Joel H. Kramer, PsyD - US grants

DESCRIPTION (provided by applicant): The overall goal of this project is to define the characteristics and neuroanatomical predictors of attention and executive impairments in frontotemporal dementia (FTD). FTD is a neurodegenerative disorder that differentially affects the frontal lobes. Frontally mediated deficits in attention and executive functioning are central features of FTD that have far reaching consequences for behavior, including cognitive rigidity, disinhibition, inability to sustain goal-oriented behavior, and poor functional adaptation in the context of relative preservation of memory, language, and spatial ability. Despite their importance for diagnosis and patient care, these attentional and executive deficits are poorly understood. We will study 75 patients with mild FTD, 75 severity-matched patients with AD, and 100 age-matched controls using cognitive models of attention and executive functioning that enable parsing of attention into several key components associated with anterior and posterior networks. Specific aims are to evaluate differences between FTD, AD and controls in executive control of attention, test whether specific regions of cerebral atrophy are selectively associated with impairment on attentional tasks, and evaluate the functional significance of attentional and executive deficits in FTD and AD.

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The overall objective of this contract is to develop psychometrically robust Executive Function measurement tools that are accepted by the neurology clinical trials and clinical research communities. Specific goals of the contract are: 1. To develop a core set of tasks that will address specific domains of Executive Function that is universal to patients with chronic neurological disorders (for example: stroke, traumatic brain injury, neurodegenerative disorders, epilepsy, etc.). 2. To integrate the specific following characteristics in the NINDS Executive Function test battery: o focused on two or more of the following six domains: inhibition (response suppression;interference resolution);working memory (manipulation and maintenance of information;temporal organization (time &place);set shifting (mental flexibility);self monitoring (behavioral awareness, insight);abstraction (rules, categories). o modifiable (depending on individual protocols or paradigms and individual differences) o portable (battery that can be administered in emergency room;physician offices) o programmable;replicable (flexible across laboratories) o usable across age groups o adaptable for clinical trials o utilizes naturalistic situations (virtual reality) o includes functional outcomes (sensitive to treatment, training, drugs) The NINDS is seeking an innovative approach to Executive Function measurement that will be responsive to the needs of researchers in a variety of neurological disorders and settings, with a particular emphasis on measuring outcomes in clinical trials. Determining criteria for acceptability to the neurology research community prior to specific domain tasks development and evaluating the acceptability to researchers of the final battery will be essential to successful completion of these goals.

Project Summary /Abstract The overarching goal of this project is to identify the cognitive mechanisms and neural structures that underlie the decline in executive functioning observed in aging. Several research groups, including ours, have documented age-associated decline in executive functioning and its significant impact on daily functioning. The underlying causes of this decline remain unclear, however; a clearer understanding of how various cognitive and neural changes interact to produce executive decline is needed. We propose an overarching model in which age-associated frontal atrophy, frontal hypoperfusion, and loss of white matter integrity interact to affect information processing speed and executive function. We propose to prospectively study 150 normal elderly with structural neuroimaging, perfusion, and cognitive measures at baseline and again after 36 months. We have three specific aims: 1) test the relationships between age, frontal lobe structure, frontal perfusion, white matter, and cognition cross-sectionally; 2) identify potential health and lifestyle predictors of MRI and cognitive outcomes; and 3) test the relationships between longitudinal change in MRI and longitudinal changes in cognition. This project takes advantage of newly developed techniques of high field, high resolution MRI and cognitive psychology methods of measuring processing speed and executive functioning. We are particularly focusing on white matter integrity because it may be influenced by lifestyle and health issues that are potentially treatable.

DESCRIPTION (provided by applicant): The overarching goal of this project is to determine the cognitive, neuroanatomic and physiological underpinnings of the profound deficits in behavioral regulation exhibited by patients with behavioral variant frontotemporal dementia (bvFTD). Patients with bvFTD and other frontal lobe disorders often present with severe behavioral dysfunction despite relatively intact performance on standard clinical measures of attention, working memory, problem solving, and executive function. A primary question is to what degree these behaviors reflect deficits in cognition (e.g., cognitive control, awareness of errors, error correction), or whether they reflect a primary underlying deficit in the processing of reward and punishment. We propose to study 50 patients with mild bvFTD, 50 Alzheimer's disease patients matched for demographics and dementia severity, and 50 normal controls. We will study the cognitive components of behavioral regulation by assessing conflict monitoring, error detection, and error correction, and we will evaluate the motivational components by employing reward processing paradigms. Behavioral studies will be carried out in conjunction with functional MRI to study the brain systems that mediate these behaviors. Our results will hopefully shed light on why these patients fail to inhibit inappropriate actions and offer guidance toward new interventions. PUBLIC HEALTH RELEVANCE: The Inability to control impulses and inhibit inappropriate behavior has a devastating impact on patients with frontal lobe disorders. The overarching goal of this project is to study patients with behavioral-variant frontotemporal dementia to better understand the cognitive and neurological underpinnings of these maladaptive behaviors. The potential contribution to public health lies in the hope that a better understanding of the neural systems that mediate behavioral dyscontrol will lead to improvements in care.

CORE B: ABSTRACT/SUMMARY The overarching goal of the Clinical Core is to characterize the behavioral, cognitive, motor, neuroimaging, proteomic and genetic features of ADRC subjects in novel, multidisciplinary ways, and facilitate enrollment of subjects in studies of normal and abnormal aging. The specific aims of the Clinical Core are to 1) Recruit, evaluate, and longitudinally follow cohorts of normal elderly (n=200), patients with mild cognitive impairment (MCI; n=120), mild AD (n=120), frontotemporal dementia-spectrum (n=120), and Creutzfeldt-Jakob disease (CJD; n=10); 2) Work with the Education Core to recruit, evaluate, and longitudinally follow 120 Chinese- American patients and controls; 3) Provide clinical data and well characterized subjects for research on aging and neurodegenerative disease; and 4) Work closely with the other UCSF ADRC Cores to provide integrated and comprehensively characterized subjects for research, including biological samples for genomic and proteomic research, structural and functional neuroimaging, and amyloid biomarkers. All subjects will be evaluated using the UDS plus several neurological, cognitive, and personality measures specific to UCSF to better understand the heterogeneity of and overlap between dementias, improve our ability to capture the very earliest signs of neurodegeneration, study the transition from normal aging to MCI, and elucidate underlying neural networks and mechanisms..

? DESCRIPTION (provided by applicant): There is considerable individual variability in how much and how quickly cognitive abilities change with age. The better we understand the biological mechanisms that influences if and how aging affects brain structure and function, the more able we will be to intervene effectively. The overarching goal of this renewal application is to better understand the inflammatory, vascular, and neurodegenerative mechanisms that contribute to this clinically important diversity in brain aging trajectories. We propose to increae our current cohort from 200 to 265 older normals, and continue with our detailed cognitive, neuroimaging, and biometric phenotyping over two additional time points. In addition, we propose adding novel molecular neuroimaging methods to quantify amyloid and tau burden, and carry out exploratory analyses of specific candidate genes. Our specific aims are to determine the contributions of amyloid burden and inflammatory cytokines on brain aging, determine the contributions of vascular risks and inflammatory cytokines on brain aging in amyloid negative subjects, and explore genomic, proteomic, and lifestyle factors that increase or decrease risk of cognitive and brain aging. More precise specification of these relationships will lead to better prediction and prevention of adverse cognitive aging and inform person-specific interventions.

? DESCRIPTION (provided by applicant): Chronic inflammation is a major characteristic of the typical aging process. The view that the central nervous system is immunologically privileged, however, is challenged by evidence linking low level, chronic inflammation to neurologic injury, neurodegeneration, and cognitive dysfunction. The degree of risk posed by inflammation and the underlying mechanisms of injury remain unclear. The overarching goal of this proposal is to better define the impact of chronic inflammation on brain structure and function. We propose to study four potential downstream effects of chronic inflammation on the brain: 1) Alzheimer's-related changes; 2) white matter injury; 3) network connectivity; and 4) cognition. We will longitudinally study 150 functionally normal community-dwelling subjects over the age of 65 selected from on-going, well-characterized cohorts at UCSF. We will quantify chronic inflammation using several well established markers in serum, plasma, and cerebrospinal fluid. Innovative MRI and PET molecular neuroimaging methods will measure microstructural integrity of white matter tracts, functional connectivity networks, and Alzheimer's-related deposition of brain amyloid. Cerebrospinal fluid (CSF) obtained on a subset of cases will further our understanding of specific inflammatory profiles in the periphery and brain. The cognitive phenotype(s) associated with chronic inflammation will be defined using methods from cognitive neuroscience, and we will explore potential mechanisms by which chronic inflammation interacts with brain structure and function. Results from this project will potentially guide clinial trials and identify elderly subjects with treatable and reversible risks for adverse neurological and cognitive aging.

Project Summary /Abstract Small vessel cerebrovascular disease and Alzheimer's disease are the two most common causes of cognitive decline in the elderly, but methods for determining the relative contributions of both these pathologies to functional impairment, understanding their interactions, predicting progression and defining targets for clinical trials remain underdeveloped. The overarching goal of this proposal is to further develop novel neuroimaging and serologic biomarkers of cerebrovascular disease. Accomplishing this goal will improve early detection, diagnosis, and prognosis of small vessel cerebrovascular disease in older subjects, and provide better targets and outcome metrics for clinical trials. We propose to longitudinally study 400 well characterized older subjects from ongoing projects at UCSF and UCD who present with a range of cerebrovascular burden and functional decline. Our search for biomarkers will focus on novel neuroimaging variables and measures of endothelial dysfunction. Our aims will address the relationships between these markers and measures of amyloid burden, cognition, and change over time.

PROJECT SUMMARY/ABSTRACT Frontotemporal dementia (FTD) is marked by profound impairments in decision-making; unfortunately, FTD is typically only diagnosed after patients have made significant errors in judgment. Clinically, delays in diagnosis reflect the absence of objective clinical tests for decision-making, and are missed opportunities to prevent serious harms. Scientifically, delayed diagnosis limits our ability to study decision-making deficits, as research patients with confirmed FTD tend to have more profound deficits that may not reflect early changes, and often cannot tolerate more sophisticated behavioral paradigms. This clinical and scientific gap will be addressed with neuroeconomic analyses of decision-making in presymptomatic mutation carriers from familial FTD kindreds in two large NIH-funded multicenter networks spanning the US and Canada. The central hypothesis is that early behavioral and physiological changes in FTD mutation carriers will reveal initial signs and mechanisms of impaired judgment in FTD, potentially also elucidating neural mechanisms of impaired decision-making in other neuropsychiatric disorders. 110 presymptomatic carriers and 110 noncarrier family members from these multicenter networks will be recruited for tests of decision-making on a secure web-enabled platform that enables rapid and flexible data collection from participants across North America. Guided by strong preliminary data, the central hypothesis will be tested by pursuing three specific aims: 1) Apply neuroeconomic models of decision-making to define subtle alterations in judgment in presymptomatic bvFTD mutation carriers; 2) Determine structural and functional (resting-state) MRI predictors of altered decision- making in bvFTD mutation carriers; and 3) Elucidate neural and physiological mechanisms underlying behavioral change in mutation carriers. Under the first two aims, the web-enabled platform will assay neuroeconomic parameters such as loss aversion, framing effects, and interpersonal decision-making; which will then be analyzed in conjunction with a rich dataset of cognitive and neuroimaging measures already being collected per protocol across network sites. Under Aim 3, behavioral performance on the web-enabled platform will be used to select a subset of mutation carriers and noncarriers for more detailed in-person physiological and task-based fMRI testing. This web-enabled approach is innovative, because while other researchers have begun to use online methods to administer tasks to large numbers of participants at home, this strategy allows the evaluation of hypotheses involving neuroimaging and standardized measures that cannot be performed online. This combines the strengths of traditional on-site evaluation with the flexibility and scaling advantages of newer online methods. The proposed work will thus make a significant contribution by applying novel methods and more precise neuroeconomic measures of decision-making in a large sample of presymptomatic gene carriers, addressing a major limitation to research on some of the earliest and most damaging symptoms of FTD.

PROJECT SUMMARY /ABSTRACT (from the Parent Grant) There is considerable individual variability in how much and how quickly cognitive abilities change with age. The better we understand the biological mechanisms that influences if and how aging affects brain structure and function, the more able we will be to intervene effectively in a person-specific manner. The overarching goal of this renewal application is to better understand the inflammatory, vascular, neurodegenerative, and lifestyle/behavioral contributions to this clinically important diversity in brain aging trajectories. We propose to continue following our deeply phenotyped cohort of 250 functionally intact older normals with our detailed cognitive, neuroimaging, and biometric characterizing over two additional time points. Our first aim is to define the separate and interactive pathways by which biologic and lifestyle variables influence age-related decline in brain structure and function Our second aim will determine of predictive value of innovative plasma markers of proteins associated with Alzheimer?s and neurodegeneration. Our third aim will incorporate innovative, objective, real-time measures of sleep and physical activity. Accomplishing these aims will have a highly significant impact on the field. Validating plasma biomarkers of pathology and clarifying the complex interplay of factors that influence brain aging trajectories will lead to better prediction and prevention of adverse brain aging and inform person-specific interventions.

PROJECT SUMMARY/ABSTRACT Small vessel cerebrovascular disease is common in the elderly and is a well-known contributor to cognitive decline. A major gap in the field, however, is the ongoing need for reliable and reproducible biologic markers of vascular disease suitable for early detection, disease monitoring, and measuring treatment efficacy. The overarching goal of this proposal is to clinically validate novel neuroimaging and fluid-based biomarkers of a cerebrovascular disease selected by the NINDs and developed during the first five years of the MarkVCID consortium. We propose to longitudinally follow a cohort of 200 diverse, older subjects who present with a range of cerebrovascular burdens and cognitive complaints, and functional decline. Our aims are to validate the MarkVCID biomarkers and address possible interactions between these biomarkers and Alzheimer?s disease pathophysiology. Accomplishing these goals will improve the early detection, diagnosis, and prognosis of small vessel cerebrovascular disease in older subjects and provide better targets and outcome metrics for clinical trials.