Jane Paulsen - US grants

Tardive dyskinesia (TD), a disorder of involuntary movements, is arguably one of the most serious iatrogenic effects of the neuroleptic treatment of schizophrenia. Although the pathophysiology and anatomical substrate of TD has not been established, research has implicated the basal ganglia as one of the primary sites of dysfunction. Many researchers have attempted to identify clinical and neurobiological variables that are either associated with the disorder or that are risk factors for its development. For instance, most available studies show that schizophrenics with TD demonstrate more severe cognitive deficits than schizophrenic patients without TD. Although impairments have been demonstrated on a variety of tasks, the majority of studies have indicated differences in tasks requiring learning and memory. One away to further investigate the- neuropsychological profile of persons with TD is to arrow from literature examining other basal ganglia disorders. A number of studies have shown that patients with basal ganglia dysfunction demonstrate specific impairments in procedural learning and memory. The overall goal of the proposed project is to examine the integrity of both procedural and declarative memory systems in schizophrenic patients with TD. Although several investigators have suggested that patients with TD exhibit impairments in the declarative memory system; no study has investigated TD patients' performance on tasks requiring procedural learning and memory. - One hundred twenty subjects will be evaluated on tests of declarative and procedural learning and memory. Procedural tests include one traditional measure (rotor pursuit) and two new measures (prism adaptation and reaction time tracking). Declarative tests include standardized tests of clinical neuropsychology. This investigation is particularly important given the implications of the basal ganglia in procedural knowledge. Improved understanding of learning and memory deficits in TD may lead to (a) more precise characterization of different types of procedural and declarative memory systems in patients with basal ganglia dysfunction; (b) better understanding of the potential effects of neuroleptic exposure to dissociable memory systems; (c) future development of more sensitive clinical tests for early detection of procedural. deficits in patients with basal ganglia dysfunction; (d) better understanding of brain mechanisms related to tardive dyskinesia.

DESCRIPTION (Adapted from applicant's abstract): The identification, diagnosis, and effective management of psychiatric symptoms in Alzheimer's Disease (AD) are critical to reduce the cost of health care, to increase practitioner efficiency and to improve the quality of life for AD patients and their caregivers. Until research finds a means of treating AD with curative measures, symptoms such as delusions and hallucinations must be aggressively identified, diagnosed, and managed. Although recent research has shown a high prevalence of psychosis in AD and has implicated a worse prognosis for those AD patients with psychosis, the risk factors for and underlying mechanisms of psychosis in AD are poorly understood. The proposed project will be the first study to prospectively investigate the neuropsychologic factors associated with psychosis in AD. With the aim of exploring the heterogeneity of behavioral presentation and course in AD, the proposed studies are designed to prospectively compare the neuropsychological performances of AD patients who develop psychosis with AD patients who do not develop psychosis. Furthermore, the current proposal will retrospectively analyze the neuropsychological performances of AD patients currently enrolled in the research centers at UCSD who are identified as having psychosis.

Neuropsychological tools have been used to detect early disease, to assist with differential diagnosis of dementia syndromes, and to document progression of disease over time. Despite these significant advances in the cognitive characterization of specific degenerative diseases, much remains to be done (a) to better utilize neuropsychological measures as predictors of clinical heterogeneity in dementia (such as the use of specific cognitive abilities as markers for psychosis and early institutionalization), (b) to use cognitive performances as indicators of preclinical disease states (such as the use of cognitive assessment to document the presence of disease in pre- choreic individuals carrying the HD gene), and (c) to design cognitive measures to stimulate activation of specific brain areas for use in functional imaging studies. This Independent Scientist Award (K02) will allow the candidate to devote at least 80 percent of her time to research and related duties by release from teaching, administration, clinical work, and other responsibilities. The application proposes an integrated research development plan that includes (a) the further development of the candidate's dementia research emphasizing neuropsychological evaluations to understand behavioral heterogeneity in Alzheimer's disease and neuropsychological evaluations to document early detection and progression of Huntington's disease; and (b) the further development of knowledge in functional imaging to allow the candidate to assess relations among specific cognitive skills and brain functions in dementia. She also proposes to strengthen her statistical skills to be used in the analysis of data from these studies. This award will facilitate the candidate's research efforts towards understanding brain-behavior relations in dementia and using this knowledge to assist families and individuals in treatment planning for the future.

Overall Aims 1. To define the fundamental cognitive deficits in patients with schizophrenia, using principles adapted from cognitive and experimental neuropsychology. 2. To examine the neural circuit hypotheses of schizophrenia by investigating cognition in other conditions with known neural mechanisms that can serve as "Model syndromes" such as Huntington's disease or patients with circumscribed lesions. 3. To study the relationships between disordered cognition and psychopathology using patients with mood disorders and/or with psychotic disorders. 4. To develop and apply new cognitive tasks to patients with schizophrenia, emphasizing tests found to be sensitive to brain areas considered abnormal (according to imaging and/or animal studies) in schizophrenia.

DESCRIPTION (provided by applicant): Although treatments in animal models for HD have proven successful, and several clinical trials are underway in persons with manifest HD, there currently exists no methodology in which to test experimental therapeutics prior to diagnosis of manifest motor disease. The Predict-HD study is designed to provide essential methodology for the initiation of preventive clinical trials in Huntington's disease (HD). Early identification of neurological disease is imperative so that intervention using protective, gene therapy, and regenerative strategies can be initiated at high levels of life quality and prior to the occurence of irreversible cellular injury. The Predict-HD study has successfully recruited nearly 500 healthy participants who had previously undergone genetic testing for the HD expansion. Annual measures of brain imaging and cognitive performance are obtained in concert with other demographic, clinical and genetic information. Findings already suggest a remarkable convergence of the first detectable decline in brain morphology, motor skill, and cognitive ability at about 15 years prior to traditional motor diagnosis. This is notably earlier than had generally suspected and represents a major advance in our understanding of HD. With completion of the requested 3-year continuation of the Predict-HD study we will have longitudinal observations that allow us to: 1) Test and refine the model of early HD changes suggested by our baseline data; 2) Determine which measures of functional decline are concurrent with measureable brain morphology changes; and 3) Better understanding of the relationships among striatal and cortical changes, DNA repeat length, and clinical phenotype in HD. Completion of Predict-HD will result in a methodology and a cohort that can be readily applied to presymptomatic treatments as they become available. In addition to the contribution this will make towards early intervention in HD, our findings are likely to improve our understanding of the functional pathophysiology of other neurodegenerative and genetic illnesses.

disease /disorder onset; neurogenetics; Huntington's disease; nucleic acid repetitive sequence; nerve /myelin protein; clinical research; human subject;

clinical research; Huntington's disease; university; biomedical facility;

genetic susceptibility; neurogenetics; Huntington's disease; longitudinal human study; nerve /myelin protein; nucleic acid repetitive sequence; clinical research; human subject;

DESCRIPTION (provided by applicant): This study entitled "Response of a Sample Population with the Deleterious HD allele" (RESPOND-HD) will examine ethical, legal, and social considerations that may affect the experience of persons following genetic testing for Huntington's disease (HD). HD is a genetic brain disease that typically begins in mid-life. Since predictive testing for HD was one of the first genetic tests available for later onset disorders, research in HD has traditionally helped define issues for ethical, legal and social aspects of genetic disorders. As knowledge of the human genome increases, public apprehension concerning the use of such genetic information has grown correspondingly. Although practice standards in medicine generally require that health care decisions (including genetic testing) should be determined by a patient's personal values, it is difficult to assess how to fully inform consumers about predictive testing. Information understood by persons considering having a genetic test should include the clinical validity of genetic tests, availability of effective treatment, access to health care and insurance, legal and social implications of genetic information, and the psychological impact of having knowledge about one's future. Unfortunately, little is currently known about these issues following genetic testing. HD families, in particular, are appropriately concerned about social and legal consequences of being identified with a genetic illness. In this study, comparative qualitative interviews and quantitative data collection via survey and standardized rating scales will be obtained from individuals who have undergone predictive testing for the HD gene expansion. Unlike previous research, the RESPOND sample has undergone predictive testing in the past and data will allow for query of stigmatization and discrimination since receiving news of having a deleterious HD allele. Findings will examine how people perceive possible consequences, choose their behaviors, and make decisions after genetic testing. Data can be used for development of clinical care practices, research protocol, and legal policy. Over 300 persons from the NINDS-funded study entitled "Predict-HD" will be invited to participate in this study. Predict-HD is an ongoing study of biological and behavioral markers of disease in persons with a known gene expansion for HD. Data will be compared with the NHGRI-funded study entitled "PHAROS" which examines persons who are at risk for HD but chose not to undergo genetic testing. This study will be among the first to compare ethical, legal and social experiences of having known genetic risk.

[unreadable] DESCRIPTION (provided by applicant): Huntington's disease (HD) is a genetic brain disease that reveals itself in mid-life with slowly progressive dysfunction of motor, cognitive and emotional systems due to cell death in the striatum and related circuitry disruption. The genetic mutation consists of an expansion in the number of polyglutamine (CAG) repeats and the number of repeats is associated with HD onset, accounting for at least 50% of the variability in age. Efforts are underway to better understand the pathogenesis of HD and to derive more discrete estimates of its onset. In another study we are evaluating persons who have the gene mutation for HD, but do not yet demonstrate the clinical signs of illness (hereafter referred to pre-HD). Structural MRI and comprehensive neuropsychological and psychiatric assessments are being conducted to detect subtle disease before traditional motor symptoms appear. Preliminary work from our group suggests that a combined use of imaging and cognitive challenge tasks allow detection of early dysfunction. Using cognitive-activated magnetic resonance imaging (or functional MRI) we hope to increase our understanding of normal basal ganglia function and allow us to monitor and characterize the development of basal ganglia pathology in HD. Sixty pre-HD and thirty healthy control subjects will be enrolled and examined longitudinally at two time points separated by a 30-month interval. The MRI sessions will include anatomical scans to assess brain structure and functional MRI (fMRI) of four cognitive tasks sensitive to basal ganglia function: time discrimination, conceptual reasoning, motor timing, and response inhibition. The specific aims are to examine the sensitivity of fMRI in identifying neural dysfunction in pre-HD participants and to determine the association between DMA-based estimations of disease onset and indices of brain dysfunction over time. The proposed project will advance our understanding of the neurobiology of HD as well as the role of corticostriatal circuitry in mediating cognitive functions. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This R13 conference grant is to provide support for the World Congress on Huntington Disease (WCHD). The WCHD 2009 will take place September 13th through September 15th in Vancouver, British Columbia in Canada. The format of the program includes six parallel sessions (two each day of the conference), each emphasizing different aspects of research and clinical care. The conference is unique in its multidisciplinary, collaborative approach where basic scientists, clinical researchers, clinical trialists, family practitioners, nurses, social workers, counselors, psychologists, neurologists, HD family members, HD patients, HD lay organizations, private foundations, and friends join together to learn about the current state of HD and provide input into improved care and treatments. The conference will provide a forum to openly discuss "hot topics" to dialogue among the various stakeholders to decide how best to move forward. Hot topics suggested include research and genetic testing in children, whether animal studies are needed prior to human trials, and why the diagnosis of HD is given a decade after signs and symptoms are evident. The R13 will support the attendance of 6 junior investigators who would otherwise not attend and will allow participation from senior investigators from related fields to encourage greater cross-talk among the brain diseases. Continuing education is available and conference proceedings will be published on the WEB and in Clinical Genetics.

DESCRIPTION (provided by applicant): This project proposes the mining of plasma and cerebrospinal fluid (CSF) biomarkers of disease progression in Huntington Disease (HD) using the latest analytical tools to accelerate future treatment studies.

Project Summary Over the past decade, we have been building, parsing and wrangling systems for extracting neurodegeneration and neurodevelopment biomarkers from high-dimensional magnetic resonance (MR) imagery at 1 mm3 scale which are discriminating. At the same time, large and complex data sets and networks of segmented structures are becoming increasingly available to the research community such as Predict-HD, Track-HD, ADNI, and SchizConnect. Neuroscientists and clinicians are interested in tracking biomarkers which characterize rates of atrophy in anatomical networks, onset of or changepoint times of spread through the networks, and prediction of risk to conversion as determined by clinical symptoms. These wrangling and modeling methods are novel. Our biomarkers are extracted via brain mapping technologies based on diffeomorphometry, the study of morphological change via diffeomorphic tracking of anatomical coordinate systems at the sub millimeter scale. Like stereology, diffeomorphometry discovers high-dimensional features signalling neurodegeneration and neurodevelopment via tight integration of random field based statistical methods via large deviation empirical probability estimators calculated via high-dimensional permutation testing. Family-wise rates are calculated for group comparisons, and have been advanced changepoint modelling allowing us to explicitly estimate the spread of progression of anatomical feature change through the networked structures associated to neurodegeneration - Alzheimer's Disease (AD) and Huntingdon's Disease (HD) and neurodevelopment - Schizophrenia (SZ) and Attention Deficit and Hyperactive Disorder (ADHD). These tools will be disseminated and tested via MriCloud. We will perform three specific aims. Aim 1 will use our MriCloud architecture to deploy a Multi-Atlas Brain Mapping module for mapping an ontology of approximately 400 structures to T1 and DTI data. The architecture will support many atlases which are matched across a broad range of age from pediatric to geriatric groups, and as well as several diseases. Aim 2 will deploy a Statistical Shape Diffeomorphometry module consisting of pipelines for a) generating templates of structures from populations of cross-sectional datasets, b) data reduction to templates for cross-sectional and longitudinal geodesic mappings, and c) multiple hypothesis testing procedures based on vertex, Laplace-Beltrami basis functions and PCA basis functions. Users with their own ontology definitions of the subcortical structures will be able to generate population templates and visualize the statistics in template coordinates. Aim 3 will generate a webportal for users to use modules from Aims 1 and 2 to examine abnormalities in networks of structures such as the striatum, thalamus, amygdala and hippocampus.

Project Summary Huntington disease (HD) is a fatal, costly, autosomal dominant neurodegenerative disease with no available disease-modifying treatments. While genetic testing can identify the presence of the mutant HTT gene, there are no markers to document the initiation of pathological changes or demarcate when preventive interventions are optimal to maximize quality of life. While clinical trials to slow progression and delay or prevent onset are beginning, methods to assess their efficacy are lacking. The proposed research will fill these gaps in our ability to design preventive clinical trials for HD. First, we will use the legacy PREDICT data to develop statistical models of onset, progression rate and phenotypic heterogeneity and then we will recruit 250 participants to complete the field's best Clinical Outcome Assessments (COAs) for premanifest HD and subject them to clinimetric tests of reliability, validity and responsiveness so future preventive trialists can utilize the information to design well-powered and efficient trials to delay the onset or slow the progression of HD

Project Summary/Abstract Our group completed the natural history study of premanifest Huntington disease (HD) entitled Predict-HD which evaluated over 1400 research volunteers who were healthy but had undergone the predictive test for the gene that causes HD. Findings revealed that signs and symptoms of HD were evident up to 15 years before the traditional diagnosis of HD was given in the clinic. From these data we were able to develop models of prognosis, disease progression and prediction of HD onset. Disease-modifying clinical trials are currently underway to slow the progression, or delay the onset, of HD. More recently, a collaborative group published an assay to measure the amount of mutant huntingtin protein in the cerebral spinal fluid of HD participants. Questions of central importance to the success of this measure for clinical trials require investigation: (1) how reliable is the measure in the same person when repeated (intra-subject test-retest reliability); (2) how reliable is the measure in the same person when analyzed by two different labs (inter-lab reliability); (3) does the measure reflect disease symptoms (content validity); (4) does the measure predict meaningful disease outcomes (prognostic validity); (5) does the measure track disease progression or severity; and (6) how many (and what stage of HD) research subjects do we need to know with confidence that an intervention is working (i.e., delaying onset/slowing progression)? The proposed research study will address all of these limitations to more effectively test new experimental interventions such as gene therapies and new drugs. Findings will immediately inform how the field should best design preventive clinical trials for HD.

Project Summary/Abstract Our group completed the natural history study of premanifest Huntington disease (HD) entitled Predict-HD which evaluated over 1400 research volunteers who were healthy but had undergone the predictive test for the gene that causes HD. Findings revealed that signs and symptoms of HD were evident up to 15 years before the traditional diagnosis of HD was given in the clinic. From these data we were able to develop models of prognosis, disease progression and prediction of HD onset. Disease-modifying clinical trials are currently underway to slow the progression, or delay the onset, of HD. More recently, a collaborative group published an assay to measure the amount of mutant huntingtin protein in the cerebral spinal fluid of HD participants. Questions of central importance to the success of this measure for clinical trials require investigation: (1) how reliable is the measure in the same person when repeated (intra-subject test-retest reliability); (2) how reliable is the measure in the same person when analyzed by two different labs (inter-lab reliability); (3) does the measure reflect disease symptoms (content validity); (4) does the measure predict meaningful disease outcomes (prognostic validity); (5) does the measure track disease progression or severity; and (6) how many (and what stage of HD) research subjects do we need to know with confidence that an intervention is working (i.e., delaying onset/slowing progression)? The proposed research study will address all of these limitations to more effectively test new experimental interventions such as gene therapies and new drugs. Findings will immediately inform how the field should best design preventive clinical trials for HD.

Project Summary/Abstract Our group completed the natural history study of premanifest Huntington disease (HD) entitled Predict-HD which evaluated over 1400 research volunteers who were healthy but had undergone the predictive test for the gene that causes HD. Findings revealed that signs and symptoms of HD were evident up to 15 years before the traditional diagnosis of HD was given in the clinic. From these data we were able to develop models of prognosis, disease progression and prediction of HD onset. Disease-modifying clinical trials are currently underway to slow the progression, or delay the onset, of HD. More recently, a collaborative group published an assay to measure the amount of mutant huntingtin protein in the cerebral spinal fluid of HD participants. Questions of central importance to the success of this measure for clinical trials require investigation: (1) how reliable is the measure in the same person when repeated (intra-subject test-retest reliability); (2) how reliable is the measure in the same person when analyzed by two different labs (inter-lab reliability); (3) does the measure reflect disease symptoms (content validity); (4) does the measure predict meaningful disease outcomes (prognostic validity); (5) does the measure track disease progression or severity; and (6) how many (and what stage of HD) research subjects do we need to know with confidence that an intervention is working (i.e., delaying onset/slowing progression)? The proposed research study will address all of these limitations to more effectively test new experimental interventions such as gene therapies and new drugs. Findings will immediately inform how the field should best design preventive clinical trials for HD.

Project Summary/Abstract The project addresses vascular contributions to cognitive impairment and dementia (VCID) using a design that exploits the enrollment of persons with the autosomal dominant gene for Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Exploration of VCID by focusing on the rare heritable monogenic disorder, CADASIL, will advance knowledge of the full spectrum of vascular dementia from presymptomatic gene carriers through dementia and will facilitate an examination of mixed dementia in CADASIL participants also having AD. This research is novel from any other in its efforts to study a single-gene vascular dementia group throughout the life span in an effort to reduce vascular dementia heterogeneities selecting persons enriched for certain future vascular disease secondary to NOTCH3 gene mutation. CADASIL is caused by a mutation in the gene NOTCH3, which encodes a receptor protein. Although rare, CADASIL is the most common heritable cause (due to a single gene mutation) of vascular dementia. Many consider CADASIL to be a good single gene model of small vessel disease and vascular dementia. By improving our understanding of CADASIL and its progression, we will be better able to understand VCID as well as mixed dementias having both CADASIL and the most common sporadic dementia, Alzheimer's disease. This is particularly important because of the fact that many cases of Alzheimer's disease have co- occurring vascular dementia. More than 200 genetic variations in NOTCH3 have been identified, but it is not known which cause milder, or more severe, forms of VCID. Furthermore, among the NOTCH3 mutations known to cause CADASIL, and even within CADASIL families, there is wide variability in age at onset, disease progression, brain imaging abnormalities and presentation of symptoms. Some recent data reported by the CADASIL European Consortium suggests that patients with mutations in certain parts of NOTCH3 cause a more severe form of CADASIL than do mutations in other parts of the gene. It's also likely that variations in other genes influence the effect of NOTCH3 mutations on VCID. Unfortunately, no large cohort of CADASIL patients for clinical research has been organized in North America. Better understanding of the associations between clinical presentation, potential disease modifiers (i.e., risk factors) and NOTCH3, as well as other gene variations in a new cohort in the United States could improve understanding of the causes and severity contributions to various forms of small-vessel disease and vascular dementia. To accomplish this, we will recruit, characterize and follow longitudinally a cohort of 400 NOTCH3 variant/mutation carriers, plus 100 non- carriers as controls, from U.S. CADASIL families. Participants will be evaluated every 18 months with detailed neurological, cognitive, behavioral, functional, blood, genetic and brain MRI assessments. This study will provide critical information regarding CADASIL that will also advance understanding for the most common type of mixed dementias (viz., VCID and AD).