Gregory G. Brown - US grants

The overall aim of this project is to determine, using 31-Phosphorous (31P) and proton (1H) nuclear magnetic resonance (NMR) spectroscopy, if brain metabolic markers exist that will distinguish Alzheimer's disease from dementia associated with multiple sites of subcortical ischemia. A five year longitudinal study will investigate clinical, imaging (magnetic resonance imaging, MRI), metabolic (in vivo 31P and 1H NMR) and neuropathologic data in selected patients with multiple subcortical ischemic dementia (MSID), Alzheimer's disease (AD), or mixed AD and vascular disease. and in nondemented elderly controls. The study aims to characterize changes in brain energy phosphate, phospholipid metabolism, pH, free magnesium, N-acetyl aspartate, and cholinated compounds that might accurately predict clinical and pathologic diagnoses of AD, MSID, and mixed MSID/AD. Further, two hypotheses will be tested to explain the shift towards the high energy phosphate end of the phosphorus spectrum previously reported in MSID. One hypothesis attributes the shift to a decreased utilization of molecular energy in superficial brain regions disconnected from neuronal input by subcortical lesions. The other hypothesis attributes the shift to increased astrocytic reactivity in cortical regions that have been subjected to mild levels of ischemia. The first hypothesis predicts that the extent of the high energy phosphate shift should be correlated with the extent and location of the subcortical white matter hyperintensities observed on MRI. The second hypothesis predicts that MSID patients with a shift towards the high energy phosphate end of the phosphorus spectrum will have microcavities and increased glial immunoreactivity in cortical regions where spectra are obtained, even though these areas appeared to be normal on MRI.

The general aim of this study is to gain a better understanding of a phenomena that we have observed in a large minority (about 40%) of non-demented patients with Parkinson's disease. The phenomena involves PD patients showing a greater degree of semantic facilitation (priming) than controls on a version of the lexical decision task used in our laboratory. Our general strategy in studying this phenomena will be to determine whether this counterintuitive effect can be related to any of the other cognitive and motor abnormalities present in non-demented PD patients. Three potential explanations for increased semantic priming in PD will be considered: the motor slowing facilitation hypotheses, the degraded semantic knowledge hypothesis, and the impaired decision making hypothesis. The first experiment will seek to determine whether motor slowing and reduced recognition vocabulary contribute to semantic facilitation on a word pronunciation task, where postlexical decision making processes contribute little to performance. This experiment will compare the performance of Parkinson patients on and off anti-Parkinsonian medication. The second experiment will manipulate the type of prime (associative vs categorical) and the base rates for words appearing on the lexical decision task in order to influence the decision making strategy of subjects. The third experiment will attempt to determine whether increased semantic priming is greatest for words about which subjects have degraded semantic knowledge. This study will attempt to replicate previous work in Alzheimer's disease and extend the results to demented and nondemented patients with Parkinsonism. Furthermore, this study will aim to determine whether the breakdown of semantic knowledge, when it is observed in dementing conditions, involves specific words or specific case relations. Data from this study may help clarify inconsistent findings in the literature about lexical decision making in Parkinsonism. They may also establish the importance of the neglected decision making stage of lexical decision performance and help with the interpretation of lexical decision results obtained in other aphasic and degenerative conditions. These experiments may contribute to the development of a neuropharmacologic theory of cognitive functioning in Parkinsonism and may identify a subgroup of nondemented Parkinson patients at risk for cognitive dysfunction.

The overall aim of this project is to determine, using 31-Phosphorous (31P) and proton (1H) nuclear magnetic resonance (NMR) spectroscopy, if brain metabolic markers exist that will distinguish Alzheimer's disease from dementia associated with multiple sites of subcortical ischemia. A five year longitudinal study will investigate clinical, imaging (magnetic resonance imaging, MRI), metabolic (in vivo 31P and 1H NMR) and neuropathologic data in selected patients with multiple subcortical ischemic dementia (MSID), Alzheimer's disease (AD), or mixed AD and vascular disease. and in nondemented elderly controls. The study aims to characterize changes in brain energy phosphate, phospholipid metabolism, pH, free magnesium, N-acetyl aspartate, and cholinated compounds that might accurately predict clinical and pathologic diagnoses of AD, MSID, and mixed MSID/AD. Further, two hypotheses will be tested to explain the shift towards the high energy phosphate end of the phosphorus spectrum previously reported in MSID. One hypothesis attributes the shift to a decreased utilization of molecular energy in superficial brain regions disconnected from neuronal input by subcortical lesions. The other hypothesis attributes the shift to increased astrocytic reactivity in cortical regions that have been subjected to mild levels of ischemia. The first hypothesis predicts that the extent of the high energy phosphate shift should be correlated with the extent and location of the subcortical white matter hyperintensities observed on MRI. The second hypothesis predicts that MSID patients with a shift towards the high energy phosphate end of the phosphorus spectrum will have microcavities and increased glial immunoreactivity in cortical regions where spectra are obtained, even though these areas appeared to be normal on MRI.

DESCRIPTION (provided by applicant): Despite the common and debilitating effects of post-traumatic stress disorder (PTSD), many current drug therapies for chronic PTSD leave residual symptoms. The development of improved therapeutic approaches for treating and/or preventing PTSD is likely to result from the better understanding of the neurobiology of PTSD that can be gained from animal model refinement. To create a model of PTSD pathology for treatment and mechanistic studies we propose to examine the association between two consistent biomarkers linked to PTSD symptom severity: (1) disruptions in hippocampal structure and function and (2) increases in CRF levels in cerebrospinal fluid (CSF). The project aims to determine if CRF hypersignaling is sufficient to induce hippocampal alterations and if these effects are reversible. The project uses a novel integration of ultra high- resolution, manganese-enhanced magnetic resonance imaging (MEMRI) with perfusion MRI to study hippocampal volume and blood flow in a transgenic mouse model of PTSD. The study's specific aim is to examine hippocampal volume and function before and after transient over expression of corticotropin releasing factor (CRFOE) in the forebrain. In a between group, longitudinal design, 24 transgenic mice that transiently over-express CRF when treated with doxycycline (Camk2a-rTta2 dox-on system combined with tet-o-CRF transgene) will be compared with 24 untreated mice at baseline, following one month of doxycline treatment for the experimental group and 100 days following termination of doxycycline treatment. Previous research has shown that the proposed transgenic mouse model has temporal and regional control over CRF expression via the Camk2a-rTta2 transgene technology. Mutant mice treated for 3 weeks with doxycycline chow exhibit an up to 2-3 fold increase in CRF mRNA in hippocampus and cortex, robust increases in CRF peptide in hippocampus, while cerebellum, brainstem and other non-forebrain regions remain unchanged. These mice also exhibit behavioral impairments on hippocampal-dependent memory tasks. The feasibility of the study is demonstrated by the establishment of the dual transgenic mouse model at UCSD and by the implementation at UCSD of an ultra high-resolution, MEMRI and mouse MRI perfusion protocols. The study design takes advantage of the repeatability of MRI and will involve imaging protocols that directly translate into human PTSD studies. The study is consistent with Objective 3 of the NIMH strategic plan to develop new and better interventions for people with mental illnesses. The potential impact of the study is related to the temporal control of CRF over-expression as a means to study the timing of interventions that might protect or reverse the hippocampal dysfunction observed in PTSD. This timing information should aid in the optimization of animal treatment studies and could provide information about the etiology of hippocampal dysfunction in stress disorders in general and PTSD in particular. PUBLIC HEALTH RELEVANCE: Despite the common and debilitating effects of post-traumatic stress disorder (PTSD), many current drug therapies for chronic PTSD leave residual symptoms. The proposed study aims to validate a mouse model of PTSD that uses magnetic resonance imaging to assess hippocampal tissue volume and blood flow before and following the transient release of corticotropin releasing factor, a neuropeptide involved in the regulation of the stress response. If successful, the mouse model could serve as a neurobiological platform for testing new interventions that protect against and/or treat PTSD.

NEUROIMAGING(Nl)CORE Given the adverse effects of HIV infection (HIV+) and methamphetamine use (METH+) oh brain structure and function, their combined effects, whether additive or synergistic, would be expected to produce a significant brain disorder. Moreover, as treatment of HIV infection has improved longevity and as the large cohort of METH users age, brain changes related to aging and to the comorbidities of aging are likely to contribute to HIV+ and METH+ related alterations in brain structure and function. In particular, age-related cerebrovascular disease might alter cerebral blood flow, potentiate white matter changes and alter gray matter volume. Aging is also likely to exacerbate changes in brain connectivity expected from white matter changes associated with HIV+ and METH+. Whether the aging contribution to changes of brain structure and function is additive or synergistic to that expected from HIV infection or METH use are unknown. This Core proposes to use translational multi-modal imaging to support investigations into the extent to which aging mediates brain changes associated with HIV infection, methamphetamine dependence and their interaction. To support these investigations the Nl Core Resource Objectives are to: (1) provide TMARC investigators with a core set of human and mouse imaging data; (2) provide specialized imaging protocols and advanced image analysis tools to support new directions in emerging imaging technologies; and (3) train investigators in imaging methods. The Nl Core Scientific Objectives are to: (1) investigate the separate and joint brain abnormalities underlying the neuropsychological and functional disabilities of patients with HIV infection and METH use and their interaction with aging; (2) use multimodal imaging methods to link white matter changes seen in METH use and HIV infection to alterations of functional connections among brain centers; (3) use magnetic resonance imaging protocols comparable to those used in human studies to link human imaging findings to imaging findings in mouse models of HIV infection and methamphetamine use.