Stephanie A. Cosentino, Ph.D. - US grants

DESCRIPTION (provided by applicant): Disordered awareness of memory loss is a striking symptom displayed by a subset of patients with early Alzheimer's disease (AD). This metacognitive disturbance threatens patient safety and poses significant challenges for clinicians and caregivers, yet virtually nothing is known regarding its etiology, nature, clinical correlates, neuroanatomic substrates, or prognostic relevance. The proposed study aims to break ground in the study of metacognition in AD by implementing a rigorous methodological framework that will objectively measure specific memory monitoring abilities across patients with a range of awareness levels. Carefully manipulating the experimental task to assess online error recognition and implicit learning will shed light on the disrupted mechanisms that give rise to disordered awareness of memory loss in AD. The proposed study will also examine the neuroanatomic context in which disordered awareness occurs by evaluating metacognitive variables in relation to the integrity of specific areas of the brain previously linked with aspects of self-awareness. Structural and functional imaging modalities will be applied to evaluate this issue. Finally, the proposed study will bridge the gap between cognitive assesment and clinical utility by examining the manner in which deficits in metamemory relate to decision making capacity and quality of life, two critical issues in the everyday lives of persons with Alzheimer's disease. Future neuroimaging, cognitive and metacognitive evaluations will be done in the context of a community based, longitudinal study. Such a framework will facilitate study of metacognitive change in individuals through the course of normal cognition, memory decline, and dementia diagnosis, bearing particular light on awareness of deficit in the earliest stages of memory loss, before patients present to the clinic. Results may have significant implications for the diagnosis of Mild Cognitive Impairment (MCI), a condition which is believed to herald the onset of AD, but is defined in part by subjective memory complaint. Results may also inform the assessment of capacity to provide informed consent for research participation in persons with AD. To the extent that disordered awareness is associated with a particular neuroanatomic profile, and disordered awareness reduces decision making capacity, research programs may systematically exclude a clinical subtype, of AD. The proposed study serves as a spring board for studying these and other clinically relevant issues.

DESCRIPTION (provided by applicant): Discoveries about the genetic bases of frontotemporal lobar dementia (FTLD) have provided researchers with an unprecedented ability to characterize the pre-symptomatic stages of this disease. This capability is critical to ascertaining the earliest clinical features of the disease and identifying biomarkers that can be used for early diagnosis and in treatment studies. The proposed project will examine individuals from a single family with a genetic mutation for FTLD who are approaching the age of disease onset, offering a unique and highly controlled environment in which to identify the earliest clinical features and biomarkers of this devastating disease. Specifically, this study proposes to follow the offspring generation of a large family with a known mutation in the MAPT (tau) gene to determine the earliest clinical features of FTLD and the variables which may modify disease onset and course. At least 90 members of the offspring generation of a single family will be offered participation in a longitudinal study examining cognition, behavior, psychiatric symptoms, and lifestyle features. Moreover, this proposal includes the use of state of the art neuroimaging tools including both structural and functional modalities, gray and white matter quantification, and regional and network analyses to detect the earliest signs of disease. Individuals will undergo genetic testing to determine carrier status, will be comprehensively characterized at baseline, and will be followed annually over the course of the study to examine change in clinical and imaging variables over time as a function of carrier status. Additionally, the proposed study will carefully characterize lifetime physical activity and alcohol and recreational drug use to determine if these lifestyle variables are early manifestations of disease and / or modify disease onset and course. Finally, biological specimens including cerebrospinal fluid and blood plasma will be longitudinally collected in an effort to characterize changes in brain protein levels that may provide early information regarding the onset and course of disease.

Essential tremor (ET) is among the most prevalent neurological diseases. Although it was long considered a purely motor disorder, ET is increasingly being regarded as more complex, with an emerging recognition of cognitive dysfunction. While cognitive deficits can be mild, other patients dement. Several epidemiological studies reveal a higher prevalence of mild cognitive impairment (MCI) and 1.5 to 2-fold increased risk of Alzheimer's disease (AD) in ET. Yet the study of cognition/dementia in ET is nascent. Our data are limited and patchy - the most basic ?whats? (i.e., clinical features, clinical course) and ?whys? (i.e., postmortem basis) are uncharted. In sum, there is a cognitive side to ET, and we know little about it. For the past 4 years, we have established and begun to follow an ET cohort to address several of these unknowns (Clinical-Pathological Study of Cognitive Impairment in ET, COGNET). COGNET is the largest (230 enrolled; 195 living), most comprehensive, and only active prospective cohort of ET patients. Key elements are detailed, motor-free, longitudinal cognitive testing, consensus cognitive diagnoses (normal cognition [NC], MCI, dementia), and autopsy data. The study called for a baseline and two follow-up assessments. Currently, mean follow-up from baseline is only 1.50 ± 0.21 years (range = 0.31 - 2.29). Thirty-five died. The data have allowed us to begin to characterize the cognitive deficits in ET and study their pathological bases. Yet, there remain large, obvious gaps in knowledge. First, clinically, are the cognitive impairments in ET progressive? Do they progress at a faster rate than in the general population? What are the conversion rates to MCI and dementia? What are the clinical predictors of cognitive decline? Are cognitive deficits characteristic of AD predictive of worse clinical outcomes? It turns out that we know virtually nothing about the predictors, course and outcomes of cognitive impairments in ET, and such information cannot simply be taken from the general population. With a cohort now successfully assembled and longitudinal cognitive phenotyping ongoing, COGNET is poised to tackle important prognostic issues regarding the predictors and dynamics of cognitive deficits in ET (Aim 1). Second, pathologically, what is the basis for cognitive deficits in ET? Our studies point to heterogeneous deficits with heterogeneous bases, including AD pathologies. We only have 35 postmortems, and our nascent study of the pathological basis for cognitive deficits must grow and come to maturity (Aim 2). We now propose to continue this cohort, adding new measures to characterize the predictors and outcomes of cognitive impairments in ET. We propose enrolling 100 additional ET cases (proposed total n = 295). AIM 1. To provide the first long-term prospective, longitudinal characterization of cognition in ET to address unanswered prognostic questions about cognitive impairment in ET (e.g., conversion rates to MCI and dementia). AIM 2. To finalize our clinicopatho- logical study of ET by comparing the neuropathological features of 100 ET to 300 matched non-ET cases, and identifying the cognitive predictors of specific neuropathologies, particularly AD and other tauopathies.

DESCRIPTION (provided by applicant): The Long Life Family Study (LLFS), established in 2005 in response to an NIA RFA, enrolled families enriched for exceptional longevity (EL), to discover factors that contribute to healthy aging and survival. From 2006 to 2009, LLFS enrolled 539 sibships (G1), their offspring (G2) and spouses (total 4,953). Comparison with a referent cohort reveals that LLFS families have strong exceptional clustering of EL. The G2 offspring have a variety of Healthy Aging Phenotypes (HAPs), defined as an unusually low age-specific prevalence of one or more specific conditions or risk factors, compared to population-based cohorts suggesting enrichment of shared (possibly genetic) protective effects in LLFS families. In the second funding period (2010-2013), we conducted a 2.5 million SNP GWAS (dbGaP phs000397); developed a high-throughput technique and sequenced ~450 candidate genes and replicated many variants and found additional ones associated with Healthy Aging Phenotypes (HAP) and longevity. 54% of LLFS G1 and 92% of G2 remain alive. Participant retention has been 94%. We now propose a third funding period to conduct a second in-person examination (V2) to prospectively study rates of change in HAPs with age and identify genetic and other factors contributing to HAPs and longevity. We hypothesize that EL and HAPs entail common and rare variants that individually have modest effects, but which in combinations strongly influence longevity and specific HAPs, and may only be detectable in family studies enriched for HAPs, such as LLFS. HAPs evaluated at the initial in-person visit show strong linkage peaks which are not explained by common haplotypes interrogated by GWAS (HLODs ranging from 6.0-45.1). These are likely driven by rare, lineage-private alleles that will only be found by sequencing specific families, and may point to important new biology. Specific Aim 1 is to conduct a second in-home examination on all surviving LLFS participants. Specific Aim 2 is to analyze cross-sectional and longitudinal phenotypes. The goal is to identify pathways for EL and HAPs by characterizing the shared and distinct LLFS phenotypes and environmental factors. We will characterize individual longitudinal patterns of HAPs to identify subgroups showing similar patterns and exceptional phenotypes. We will test whether these HAPs are heritable, and test for differences with internal and external referent groups. Specific Aim 3 is to find genes/variants associated with cross-sectional and longitudinal phenotypes using a) Whole Exome Sequencing to comprehensively search for coding variants associated with HAPs and EL and b) Targeted Regulatory Sequencing of regions under linkage peaks for HAPs in selected families showing the strongest linkage evidence. Specific Aim 4 is to replicate our genetic and epidemiological findings in other aging study cohorts. This study could lead to the discovery of pathways and potential therapeutic/prevention targets affecting HAPs and EL. A Data Management and Coordinating Center and 4 Field Centers comprise the major components of the LLFS. This renewal application is submitted by the Duke Uni./Uni. of Southern Denmark Field Center.

DESCRIPTION (provided by applicant): The Long Life Family Study (LLFS), established in 2005 in response to an NIA RFA, enrolled families enriched for exceptional longevity (EL), to discover factors that contribute to healthy aging and survival. From 2006 to 2009, LLFS enrolled 539 sibships (G1), their offspring (G2) and spouses (total 4,953). Comparison with a referent cohort reveals that LLFS families have strong exceptional clustering of EL. The G2 offspring have a variety of Healthy Aging Phenotypes (HAPs), defined as an unusually low age-specific prevalence of one or more specific conditions or risk factors, compared to population-based cohorts suggesting enrichment of shared (possibly genetic) protective effects in LLFS families. In the second funding period (2010-2013), we conducted a 2.5 million SNP GWAS (dbGaP phs000397); developed a high-throughput technique and sequenced ~450 candidate genes and replicated many variants and found additional ones associated with Healthy Aging Phenotypes (HAP) and longevity. 54% of LLFS G1 and 92% of G2 remain alive. Participant retention has been 94%. We now propose a third funding period to conduct a second in-person examination (V2) to prospectively study rates of change in HAPs with age and identify genetic and other factors contributing to HAPs and longevity. We hypothesize that EL and HAPs entail common and rare variants that individually have modest effects, but which in combinations strongly influence longevity and specific HAPs, and may only be detectable in family studies enriched for HAPs, such as LLFS. HAPs evaluated at the initial in-person visit show strong linkage peaks which are not explained by common haplotypes interrogated by GWAS (HLODs ranging from 6.0-45.1). These are likely driven by rare, lineage-private alleles that will only be found by sequencing specific families, and may point to important new biology. Specific Aim 1 is to conduct a second in-home examination on all surviving LLFS participants. Specific Aim 2 is to analyze cross-sectional and longitudinal phenotypes. The goal is to identify pathways for EL and HAPs by characterizing the shared and distinct LLFS phenotypes and environmental factors. We will characterize individual longitudinal patterns of HAPs to identify subgroups showing similar patterns and exceptional phenotypes. We will test whether these HAPs are heritable, and test for differences with internal and external referent groups. Specific Aim 3 is to find genes/variants associated with cross-sectional and longitudinal phenotypes using a) Whole Exome Sequencing to comprehensively search for coding variants associated with HAPs and EL and b) Targeted Regulatory Sequencing of regions under linkage peaks for HAPs in selected families showing the strongest linkage evidence. Specific Aim 4 is to replicate our genetic and epidemiological findings in other aging study cohorts. This study could lead to the discovery of pathways and potential therapeutic/prevention targets affecting HAPs and EL. A Data Management and Coordinating Center and 4 Field Centers comprise the major components of the LLFS. This renewal application is submitted by the Duke Uni./Uni. of Southern Denmark Field Center.

In the field of cognitive aging, there is an urgent push to identify the markers of pre-clinical Alzheimer?s disease (AD) in order to move pharmacologic intervention earlier in the disease spectrum to a time when it can be most effective. There is growing interest in subjective cognitive decline (SCD) as a potential marker of pre-clinical AD. SCD, or the perception that one?s cognition has declined despite ?normal? performance on standard diagnostic testing, is an important health outcome that is concerning to many older adults, and leads some to seek medical attention. Determining the extent to which SCD may serve as a pre-clinical marker of AD is of great value, as SCD is non-invasive, inexpensive, and easily obtainable. However, SCD is a complex, multi-factorial construct. In order to determine its true utility as a marker of pre-clinical AD, it is critical to comprehensively characterize the factors that influence SCD, and that affect the degree to which SCD reflects ?true? or actual cognitive functioning. Indeed, SCD is certain to reflect not only a person?s actual cognitive functioning, but also task-specific factors (i.e., how SCD is measured) and person-specific factors (e.g., how good one is at self- evaluation; how old one feels; what one believes about aging). The goals of this longitudinal proposal are to examine novel task-specific and person-specific factors that are likely to influence SCD and/or its association with actual (objectively measured) cognition in 200 older adults. A key aspect of the proposed study is the inclusion of sensitive, objective cognitive outcomes that will enable a more precise examination of the association between SCD and objective cognition than has been conducted thus far. The first objective cognitive outcome is performance on a visual short term memory (STM) binding task shown to be highly sensitive and specific to AD pathology when standard neuropsychological testing is within normal limits. We will also examine attentional control as a measure of non-memory changes that may signal early AD before memory changes are apparent in some individuals. A final critical outcome is cognitive change over time, enabling examination of subtle decline in cognition that may occur when individuals still perform within the normal range on cross-sectional testing. Taken together, these aims embody key issues recently identified by the SCD Working Group (2014) as critical for advancing the current state of knowledge on SCD, and will contribute to a novel model of SCD. Results from the proposed study will provide specific guidelines for how to assess and interpret SCD in older adults, and will set the stage for determining how and when SCD may be used as an indicator of preclinical Alzheimer?s disease.

PROJECT SUMMARY As the population of older adults increases dramatically, age-related illnesses such as Alzheimer?s disease (AD) and other degenerative disorders present a great public health burden, currently affecting an estimated to 5.4 million Americans. It is well documented that older adults from ethnic minority and lower socioeconomic backgrounds are at increased risk for AD and other disorders of aging. There is thus an urgent need to increase the number of scientists from diverse backgrounds who are committed to the study of aging and age- related health disparities. The proposed Summer of Translational Aging Research for Undergraduates (STAR U) program is guided by three axioms related to biomedical research on aging: 1. The diversity of the older adult population is increasing and there are systematic racial/ethnic disparities related to disorders of aging that are poorly understood; 2. Scientific advancement relies upon diversity of background, experience, ideas, and perspectives; increasing the diversity of scientists involved with biomedical research of aging is necessary to provide the cultural sensitivity and knowledge to understand sources of disparities in aging; and 3. Despite increases in the number of underrepresented minorities receiving higher education, a large percentage do not pursue careers in science. STAR U seeks to overcome historic barriers that have prevented such students from pursuing careers in scientific and aging research. Through a structured summer research program, STAR U will provide 10-12 students per year with: 1) individual, tailored research mentorships in the neuroscience of aging; 2) a range of translational learning opportunities; and 3) professional networking and social experiences. Research opportunities will span areas such as patient-oriented clinical research, cognitive neuroscience, basic science, and the epidemiological study of cognitive aging and its disorders. STAR U students will gather formally once per week for a two-hour seminar session that will include one hour devoted to a scientific topic, and one hour devoted to professional/academic development. Scientific training will focus on major themes in aging research, research methodologies, and general content areas relevant to developing scientific careers. Personal and professional development will be fostered through social gatherings as well as seminars on career development, learning how to find and work effectively with mentors, balance personal and professional demands, choosing the type of graduate training that is most appropriate for them, communicating effectively in science, and applying to graduate/medical school effectively. The long-term goal of the Summer of Translational Aging Research for Undergraduates is to enhance the field of aging and age-related disparities research by infusing it with diverse, well-trained scientists.!

RESEARCH EDUCATION COMPONENT PROJECT SUMMARY/ABSTRACT In Alzheimer?s Disease and Related Dementias (ADRD), a rapidly developing field has gained comprehensive insights into a host of likely complementary disease mechanisms, shedding light on relevant genetic and environmental factors, a continuum of neuropathological abnormalities, biomarkers that represent the earliest stages of disease, and an array of clinical presentations. Yet, large gaps in knowledge remain regarding disease modeling, genetics and pathophysiology, and of course, treatment. The Columbia University (CU) Research Education Component (REC) will be a comprehensive training program to effectively and efficiently develop the next generation of ADRD leaders poised to make breakthroughs in ADRD research through both established and novel research methods. The CU REC Training Program will provide training for researchers comprising two distinct groups: a) those entering ADRD research through conventional training paths (e.g., neurologists, neuropsychologists, basic and translational researchers) with great promise to contribute to the field in the near term, and b) researchers from non-conventional paths (e.g., bioinformatics/data science, engineering, public health, and allied health) who have demonstrated unique and accomplished research skills, which if reoriented to ADRD, could make novel and important impacts on ADRD research. The REC Training Program enhances primary aims of the CU ADRC: to enable and enhance ongoing research efforts in ADRD at CU, and support a diverse group of ADRD researchers making these discoveries. The CU REC Training Program provides a structured framework that promising junior researchers, identified through our vast institutional research infrastructure, can leverage to establish successful careers in ADRD. With ongoing, multidisciplinary mentorship tied to a structured research project, effectively supported junior researchers can independently develop hypotheses, critically appraise related literature, and frame a sophisticated approach to an appropriately honed research question. Training will include an individualized development plan tailored to each trainee and his or her current and future career steps, enabling a foundational understanding from which to launch a successful research career. This program will build upon the longstanding practices of the CU ADRC and Department of Neurology, the latter having the highest track record of trainees becoming academic neurologists of any institution in the world. In sum, the overarching goal of the REC Training Program is to develop the next generation of ADRD researchers by: 1) identifying 3-5 junior investigators with promise for making significant contributions to the field of ADRD (Aim 1); 2) drawing trainees from ADRD fields as well as fields beyond traditional pathways to ADRD research, especially those from diverse backgrounds (Aim 2); and 3) providing all trainees with an individualized development plan that includes multidisciplinary mentorship, experiences within the expansive internal research and education program at CU, and an integrated plan to understand how to access and achieve sustained grant support towards next career steps (Aim 3).

The Long Life Family Study (LLFS) has enrolled 4,953 participants in 539 pedigrees in the USA and Denmark that are enriched for exceptional longevity, and has measured them longitudinally in two extensive in-home visits measuring key healthy aging phenotypes in all of the major domains of the aging process. We have demonstrated through many publications that selecting on longevity in the first (proband) generation, results in the second (offspring) generation being much healthier than average in many key phenotypes. However, the pedigrees are heterogeneous by phenotype, with different families showing familial clustering of protection in cognition, grip strength, pulmonary function, blood pressure, etc. Further, comprehensive linkage analysis of the LLFS sample identifies extremely strong genetic linkage peaks for cross-sectional as well as longitudinal trajectory rates of change phenotypes for a wide variety of healthy aging domains such as exceptional cognitive performance and lack of Alzheimer?s disease. These peaks are NOT explained by GWAS SNPs (or those that can be imputed by GWAS). Pedigree specific LODs and preliminary deep sequencing suggests that these peaks are driven by rare, protective variants running in selected pedigrees. We propose to do Whole Genome Sequencing on this unique cohort, to identify the rare protective variants driving these strong linkage peaks. We propose to continue longitudinal assessment of the cohort with a third in-person visit, which will allow us to assess potential non-linear patterns of aging, and adding formal assessment of dementia diagnosis for Alzheimer?s Disease and other dementia types, which will increase specificity and power to discover and follow- up on protective variants against Alzheimer?s Disease and other dementia diagnoses. For pedigrees driving multiple strong linkage peaks, we also propose to phenotypically measure the third generation (grandchildren), as these are likely to carry more copies of the rare protective alleles running in these families, which will exponentially increase our power to resolve them. Preliminary evidence from the Danish Medical Registry suggests that, at least in Denmark, the protection persists into this third generation, with significantly lower rates of medical conditions across the disease spectrum. We also propose to do extensive transcriptomics, methylomics, and proteomics on these selected high linkage pedigrees, to begin to move from ?statistically associated variants/loci? to the biological genes of action, since we expect most of the driving variants will be regulatory and non-coding. It is critical to find the modes of action of these rare protective variants. We also propose to do metabolomics on the entire LLFS cohort, longitudinally, with the goal of identifying novel biomarkers of healthy aging and resistance to diseases such as Alzheimer?s in this unusually heathy cohort. Combined with a systems biology/network approach to data integration of the proposed ?Big Data?, such biomarkers would improve our power to detect even more novel protective genetic variants and identify the genetic signatures and pathways of genes conferring protection in this unique cohort to prevent onset of major diseases such as diabetes, cardiovascular disease, cancer and Alzheimer?s Disease and other dementia types.