John M. Ringman, M.D., M.S. - US grants

DESCRIPTION (provided by applicant): As interventions that affect the course of Alzheimer's disease (AD) become available, it will be more important to diagnose AD at its earliest stages. The goal of this project is to identify, using functional magnetic resonance imaging (fMRI), changes in cerebral physiology occurring in the pre-symptomatic phase of AD by studying persons with Presenilin-1 (PS1) mutations giving rise to autosomal dominant AD. As a career development award another goal is to train the principal investigator in the design, implementation, and interpretation of fMRI experiments. The specific aims are: 1) To establish if there are changes in the pattern of cerebral activity associated with episodic memory detectable on fMRI prior to overt decline in cognitive function in persons destined to develop PSI-related AD, 2) To establish if there are changes on fMRI in the pattern of cerebral activity associated with a test of executive function in this population, and 3) To determine if these changes occur as early as young adulthood. We will compare blood oxygen level dependent fMRI measures between 24 PS1 mutation carriers and 24 non-carriers during performance of two memory tasks and a test of executive function. The subjects will be pre-symptomatic at-risk members of 6 Mexican families with PS1 mutations determinant for early-onset AD. Subjects will undergo genetic testing, 3 hours of cognitive testing, and fMRI scanning over two days. The memory tasks will consist of: 1) a auditory paired-associate word memory test, and a 2) a semantic encoding task followed by a recognition test. A test of executive function will also be given in which subjects repress a natural button-press response on some trials. Analyses will include both within-subjects comparisons of regions of interest and group-averaged statistical parametric mapping comparisons. FMRI measures will also be compared between PS1 mutation carriers and non-carriers in young and older age groups. The lead researcher has fellowship training in dementia and seeks to become independent in cognitive research, including functional neuroimaging modalities such as fMRI. This award will allow time for the research and necessary classes in functional imaging, statistics, and cognitive science. UCI, with its strong dementia research program, growing MRI capabilities and opportunity to collaborate at the nearby UCLA Brain Imaging Center, is an excellent environment for this endeavor.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This is a safety and tolerability study investigating the effects of two different doses of curcumin C3 complex[unreadable]vs. placebo taken daily over a period of 6 months in subjects with mild-moderate Alzheimer's disease (AD). The study will also look at the effects of these doses of curcumin C3 complex[unreadable] vs. placebo on a number of biological endpoints.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Specific Aims: 1. To determine if pre-clinical PS1 mutation carriers will perform significantly worse than their non-mutation carrying kin on neuropsychological tests measuring episodic memory and executive function as they approach the age of disease onset. 2. To determine if pre-clinical PS1 mutation carriers will have a higher prevalence of depression and higher levels of depressive symptoms than their non-mutation carrying kin despite being unaware of their genetic status. 3. To determine if biomarkers of AD pathogenesis such as CSF Ab oligomers will be found to be elevated in pre-clinical PS1 mutation carriers.

Affect; Amyloid; Amyloid Plaques; Amyloid Substance; Biologic Marker; Biological Markers; Blood - brain barrier anatomy; Blood-Brain Barrier; Brain; CRISP; Cholest-5-en-3-ol (3beta)-; Cholesterol; Cholesterol, Dietary; Clinical Trials; Clinical Trials, Unspecified; Cognitive; Computer Retrieval of Information on Scientific Projects Database; Data; Deposit; Deposition; Diet; Dietary Cholesterol; Encephalon; Encephalons; Funding; Grant; Hemato-Encephalic Barrier; Institution; Intervention; Intervention Strategies; Investigators; Lead; Link; Mammals, Mice; Mice; Molecular Marker; Murine; Mus; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nervous System, Brain; Neuritic Plaques; Pb element; Process; Production; Research; Research Personnel; Research Resources; Researchers; Resources; Risk Factors; Safety; Senile Plaques; Signature Molecule; Source; United States National Institutes of Health; amyloid beta plaque; amyloid-b plaque; biomarker; clinical investigation; cognitive function; cored plaque; diffuse plaque; heavy metal Pb; heavy metal lead; interventional strategy; neuropathology

The Clinical Core of the UCLA ADRC is a critical vehicle for implementing the Center's theme of the Therapeutic Imperative, augmenting UCLA's ability to perform cutting edge research into identifying the causes of, and improving our ability to diagnose and treat Alzheimer's disease and other dementias. The Clinical Core serves as a link between populations at risk for various forms of dementia and research. Specific aims of the Core are to 1) characterize persons with MCI, AD, non-AD dementias and controls, 2) characterize familial and presymptomatic Familial AD 3) retain and follow subjects longitudinally, 4) increase minority representation in dementia research, 5) provide reliable and valid data to the DMSC and to the NACC, 6), support other ADRC cores and projects, and 7) support other dementia research projects outside of the ADRC. In this proposal, we extend our abilities to achieve these goals through several new initiatives. We anticipate increasing our overall capacity to assess patients and enroll them into the NACC database with a goal of performing 130 new UDS assessments and 180 follow-up visits per year by the end of the funding period. We are making the characterization of biomarkers of AD a priority with innovative imaging studies and the acquisition of plasma, DNA, and CSF on all consenting subjects for banking for collaborative studies. We are expanding our abilities to characterize the nature, causes and ways of assessing cognitive impairment in the Hispanic elderly by increasing our presence at the Olive View Medical Center that serves a largely Hispanic population. New, highly sensitive cognitive assessment tools are being studied in the Neuropsychology Laboratory. By performing pioneering, comprehensive assessments of persons with or at-risk for FAD, we extend our understanding of AD into the presymptomatic period Persons in the FAD cohort being studied at UCLA are largely of Mexican origin, providing an opportunity to assess the utility of cognitive measures in the diagnosis of AD in this population. We have initiated new operating procedures that include safeguards insuring that appropriate informed consent is obtained prior to data entry.

DESCRIPTION (provided by applicant): The UCLA Alzheimer's Disease Research Center (ADRC) supports cutting edge research in an environment that mentors junior investigators;attracts numerous researchers;hosts a pilot project program that allows investigators to gamer preliminary data for more advanced studies;collaborates with the National Alzheimer's Coordination Center (NACC) as well as other Alzheimer disease (AD) related investigators locally, nationally and internationally;extends AD research to women and minorities;and works closely with community and advocacy groups including the Alzheimer's Association. The UCLA ADRC is comprised of 6 cores and proposes 3 projects in this renewal application. Cores include: Administrative, Clinical, Data Management and Statistics, Neuropathology, Recruitment and Education, and Neuroimaging and Biomarkers. The three projects include an investigation of MRI techniques applicable to clinical trials and population studies (Project 1;Liana Apostolova;Junior Investigator), a study of the comparative information to be gained from FDDNP and Pittsburg Compound B molecular imaging and their relationship to CSF and plasma biomarkers (Project 2;Gary Small);and a study of antibodies that inhibit amyloid 6 and tau aggregation and may represent novel interventions in AD (Project 3;David Eisenberg). The Theme of the UCLA ADRC is The Therapeutic Imperative, emphasizing the urgency of developing new treatments for AD. Resource use, core organization, project selection, collaboration, and educational activities are prioritized according to their integration with the Center theme. Clinical Core is following 120 patients;Recruitment and Education Core sponsored lectures reaching 20,000 participants;Neuropathology Core performed autopsies on Center patients who died, and non-Center patients to augment tissue distribution. This application has a major emphasis on biomarkers as a key aspect of advancing new therapies for AD. A familial AD cohort is included in this renewal application and a new minority site (Harbor View Medical Center) has been added. Innovations in advancing research are proposed in each Core of this proposal. Each core has responded to criticisms and recommendations from the 2008 review in this renewal application.

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a growing health problem worldwide and currently available treatments are of limited efficacy. Prevention of AD may be a more relevant goal, particularly in lower and middle-income countries. Studies of AD prevention however, are challenging, in part because of the unpredictable onset of the disease in elderly individuals. Persons inheriting mutations causing fully-penetrant autosomal dominant familial AD (FAD) provide an informative and motivated population for assessing the efficacy of AD prevention strategies. The PI has been working with clinician investigators in Mexico for 10 years, characterizing multiple families with FAD due to PSEN1 or APP mutations. Multi-center collaborative efforts to perform prevention trials in preclinical persons carrying FAD mutations are underway (the Dominantly Inherited Alzheimer Network in which the PI is a site investigator and the Alzheimer Prevention Initiative) but such efforts have not reached Mexico. The capacity to perform FAD prevention trials in Mexico may be limited due to lack of understanding among families and physicians of the disease and its genetic nature as well as by the availability of infrastructure including personnel appropriately trained to perform such studies. The goal of this project is to enhance the ability of Mexican investigators to perform such studies through the following specific aims: Aim 1) Enhance local capacity to perform quality cognitive, clinical, imaging, and biochemical assessments as outcome measures for prevention trials in Mexico. This project will be the planning stage in which the possibility of exchange programs wherein health professionals from Mexico come to the UCLA to receive specialty training in dementia diagnosis, management, and research will be explored. Aim 2) Investigate attitudes towards and promote education regarding AD, genetics, FAD, and prevention trial procedures among members of families with FAD in Mexico. Aim 3) Establish a registry of persons eligible for participation in prevention trials for FAD.

? DESCRIPTION (provided by applicant): It is now clear that Alzheimer's disease is not a unitary phenomenon and that it can be divided into subtypes by their genetic origins, each of which may have distinct pathogenetic cascades and therefore may respond differentially to treatments. The Human Connectome Project (HCP) protocol provides the unique opportunity to comprehensively characterize imaging and clinical phenotypes of these AD subtypes. By applying the HCP protocol to persons at-risk for fully-penetrant autosomal dominant AD (ADAD due to either the A431E PSEN1 or V717I APP mutations) in conjunction with positron emission tomography (PET) imaging of tau using the novel ligand 18F-T807, we will be able to test the hypothesis that tau pathology spreads in a trans-synaptic manner along definable neural pathways. Applying the HCP protocol to this unique population will provide the opportunity to test the hypothesis of transynaptic spread of tau in the etiology of AD and provide the opportunity to differentiate pathological processes in subtypes of AD and therefore inform approaches to treatment. As PSEN1-related AD can present with spastic paraparesis, an easily assessed phenotype, we will be able to relate the neurophysiological parameters of central nervous system conduction time to connectivity measures in the HCP, helping to understand this characteristic and also validating HCP measures. We propose the following specific aims: 1) Perform network analyses relating the sequence of cortical deposition of neurofibrillary tangles measured using tau PET to white matter pathways and clinical status. 2) Identify connectomic (structural, functional, and connectional) and cerebral perfusion (ASL) MRI differences during neurodegeneration due to autosomal dominant AD mutations (ADAD due to specific mutations in the PSEN1 and APP genes) potentially revealing diverse pathological phenotypes. 3) Identify connectomic and cerebral perfusion MRI differences between AD of early (due to PSEN1 and APP mutations) and late onset (LOAD, associated or not with the APOE e4 allele). 4) Identify the connectomic bases for changes in central conduction times in motor pathways in ADAD and LOAD using TMS. This study will leverage the relatedness among persons with the A431E PSEN1 and V717I APP mutations to estimate mutation-associated variability in the connectome MRI. It will also provide the opportunity to explore variability of te connectome associated with Mexican Mestizo origin, a population typically under-represented in Alzheimer's and other neuroscientific research. Finally, by adopting the HCP phenotyping protocol into Spanish and applying it in this population, we will create a database to enable additional future studies in Latinos, a growing segment of the U.S. population.

Project Summary/Abstract While Alzheimer's disease (AD) is the most common cause of dementia, the contribution of vascular factors to cognitive impairment and dementia is becoming increasingly recognized. Vascular cognitive impairment and dementia (VCID) is most commonly caused by cerebral small vessel disease (SVD). To date, cerebral small vessels including arterioles, capillaries and venules are inaccessible to existing imaging technologies. Characteristic parenchymal lesions on MRI, such as lacunar infarcts, white matter lesions, and microbleeds, have been adopted as markers of SVD. However, these parenchymal lesions are the consequences of SVD rather than the surrogate markers of microvascular changes, and are unsuitable for early interventions to change the course of VCID. During the past few years, our group has spearheaded the development of a suite of cutting edge MRI technologies for in vivo and noninvasive assessment of microvascular structure and function, including (1) high-resolution black blood MRI for direct imaging of perforating arteries; (2) arterial spin labeling (ASL) techniques for mapping microvascular perfusion, arterial stiffness or vascular compliance (VC) of small arteries/arterioles, and water exchange rate across the blood-brain barrier (BBB). Furthermore, we recently developed quantitative metrics for retinal capillary density and morphology using an FDA approved optical coherence tomography angiography (OCTA) platform. This method allows clinically feasible, in vivo and completely noninvasive imaging of retinal arterioles and capillaries with a spatial resolution of ~10 microns. Capitalizing on our extensive technical expertise and longstanding track record of clinical studies on VCID, we propose this UH2/UH3 project to further develop and evaluate a suite of MRI and OCTA markers for assessing the structure and function of cerebral and retinal microvasculature, in a cohort of Latino subjects enrolled in the Los Angeles Latino Eye Study (LALES) and in the study of autosomal dominant AD in persons of Mexican origin (Estudio de Enfermedad de Alzheimer en Jalisciences, or EEAJ). During the UH2 phase, we will further develop and evaluate the proposed MRI and OCTA imaging markers of SVD, establish their test-retest repeatability and clinical utility. We will work with the other participating sites and with the Coordinating Center to establish collaborative parameters and agreements of the consortium. During the UH3 phase, we will contribute to and execute cross-site research studies as designed by the consortium. We will perform unified and comprehensive clinical, cognitive, imaging, genetic and biochemical assessments on the cohort of LALES and EEAJ participants locally and perform data analyses as required by the consortium. At the closing of this project, we expect to develop the suite of microvascular imaging markers to readiness to enter into large-scale multi-site clinical validation studies toward FDA qualification for phase II and phase III clinical trials on small vessel disease to prevent and treat VCID.

Title: Motor, Visual, and Olfactory Changes in Genetic Subtypes of Alzheimer's Disease Though changes in cognition are the most salient features of Alzheimer's disease (AD), subtle changes in sensation and motor function occur early in the course of AD and might serve as biomarkers and provide clues as to the cascade of events leading to progressive disability. We will perform baseline (n = 135) and 3-year f/u evaluations (n = 60) in an ongoing study using the Human Connectome Project (HCP) protocol of persons of Mexican descent with and at-risk for autosomal dominant (ADAD) and late-onset AD (LOAD) in order to achieve the following specific aims: Specific Aim 1a) To define the underlying cause and mechanisms of gait abnormalities in ADAD and LOAD, we will characterize motor and gait function using the NIH toolbox, the HCP imaging protocol, and tau PET imaging with flortaucipir. Specific Aim 1b) To characterize the onset and course of cortical hyperexcitability in ADAD and LOAD using single-pulse TMS. Specific Aim 2a) To characterize clinically relevant visual deficits in persons with and at-risk for ADAD and LOAD using standardized functional measures including logMAR based visual acuity, contrast sensitivity, as well as low and high contrast reading speed. Specific Aim 2b) To define the underlying etiology of visual deficits by performing high-resolution, in- vivo imaging of central and peripheral visual pathway structures including retinal nerve fiber layer (RNFL), retinal capillary density, volume of optic nerve/chiasm and the lateral geniculate nucleus (LGN) and connectivity using the HCP. Specific Aim 3) To characterize deficits in olfaction occurring in persons with and at-risk for ADAD and LOAD, we will assess olfaction using the University of Pennsylvania Smell Identification Test (UPSIT) and relate this to tau pathology and connectivity in the olfactory system measured using the HCP. Comprehensive characterization of motor and sensory changes in ADAD and LOAD could identify biomarkers for diagnosis, prognosis, and therapeutics targets in the management of the disease. 1

The study of persons with or at-risk for genetically-determined autosomal dominant Alzheimer?s disease (ADAD) due to mutations in the PSEN and APP genes has made tremendous contributions to our understanding of AD in general. As the future development of AD in persons inheriting ADAD mutations can be reliably predicted, one can define the disease phenotype and changes occurring during the presymptomatic phase of the disease with great sensitivity, enabling the evaluation of other factors influencing disease course (e.g. modifying genes, effects of putative disease-modifying interventions). Such research is facilitated by the identification of large families sharing the same genetic predisposition, an approach that has been best implemented in an extended family in Colombia with a common mutation in PSEN1 (E280A). A similar founder effect for a distinct mutation in PSEN1 (A431E) and another large family with a different ADAD-causing mutation in APP (V717I) has been identified in the State of Jalisco in Mexico but to date these families have been understudied. The goal of the current application is to facilitate the performance of clinical studies of this population by investigators in Jalisco. This will be achieved through the following specific aims: Specific Aim #1) To characterize and follow persons with and at-risk for ADAD in Jalisco by harmonizing measures between the Centro de Investigación Biomédica de Occidente Genetics clinic in Guadalajara, the University of Guadalajara Polyclinic in Tepatitlan, and the USC Alzheimer?s Disease Research Center. By providing gene-sequencing technology and training, we will also enable the genetic characterization of this population. Specific Aim #2) To perform studies to identify genes that affect the age of disease onset and the presence of leg stiffness in ADAD. Specific Aim #3) To improve the ability of clinicians and researchers in Jalisco to deliver presymptomatic genetic counseling for persons at-risk for ADAD, thus optimizing autonomy with regards to research participation. This project will improve our understanding of the pathophysiology of ADAD and lay the groundwork for future studies of this informative population in Mexico.

PROJECT SUMMARY/ABSTRACT The MarkVCID consortium was established in 2016 to pursue the initial stages of multi-site validation of 7 imaging-based and 4 fluid-based candidate biomarkers for small vessel vascular contributions to cognitive impairment and dementia (VCID). As one of the 7 participating sites, our team at the University of Southern California (USC) has analyzed and optimized candidate VCID biomarkers during the UH2 phase (years 1-2) and participated in the consortium-wide program of biomarker scaling-up, multi-site protocol implementation, and initial multi-site validation during the UH3 phase (years 3-5). USC has led the consortium-wide development and implementation of the optical coherence tomography angiography (OCTA) biomarker kit which is based on an FDA-approved device that allows in vivo and completely noninvasive imaging of retinal capillaries with a spatial resolution of ~10 microns. We have also participated in the validation of the other 6 MRI based candidate biomarkers while contributing blood samples for the validation of the 3 plasma-based candidate biomarkers. The primary objective of the next 5 years is to carry out comprehensive multi-site clinical validation of candidate VCID biomarkers in longitudinal studies of diverse populations that are typical in clinical settings in the US. Capitalizing on the high racial diversity in Los Angeles, we plan to enroll a multiethnic longitudinal cohort of at least 200 subjects that are enriched for small vessel VCID, including 100 Latinx subjects from the Los Angeles Latino Eye Study (LALES), 50 African Americans (AAs) enrolled in the African American Eye Disease Study (AFEDS), and 50 Caucasian participants from the Clinical Core of the USC ADRC. We have performed pilot studies in both Latinx and AA subjects (the two largest minority groups in the US) using MarkVCID protocols to show the feasibility of conducting such studies in a multiethnic cohort. We have also built a multiethnic team of investigators, technical staff, research coordinators, and community outreach staff to streamline enrollment, achieve the recruitment milestones, and perform longitudinal follow-up studies. Our team includes established expertise, equipment and infrastructure for OCTA, MRI, fluid biomarker and clinical/cognitive evaluation of VCID, as well as a proven track record in the sharing of de-identified clinical data through the Laboratory of Neuro Imaging (LONI) for the second phase of MarkVCID project.