Brain health operationalized as brain parenchymal fraction impacts stroke severity both in acute phase and 3 months post-stroke

Stroke lesion imaging alone is not sufficient to predict stroke severity and outcome at a clinically meaningful level, and non-lesional factors are to be defined to enable stroke prognosis and individually tailored therapy. While brain health concept is mainly discussed in the context of primary prevention of neurological diseases, quantitative parameters of brain health such as brain parenchymal fraction (BPF) might be associated with better maintenance of function and compensation in (acute) brain pathology. We aimed to investigate whether BPF independently mediates neurological impairment and functional outcome after stroke. We retrospectively analysed patients with first-ever middle cerebral artery stroke. We used generalized linear models with gamma distribution and log link to model neurological impairment (NIH Stroke Scale [NIHSS] 24h and 3 months) and ordinal logistic regression to model functional outcome at 3 months (modified Rankin Scale [mRS], 0-6) with the independent variables age, sex, BPF, and lesion size. We analysed data of 832 patients (mean age 67.7±15.3, female 43.5%, median NIHSS 24h 3[1, 6]). A higher BPF was associated with lower neurological impairment: 10% higher BPF was associated with a 16% reduction of NIHSS 24h (mean ratio 0.840, 95% CI 0.751-0.940) and a 15% reduction of NIHSS 3 months (mean ratio 0.845, 95% CI 0.745-0.957) independent of age, sex, and lesion size. Similarly, BPF had an independent protective effect on functional disability 3 months post-stroke (10% higher BPF decreased the odds of worse outcome for 1 mRS point by OR 0.593; 95% CI 0.407-0.864). Brain health, operationalized as BPF, is independently associated with lower neurological impairment both 24h and 3 months post-stroke and better functional stroke outcome. BPF might improve the prediction of stroke outcome and explain inter-individual variability in lesion-outcome associations: the same lesion load leads to higher neurological impairment in the presence of brain atrophy, whereas the lesion burden might be clinically less apparent in healthier brains. The data might improve personalized treatment prospects and suggests that efforts on improvement of brain health might represent both the primary and secondary reduction of burden of stroke.