Hanzhang Lu, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): The long-term goal of this research is to establish a robust and accurate MRI method for estimating absolute cerebral blood volume (CBV) and to use this technique for clinical studies of brain diseases, such as acute stroke and Alzheimer's Disease. For this project, the specific aims are: 1) To develop the pulse sequence and related algorithms that allow quantification of absolute CBV using pre- and post-contrast MR images; 2) To evaluate the effects of other confounding factors, to optimize the imaging protocol, and to validate the MRI results using PET CBV measurements. CBV, defined as ml of blood per 100 ml of brain tissue, is an important physiological marker in many neurovascular diseases. Furthermore, it is of critical value in the diagnosis and/or monitoring of treatment for many other brain diseases that are non-vascular in origin. Existing techniques for the measurement of CBV either suffer from limited spatial resolution (e.g. PET) or require additional knowledge about the arterial input function (e.g. dynamic susceptibility contrast MRI). In this project, a novel approach will be developed for the accurate measurement of absolute CBV using Vascular-Space-Occupancy (VASO) MRI, a blood-nulling pulse sequence, in combination with the T1 shortening effect of the contrast agent Gd-DTPA. Two VASO images are acquired before and after contrast agent injection, resulting in a difference image that can be used to determine CBV. The key novelty of the proposed approach is that the estimation of CBV does not require knowledge or assumptions about vascular morphology. This is expected to provide a more accurate estimation of CBV compared with existing methods. The imaging protocol will be optimized by investigating various confounding factors that may cause error in the CBV estimation, including contrast agent concentration, MR receiver coil sensitivity profile, transverse relaxation effect of the contrast agent, effect of water exchange in the capillary bed, and effect of leakage in the blood-brain-barrier. The MRI CBV results will be validated using PET CBV measurements. Relevance: Many diseases in the brain are related to the blood supply to the brain. Therefore, it is of substantial value for physicians to have knowledge about the amout of blood present in the brain, often referred to as cerebral blood volume (CBV). In this project, a new technique will be developed to measure CBV in human brain using MRI. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The central theme of this project is a T2-Relaxation-Under-Spin-Taggin (TRUST) technique for quantitative measurement of venous blood oxygenation. The work in the current cycle has focused on its utility in fMRI normalization. In the next cycle, we will have two research foci. One is to continue our efforts on fMRI normalization and its dissemination (Aim 1). The other is to examine a new utility of TRUST in evaluations of brain oxygen utilization (Aims 2 and 3). Since oxidative metabolism is the predominant mode of energy generation (ATP production) in the brain, the ability to measure brain oxygen utilization on a standard clinical scanner will have a profound impact in many brain disorders. FMRI provides a non-invasive approach to assess brain function and has the potential of broad clinical applications. A main limitation of the current fMRI technique is that the signal is an indirect measurement of neural activity and is influenced by non-neural factors such as vascular properties of the brain. In the current funding cycle, we have shown that fMRI signal can be normalized with a cost-effective approach, by accounting for baseline venous oxygenation measured with a TRUST MRI technique. We further showed the utility of this normalization in better detection of disease effects or medication effects on neural activity. Our next goal is to make this tool benefit the broader scientific community. Therefore, in the next cycle, one of our emphases is the dissemination of the TRUST technique and the associated fMRI normalization method. We will conduct a multi-site study (in Aim 1) by leveraging resources of several other NIH-funded fMRI projects and adding our 1.2-min TRUST protocol to their scan sessions. We will test whether the TRUST technique can provide reliable estimation of venous oxygenation across sites, through which we aim to show that TRUST- based fMRI normalization can benefit a wide spectrum of fMRI studies with relatively little added costs. Aside from its utility in fMRI normalization, the TRUST technique and the associated measure of venous oxygenation can be extended to estimate cerebral metabolic rate of oxygen (CMRO2), a key marker for tissue viability and brain function. The availability of a clinically practical CMRO2 technique will find immediate applications in many disorders, such as neurodegenerative diseases and metabolic syndrome. The other emphasis of the proposed project will therefore be the further development of MRI techniques to allow a quantitative measurement of CMRO2. Aim 2 will focus on a global technique which, although not providing regional values, is expected to be fast (<5 min scan time) and highly reliable (coefficient of variation, CoV < 4%), and its utility in Alzheimer's Disease will be examined. Aim 3 will further push the envelope of technology by focusing on the development and validation of a novel pulse sequence, T2-Relaxation-Under-Phase- Contrast (TRU-PC) MRI, which provides a regional estimation of oxygenation and CMRO2.

Project Summary/Abstract: Early diagnosis of Alzheimer?s disease (AD) is important, as therapeutic interventions such as amyloid immunization are thought to be most beneficial at this stage of the disease. Therefore, the emphasis in AD research is shifting toward understanding the process by which high-risk elderly individuals begin to develop brain abnormality, at a time when they are still cognitively normal. Apolipoprotein E allele 4 (APOE4) is the largest known genetic risk factor for sporadic Alzheimer?s disease. Carriers of APOE4 gene have between 10 and 30 times the risk of developing AD, as compared to those not carrying APOE4. Therefore, understanding neurobiological differences between APOE4 carriers and non-carriers will have a significant benefit in this high-risk population and will also help elucidate early AD mechanisms in general. Brain metabolism has been hypothesized as one of the earliest imaging markers of AD in the recent consensus model. To date, brain metabolism in AD is primarily measured with Fludeoxyglucose (FDG) PET. However, the presence of ionizing radiation and the lack of absolute quantification make the technique less frequently used in studies of cognitively normal subjects. Our laboratory has recently developed and validated a technique to measure the brain?s oxygen extraction fraction and metabolism with MRI. The technique does not require any exogenous tracer, can be completed within five minutes on a standard 3T, has a high test- retest reproducibility, and has recently been evaluated in a multi-site setting. This project represents the first application of this novel technique in prodromal AD. The central hypothesis of this project that elderly individuals with high risk to develop AD, e.g. APOE4 carriers, will show abnormal brain metabolic features, at an early time when their cognition is still normal. We have a cost-effective, time-limited window of opportunity to test this hypothesis, by leveraging rich resources of the NIH-funded ?Biomarkers for Older Controls at Risk for Dementia (BIOCARD)? study. The BIOCARD Study is a longitudinal, observational study of 278 elderly individuals. We have obtained approval from the BIOCARD study to include the brain metabolism sequences in the MRI protocol, and the preliminary studies have shown a potential effect of APOE4. Therefore, we are in a unique position to thoroughly examine the role of imaging markers in the onset of neurodegeneration in high-risk individuals. Our Specific Aims are 1) Examine the relationship between brain oxygen metabolic markers and APOE4 in cognitively normal elderly individuals; 2) Investigate whether the association between high AD risk and aberrant brain metabolism can be extended to other risk factors such as tauopathy and amyloid protein. Impact: The impact of this work is that we will establish an early biomarker to detect neurodegeneration in individuals with a high risk to develop Alzheimer?s disease, at a time when they are still cognitively normal and when intervention may be most effective.

Project Summary/Abstract: Small vessel cerebrovascular disease is a major risk factor in Alzheimer?s disease. However, quantitative biomarkers that are suitable for use as endpoints in clinical trials for these conditions are still lacking. The goals of the present project are to 1) in the UH2 phase, evaluate and identify MRI-based microvascular biomarkers that are diagnostic and predictive, with a particular focus on a novel marker referred to as cerebrovascular reactivity; 2) in the UH3 phase, work with the Coordinating Center and other projects in the consortium to further evaluate the most promising biomarker candidates in a multi-site setting. Conventional anatomic imaging (e.g. T2-FLAIR) can identify white matter hyperintensities that represent the consequence of small vessel damage. In this project, we will emphasize several newer techniques that probe the potential physiological driving force of small vessel cognitive impairment and dementia (VCID). Specifically, we will focus on a marker indexing the dynamic coupling capacity of the neurovascular unit, referred to here as cerebrovascular reactivity (CVR). Our previously studies on CVR have revealed that: 1) CVR is three times as sensitive to age as resting perfusion. 2) CVR is diminished in patients with AD dementia. 3) Decline in processing speed (over four years) is significantly associated with CVR decline (over four years). 4) CVR of the brain is strongly correlated with structural lesions as seen on T2-FLAIR. Therefore, the present project will emphasize the development of CVR MRI as a small vessel imaging biomarker, with additional consideration of several other microvascular parameters including microbleeds count and cerebral blood flow (CBF). These small vessel measures (vascular imaging markers) will be combined into a composite index based on their contributions to cognitive impairment, which will form a composite imaging biomarker for diagnosis, prediction, and target engagement of VCID. Our Specific Aims in the UH2 phase are: 1) Examine the association between cognitive function and candidate vascular imaging markers in a group of elderly individuals with mixed vascular and Alzheimer?s pathology; 2) Conduct technical assessment of the vascular imaging methods to show that they are multi-site ready in terms of applicability and reproducibility; 3) Work with Coordinating Center and other Development Projects to establish the consortium in preparation for the UH3 phase. Quantifiable milestones have been defined for these aims and for the readiness of the project to enter the UH3 phase, in which the specific aim is to perform collaborative studies as part of the small vessel biomarker consortium to further evaluate and develop the most promising biomarker candidates. Impact: Upon the completion of this project, we will have developed a small vessel imaging biomarker that is ready for large scale multi-site clinical validation studies.

? DESCRIPTION (provided by applicant): Vascular imaging of the brain has played an important role in the management of a variety of brain disorders, such as intracranial stenosis, carotid artery stenosis, stroke, small vessel diseases, brain tumor, traumatic brain injury, Moyamoya disease, and drug-addictive conditions. Both baseline examinations and stress tests are commonly used in clinical practice and they provide complementary information. However, a major limitation is that collection of all of this information requires separate scans and, in some cases, separate visits. This limitation increases patient burden and significantly escalates the cost of care. Therefore, the goal of this R21 project is to develop advanced methods to perform a one-stop-shop imaging of vascular physiology that provides multiple domains of information. The proposed technique uses the time of a single scan to apply both O2 and CO2 gas inhalation tasks, which provide baseline and vascular reactivity information, respectively, and tracks the gas bolus to obtain transit time information, as well as extracting functional connectivity networks from the same dataset. CO2 and O2 are important components of our body's metabolic pathway, but they also have interesting vascular properties in the context of brain perfusion imaging. CO2 is a potent vasodilator and can be used to measure vascular reactivity. O2 is inert to blood vessels but its inhalation changes BOLD MRI signal, which allows the estimation of an index of baseline cerebral blood volume (CBV). Furthermore, with our novel breathing paradigm, both CO2 and O2 tasks can be completed concomitantly with the duration of one scan. Additionally, inhaled O2 and CO2 can serve as boluses in the blood stream for the measurement of bolus time-to-peak (TTP). Finally, BOLD MRI data acquired during gas-inhalation tasks can be used for the analysis of functional connectivity networks of the brain. Therefore, our central hypothesis is that a single MRI scan with the proposed procedure will simultaneously provide baseline CBV, cerebrovascular reactivity, time-to-peak, and resting-state functional connectivity. We will first conduct development of the technique in healthy controls (in Aim 1), then perform validation and initial clinical demonstration in patients with intracranial arterial stenosis (in Aim 2). Impact: The impact on clinical practice is that cerebrovascular patients who require both baseline and reactivity assessment will be able to complete the whole procedure with just one visit of 10-15 minutes (as opposed to two visits of 90 minutes each). Additionally, patients who are allergic to conventional contrast agent will have access to an alternative contrast agent (i.e. O2 and CO2 gases) for their vascular imaging needs.

Project summary/Abstract: Alzheimer?s disease (AD) is a devastating disease that affects more than five million people in the U.S. alone. Early neurodegeneration biomarkers can play an important role in clinical trials of AD, especially biomarkers that are non-invasive, inexpensive, and radiation-free. Our laboratory has recently developed and validated a technique, T2-Relaxation-Under-Spin-Tagging (TRUST), to measure the brain?s oxygen extraction fraction (OEF) and metabolism with MRI. The technique does not require any exogenous tracer, can be completed within 5 minutes on a standard 3T, has high test-retest reproducibility, and has been successfully evaluated in a multi-site setting. Mounting evidence suggests that OEF is a potential marker of neurodegeneration in AD. First, we have shown that patients with amnestic Mild Cognitive Impairment (MCI), a mild form of AD, have significantly diminished OEF. Second, cognitively normal elderly individuals with genetic risk to developed AD, e.g. APOE4 carriers, have reduced OEF. Finally, brain oxygen extraction and metabolism have also been found to be associated with cognitive dysfunction and tauopathy measured from the CSF. To validate the oxygen metabolism biomarker using gold-standard measures of neurodegeneration, human studies often require a long follow-up period and a relatively high cost. Therefore, it is logical to first conduct an exploratory/developmental (R21) study to demonstrate the plausibility of such hypothesis in animal models. Toward this goal, we propose a longitudinal study in AD mouse model using a novel oxygenation MRI technique, and validate its association with neurodegeneration as measured by histology. This study has two specific aims. Aim 1 is to determine cross-sectional and longitudinal characteristics of brain oxygenation and metabolism in AD mouse model relative to control mice. We will measure OEF and cerebral metabolic rate of oxygen (CMRO2) in a novel AD model that our co-investigator, Dr. Wong, recently developed. We hypothesize that cross-sectionally OEF will be lower in the AD mice compared to control mice, and the difference will be more pronounced at an advanced age. Longitudinally, OEF in the AD mice will show progressive decrease starting 6 months of age. Aim 2 is to validate the imaging biomarkers with histological measurement of neurodegeneration. The animals undergoing imaging will be sacrificed at three time points (a sub-sample at each time point) and histology will be performed to measure neuron count and tau burden. Imaging markers will be compared to these histological measures to determine the degree to which they can predict current and future neurodegeneration. Impact: Upon the completion of this study, we will have established a concrete relationship between imaging measures of brain oxygen metabolism and hallmarks of AD pathology such as tauopathy and amyloidosis, which will provide a strong foundation for human validation studies in a larger-scale project.

Project Summary/Abstract: Ischemic stroke is a major health problem worldwide. In the United States, it is the fourth leading cause of death and the leading cause of major disability. It is estimated that more than 700,000 Americans experience new or recurrent stroke each year. Perfusion imaging plays an important role in virtually all stages of stroke and related cerebrovascular diseases. At present, most clinical perfusion imaging requires the use of contrast agents, e.g. gadolinium (Gd) in MRI. However, Gd perfusion MRI cannot be used or fails to be used in 10-20% of patients, due to a variety of reasons, such as allergic reactions, low glomerular filtration rate, difficulties in placing an intravenous line that is suitable for a rapid injection, or human errors in the timing of injection. Therefore, an alternative technique to Gd-perfusion will benefit a substantial number of patients in clinical practice. Arterial Spin Labeling (ASL) MRI allows for non-contrast evaluation of cerebral blood flow (CBF). However, in its current form, it cannot provide information equivalent to that obtained by contrast-agent-based perfusion imaging. This is because CBF is of limited value in stroke delineation. The most useful parameter in Gd- perfusion is Tmax or bolus-arrive-time (BAT), yet they cannot be measured reliably with current ASL methods. This application will develop a novel non-contrast perfusion technique that applies a new principle of MR fingerprinting (MRF) to ASL. The major strength of this technique is that it allows for simultaneous estimations of six parameters, CBF, BAT, T1, B1+, blood volume, and arterial travel time, in a single scan. Aim 1 is the development of the MRF-ASL MRI technique. We will develop MRF-ASL sequence timing for efficient encoding of perfusion parameters. We will also develop k-space undersampling strategies to obtain high spatial resolution perfusion imaging without increasing echo-train length. We will conduct validation of the technique using Gd-based perfusion MRI. Aim 2 of this project will develop a cloud-based ASL analysis platform that can provide researchers and clinicians with an installation-free, operating-system independent tool for ASL analysis (of MRF-ASL as well as all other types of ASL data). Our clinical team at Johns Hopkins has a long-standing interest in mechanistic and therapeutic studies of sub-acute stroke. Therefore, Aim 3 of the present project is to demonstrate the initial clinical utility of the technique in sub-acute stroke. Finally, it should be emphasized that, although the present project focuses on its clinical applications in cerebrovascular diseases, the method developed also has important utility in other brain diseases, such neurodegenerative diseases (e.g. Alzheimer?s, Parkinson?s, Huntington?s diseases), psychiatric diseases (e.g. schizophrenia, depression, autism, ADHD), and tumor (primary and metastatic brain tumor). Thus, this technique is expected to have a broad clinical impact.

Project Summary/Abstract: Cerebrovascular imaging has a broad impact in a variety of brain disorders, including cerebrovascular diseases such as stroke, arterial stenosis, Moymoya disease, small vessel diseases, and vascular dementia, but also in other neurological conditions such as brain tumor and traumatic brain injury. Current clinical practice of cerebrovascular imaging requires multiple scans and, in some cases, multiple visits in order to obtain a complete assessment of the brain?s vascular health that includes perfusion, hemodynamic parameter, and flow reserve. This limitation increases patient burden and significantly escalates the cost of care. Therefore, the goal of the present project is to develop novel methods to perform an integrated vascular (iVas) imaging that provides all relevant physiological information in a single scan (<10 minutes). The proposed iVas-MRI technique will apply concomitant O2 and CO2 gas inhalation (but with different timing) and will simultaneously measure cerebral blood volume (CBV), cerebrovascular reactivity (CVR), bolus time-to-peak (TTP), and functional connectivity networks from the same dataset. Aim 1 will develop three key components of the iVas-MRI technique, specifically concomitant O2 and CO2 gas-inhalation paradigm, high spatial-resolution MRI pulse sequence, and multi-parametric data processing algorithm. A cloud-based computation platform will also be developed for standardization of the analysis and future dissemination of the technique. Aim 2 will conduct validation and multi-vendor assessment of the iVas-MRI technique. We will compare results of the iVas-MRI technique to those of standard techniques and will examine across-vendor reproducibility of the proposed technique by scanning each participant on three MRI systems manufactured by General Electric, Philips, and Siemens, respectively. Aim 3 will apply the technique in patients with Moyamoya disease and study its potential value in both the diagnosis and treatment monitoring of this condition. We will first examine the utility of iVas-MRI in predicting clinical outcomes in a cross-sectional setting. Then, through serial MRIs, we will examine the utility of iVas-MRI in differentiating treatment benefits of two most commonly performed surgical procedures in Moyamoya patients, specifically direct versus indirect bypass surgery. The long-term impact of this work on clinical practice is that patients with cerebrovascular diseases will have their vascular imaging scan done in just one visit of less than 10 minutes (as opposed to multiple visits and several scans). Additionally, patients who are allergic to conventional contrast agent will have access to an alternative contrast agent (i.e. O2 and CO2 gases) for their vascular imaging needs.

Project Summary/Abstract: Because of disappointing outcomes of recent clinical trials of anti-amyloid therapy in Alzheimer?s Disease (AD), the field is increasingly interested in elucidating alternative disease mechanisms which may lead to new therapeutic targets that are complementary to anti-amyloid treatment. Extensive literature using post-mortem tissue has suggested that damage to the blood-brain-barrier (BBB) is intricately involved in the pathogenesis of AD. Furthermore, recent studies in animal models suggested a direct link between BBB damage and accumulation of amyloid plaques, in that aggregation of the amyloid protein may be part of an inflammatory response of the brain to pathogen entry, presumably following BBB leakage. However, in vivo studies of BBB in AD are scarce. A method commonly used to evaluate BBB permeability in humans is by administering Gadolinium (Gd) based contrast agent while measuring and modeling dynamic contrast-enhanced (DCE) MRI signal. However, contrast-enhanced MRI is not a common procedure in AD research and has not been used in large-scale or multi-site studies. Therefore, a non-contrast technique to assess BBB permeability is of particular importance in AD research and, if successful, can feasibly translate to clinical screening and monitoring of treatment. The central goal of this application is to develop an MRI technique to measure BBB permeability to water, without using any exogenous agent. MRI can probe water BBB permeability by determining what fraction of the incoming arterial water enters the brain and what fraction remains in the vessel and drains to the vein. This project consists of three logical aims. Aim 1 will develop novel MRI pulse sequences to quantitatively evaluate permeability-surface-area product (PS) of BBB in both global and regional fashion. Aim 2 will validate the non- contrast method with Gd-contrast based technique in humans and with fluorescent microscopy in animal models following osmotic opening of BBB. Aim 3 will conduct clinical application of the technique in elderly individuals who have an established genetic risk to develop Alzheimer?s Disease (AD), i.e. APOE4-carriers. We will compare BBB permeability with amyloid burden and cognitive function, and study their causal relationship through a mediational model analysis. We will also compare the non-contrast permeability results to those using an invasive method of CSF sampling as well as using DCE MRI. The impact of this work is that we will develop a novel non-contrast technique to evaluate BBB permeability in humans. The technique can be completed within 5 minutes on a standard 3T MRI. The outcome of the measurement is in physiological unit of ml water/100g brain/min, thus can be feasibly compared across sites or modalities. This technique will have broad clinical utility, as injury of BBB is implicated in many brain diseases. In this application, we will demonstrate the utility of this technique in AD.

SUMMARY The importance of biomarkers in clinical practice and regulatory science is difficult to overstate. The ultimate goal for clinical care of the future is to determine the most appropriate therapy for each patient?s unique version of a particular disease. This concept of precision medicine has been identified as a national priority in the USA, leading to a need for biomarkers that can provide objective and reproducible information. In addition, regulatory science for the approval of new qualified drugs and medical technologies has an urgent need for qualified biomarkers to report on the success or failure of these drugs and technologies. Imaging biomarkers, providing in situ ?biopsies?, have the potential to provide such specific information and, ultimately, to improve routine clinical care and speed up development of new treatments. The overall goal of this Resource therefore is to develop novel noninvasive MRI candidate biomarkers that can ultimately be used for: (i) personalized assessment of patients for diagnosis, prognosis, and treatment monitoring; (ii) monitoring of the development of new medical technologies and drugs, i.e. for better guiding of clinical trials. The significance of our proposed developments lies in providing the fundamental design and initial testing (i.e. not clinical trials itself) of new MRI candidate biomarkers with the potential to provide surrogate quantitative imaging endpoints that are as close as possible to clinical endpoints. As such, this Resource will focus on designing, calibrating and standardizing new magnetic resonance (MR) technologies to provide reliable measures across sessions, scanners, and raters. This technology will then be disseminated for larger scale patient studies to allow clinical validation. The MRI Resource for Physiologic, Metabolic and Anatomic Biomarkers is an interdepartmental and interdisciplinary consortium combining facilities and expertise of the F.M. Kirby Research Center at Kennedy Krieger Institute (KKI), the Department of Radiology at Johns Hopkins University (JHU) School of Medicine, the Center for Imaging Science at the JHU Whiting School of Engineering, and the Department of Biostatistics at the JHU Bloomberg School of Public Health. We propose 4 TRD projects, 3 on MR acquisition approaches and one bringing them together with advanced multi-scale data analysis methods that include machine learning. To assure a proper choice of technologies, we will interact closely with a group of clinical and research experts in a push-pull relationship through collaborative projects (CPs) that focus on brain diseases, disorders, and injuries that have a need for new quantitative MR technology to better and noninvasively assess them. These include anemia/ischemia and related white matter hyperintensity lesions (CPs 1,5), aging, cerebrovascular disease, and dementia (CPs 2,7,10), traumatic brain injury (CP4), glymphatic function (CP6), pain (CP8) and addiction (CP9). As an initial testbed for our methods, we also have a group of service projects (SPs) to which we will provide both data acquisition methods and data analysis software. Finally, we will train investigators in their use and disseminate methods nationwide and to MRI manufacturers for even broader application.

Project Summary/Abstract: Extant literature suggests that damage to the blood-brain barrier (BBB) is intricately involved in the pathogenesis of Alzheimer's disease and related dementia (ADRD). For example, post-mortem studies demonstrated that ADRD brain is characterized by the accumulation of blood-derived proteins, degeneration of BBB-specific cells, and injury of vascular endothelium. However, the relationship of BBB damage to pathological hallmarks of dementia such as beta-amyloid, tau, and cerebral small vessel disease are not well understood, particularly in humans. This is primarily attributed to a scarcity of in vivo techniques to evaluate BBB function. The PI is a leading expert in non-invasive imaging of microvascular function, and his laboratory has recently developed, optimized, and validated a MRI technique to assess BBB permeability to water molecules. Our preliminary studies using this novel technique has shown strong evidence that 1) Significant BBB breakdown can be detected in patients with mild cognitive impairment (MCI) using non-contrast MRI; 2) the extent of BBB breakdown is associated with amyloid burden; and 3) BBB function can predict cognitive function, particularly in the memory domain. The central goal of this application is therefore to capitalize on these technical advances and characterize BBB breakdown in MCI and early dementia, and to understand its causal relationship to both AD and small vessel pathology. BBB permeability to three molecules of different sizes, specifically water (molecular weight 18 g/mol), Gadolinium MRI contrast agent (molecular weight 547 g/mol), and albumin (molecular weight 66K g/mol) will be measured in the same participants. Human patient studies will be paralleled by studies in animal models so that clinically relevant discoveries can be validated in experimental models. The role of inflammation in BBB breakdown will also be examined. These relationships will be studied in both cross-sectional and longitudinal manner. This multi-modality, multi-disciplinary project has three Aims. Aim 1 will examine the cross-sectional relationship between BBB breakdown, amyloid, tau pathology, small vessel pathology, and inflammatory markers in 125 elderly participants including cognitively normals, MCI, and early dementia. The inter-relationships among these variables will be studied in the framework of a mechanistic model. Aim 2 will conduct a 30-month follow-up of these participants and investigate the longitudinal relationship between BBB breakdown and progression of AD pathology, small vessel pathology, inflammatory markers, and cognitive function. Finally, in Aim 3, we will validate the pathological underpinnings of BBB dysfunction in ADRD using two novel rodent models that our collaborators have developed for AD and small vessel disease, respectively. These rodent models with relatively pure pathology are expected to reveal more definitive relationships between BBB breakdown and AD and small vessel pathology.

TRD 1: Quantitative Imaging of Physiological Markers Lead Principal investigator: Hanzhang Lu, Professor of Radiology Co-investigators: Jim Pekar, Qin Qin, Jun Hua, Peiying Liu, Wenbo Li This TRD will develop physiological MRI techniques that provide quantitative and biologically interpretable measures of the brain. We will develop methods to probe basal physiological parameters including cerebral blood flow (CBF), bolus arrival time (BAT), oxygen extraction fraction (OEF), and blood-brain barrier (BBB) permeability. We will also develop techniques to assess dynamic physiological parameters including cerebrovascular reactivity (CVR), arterial pulsatility, and vascular compliance (VC). We will achieve these goals through systematic development of novel pulse sequences, models, and data processing methods. To allow these sophisticated measures to be obtained with clinically practical time, fast acquisition methods will be integrated into our techniques such as compressed sensing, multi-band/simultaneous-multi-slice, parallel imaging, variable-density spiral sampling, and stack-of-stars 3D acquisition. Multi- contrast imaging (e.g. combining physiological with anatomic imaging) will be achieved by MR Fingerprinting (MRF). To improve the speed and reliability of parametric estimations, especially for MRF-type of acquisitions, deep learning methods will also be applied. To ensure readiness of these techniques for biomarker testing, small-scale standardization and compatibility assessments will be performed which include intra- session, inter-session, inter-vendor, inter-rater test-retest, and cloud-based MRI data processing. The development of the techniques will be conducted with close interactions (so-called ?push-pull relationship?) with the Collaborative Projects (CPs) and in collaboration with other TRDs. Additionally, these tools, once fully tested, will be disseminated to the Service Projects (SPs) and other interested researchers.

Project Summary/Abstract: Small-vessel-related vascular contributions to cognitive impairment and dementia (VCID) represent the second leading cause of cognitive dysfunction in older individuals. However, quantitative biomarkers indexing key vascular processes related to VCID that are suitable for use as endpoints in clinical trials are still lacking. The goals of the present application are to 1) participate in the multi-site clinical validation of up to six biomarkers selected by the NINDS through a longitudinal study of diverse all-comers with cognitive complaints and/or early symptomatic signs of cognitive impairment and dementia potentially associated with small vessel disease; 2) lead the multi-site clinical validation of cerebrovascular reactivity (CVR) biomarker in all-comers, if the CVR biomarker is selected to move onto the next-phase study. The present application is a Renewal of UH2/3 NS100588 under RFA-NS-16-020. As one of the funded participating sites of the above-mentioned RFA, hereafter referred to as MarkVCID I study, our team at JHU has made significant contributions to the Consortium: 1) In the UH2 phase, we developed a CVR MRI candidate biomarker and collected data to support its selection by the NINDS to become one of the eleven biomarkers that transited into the UH3 phase; 2) In the UH2 phase, we worked with other sites to standardize MRI, biofluid, clinical, and neuropsychological measures and implemented candidate biomarkers proposed by other sites locally at our site; 3) In the UH3 phase, we participated in the multi-site instrumental and biological validation of biomarkers approved by the NINDS; 4) In the UH3 phase, we led the multi-site instrumental and biological validation of the CVR candidate biomarker. Importantly, our site has the scientific expertise and equipment that are necessary to perform any of the 11 biomarkers currently under consideration; 5) We participated in all Consortium-wide activities such as annual conferences, committee meetings, and calls. In the present application, we propose four Specific Aims. Aim 1 will enroll 220 participants of diverse all-comers that are typical in clinical settings in the United States during the first two years of the project and collect the NINDS-approved biomarker measures. Aim 2 will conduct longitudinal follow-up in a minimum of 200 participants in the latter three years of the project. Aim 3 will provide inputs and participate in the Consortium-wide activities such as serving on committees, discussing protocols, attending and presenting in the annual conferences, participating in multi-site data processing and validation, and sharing data and biospecimens with researchers within and outside the Consortium. In Aim 4 we will lead multi-site clinical validation of cerebrovascular reactivity (CVR) biomarker if CVR is selected to move on to the next phase. Impact: Upon the completion of this project, we will have developed a set of VCID biomarkers that are ready for future clinical trials, including large phase III trials, of VCID.