Table 3.

Noninvasive clinical imaging biomarkers for detecting evolving entities under the umbrella of theranostics in neuro-oncology

Category in Multilevel Imaging	Imaging Modality / Metric	Distinctive Image Features	Observational Target / Decision-making Role	References
Anatomical structure	CT, MRI: Contrast enhancement	Standard for detection, delineation, and response assessment of tumor High resolution in tumor enhancement, evaluation of the tumor vascularity CT: Ionizing radiation Iodine-based contrast agent (the risk of immediate HSRs) MRI: Non-ionizing radiation Gadolinium-based contrast agent (the risk of NSF)	Identify blood products or calcification within the tumor Prognostic/surrogate imaging biomarker in nearly all cancers	[170–172]
	MRI: T2-FLAIR	To suppress the signal originating from bulk fluid including CSF for better visualization of vasogenic edema Near the cortex and ventricle where CSF can inhibit lesion detection Assessment of white matter tumor involvement and related edema	Detection of subtle changes at the periphery of the hemispheres, periventricular region closes to CSF Best for lesion at brain and CSF interfaces Highly specific imaging biomarker in T2-FLAIR mismatch sign	[173]
Functional physiology	MRI: DWI, DTI, ADC, DKI	Brownian motion of water particles at the microscopic level within biological tissues DTI: isotropy, anisotropy ADC: track the rate of microscopic water diffusion within tissues DKI: dimensionless metric that quantifies the degree of deviation from Gaussian diffusion behavior	Provided neurosurgeons with new tools to overcome the challenge of differentiating healthy tissue from tumor-infiltrated tissue Resective surgery: removing patients with tumors found to be embedded in or in close proximity to functionally important regions; ADC change in response to extracellular (vasogenic; normal or increased diffusion) and cellular (cytotoxic; restricted diffusion) forms of edema Describe the degree of structure of a biological tissue / Enable quantification of non-random diffusion of water due to structural features present in tissues Predictive imaging biomarker before neurosurgery	[174–179]
	MRI: PWI, ASL,DCE, DSC,	Insight into the hemodynamic change by bolus-tracking through the first pass of contrast agent,i.e., either endogenous (arterial water) or exogenous (gadolinium) contrast agents Assessment of blood flow into the mass / tumor to study the brain microvascular component ASL: magnetically labeled the protons in the arterial blood as an endogenous tracer by radiofrequency pulses (without the exogenous injection of contrast media) in technique, i.e., continuous ASL and pulsed ASL, it the most commonly derived is cerebral blood flow information DCE: providing insight into the nature of the bulk tissue properties at the microvascular level compartment (plasma space and extra-vascular-extracellular space) in pharmacokinetic model DSC: performing with intravenous bolus injection of a paramagnetic contrast agent or a particulate agent of superparamagnetic iron oxide using T2-WI or T2*-WI, and the most commonly used MR perfusion technique of the neuro-oncology	Provide clinically useful physiologic information using pharmacokinetic models to complement conventional contrast-enhanced MR imaging, particularly of brain tumors and stroke Diagnosis of tumors and the evaluation of the treatment response in differentiating recurrent tumoral disease from therapy-related necrosis Predictive/progression /prognostic evaluation imaging biomarker with overall survival in progression-free survival, and pharmacodynamic biomarker	[180–184]
Molecular metabolism	MRI: MRS	The most using the proton ( 1 H) nucleus because of its high sensitivity and ease of implementation for MR examination Spatial localization techniques (i.e., single-voxel: PRESS, STEAM sequences and multivoxel: chemical shift imaging for phase-encoding) record spectra from regions via spatial distribution of metabolites within the brain	Metabolic markers provide neuroimaging biomarker of normal biological and pathological processes or response to a therapeutic intervention metabolism on biochemical changes, define different metabolic tumor phenotypes MRS in tumor classification, tumors versus nonneoplastic lesions, prediction of survival, treatment planning, monitoring of therapy, and post-therapy evaluation Diagnosis/progression /prognostic evaluation imaging biomarker	[185, 186]
	PET: 18F-FDG	PET: optimize/minimize injected dose of radiotracer 18F-FDG (T1/2 = 110 min) is commonly used to detect metabolically active malignant tumor/lesion (i.e., increased glucose uptake and glycolysis of cancer cells) Gamma rays are emitted and detected by gamma cameras to form a three-dimensional image PET scanners can incorporate a CT or MRI scanner (i.e., PET/CT or PET/MRI) hybrid imaging Depicting metabolic abnormalities before morphological alterations occur and identifying the cellular level changes even the immune cell tracking	Accurate diagnosis and staging are essential for the optimal management of cancer patients Monitoring response to therapy and permitting timely modification of therapeutic regimens Diagnosis/progression /prognostic evaluation imaging biomarker	[187–189]