Network analysis of canine brain morphometry links tumour risk to oestrogen deficiency and accelerated brain ageing

Background Structural ‘brain age’ is a valuable but complex biomarker for several brain disorders. The dog is an unrivalled comparator for neurological disease modeling, however brain phenotypic diversity among pedigrees creates computational and statistical challenges. Methods We applied unbiased network correlation analysis in dogs to explore complex interactions between brain morphometrics, patient metadata, and neurological disease. Twenty-four parameters measured from each of 286 brain magnetic resonance imaging scans generated 9,438 data points that were used to cluster canine patients according to their brain morphometry profiles. The network was then explored for statistically significant enrichments within breed, sex, age, and diagnostic categories. Findings Morphometric comparisons revealed an advanced ‘aged-brain’ profile in the Boxer breed, consisting of a small brain length, width, and volume, combined with ventriculomegaly. Key features of this profile were paralleled in neutered female dogs which, relative to un-neutered females, had an 11-fold greater risk of developing primary brain tumours. Enrichment analysis confirmed that Boxers and geriatric individuals were enriched for brain tumour diagnoses, despite a lack of geriatric Boxers within the cohort. Interpretation These findings suggest that accelerated brain ageing might contribute to tumour risk in Boxers and may be influenced by oestrogen deficiency — a risk factor for dementia and brain tumours in humans. We propose that morphometric features of brain ageing in dogs, like humans, might better predict neurological disease risk than a patient’s chronological age. Funding Wellcome Trust Integrated Training Fellowship for Veterinarians (096409/Z/11/Z to N.M.R) and an MSD Animal Health Connect Bursary (to O.M.S.).