Hemodynamic molecular imaging of tumor-associated enzyme activity in the living brain

Molecular imaging could have great utility for detecting, classifying, and guiding treatment of brain disorders, but existing probes offer limited capability for assessing relevant physiological parameters. Here, we describe a potent approach for noninvasive mapping of cancer-associated enzyme activity using a molecular sensor that acts on the vasculature, providing a diagnostic readout via local changes in hemodynamic image contrast. The sensor is targeted at the fibroblast activation protein (FAP), an extracellular dipeptidase and clinically relevant biomarker of brain tumor biology. Optimal FAP sensor variants were identified by screening a series of prototypes for responsiveness in a cell-based bioassay. The best variant was then applied for quantitative neuroimaging of FAP activity in rats, where it reveals nanomolar-scale FAP expression by xenografted cells. The activated probe also induces robust hemodynamic contrast in nonhuman primate brain. This work thus demonstrates a potentially translatable strategy for ultrasensitive functional imaging of molecular targets in neuromedicine.

Multiparametric Microstructural MRI and Machine Learning Classification Yields High Diagnostic Accuracy in Amyotrophic Lateral Sclerosis: Proof of Concept

The potential of multiparametric quantitative neuroimaging has been extensively discussed as a diagnostic tool in amyotrophic lateral sclerosis (ALS). In the past, the integration of multimodal, quantitative data into a useful diagnostic classifier was a major challenge. With recent advances in the field, machine learning in a data driven approach is a potential solution: neuroimaging biomarkers in ALS are mainly observed in the cerebral microstructure, with diffusion tensor imaging (DTI) and texture analysis as promising approaches. We set out to combine these neuroimaging markers as age-corrected features in a machine learning model with a cohort of 502 subjects, divided into 404 patients with ALS and 98 healthy controls. We calculated a linear support vector classifier (SVC) which is a very robust model and then verified the results with a multilayer perceptron (MLP)/neural network. Both classifiers were able to separate ALS patients from controls with receiver operating characteristic (ROC) curves showing an area under the curve (AUC) of 0.87–0.88 (“good”) for the SVC and 0.88–0.91 (“good” to “excellent”) for the MLP. Among the coefficients of the SVC, texture data contributed the most to a correct classification. We consider these results as a proof of concept that demonstrated the power of machine learning in the application of multiparametric quantitative neuroimaging data to ALS.

Prospective Quantitative Neuroimaging Analysis of Putative Temporal Lobe Epilepsy

Purpose: A prospective study of individual and combined quantitative imaging applications for lateralizing epileptogenicity was performed in a cohort of consecutive patients with a putative diagnosis of mesial temporal lobe epilepsy (mTLE).Methods: Quantitative metrics were applied to MRI and nuclear medicine imaging studies as part of a comprehensive presurgical investigation. The neuroimaging analytics were conducted remotely to remove bias. All quantitative lateralizing tools were trained using a separate dataset. Outcomes were determined after 2 years. Of those treated, some underwent resection, and others were implanted with a responsive neurostimulation (RNS) device.Results: Forty-eight consecutive cases underwent evaluation using nine attributes of individual or combinations of neuroimaging modalities: 1) hippocampal volume, 2) FLAIR signal, 3) PET profile, 4) multistructural analysis (MSA), 5) multimodal model analysis (MMM), 6) DTI uncertainty analysis, 7) DTI connectivity, and 9) fMRI connectivity. Of the 24 patients undergoing resection, MSA, MMM, and PET proved most effective in predicting an Engel class 1 outcome (>80% accuracy). Both hippocampal volume and FLAIR signal analysis showed 76% and 69% concordance with an Engel class 1 outcome, respectively.Conclusion: Quantitative multimodal neuroimaging in the context of a putative mTLE aids in declaring laterality. The degree to which there is disagreement among the various quantitative neuroimaging metrics will judge whether epileptogenicity can be confined sufficiently to a particular temporal lobe to warrant further study and choice of therapy. Prediction models will improve with continued exploration of combined optimal neuroimaging metrics.

Improved neuropathological identification of traumatic brain injury through quantitative neuroimaging and neural network analyses: Some practical approaches for the neurorehabilitation clinician

BACKGROUND: Quantitative neuroimaging analyses have the potential to provide additional information about the neuropathology of traumatic brain injury (TBI) that more thoroughly informs the neurorehabilitation clinician. OBJECTIVE: Quantitative neuroimaging is typically not covered in the standard radiological report, but often can be extracted via post-processing of clinical neuroimaging studies, provided that the proper volume acquisition sequences were originally obtained. METHODS: Research and commercially available quantitative neuroimaging methods provide region of interest (ROI) quantification metrics, lesion burden volumetrics and cortical thickness measures, degree of focal encephalomalacia, white matter (WM) abnormalities and residual hemorrhagic pathology. If present, diffusion tensor imaging (DTI) provides a variety of techniques that aid in evaluating WM integrity. Using quantitatively identified structural and ROI neuropathological changes are most informative when done from a neural network approach. RESULTS: Viewing quantitatively identifiable damage from a neural network perspective provides the neurorehabilitation clinician with an additional tool for linking brain pathology to understand symptoms, problems and deficits as well as aid neuropsychological test interpretation. All of these analyses can be displayed in graphic form, including3-D image analysis. A case study approach is used to demonstrate the utility of quantitative neuroimaging and network analyses in TBI. CONCLUSIONS: Quantitative neuroimaging may provide additional useful information for the neurorehabilitation clinician.

Hemodynamic molecular imaging of tumor-associated enzyme activity in the living brain.

Molecular imaging could have great utility for detecting, classifying, and guiding treatment of brain disorders, but existing probes offer limited capability for assessing relevant physiological parameters. Here we describe a potent approach for noninvasive mapping of cancer-associated enzyme activity using a molecular sensor that acts on the vasculature, providing a diagnostic readout via local changes in hemodynamic image contrast. The sensor is targeted at the fibroblast activation protein (FAP), an extracellular dipeptidase and clinically relevant biomarker of brain tumor biology. Optimal FAP sensor variants were identified by screening a series of prototypes for responsiveness in a cell-based bioassay. The best variant was then applied for quantitative neuroimaging of FAP activity in rats, where it reveals nanomolar-scale FAP expression by xenografted tumor cells. The activated probe also induces robust hemodynamic contrast in nonhuman primate brain. This work thus demonstrates a translatable strategy for ultrasensitive functional imaging of molecular targets in neuromedicine.

Brain-age predicts subsequent dementia in memory clinic patients

INTRODUCTION: Research into quantitative neuroimaging biomarkers of dementia risk rarely uses data representative of everyday clinic practice. METHODS: We analysed T1-weighted MRI scans from memory clinic patients (n=1140; 60.2% female and mean [SD] age of 70.0 [10.8] years) to derive "brain-age", an index of age-related brain health. We determined which patients went on to develop dementia (n=476) via linkage to electronic health records. RESULTS: Cox regression indicated a 3% increased risk of dementia per brain-PAD year (brain-PAD = brain-age minus chronological age), HR(95% CI)=1.03(1.02, 1.04), p<0.001, adjusted for age, age^2, sex, MMSE and normalised brain volume. Brain-PAD remained significant even with a minimum time-to-diagnosis of 3 years (HR=1.06) and with MMSE score above 26 (HR=1.03). DISCUSSION: Memory clinic patients with older appearing brains are more likely to receive a subsequent dementia diagnosis. These results from a "real-world" dataset suggest quantitative neuroimaging biomarkers like brain-age could be readily used in the clinic.