Jason Brandt, Ph.D. - US grants

Advances in molecular genetics will soon allow presymptomatic diagnosis of (or determination of increased genetic risk for) a large number of neuropsychiatric disorders. Such testing will enable researchers to study the evolution of disease in those determined to be at high genetic risk. More importantly, presymptomatic detection of disease will guide treatment, early intervention and prevention efforts. A-research program on testing for Huntington's disease (HD) using linked DNA markers was established at Johns Hopkins University in September 1986. The purpose of this research has been to determine: 1) the psychological and social consequences of presymptomatic diagnosis, 2) whether pre-testing characteristics can predict those consequences in individual cases, and 3) whether pre-testing education and counseling and post-test clinical follow- up can prevent or palliate morbid responses. To date, 38 healthy people at risk for HD have had informative predictive tests, and another 41 who want genetic testing are in the protocol. In the proposed continuation of this program, we will greatly increase the subject sample. We will enroll 150 new at-risk subjects and continue to evaluate all subjects tested (as well as those with uninformative tests and those who are non-tested controls) at regular intervals after testing to discover the psychological responses to knowledge of one's genetic status. We predict that: 1) those who test positive for the marker will, as a group, be slightly more distressed after testing than those who test negative, but will remain within normal limits on psychological tests and psychiatric interviews, and 2) social variables, personality characteristics, and psychological distress prior to genetic testing will be predictive of psychological and social outcome. Most of those who test positive for the genetic marker, and an individually-matched sample of those who test negative, will have semi-annual neurological, psychiatric, and neuropsychological evaluations, as well as annual MRI scans for quantitative brain volumetric studies and 18F-2-deoxyglucose PET scans for assessment of changes in regional brain metabolism. Using these techniques, we hope to be able to document the very earliest manifestations of disease onset. The hypothesis to be tested is that those who test positive for the marker will display morphologic changes in the caudate on MRI and reduced striatal glucose metabolism on PET prior to the emergence at risk for HD to determine the magnitude of the demand for presymptomatic testing and the variables that determine whether people risk for other neuropsychiatric disorders will seek predictive DNA testing.

This application requests continued funding for our highly successful program of Research Training in the Dementias of Aging. This program, which began in 1987, teaches postdoctoral physicians and psychologists how to conduct high quality research on disorders of great public health significance among the elderly. Most of the research training is the context of currently-funded projects at the Johns Hopkins School of Medicine. These include clinical and population-based surveys, longitudinal follow-up studies, laboratory-based case-control studies and clinical trials in Alzheimer's disease, Huntington's disease, Down's syndrome, delirium, and other syndromes of cognitive impairment. Research settings include the community, general hospital, and the nursing home, in addition to the laboratory. A large number of projects in the clinical neurosciences are currently available to fellows, with particular emphases on: instrument and measurement development; correlations between clinical/functional indicators and brain abnormalities revealed by neuroimaging methods; and application of genetic knowledge and methodology to the problems of dementing illnesses. Fellows receive two years of research tutelage and supervised experience, a full didactic program, and experience in the neuropsychiatry clinics. Past graduates of this training program have gone on to successful hospital and medical-school-based careers as clinical investigators.

Genetic linkages have been found to a number of neuropsychiatric disorders. In many cases, these discoveries will allow the development of presymptomatic diagnostic tests. Such testing will enable researchers to study the evolution of disease in those determined to be at high genetic risk. More importantly, presymptomatic detection of disease will guide treatment, early intervention, and prevention efforts. There has been great concern, however, about potential harmful effects of disclosing high genetic risk, especially for currently-incurable illnesses. A research program on testing for Huntington's disease (HD) using linked chromosome-4 markers was initiated in 1986. The purpose of this research has been to determine: 1) whether those with and without the linked DNA marker differ in their baseline neuropsychological and psychiatric characteristics, 2) the psychological and social consequences of presymptomatic diagnosis, 3) whether baseline characteristics can predict those consequences in individual cases, and 4) whether pre- testing education and counseling and post-test clinical follow-up can prevent or palliate morbid responses. To date, 74 healthy people at risk for HD have had informative tests, and another 42 who want genetic testing are in the protocol. In the proposed five-year continuation of this program, 90 new at-risk subjects will be entered into the testing protocol. All subjects will continue to be evaluated neurologically, psychiatrically, and neuropsychologically at regular intervals after disclosure of DNA test results. This application also contains two new initiatives. First, we will examine regional cerebral blood flow using the (15)O-labeled water PET technique in those subjects who test positive for the HD marker when they begin to display subtle changes in neurologic, affective, or cognitive status. This will enable us to determine which minor symptoms after testing herald disease onset, and will allow us to test hypotheses concerning the association of regional cerebral blood flow alterations with particular aspects of the clinical syndrome. The second new initiative consists of data analytic studies on the calculation of risk for HD based on linkage results. Using both real data from tested pedigrees and simulated data, the influence on estimation of risk of such factors as number of markers used, assumed allele frequencies, errors in ascribing paternity, and misdiagnosis of HD in relatives will be evaluated.

Determine if the regional cerebral blood flow (rCBF) of patients with isolated amnestic syndromes differs from that of healthy persons, particularly during performance of memory tasks.

Past efforts have focused on developing a well-characterized cohort of patients for longitudinal studies of the dementia syndrome of Huntington's disease (HD). To that end, groups of 80 HD patients and 22 control subjects have been recruited. In the next five years, the patient sample will be augmented with patients of early and late onset age Clinical Core. We will follow that cohort of 150 patients and 40 gene-negative controls in our Longitudinal Core Study to characterize, for the first time, the natural history of dementia in HD. This study is a collaborative effort between this Project. Neuroimaging Project and the Clinical Core. The cognitive data from this longitudinal study will be analyzed in conjunction with the annual assessments of disease severity as indexed by clinical measures (neuroimaging) obtained biannually on the same patients. The pattern and rate of cognitive decline will be examined, and the relative contributions of severity and rate of striatal and cortical atrophy, CAG repeat length (CoreD), and onset age to differences in rates of decline will be determined. The delineation of the natural history of dementia in HD will be helpful to clinicians in managing patient care, and will be particularly relevant for future clinical trials of potential therapeutic agents. Voluntary motor impairment is prominent in HD, but has not been examined extensively. Severity of impairment appears to vary across patients and across motor tasks. Voluntary motor performance will be assessed in mildly to moderately affected patients using the motor impairment scale from the Quantitated Neurological Exam, a limb apraxia battery, motor learning tasks, and tasks assessing the timing programming and sequencing of motor actions. Motor task performance will be related to cortical and subcortical atrophy to determine the anatomical correlates of impaired voluntary movement in HD, and to the Huntington's Disease Activities of Daily Living Scale to assess the impact of voluntary motor impairment on functional abilities. These studies will delineate those aspects of voluntary motor performance most affected in HD and lead to a better understanding of the anatomical correlates of voluntary motor activity in general.

Regional cerebral blood flow and structural brain changes are being studied through a 5-year longitudinal protocol involving asymptomatic persons with and without the Huntington's disease mutation. This will document the earliest neuroimaging evidence of HD and the relation between neuroimaging changes and clinical course. We have enrolled 25 mutation-carriers and 29 non-carriers. First year follow-up scans have been completed on 13 carriers; second year follow-up scans have been completed on 3 carriers. Repeat scans have been completed on 5 non- carriers.

DESCRIPTION (from the abstract): The overall goal of this project is to facilitate the discovery and implementation of rational therapy for HD by careful analysis of the unique clinical data generated in the Clinical Core, defining the determinants of the course of HD. This will be accomplished by examining three different sets of hypotheses. In Specific Aim 1, we will test the hypothesis that CAG repeat number and other variables can be used to develop accurate models of the onset and course of HD. We hypothesize that CAG repeat length has a small but significant influence on the rate of disease progression. We will also test the hypothesis that familial factors in addition to CAG repeat length affect the course of HD. In Specific Aim 2, we will characterize neuropsychological features of early HD, and correlates of clinical and brain abnormalities. In Specific Aim 3, we will use a novel robotic system for defining the progressive motor disorder in HD expansion positive individuals and HD patients. In Specific Aim 4, we will test the hypothesis that diseases similar to HD are also caused by CAG expansion mutations. We will identify the genetic etiology of one of these diseases. In summary, we will provide new approaches for understanding HD?s clinical course, which will provide clues to pathogenesis and the development of novel treatment strategies.

Patients with early AD exhibit impairments in the monitoring and control of cognitive processing (i.e., executive dysfunction [ED]). Recent evidence suggests that the appearance of ED in elderly persons with mild cognitive impairment (MCI) may be a precursor of dementia. However, executive function encompasses several different, dissociable, cognitive processes, and the relevance of particular executive deficits to functional decline has not yet been established. In addition, MCI has been variably defined, and precisely which patients are at high risk for functional decline leading to dementia is not yet clear. Therefore, the primary goals of this study are: 1) to determine the specific executive domains that are impaired in patients with amnestic and nonamnestic forms of MCI; 2) to determine the extent to which particular executive impairments affect everyday functioning differentially in these groups; 3) to determine whether ED among subtypes of MCI is predictive of subsequent functional decline, measured by the sum of boxes from the Clinical Dementia Rating scale (CDR-SB); and 4) to test a factor analytic model of executive functioning in normal elderly and those with MCI. Patients with amnestic MCI, nonamnestic MCI and normal control participants will be recruited. They will be studied with 18 cognitive tasks that are proposed to assess six conceptually distinct domains of executive function: 1) inhibition of prepotent responses; 2) decision-making and judgment; 3) planning and sequencing; 4) concept/rule learning and set shifting; 5) spontaneous flexibility and generativity; and 6) working memory and resource-sharing. Confirmatory factor analysis will be used to test and validate this cognitive model, which will be modified if necessary. Questionnaires assessing subjects' everyday functioning will be completed by knowledgeable informants to assess the impact of ED in daily life. The executive factor scores of the two MCI groups and the normal control group will be compared with regression models for multivariate outcomes. They will also be examined as predictors in regression models of scores on the Dysexecutive Questionnaire and the ADCS/MCI-ADL scale. All participants will have annual clinical re-evaluations, and incident cases of dementia will be recorded. Two years later, all available subjects will be re-examined with the executive function tasks and questionnaires. The re-test data will allow us to determine the progression of particular executive impairments and their predictive validity as pre-dementia markers of functional decline (CDR-SB score) in amnestic and nonamnestic MCI.