Mark W. Bondi - US grants

The proposed studies will retrospectively examine the role of familial risk in the neuropsychological abilities of elderly individuals with a positive family history for progressive dementia (FHPD+). The FHPD+ subjects will be recruited from the existing cohort of nondemented elderly subjects from the National Alzheimer's Disease Research Center (ADRC) of the University of California, San Diego (UCSD), School of Medicine, Retrospective analyses of neuropsychological abilities will be performed on behavioral data gathered from these individuals. FHPD+ subjects will be identified by medical/family history interviews obtained by the ADRC, and will be group-matched and compared to nondemented elderly from the ADRC who have not identified a family history for dementia (FH). Furthermore, an additional cohort of normal elderly individuals will be recruited from the community for prospective analyses. These subjects will be identified as first-degree relatives of autopsy-confirmed AD patients who have been examined by the Neuropathology Core of the ADRC (i.e., subjects with a positive family history for "definite" Alzheimer's disease; FHAD+). These FHAD+ subjects will be recruited in an effort to employ more rigorous methods in identifying familial risk. Along with tests selected from the neuropsychological battery normally given to ADRC subjects, a novel battery of clinical and experimental neuropsychologic tests of sustained and divided attention, as well as tests designed to quantify strategy use in problem-solving and memory, and will be administered. The proposed studies will extend our knowledge of the neuropsychologic characteristics of very early DAT, and help to determine whether preclinical cognitive markers exist in certain genetically susceptible individuals at risk for the development of Alzheimer's disease.

DESCRIPTION: (provided by applicant) Alzheimer' s disease (AD) represents one of the most important and challenging public health concerns that will affect this country in the coming decades, since it most severely affects the fastest growing segment of our population: individuals age 85 and older. The ability to identify nondemented older adults who are in a preclinical phase of AD will have far-reaching implications for both improved early diagnosis and use of anti-dementia pharmacologic therapies. Such drugs treatments aimed at slowing the progression of AD ('neuroprotection') will be most effective if applied at the earliest stages of AD before significant neuronal losses have occurred, which provides an important rationale for making accurate preclinical diagnoses of AD. However, one of the remaining obstacles to such efforts centers on the difficulty in accurately identifying individuals with incipient AD before their deficits become clinically apparent (i.e., prior to both cognitive and functional decline). We propose to recruit and follow a group of nondemented older adults at high risk for AD in an effort to better detect and characterize its preclinical stage. Individuals age 85 and older (oldest-old), and individuals with the E4 allele of the apolipoprotein E gene (ApoE), both have significantly elevated risks of developing AD. However, advanced age or ApoF E4 genotype alone are insufficient in determining who will develop AD. We propose to conduct a five-year longitudinal study of the oldest-old in which the combination of neuropsychologic, neuroimaging, and genetic assessments will be examined, relative to the young-old (ages 65-75), in an effort to identify the most salient preclinical markers of AD. Because the underlying neuropathologic changes in AD may differ between the young-old and the oldest-old, a secondary goal will be to determine the unique patterns and contributions of these multi-modal assessments to the diagnosis of AD in the oldest-old. The proposed study will (a) examine the utility of neuropsychologic, magnetic resonance (MR) morphometric, and genetic susceptibility markers in order to determine the pattern of impaired brain structures and processes associated with the preclinical phase of AD in the oldest-old; and (b) conduct exploratory analyses to determine whether our neuropsychologic measures are associated with early structural abnormalities (as detected by MR imaging and neuropathologic indices) in at-risk individuals. Improving our ability to detect AD preclinically will be of critical importance for the oldest-old, who are the fastest growing high-risk population. Furthermore, an improved understanding of the brain mechanisms associated with the earliest cognitive changes in at-risk groups will advance our ability to target those who stand to benefit most from early pharmacologic intervention.

Alzheimer's disease (AD) represents one of the most important and challenging public health concerns that will affect this country in the coming decades. The ability to identify older adults who are in a preclinical phase of AD will have far-reaching implications for both improved early diagnosis and use of cognitive enhancing pharmacologic therapies. Such treatments aimed at slowing progression ("neuroprotection") will be most effective if applied at the earliest stages before significant neuronal losses have occurred. However, one of the remaining obstacles to such efforts centers on the difficulty in accurately identifying individuals with incipient AD before their deficits are clinically apparent (i.e., prior to both cognitive and functional decline). We propose to recruit and follow a group of nondemented older adults at high risk for AD in an effort to better detect and characterize its preclinical stage. Individuals with mild cognitive impairment (MCI), and individuals with the epsilon-4 allele of the apolipoprotein E gene (APOE epsilon4), both have significantly elevated risks of developing AD. However, MCI and APOE epsilon4 genotype alone are insufficient in determining who will develop AD. We propose to conduct a five-year longitudinal study of MCI- and APOE-related risk in which the combination of initial cross-sectional functional magnetic resonance imaging (fMRI) and genetic assessments will be combined with longitudinal clinical and neuropsychologic outcomes in an effort to identify the most salient predictors of AD. Based on our preliminary studies, we expect that at-risk older adults will exhibit a greater degree of compensatory brain activity during episodic memory encoding than will low-risk normal older adults, and the degree of compensatory activity will be predictive of conversion to AD. In a 2 (MCI vs. normal control [NC]) x 2 (APOE epsilon4 vs. non-epsilon4) design, we will examine blood oxygen level dependent (BOLD) brain activation associated with verbal episodic learning and recall in a variety of brain regions (e.g., medial temporal, frontal, parietal, posterior cingulate). Specifically, the proposed study will (a) examine the relationship between MCI, APOE genotype, and brain signal intensities during episodic memory encoding in the four groups (i.e., MCI/epsilon4; MCI/non-epsilon4; NC/epsilon4; NC/non-epsilon4); (b) determine whether a differential BOLD response in APOE epsilon4 persons--if present--represents a predictor of AD, or is it present across the life span and therefore a normal phenotypic variant independent of underlying AD pathogenesis? This latter aim will be explored by the examination of a cross-sectional young adult sample of APOE epsilon4 and non-epsilon4 persons for comparison of BOLD response patterns to the older adults; and (c) examine for interactions between episodic encoding-related brain activity and other important clinical (e.g., rate of episodic memory decline; conversion to AD), neuropsychologic (e.g., clinical memory measures), and imaging indices (e.g., structural MRI-based medial temporal lobe volumes; arterial spin labeling indices of blood perfusion).

Alzheimer's disease (AD) represents one of the most important and challenging public health concerns that will affect this country in the coming decades. The ability to identify older adults who are in a preclinical phase of AD will have far-reaching implications for both improved early diagnosis and use of cognitive enhancing pharmacologic therapies. Such treatments aimed at slowing progression ("neuroprotection") will be most effective if applied at the earliest stages before significant neuronal losses have occurred. However, one of the remaining obstacles to such efforts centers on the difficulty in accurately identifying individuals with incipient AD before their deficits are clinically apparent (i.e., prior to both cognitive and functional decline). We propose to recruit and follow a group of nondemented older adults at high risk for AD in an effort to better detect and characterize its preclinical stage. Individuals with mild cognitive impairment (MCI), and individuals with the epsilon-4 allele of the apolipoprotein E gene (APOE epsilon4), both have significantly elevated risks of developing AD. However, MCI and APOE epsilon4 genotype alone are insufficient in determining who will develop AD. We propose to conduct a five-year longitudinal study of MCI- and APOE-related risk in which the combination of initial cross-sectional functional magnetic resonance imaging (fMRI) and genetic assessments will be combined with longitudinal clinical and neuropsychologic outcomes in an effort to identify the most salient predictors of AD. Based on our preliminary studies, we expect that at-risk older adults will exhibit a greater degree of compensatory brain activity during episodic memory encoding than will low-risk normal older adults, and the degree of compensatory activity will be predictive of conversion to AD. In a 2 (MCI vs. normal control [NC]) x 2 (APOE epsilon4 vs. non-epsilon4) design, we will examine blood oxygen level dependent (BOLD) brain activation associated with verbal episodic learning and recall in a variety of brain regions (e.g., medial temporal, frontal, parietal, posterior cingulate). Specifically, the proposed study will (a) examine the relationship between MCI, APOE genotype, and brain signal intensities during episodic memory encoding in the four groups (i.e., MCI/epsilon4; MCI/non-epsilon4; NC/epsilon4; NC/non-epsilon4); (b) determine whether a differential BOLD response in APOE epsilon4 persons--if present--represents a predictor of AD, or is it present across the life span and therefore a normal phenotypic variant independent of underlying AD pathogenesis? This latter aim will be explored by the examination of a cross-sectional young adult sample of APOE epsilon4 and non-epsilon4 persons for comparison of BOLD response patterns to the older adults; and (c) examine for interactions between episodic encoding-related brain activity and other important clinical (e.g., rate of episodic memory decline; conversion to AD), neuropsychologic (e.g., clinical memory measures), and imaging indices (e.g., structural MRI-based medial temporal lobe volumes; arterial spin labeling indices of blood perfusion).

DESCRIPTION (provided by applicant): This proposal requests continued NIA funding for the Midcareer Investigator Award in Patient-Oriented Research (K24) to Mark W. Bondi, PhD. During the first 5 years of support provided by the K24 award, Dr. Bondi has upgraded his own skill set as a research mentor by completing focused training with arterial spin labeling (ASL) and diffusion tensor imaging (DTI) MRI techniques and implementing them in his research lab with his trainees. During this period, he has obtained four patient-oriented research grants (R01, R43, and R44 grants from the NIA and an Investigator-Initiated Research Grant from the Alzheimer's Association). He has also served as primary mentor or co-mentor to 12 clinician-scientists in training. Eight of these trainees have gone on to receive either mentored or independent research support, or both, from NIH (4 NRSA; 1 SC3), the Dept of Veterans Affairs (4 VA Career Development Awards), the Dept of Defense (2 Investigator-Initiated Grants), and private foundations (3 New Investigator Research Grants from the Alzheimer's Association; 1 New Investigator Grant from AFAR). Furthermore, all of the mentees have published one or more first- authored peer-reviewed research papers reporting their work (40 unique mentee publications since 2007), and eight trainees from his lab now work in full-time academic patient-oriented faculty or research positions. The need for training and support of nascent patient-oriented researchers is both acute and profound. UCSD and the VASDHS are fortunate to have several formal training programs (including departmental T32 training grants and VA post-doctoral fellowship programs) to support the structured didactic training of clinician- scientists. Each of these programs requires the availability of skilled mentors. The K24 award permits Dr. Bondi, an established and productive clinician scientist whose integrative work in neuropsychology and neuroimaging has helped to shape our understanding of the prodromal period of Alzheimer's disease (AD), to devote substantial time to mentoring new patient-oriented researchers. It also provides him with time to enhance his own research skills in order to mentor new clinical investigators and to conduct meritorious patient-oriented research. This proposed one-time opportunity for 5 years of continued support will focus on facilitating the convergence of his research group's expertise in neuropsychology and neuroimaging studies with their growing skill and interest in the utilization of biomarkers in support of characterizing the prodromal period of dementia. With the help of several identified 'resource' experts in advanced neuroimaging and CSF biomarker techniques, Dr. Bondi proposes to enrich and deepen his research expertise in these areas with the dual aims of (1) maintaining his group's efforts at the vanguard of early detection research, and (2) simultaneously transmitting these skills to the clinician scientists he mentors in an effort to advance their own careers in patient-oriented research in early detection, diagnosis and clinical outcomes in dementia.

? DESCRIPTION (provided by applicant): In Response to PA-13-168 (Secondary Analyses of Existing Data Sets and Stored Biospecimens To Address Clinical Aging Research Questions (R01)). Despite increasing sophistication in the application of biomarkers to the study of mild forms of cognitive impairment (MCI), sophistication in profiling cognition has not been commensurate. Criteria for MCI diagnosis in many large-scale studies rely on a single cognitive test score, screening measures, rating scales and clinical judgment, resulting in coarse characterizations of the types or severity of MCI being studied despite the availability of rich neuropsychological data from such studies. We propose to apply our novel actuarial neuropsychological and statistical methods to more accurately diagnose MCI and predict its progression. Applying these methods to large-scale existing open source (ADCS donepezil trial, ADNI, NACC/UDS) and institutional (FHS, MCSA, WHICAP) datasets will uncover stronger relationships between biomarkers, cognition, pathology, and progression rates, and will result in stronger treatment effects in clinical trials aimed at MCI. Our methods will improve effect sizes that inform power analyses for clinical trials and reduce the number of patients needed for such trials. Finally, our methods will be implemented to improve the NIA-AA operational definition of 'subtle cognitive decline' in Preclinical AD. These improvements will have important impacts on prospective design of future biomarker and clinical trial studies. Specific aims: Aim 1. Actuarial neuropsychological criteria for MCI diagnosis will better specify cognitive phenotypes as well as identify possible diagnostic errors from conventional criteria; removal of the resultant false positive (i.e., cognitively normal via neuropsychological criteria) cases and addition of false negative (i.e., `missed') cases will strengthen biomarker and trial findings from several large-scale studies. Aim 2. Empirically derived MCI diagnostic criteria will result in more efficient tril and study designs (i.e., studies that need fewer subjects) compared to conventional MCI criteria. Aim 3. An operational definition of subtle cognitive decline based on extensions of the above neuropsychological MCI criteria will improve characterization of NIA-AA criteria for Preclinical AD. Aim 4. In exploratory analyses, we will use novel computational tools to harmonize and combine 1) cognitive and 2) multi-marker profiles predictive of progression/pathology across multiple datasets. Demonstrations of improvement in diagnostic precision in MCI and Preclinical AD will have an important impact on prospective design of future studies of genetics, biomarkers, treatments and ultimately prevention. If successful, we will be able to more clearly model effects of biomarkers changes and neurodegeneration, together with factors such as age and comorbidities, on specific profiles and trajectories of cognitive decline.

The original theory offered by Braak & Braak (1991)?that neurofibrillary tangle pathology proceeds along well-­ defined predilection sites beginning in the medial temporal cortex?has been modified by the same author to  suggest  that  the  pathologic  process  instead  commences  in  the  lower  brainstem  (Braak  et  al  2011).    The  first  visible pathologic changes are now thought to occur in the locus coeruleus (LC) and then spread via its axonal  projections  to  transentorhinal/entorhinal  cortex  (TEC).    We  propose  to  study  LC  change  using  a  novel  computational  morphology  method,  combined  with  novel  methods  of  measuring  white  matter  microstructural  tractography  and  functional  connectivity  to  TEC.    These  new  methods  are  designed  to  overcome  major  shortcomings in current neuro-­MRI analysis methods that limit the ability to detect subtle structural and functional  changes associated with early AD.  Such alterations across the aging-­MCI-­AD continuum, as well as in those  cognitively normal individuals with risk factors for AD (e.g., CSF AD biomarkers;? apolipoprotein E e?4 carriers),  would  provide  significant  advances  in  our  understanding  of  the  pathogenesis  of  AD  across  clinical  transition  points and perhaps during this ?silent? period (i.e., prior to the occurrence of traditional AD biomarker positivities).   Using our newly developed diagnostic and MRI metrics, we propose to quantify variations in LC morphology and  its projections to TEC (which we term the LC-­TEC system).  Aim  1.  Examine  locus  coeruleus  morphology,  contrast,  and  associated  cortical  thickness.    Morphological  variations will be characterized by spherical wave decomposition (SWD) of high-­resolution anatomical MRI data  supplemented by recent contrast ratio (Takahashi et al. 2015) analyses of T1 Fast Spin Echo MRI scans.    Aim 2. Examine structural connectivity of the LC-­TEC system.  Neural connectivity will be characterized by our  novel diffusion tensor imaging (DTI) tractography method (geometric-­optic based entropy spectrum pathways,  GO-­ESP DTI) to quantify afferent and efferent pathways between the LC and TEC, and efferent projections from  the LC to cerebellum and cortex.    Aim 3.  Examine functional connectivity of the LC-­TEC system. Resting state functional modes and connectivity  will be derived from our novel entropy field decomposition (EFD) analysis of rsFMRI data guided by the prediction  that AD tauopathy in its earliest phases is not determined by large losses of neurons but by enormous numbers  of  nerve  cells  that  survive  with  limited  functionality  (Braak  &  Del  Tredici  2015);?  alterations  in  functional  connectivity of the LC-­TEC system will serve as a surrogate marker of this limited functionality.    Demonstrations  of  improvement  in  diagnostic  and  imaging  precision  in  Preclinical  AD  will  have  an  important  impact on prospective design of future studies and, if successful, produce new biomarker assessment modalities  and fundamental shifts in our therapeutic targets for AD. 

Project Summary/Abstract Dementia represents one of the most important public health concerns to affect us in the coming decades. Among the most important research goals will be to identify the earliest, most reliable and easily obtainable markers of degeneration, because early identification of individuals most likely to decline now represents the most promising window for therapeutic interventions. We propose to examine pupillary responses as a novel early biomarker of Alzheimer's disease (AD) pathogenesis and staging. Unlike neuroimaging and cerebrospinal fluid (CSF) biomarkers, pupillary responses can be measured in as little as 5 minutes using a minimally-invasive, inexpensive, simple handheld device that could potentially enjoy widespread utility for screening in the context of a typical doctor's office visit. Pupil dilation recorded during simple cognitive tasks (e.g., digit span) provides a biomarker of the extent of cognitive effort or resource allocation required to achieve a given test score. Pupillary responses may be more sensitive to cognitive decline, because clinically meaningful declines in test scores become manifest only when the capacity to compensate is exceeded. If one person requires more effort to achieve the same score as another, that person is likely to be closer to maximum compensatory capacity and, therefore, is at higher risk for decline. Equally important, pupillary responses reflect locus coeruleus (LC) functioning, and postmortem studies implicate the LC as an early site of AD pathogenesis and degenerative changes with disease progression. Thus, pupillary responses may serve as a specific biomarker of functional alterations in a brain system affected by the earliest manifestations of AD. The proposed study will evaluate a model of LC system alterations across the aging-mild cognitive impairment (MCI)-AD continuum using (1) an innovative pupillometric evaluation of the functional integrity of the LC system, (2) examination of the structural integrity of the LC using recently-developed novel MRI methods, (3) a panel of CSF AD biomarkers (A?, P-tau, and total tau) anchoring participants to the existing pathophysiology involved in AD progression, and (4) innovative diagnostic and staging approaches to characterize the timeline of changes across the aging-MCI-AD continuum. Specifically, we propose to record pupillary responses during cognitive tasks, collect gold-standard CSF biomarkers of AD, and use an innovative MRI methodology to visualize neuromelanin-containing LC nuclei in 128 cognitively-normal (CN) individuals, 64 participants with amnestic MCI (aMCI), and 20 with AD. The specific aims are to determine whether pupillary responses are associated with early risk and staging of AD and whether pupillary responses are associated with LC neuronal degeneration on MRI across the aging-MCI-AD continuum. We predict that the relationship between pupillary responses and risk and progression of AD will be curvilinear following an inverted-U function, such that preclinical individuals at greater risk for AD and aMCI individuals will show compensatory effort (greater pupil dilation), but with advancing disease and greater LC dysfunction, compensatory capacity will be overloaded, resulting in decline in pupil dilation in AD.

RESEARCH EDUCATION COMPONENT SUMMARY/ ABSTRACT The overarching goal of the Research Education Component (REC) of the Shiley-Marcos Alzheimer?s Disease Research Center (ADRC) at UC San Diego is to support the research education and mentoring of outstanding junior-level scientists (defined as advanced postdoctoral fellows and assistant professors) to advance our understanding of the complex and heterogenous nature of Alzheimer?s disease and related dementias (ADRD). To realize this goal the Shiley-Marcos ADRC REC (1) has developed a detailed recruitment plan to recruit a diverse cadre of outstanding trainees to the program each year, (2) will provide a solid foundational platform to prepare this diverse research workforce with transdisciplinary expertise and ability, and (3) engage our trainees and their mentors in the team science initiatives necessary to meet the ambitious goals of the National Plan to address Alzheimer's Disease to prevent and treat ADRD by 2025. The REC specific aims are to: 1) Develop the careers of advanced postdoctoral and junior faculty researchers, who have demonstrated outstanding research potential and an interest in research focused on understanding factors that affect etiology and outcomes in ADRD; and 2) Provide mentorship, education, career development activities and a broad array of educational and infrastructural resources across the multiple sites afforded by our rich academic and clinical settings (e.g., School of Medicine, main campus, VA, and affiliated institutions such as the Salk Institute for Biological Studies) to enable our REC scientists to enhance their expertise in ADRD research and research methods, successfully complete their research, present and publish their work, and attain independent research and/or career development funding. The Shiley-Marcos ADRC REC program will be directed by four Leaders from the School of Medicine and main campuses at UC San Diego: Dr. Bondi (UCSD ? Psychiatry; VA ? Psychology / Neuropsychology), McEvoy (UCSD - Radiology), Moore (UCSD ? Medicine / Geriatrics) and Patrick (UCSD ? Neurobiology / Biological Sciences). The four Leaders have complementary scientific skills (e.g., basic vs. clinical science), reside in multiple campus localities, and have collaborated to develop this program using the team science model. The Program Faculty have been assembled with the goals of diversity with respect to their disciplines, research and advanced mentoring skills, and affiliations. The REC Leaders will continuously and objectively monitor the effectiveness of the training program, dynamically modifying the program based on feedback from mentors, mentees, and the ADRC Executive Committee, to provide the highest quality training program possible.