Kenda Alhadid1, Robert W. Regenhardt1, Natalia S. Rost1, Markus D. Schirmer11- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA,USA. Correspondence:Markus D. Schirmermschirmer1@mgh.harvard.eduKeywords: arterial ischemic stroke, brain volume, brain parenchymal fraction, BPF, modified Rankin Scale, mRSAbstractObjective: To assess if brain volume at the time of ischemic stroke injury is a better biomarker of functional outcome than brain atrophy.Background: Brain parenchymal fraction (BPF) has been used as a surrogate measure of global brain atrophy, and as a neuroimaging biomarker of brain reserve in studies evaluating clinical outcomes after brain injury. Brain volume itself is affected by natural aging, cardiovascular risk factors, and biological sex, amongst other factors. Recent works have shown that brain volume at the time of injury can influence functional outcomes, where larger brain volumes are associated with better outcomes. Methods: Acute ischemic stroke cases at a single center between 2003 and 2011, with MR neuroimaging obtained within 48 hours from presentation were eligible. Functional outcomes UHSUHVHQWHG E\ WKH PRGLILHG 5DQNLQ 6FRUH P56 DW GD\V SRVW DGPLVVLRQ P56 GHHPHG D favorable outcome) were obtained via patient interview or per chart review. Deep learning enabled automated segmentation pipelines were used to calculate brain volume, intracranial volume (ICV), and BPF on the acute neuroimaging data. Patient outcomes were modeled through logistic regressions, and model comparison was conducted using the Bayes Information Criterion (BIC). Results: 467 patients with arterial ischemic stroke were included in the analysis. Median age was 65.8 (interquartile range: 55.3-76.3) years, and 65.3% were male. In both models, age and a larger stroke lesion volume were associated with worse functional outcomes. Higher BPF and a larger brain volume were both associated with favorable functional outcomes, however, comparison of both models suggested that the brain volume model (BIC=501) explains the data better compared to the BPF model (BIC=511).Conclusions: The extent of global brain atrophy (and its surrogate biomarker BPF) has been regarded as an important biomarker of post-stroke functional outcomes and resilience to acute injury. Here, we demonstrate that a higher global brain volume at the time of injury better explains favorable functional outcomes, which can be directly clinically assessed.
Brain volume (cc; median [IQR]) 1306.9 [1190.9, 1413.9] mRS (> 2; %) 118 (24.8) The parameters of both outcome models are summarized in Table 2 and Figure 2. All assumptions of the logistic regression models were fulfilled. In both models, older patients and patients with larger stroke lesion volume had worse outcomes. Male sex was only found to be significant in the BPF outcome model, where male patients demonstrated better functional outcomes. Both higher BPF, i.e. less brain atrophy, and higher brain volume led to better functional outcomes. 4 Table 2. Summary of model parameter estimates. (HTN: hypertensive; DM2: Diabetes Mellitus Type 2; BPF: brain parenchymal fraction) BPF p Brain volume p Intercept 2.95 0.366 1.78 0.266 Age 0.25 0.019 0.25 0.010 Sex (M) 0.88 <0.001 0.36 0.194 HTN 0.20 0.506 0.08 0.792 DM2 0.54 0.056 0.47 0.105 Non-Smoker 0.08 0.737 0.02 0.919 log(Lesion Volume) 0.34 <0.001 0.35 <0.001 BPF 7.32 0.038
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Brain volume 3.83 <0.001 Evaluating BIC for both models resulted in 511 and 501 for the model based on BPF and brain volume, respectively. The comparison of both models suggest that the brain volume model explains the observed data EHWWHU(cid:3)WKDQ(cid:3)WKH(cid:3)FRUUHVSRQGLQJ(cid:3)EDVH(cid:3)PRGHO(cid:15)(cid:3)ZLWK(cid:3)%,&(cid:3) (cid:3)(cid:20)(cid:19)(cid:17) Figure 2. Graphical representation of parameter estimates including 95% confidence intervals. (BIC: Bayes Information Criterion; HTN: hypertensive; DM2: Diabetes Mellitus Type 2; BPF: brain parenchymal fraction). 4
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Discussion In this work, we highlight the significant role of brain volume and its association with functional outcomes after ischemic stroke. In a large cohort of AIS patients, we demonstrated that uncorrected brain volume at the time of injury is a better biomarker of stroke outcomes compared to brain atrophy. We derived brain volume and intracranial volume estimates automatically on clinical MRI sequences using a deep-learning enabled pipeline. This allowed the extraction of this important parameter from 5 clinical imaging data obtained as standard of care for patients with acute stroke presentations. Our results indicate that a larger brain volume at the time of acute injury leads to better functional outcome. In two models comparing brain volume and BPF, ZH(cid:3) GHWHUPLQHG(cid:3) D(cid:3) %,&(cid:3) (cid:3) (cid:20)(cid:19)(cid:15)(cid:3) SURYLGLQJ(cid:3) VWURQJ(cid:3) evidence that the brain volume model outperforms the BPF model.(23)
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The relationship between larger brain volume and higher cognitive abilities has been consistently reported,(8,24) with more recent work delineating the underlying microstructural architecture observed in larger brain volumes that could explain this benefit. It is put forth that larger cortices benefit from the increased processing power of a higher number of neurons, with concomitant lower neurite density and orientation dispersion maximizing network efficiency and reducing energy demand.(12) Importantly, other prior works have shown that total brain volume was a significant determinant of measured, and patient reported, functional outcomes after ischemic stroke.(14,15) This may further relate to the concepts of brain and effective reserve, which aims to quaQWLI\(cid:3) WKH(cid:3) EUDLQV(cid:3) DELOLW\(cid:3) WR(cid:3) compensate for negative effects, such as sudden vascular events.(25,26) Our data show that brain volume, without normalizing for intracranial volume, was a better determ
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