Image-guided subject-specific modeling of glymphatic transport and amyloid deposition.

The glymphatic system is a brain-wide system of perivascular networks that facilitate exchange of cerebrospinal fluid (CSF) and interstitial fluid (ISF) to remove waste products from the brain. A greater understanding of the mechanisms for glymphatic transport may provide insight into how amyloid beta (Aß) and tau agglomerates, key biomarkers for Alzheimer's disease and other neurodegenerative diseases, accumulate and drive disease progression. In this study, we develop an image-guided computational model to describe glymphatic transport and Aß deposition throughout the brain. Aß transport and deposition are modeled using an advection-diffusion equation coupled with an irreversible amyloid accumulation (damage) model. We use immersed isogeometric analysis, stabilized using the streamline upwind Petrov-Galerkin (SUPG) method, where the transport model is constructed using parameters inferred from brain imaging data resulting in a subject-specific model that accounts for anatomical geometry and heterogeneous material properties. Both short-term (30-min) and long-term (12-month) 3D simulations of soluble amyloid transport within a mouse brain model were constructed from diffusion weighted magnetic resonance imaging (DW-MRI) data. In addition to matching short-term patterns of tracer deposition, we found that transport parameters such as CSF flow velocity play a large role in amyloid plaque deposition. The computational tools developed in this work will facilitate investigation of various hypotheses related to glymphatic transport and fundamentally advance our understanding of its role in neurodegeneration, which is crucial for the development of preventive and therapeutic interventions.

Patient specific, imaging-informed modeling of rhenium-186 nanoliposome delivery via convection-enhanced delivery in glioblastoma multiforme.

Convection-enhanced delivery of rhenium-186 (186Re)-nanoliposomes is a promising approach to provide precise delivery of large localized doses of radiation for patients with recurrent glioblastoma multiforme. Current approaches for treatment planning utilizing convection-enhanced delivery are designed for small molecule drugs and not for larger particles such as186Re-nanoliposomes. To enable the treatment planning for186Re-nanoliposomes delivery, we have developed a computational fluid dynamics approach to predict the distribution of nanoliposomes for individual patients. In this work, we construct, calibrate, and validate a family of computational fluid dynamics models to predict the spatio-temporal distribution of186Re-nanoliposomes within the brain, utilizing patient-specific pre-operative magnetic resonance imaging (MRI) to assign material properties for an advection-diffusion transport model. The model family is calibrated to single photon emission computed tomography (SPECT) images acquired during and after the infusion of186Re-nanoliposomes for five patients enrolled in a Phase I/II trial (NCT Number NCT01906385), and is validated using a leave-one-out bootstrapping methodology for predicting the final distribution of the particles. After calibration, our models are capable of predicting the mid-delivery and final spatial distribution of186Re-nanoliposomes with a Dice value of 0.69 ± 0.18 and a concordance correlation coefficient of 0.88 ± 0.12 (mean ± 95% confidence interval), using only the patient-specific, pre-operative MRI data, and calibrated model parameters from prior patients. These results demonstrate a proof-of-concept for a patient-specific modeling framework, which predicts the spatial distribution of nanoparticles. Further development of this approach could enable optimizing catheter placement for future studies employing convection-enhanced delivery.

Complications, Mortality, and Functional Decline in Patients 80 Years or Older Undergoing Major Head and Neck Ablation and Reconstruction.

Importance: Data regarding outcomes after major head and neck ablation and reconstruction in the growing geriatric population (specifically ≥80 years of age) are limited. Such information would be extremely valuable in preoperative discussions with elderly patients about their surgical risks and expected functional outcomes. Objectives: To identify patient and surgical factors associated with 30-day postoperative complications, 90-day mortality, and 90-day functional decline; to explore whether an association exists between the type of reconstructive procedure and outcome; and to create a preoperative risk stratification system for these outcomes. Design, Setting, and Participants: This retrospective, multi-institutional cohort study included patients 80 years or older undergoing pedicle or free-flap reconstruction after an ablative head and neck surgery from January 1, 2015, to December 31, 2017, at 17 academic centers. Data were analyzed from February 1 through April 20, 2019. Main Outcomes and Measures: Thirty-day serious complication rate, 90-day mortality, and 90-day decline in functional status. Preoperative comorbidity and frailty were assessed using the American Society of Anesthesiologists classification, Adult Comorbidity Evaluation-27 score, and Modified Frailty Index. Multivariable clustered logistic regressions were performed. Conjunctive consolidation was used to create a risk stratification system. Results: Among 376 patients included in the analysis (253 [67.3%] men), 281 (74.7%) underwent free-flap reconstruction. The median age was 83 years (range, 80-98 years). A total of 193 patients (51.3%) had 30-day serious complications, 30 (8.0%) died within 90 days, and 36 of those not dependent at baseline declined to dependent status (11.0%). Type of flap (free vs pedicle, bone vs no bone) was not associated with these outcomes. Variables associated with worse outcomes were age of at least 85 years (odds ratio [OR] for 90-day mortality, 1.19 [95% CI 1.14-1.26]), moderate or severe comorbidities (OR for 30-day complications, 1.80 [95% CI, 1.34-2.41]; OR for 90-day mortality, 3.33 [95% CI, 1.29-8.60]), body mass index (BMI) of less than 25 (OR for 30-day complications, 0.95 [95% CI, 0.91-0.99]), high frailty (OR for 30-day complications, 1.72 [95% CI, 1.10-2.67]), duration of surgery (OR for 90-day functional decline, 2.94 [95% CI, 1.81-4.79]), flap failure (OR for 90-day mortality, 3.56 [95% CI, 1.47-8.62]), additional operations (OR for 30-day complications, 5.40 [95% CI, 3.09-9.43]; OR for 90-day functional decline, 2.94 [95% CI, 1.81-4.79]), and surgery of the maxilla, oral cavity, or oropharynx (OR for 90-day functional decline, 2.51 [95% CI, 1.30-4.85]). Age, BMI, comorbidity, and frailty were consolidated into a novel 3-tier risk classification system. Conclusions and Relevance: Important demographic, clinical, and surgical characteristics were found to be associated with postoperative complications, mortality, and functional decline in patients 80 years or older undergoing major head and neck surgery. Free flap and bony reconstruction were not independently associated with worse outcomes. A novel risk stratification system is presented.