Lawrence Honig - US grants

DESCRIPTION (Adapted from the Applicant's Abstract): Ischemia/reperfusion injury is caused by activation of cytotoxic and inflammatory cascades during the reperfusion period. Injury in experimental animals can be modestly decreased by inhibition of either of these two pathways. They recently found the a-MSH protects against severe renal ischemia/reperfusion injury, even when started during the reperfusion period. a-MSH is a neuropeptide with broad anti-inflammatory properties. They found that a-MSH inhibits the synthesis of cytokines, chemoattractive chemokines and NO. It is not known why a-MSH is so effective in preventing ischemia/reperfusion injury. They hypothesize that a-MSH prevents the maladaptive activation of both the cytotoxic (NO) and inflammatory (neutrophile) cascade. They will investigate the following Specific Aims: In Aim #1, they will define the spectrum of activity of a-MSH in treating ischemia/reperfusion injury. They will determine when a-MSH is active during the reperfusion period and if a-MSH accelerates recovery from established renal failure. In Aim #2, they will localize the MSH receptors to specific portions of the nephron and vasculature using in situ hybridization and RT/PCR. They will also determine where a-MSH is produced. In Aim #3, they will determine the effect of a-MSH on ischemia induced cytotoxicity mediated by NO. They have preliminary evidence that a-MSH inhibits the production of iNOS during ischemia/reperfusion. They will determine if NO is responsible for tissue injury in kidneys, isolated perfused kidneys and isolated tubules subjected to ischemia. In Aim #4, they will determine the effect of a-MSH on the ischemia-induced injury mediated by neutrophiles. They will study the effect of a-MSH on neutrophile infiltration, expression of renal chemattractants and endothelial cell adhesion molecules in the ischemic models.

The Clinical Core goals are to enroll, thoroughly clinically evaluate and characterize, and longitudinally follow elderly persons from diverse ethnic backgrounds, over the spectrum from those without dementia, to those with mild cognitive impairment (MCI), and with Alzheimer's disease and related dementias. The objectives are to further understanding of the etiologies of MCI in a community-representative sample of elderly individuals of differing cultural, ethnic, and socioeconomic origins, to assess factors involved in development of MCI and conversion of MCI to AD, and to provide well-characterized patients for research projects. The core will recruit a new cohort from a special population of about 500 community or apartment-dwelling individuals who receive home health care from nearby Isabella Geriatric Center. Most of these are not demented; most are Hispanic or African American. The focus will be assessment and follow-up of MCI, and the contributions of co-morbidities. The core will provide well-characterized subjects for research studies into aging and dementia, and will follow these subjects to autopsy. Rigorous standardized subject evaluations will include medical and neurological examinations, and neuropsychological and laboratory testing. Neuroimaging using MRJ will be performed in a subset of subjects. The value of brain autopsy will be emphasized, and the core will continue close interaction with the Neuropathology Core, since autopsy neuropathological examination generates definitive data regarding the disease processes during life, and also provides valuable brain tissue for proteomic, gene expression, mitochondrial, biochemical and genomic biological investigations. The Core will interact closely with the Data Management and Statistical Core, to ensure complete and highly standardized data collection and entry, allow consistent data analysis within the ADRC and allied projects that utilize ADRC subjects, and facilitate data transfer as specified by the National Alzheimer's Coordinating Center (NACC). Clinical Core activities will be a resource for a large number of federal, pharmaceutical, and foundation research projects, including clinical drug trials, neuroimaging studies, neuropsychological instrument trials, and research studies on risk factors.

CLINICAL CORE SUMMARY The Clinical Core is the central working component of the Alzheimer s Disease Research Center, under the overall direction of the Administration Core. It is a shared resource for the entire ADRC, interacting closely with Outreach, Recruitment, & Education Core (recruitment and training), Data Management and Statistical Core (data storage, retrieval, and management), Neuropathology Core (arranging brain autopsy, and providing related clinical data), and Genetics Core (providing DNA samples for genetic analyses, and clinical data). The primary activities of the core are to recruit participants, and perform detailed evaluations of the participants, obtaining data and resources that can be used by the other Cores, Projects, and Pilot Projects, as well as nationally and internationally through collaborations and provision of data to the National Alzheimer s Coordinating Center (NACC). The Core at Columbia university proposes to continue its 24 years of recruitment of well-followed, well-characterized research participants of diverse ethnoracial background including about 40% under-represented groups: currently we have enrolled >5,700 individuals, nearly 1600 of which are in the NACC Uniform Data Set (UDS), and 40% are minorities -- including 20% Hispanic and 11% African American enrollees. During the past 8 years of UDS data collection, the Core has contributed to the UDS more participants (1596), and has more active participants (904), than any one of the other 26 NIA-Alzheimer centers. The Clinical Core emphasis is on recruitment of normal controls and persons with mild impairment, allowing greater research into normal aging, and the transition from normal aging to mild cognitive impairment (MCI) and dementia. The Core also continues to recruit participants with less usual dementias, to promote better neuropathological and molecular understanding of the mixed and atypical dementia disorders, including Dementia with Lewy Bodies, Frontotemporal Dementia, Creutzfeldt-Jakob Disease, and Vascular Cognitive Impairment and Dementia. Evaluations include detailed medical interviews and examinations, neurological examinations, NACC-UDS and Columbia-specific neuropsychological testing, blood samples for plasma and DNA preparation and storage by the Genetics Core, increasing numbers of CSF specimens and neuroimaging data including MRI, SPECT, and PET scans, and ultimately brain neuropathological specimens for the over 50% of our participants currently consenting to brain autopsy. The Core coordinates closely with Administrative, Data, Education, Genetics, and Neuropathology Cores. Participants are informed of other trials and projects, and encouraged to participate in these important imaging, instrument, drug study, and other trials. The Clinical Core provides training to students, residents, fellows, and investigators. Participant data, images, and biological specimens, including plasma, DNA, CSF, brain tissue are shared with ADRC, other Columbia, and extramural investigators to improve diagnosis, understanding and treatment of aging and dementia, promoting basic and translational research at Columbia, in the New York area, and nationwide. .

SATELLITE DIAGNOSTIC AND TREATMENT CLINIC CORE SUMMARY The Satellite Diagnostic and Treatment Clinic Core ( Satellite Core ) is a longstanding component of the ADRC. It operates together with and in the same vein as the Clinical Core, but serves the primary purpose of enriching for individuals from under-represented minority groups. Thus the Core distinguishes itself in that: (a) its primary purpose is enrollment of minorities; (b) participants also receive clinical care in addition to research evaluations; (c) it is an important part of the community enabling highly expert clinical care of persons with cognitive concerns or dementia who are part of minority groups, and may not have resources to seek such care elsewhere; (d) it serves the Spanish-speaking community. Since 2011, the Core has been at the New York State Psychiatric Institute. The aims of the Satellite Core are like those of the Clinical Core, but with emphasis on minority recruitment and care. Like the Clinical Core, there is an emphasis on recruitment of persons with milder symptoms, such as persons with mild cognitive impairment, in addition to persons with dementia. The Core also continues to recruit participants with less usual or mixed dementias, to promote better neuropathological and molecular understanding of atypical disorders, including Frontotemporal Dementia, Dementia with Lewy Bodies, and Vascular Cognitive Impairment. Risk factors differ in the minority population, and thus vascular, depressive, and other medical disease components may have greater impact in Satellite enrollees. Participants and data obtained in the Satellite Core join that of the Clinical Core as a shared resource for the entire ADRC. The Core interacts with Outreach, Recruitment, & Education Core (recruitment and training), Data Management and Statistical Core (data storage, retrieval, and management), Neuropathology Core (arranging brain autopsy, and providing related clinical data), and Genetics Core (providing DNA samples for genetic analyses, and clinical data). Primary core activities are to recruit participants, perform detailed evaluations, and provide data and resources for use by other Cores, Projects, and Pilot Projects, as well as national and international collaborations, including the National Alzheimer s Coordinating Center (NACC). Evaluations include detailed medical interviews and examinations, neurological examinations, NACC-UDS and Columbia-specific neuropsychological testing, blood samples for plasma and DNA preparation and storage by the Genetics Core, increasing CSF and neuroimaging data, and ultimately brain neuropathological specimens for participants consenting to brain autopsy. Participants are informed of other trials and projects, and encouraged to participate in these important imaging, instrument, drug study, and other trials. The Satellite Core provides training to students, residents, fellows, and investigators. Participant data, images, and biological specimens, including plasma, DNA, CSF, brain tissue are shared with ADRC, other Columbia, and extramural investigators to improve diagnosis, understanding and treatment of aging and dementia, promoting basic and translational research at Columbia, in the New York area, and nationwide.

Project Summary/Abstract Lewy body disorders include Parkinson?s Disease Dementia (PDD) and Dementia with Lewy Bodies (DLB). DLB is particularly problematic since it is often not appreciated until late stages, and often is admixed pathologically with concomitant Alzheimer?s disease (AD). Clinical care and the design of symptomatic and disease modifying trials for DLB would benefit from earlier diagnosis and reduced pathological heterogeneity. Thus, it is important to identify the extent to which Lewy Body versus AD pathology contributes to the phenotype and underlying biology of DLB, and to discover new molecular targets that specific to DLB. Clinically, we are uniquely poised to recruit a multiethnic cohort of DLB patients derived from both the local /metropolitan community, the Alzheimer?s Disease Research Center [ADRC], and the broader practice settings of the Aging and Dementia, Movement Disorders, and primary care programs at Columbia University. We will capture the continuum of cognitive impairment and extrapyramidal signs that exist in DLB. In Aim 1, we will identify and recruit an ethnically diverse (White, Hispanic, African American) cohort of 40 DLB patients per year for years 1-4, who will be followed semi-annually. We will administer the NINDS Parkinson?s Disease Biomarkers Program (PDBP) battery, the NIA National Alzheimer Coordinating Center (NACC) UDS3 with the new DLB module. In Aim 2, we will perform RNA gene expression and epigenetic (DNA methylation) profiling on dissected brain tissue from our Columbia University brain bank including cases with pathologically defined Lewy Body Disease with AD pathology (DLB/AD) and without significant AD (DLB), cases with AD, and controls to identify Lewy body specific differences primarily by comparing DLB/AD and AD. In Aim 3, we will use expression data from Aim 2, to develop biomarker assays in blood and CSF, including at RNA and protein levels. This aim will first utilize plasma from cases who have autopsy proven diagnosis, and will then be expanded to samples with clinical diagnoses.