immediate family member of Dr. Beck has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion Pharmaceuticals. An immediate family member of Dr. Beck has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Glaxo Smith Kline. An immediate family member of Dr. Beck has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis Pharmaceutical Corporation. An immediate family member of Dr. Beck has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Swedish Orphan Biovitrum AB. The institution of Dr. Beck has received research support from National Multiple Sclerosis Society. The institution of Dr. Beck has received research support from National Institutes of Health. The institution of Dr. Beck has received research support from United States Department of Defense. The institution of Dr. Beck has received research support from Consortium of Multiple Sclerosis Centers. Dr. Beck has received intellectual property interests from a discovery or technology relating to health care.

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