Alzheimers disease (AD) is a devastating disease that affects millions of Americans and imposes a huge socio- economic burden. AD-related cognitive decline is associated with the accumulation of A? (Amyloid beta) plaques and neurofibrillary tangles of hyperphosphorylated tau protein, which are insufficiently cleared and degraded by mechanisms such as the glia-lymphatic system or by transport across the blood-brain barrier (BBB). Animal research has shown that the glia-lymphatic pathway plays a substantial role in the net clearance of A?. In addition, reduction of interstitial fluid efflux to the cerebrospinal fluid, or reduction of transport across the BBB, could lessen the A? clearance. Human magnetic resonance imaging (MRI) studies have also shown that the integrity of the perivascular space (PVS), the pathway of glia-lymphatic system, is a marker of glia-lymphatic brain health and its alteration is an important feature of AD pathology. PVS alteration in AD has been shown to be independent of Amyloid uptake, implicating astroglial involvement specific to AD. Information about PVS integrity could assist clinicians with making specific diagnosis about patients AD status and mechanism. Therefore, a tool that allows non-invasive in-vivo mapping of PVS from clinical MRI is of high significance to aid AD diagnosis and disease monitoring but does not yet exist. Current clinical routine to investigate PVS is a relatively crude approach based on counting total number of observed PVS in MRI by neuro-radiologists, which is non-specific, rater-dependent, and does not capture the distribution, whole extent of PVS change nor volumetric features of the PVS. From a practical point of view, this technique is time consuming and laborious. These limitations in part have prevented neurologists from adopting PVS quantification into their clinical routine. We have developed computational techniques for mapping and quantifying PVS morphology from MRI, which enables automated and accurate quantification of PVS across the brain without the need for time consuming manual intervention. These techniques were developed on research data, which had slightly higher resolution than clinical MRI. The goal of this proposal is to validate and optimize this technology on clinical MRI data, which can be variable in quality and resolution. We also aim to develop a scanner- and hardware-agnostic deployable analytical solution for automated PVS quantification, so that PVS mapping can be performed independent of the radiology/imaging IT infrastructure. If successful, we will have a fully developed and validated backend software that enables automated assessment of PVS and aids specific AD diagnosis and disease monitoring. Upon the completion of this goal, our Phase II will focus on translation of the technology via implementation and testing of the technology in collaboration with our strategic partners in clinic (Neuroradiology division of Keck School of Medicine), industry (BioGen Inc.) and research (MarkVCID and NASA). Our ultimate goal will be to integrate PVS measures into clinical diagnosis, disease monitoring and intervention efficacy assessment, as a specific non-invasive and in-vivo imaging marker of AD pathology that can be automatically and reliably measured. Public Health Relevance Statement Project Narrative The proposed research is relevant to public health because identifying pathological alterations to the brain perivascular spaces is expected to aid in Alzheimers disease diagnosis and disease monitoring. Traditionally, assessment of perivascular spaces in clinic was limited to visual counting on MRI, which is time consuming and inaccurate. The aim of this proposal is to develop and optimize reliable automated techniques to map perivascular spaces in clinical setting.
Project Terms: Affect ; Age ; ages ; Alzheimer's Disease ; AD dementia ; Alzheimer ; Alzheimer Type Dementia ; Alzheimer disease ; Alzheimer sclerosis ; Alzheimer syndrome ; Alzheimer's ; Alzheimer's disease dementia ; Alzheimers Dementia ; Alzheimers disease ; Primary Senile Degenerative Dementia ; dementia of the Alzheimer type ; primary degenerative dementia ; senile dementia of the Alzheimer type ; Amyloid ; Amyloid Substance ; Animal Experimentation ; Animal Experimental Use ; Animal Research ; Axon ; Blood - brain barrier anatomy ; Blood-Brain Barrier ; Hemato-Encephalic Barrier ; bloodbrain barrier ; Brain ; Brain Nervous System ; Encephalon ; California ; Cerebrospinal Fluid ; cerebral spinal fluid ; spinal fluid ; Clinical Research ; Clinical Study ; Demyelinations ; Diagnosis ; Disease ; Disorder ; Feedback ; Goals ; Hippocampus (Brain) ; Ammon Horn ; Cornu Ammonis ; Hippocampus ; hippocampal ; Human ; Modern Man ; Industry ; Lymphatic System ; Lymph System ; Lymphatic Network ; Lymphatic System Reticuloendothelial System ; Magnetic Resonance Imaging ; MR Imaging ; MR Tomography ; MRI ; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance ; NMR Imaging ; NMR Tomography ; Nuclear Magnetic Resonance Imaging ; Zeugmatography ; Manuals ; Maps ; Medical Imaging ; Neuroglia ; Glia ; Glial Cells ; Kolliker's reticulum ; Neuroglial Cells ; Non-neuronal cell ; Nonneuronal cell ; nerve cement ; Pathology ; Patient Monitoring ; Play ; Positron-Emission Tomography ; PET ; PET Scan ; PET imaging ; PETSCAN ; PETT ; Positron Emission Tomography Medical Imaging ; Positron Emission Tomography Scan ; Rad.-PET ; positron emission tomographic (PET) imaging ; positron emission tomographic imaging ; positron emitting tomography ; Public Health ; Research ; Role ; social role ; medical schools ; medical college ; school of medicine ; Sensitivity and Specificity ; Sex Distribution ; Computer software ; Software ; Standardization ; Technology ; Testing ; Time ; Translating ; Translations ; Universities ; Amyloid beta-Protein ; Alzheimer beta-Protein ; Alzheimer's Amyloid beta-Protein ; Alzheimer's amyloid ; Amyloid Alzheimer's Dementia Amyloid Protein ; Amyloid Beta-Peptide ; Amyloid Protein A4 ; Amyloid β ; Amyloid β-Peptide ; Amyloid β-Protein ; Aβ ; a beta peptide ; abeta ; amyloid beta ; amyloid-b protein ; beta amyloid fibril ; soluble amyloid precursor protein ; Measures ; Neurofibrillary Tangles ; neurofibrillary degeneration ; neurofibrillary lesion ; neurofibrillary pathology ; tangle ; tau Proteins ; MT-bound tau ; microtubule bound tau ; microtubule-bound tau ; tau ; tau factor ; Ï Proteins ; Data Set ; Dataset ; Intercellular Fluid ; Interstitial Fluids ; base ; Clinical ; Phase ; Ensure ; insight ; Visual ; wasting ; Individual ; Neurologist ; United States National Aeronautics and Space Administration ; NASA ; National Aeronautics and Space Administration ; uptake ; radiologist ; Collaborations ; fluid ; liquid ; Liquid substance ; Metabolic ; clinical Diagnosis ; Morphology ; Amyloid Plaques ; Neuritic Plaques ; amyloid beta plaque ; amyloid-b plaque ; aβ plaques ; cored plaque ; diffuse plaque ; Senile Plaques ; tool ; Cognitive Disturbance ; Cognitive Impairment ; Cognitive decline ; Cognitive function abnormal ; Disturbance in cognition ; cognitive dysfunction ; cognitive loss ; Impaired cognition ; Diagnostic ; machine learned ; Machine Learning ; Adopted ; Scanning ; Clinic ; Protocol ; Protocols documentation ; Techniques ; interest ; magnetic field ; American ; human data ; success ; cohort ; Structure ; neuro-imaging ; neuroimaging ; Participant ; Intervention Strategies ; interventional strategy ; Intervention ; preventing ; prevent ; Data ; Economic Burden ; Resolution ; in vivo ; Clinical Data ; Cognitive ; Computational Technique ; Small Business Technology Transfer Research ; STTR ; Validation ; technology validation ; technology implementation ; Pathologic ; Monitor ; Lymphatic ; socioeconomics ; socio-economic ; socio-economically ; socioeconomically ; Development ; developmental ; Image ; imaging ; Pathway interactions ; pathway ; Operating System ; hyperphosphorylated tau ; hyper-phosphorylated tau ; predictive modeling ; computer based prediction ; prediction model ; protein aggregation ; insoluble aggregate ; protein aggregate ; Clinical assessments ; efficacy evaluation ; efficacy analysis ; efficacy assessment ; efficacy examination ; evaluate efficacy ; examine efficacy ; Abeta clearance ; Amyloid β clearance ; Aβ clearance ; a-beta peptide clearance ; abeta peptide clearance ; amyloid beta clearance ; amyloid beta peptide clearance ; Treatment Efficacy ; intervention efficacy ; therapeutic efficacy ; therapy efficacy ; Outcome ; Consumption ; clinically significant ; clinical significance ; in vivo imaging ; imaging in vivo ; clinical predictors ; Alzheimer's disease pathology ; AD pathology ; Alzheimer's pathology ; imaging biomarker ; imaging marker ; imaging-based biological marker ; imaging-based biomarker ; imaging-based marker ; neurovascular ; neuro-vascular ; brain health ; connectome ; vascular cognitive impairment and dementia ; cardiac disease induced cognitive impairment ; vascular contributions to cognition/dementia ; vascular contributions to cognitive impairment and dementia ; radiological imaging ; radiologic imaging ; imaging study ; amnestic mild cognitive impairment ; Infrastructure ; Alzheimer's disease related dementia ; AD related dementia ; ADRD ; Alzheimer related dementia ; Alzheimer's disease diagnosis ; Alzheimer's diagnosis ; Alzheimer's disease patient ; Alzheimer's patient ; cost estimate ; cost estimation ;
