Karen S. Marder - US grants

Dementia in Parkinson's disease (PD) is a frequent complication that often limits the efficacy of pharmacotherapy and may decrease survival. We propose that the majority of demented patients have Alzheimer's disease (AD) and dementia will be associated with the risk factors for the development of Alzheimer's disease (AD). Dementia in the remaining patients is a late effect of PD and may be due to increased exposure or a critical period of exposure to the risk factors responsible for PD. Using a case-control approach, we will collect genetic and environmental risk factor information in 150 demented PD patients, 150 nondemented PD patients and 300 healthy elderly patients, all previously identified and examined neurologically and neuropsychologically. Reliable interviews for putative environmental risk factors for both PD and dementia in PD will be developed. All patients will have their blood screened for mutations in the coding and the promoter regions of the amyloid precursor protein (APP) gene and for low level mosaicism for trisomy 21. A cell bank will be established for future investigations. A reliable family history interview will be completed in all participants for ascertainment of AD and PD in first-degree relatives of PD patients and controls. Familial aggregation of AD and PD will be assessed by comparing cumulative incidence of AD and PD in first-degree relatives of PD patients with and without dementia, with and without APP gene mutations and with onset of motor manifestations <65 and >65. Potential gene-environment interactions will be explored by comparing PD patients with and without a family history of AD and PD, and the effects of environmental factors on the development of dementia. Statistical methods will be used to develop models to predict the development of dementia based on the significant risk factors from the preliminary analysis. Cumulative incidence of AD and PD in relatives will be examined with life table methods and rate ratios will be calculated using Cox proportional hazards modeling.

neuroprotectants; human therapy evaluation; ubiquinone; Huntington's disease; combination chemotherapy; brain disorder chemotherapy; anticonvulsants; clinical research; human subject;

To examine the safety and tolerability of the Selegiline Transdermal System (STS) in HIV-seropositive patients with mild to moderate cognitive impairment. To examine the benefits of the Selegiline Transdermal System (STS) on cognitive function.

The investigators and others have previously established that there is a 2-3 fold increase in the risk of idiopathic Parkinson s disease (PD) in first-degree relatives of probands with PD compared to first-degree relatives of controls. The recent identification of a mutation in the alpha-synuclein gene is the first confirmation of a genetic etiology for PD, although this mutation is associated with young age at onset and most likely will account for a very small proportion of familial PD. PD, like Alzheimer's disease may be genetically heterogeneous and different genetic mechanisms may underlie the familial aggregation. Careful inquiry into whether there are clinical phenotypes that are more often associated with a genetic susceptibility to PD and determination of the most likely mode of inheritance of these phenotypes has important implications for the design of genetic linkage studies. The investigators propose to determine whether genetic influences are greater in families of probands with early-onset PD (less than or = 50 years) compared to late-onset PD (greater than 50 years) tremor-dominant PD compared to postural instability gait disorder (PIGD) PD. The investigators will also test (1) whether the increased risk in first- degree relatives is specific for development of these clinically defined subtypes of PD and (2) whether or not the genetic susceptibility to PD also raises risk for essential tremor. The investigators will conduct two separate case-control studies simultaneously. Study I is a family study of 300 PD patients from the multi-ethnic community of Washington Heights-Inwood. The 300 controls for these patients will be drawn from two existing cohorts of community controls. Study 2 is a family study of 200 PD patients with age of onset less than or = 50) and 200 PD patients with age of onset greater than 50 who attend the service-based Center for Parkinson's Disease at Columbia University. 400 controls will be recruited by random digit dialing using the same area codes and exchanges as the patients and frequency matching on age, gender, ethnicity and education. All first-degree relatives will be interviewed by telephone and those who screen positive for PD or ET will be examined, as will a random sample of 200 screen-negative relatives. The investigators will also determine whether or not the cumulative incidence of P to age 90 is higher in relatives of cases from the service-based sample than in relatives of cases from the community-based sample, and if so, whether this is due to sensitivity of reporting or whether the service-based sample contains a higher proportion of familial cases because of a higher proportion of cases with clinical characteristics associated with a high familial risk. The investigators will use segregation analysis to determine the most likely mode of inheritance of these clinical phenotypes in order to determine the optimal strategy for a future genetic linkage study.

This research study will examine the tolerability and safety of Lexipafant in people with HIV infection and mild to moderate cognitive impairment. In addition, effects on cognitive function, quality of life and activities of daily living will be assessed.

Plasma HIV-1 RNA levels are the best predictors of long-term clinical outcome, mortality, and response to anti-retrovirals, but the prognostic value of these markers for neurocognitive outcomes is not known. If a reduction in systemic viral burden can reverse or stabilize neurocognitive impairment[minor cognitive/motor disorder (HIV-MCMD) and HIV dementia (HIV-D)] this would have tremendous treatment implications for the 20% of AIDS patients who will eventually develop HIV-D. Moreover, if the potential reversibility of neurocognitive impairment is mediated through a reduction in plasma viral load, then aggressive therapy of HIV-MCMD may be warranted. In both cross-sectional and longitudinal analyses, we will determine if plasma HIV-1 RNA levels are independently associated with specific neurological, neuropsychological, psychiatric and functional abnormalities in a cohort of 460 men and women with advanced HIV infection seen every 6 months at the University of Rochester, Columbia University and John Hopkins University. We will determine whether change in viral load is related to the onset of HIV-MCMD and HIV-D and transition among the stages of no impairment, HIV-MCMD, and HIV-D. Longitudinal analyses will include analyses of repeated outcomes (generalized estimating equations), time to event analyses (Cox models), and transition analyses (Markov chair analyses). In similar analyses, we will determine if plasma markers of immune activation (beta2-microglobulin, TNFalpha, TNFr2, sICAM- 1) are independently associated with neurocognitive impairment. Combining a carefully conducted natural history study with sensitive molecular assays will lead to a better understanding of how plasma viral load measures can be used to predict and monitor neurocognitive outcomes.

Evaluate benefit of 1592U89 succinate, a carbocylic 2,3-ene nucleoside on neuropsychological performance in ADC patients. Secondary objectives: changes in clinical dementia, neurological status, survival, AIDS defining conditions, virological and immunological markers in plasma and CSF.

The purpose of this study is to determine the extent to which viral burden and markers of macrophage activation (tumor necrosis factor-alpha, soluble TNF-r2, beta-2-mircoglobulin) are related to severity of functional deficit in people with HIV; and which are most sensitive to variation in viral load and markers of macrophage activation.

Several recent advances in our understanding of the pathogenetic mechanisms underlying HIV dementia raise the possibility that factors other than direct infection may play a role in the development of neural cell dysfunction. Clinically dementia is associated with increased TNF-alpha in the brain, but decreased IL-1 beta. Intervention at the level of TNF-alpha appears to be a highly promising potential means of arresting the pathophysiology resulting in HIV cognitive and motor impairment. CPI-1189, an investigational drug for the treatment of Parkinson's disease and AIDS-related dementia complex, protects neuronal cells from TNF-alpha induced apoptosis and cell death in an in vitro primary human cell culture model which mimics the neuropathology associated with HIV dementia. A total of sixty subjects at six centers will be randomized to three groups. Twenty subjects will receive placebo for 10 weeks; 20 will receive 50 mg/day CPI-1189 for 10 weeks maintenance phase, subjects may enter a 12-week open-label follow-on phase during which CPI-1189 may be taken at a dose of up to 100 mg/day.

PHAROS is a unified research effort by approximately 38 centers in the Huntington Study Group in North America to study individuals at risk for Huntington's Disease who have not undergone genetic testing. It is coordinated by the Clinical Trials Coordination Center (CTCC) at the University of Rochester. The study's primary aim is to prospectively determine the phenoconversion rate in a cohort of individuals at risk for Huntington's Disease, with subjects and investigators blinded to HD gene carrier status. Secondary aims include: (1) to identify important risk factors that modify the phenoconversion rate and to compare these prospectively derived data with those of retrospective studies; (2) to assess inter-rater reliability in the determination of phenoconversion; (3) to determine the false-positive rate of phenoconversion; and (4) to assesss the ethics and feasibility of conducting a study of asymptomatic at risk individuals in a blinded setting with strict confidentiality. The study aims to enroll approximately 1000 asymptomatic subjects between the ages of 30 and 54 years old who are at risk by virtue of having had a parent or sibling with HD. Subjects will undergo double-blinded DNA testing for the trinucleotide expansion, and undergo clinical assessments every nine months for a minimum of three years.

virus load; functional ability; HIV infections; macrophage; biomarker; leukocyte activation /transformation; neuropsychological tests; major histocompatibility complex; tumor necrosis factor alpha; patient oriented research; behavioral /social science research tag; human subject; clinical research;

genetic screening; phenotype; Huntington's disease; brain disorder diagnosis; disease /disorder proneness /risk; confidentiality; experimental designs; genetic carriers; patient oriented research; human subject; clinical research;

[unreadable] DESCRIPTION (provided by applicant): In the first funding period, we compared the risk of PD in relatives of 221 PD patients with age at onset (AAO) <50 to relatives of 266 PD patients with AAO >50 and 409 controls. The magnitude of increased risk of relatives of PD cases vs. controls was similar in early-onset cases (RR: 2.9, 95%C1: 1.6-5.0) and late onset cases (RR: 2.7, 95%CI: 1.6-4.4). However in families of early-onset cases, the degree of increased risk was much greater in siblings (RR: 7.9, 95%C1: 2.5-25.5) than in parents (RR: 1.7, 95% CI: 0.9-3.3), consistent with an autosomal recessive contribution to inheritance. In late-onset families, risk was elevated in both parents and siblings, inconsistent with a recessive model. Mutations in the parkin gene have emerged as the most important causative or risk-raising factor in early-onset PD. In this second competitive renewal application, we have redesigned our study to make optimal use of 300 early onset cases already recruited at the Columbia site (200 not yet screened for parkin mutations) and the 40 PD cases with parkin mutations we have already identified. We will join with investigators at 7 other sites who will contribute an additional 600 cases with age of onset <50 and 21 identified parkin families to form a US Parkin Consortium. Our first aim is the expansion of 125 PD cases that carry parkin mutations to include 1st and 2nd degree relatives. We will determine whether the risk of psychiatric and cognitive manifestations in asymptomatic gene carriers who do not meet criteria for PD is higher than in asymptomatic non-gene carriers. Identification of a parkin carrier phenotype will provide clues to etiopathogenesis and may define the appropriate time for early therapeutic intervention. Our second aim is to define the distribution of age specific penetrance in 100 of the 125 families who were recruited solely be age of onset, so as not to bias these estimates upward by inclusion of "high risk" families recruited because they are multiplex. We will compare differences in age specific penetrance by allelotype (heterozygous vs. homozygous or compound heterozygous). The results of this study will clarify the role of parkin in genetic susceptibility and foster the development of genetic testing guidelines. The consistent finding that at least 30 percent of PD patients with parkin mutations are heterozygotes, despite that fact that inheritance was initially described as recessive, and new availability of commercial testing make this study both critical and timely. [unreadable] [unreadable]

human therapy evaluation; dietary supplements; Huntington's disease; creatine; brain disorder chemotherapy; drug screening /evaluation; clinical trials; patient oriented research; alternative medicine; human subject; nutrition related tag; clinical research;

DESCRIPTION (provided by applicant): The Columbia University Medical Center (CUMC)-Weill Cornell Medical Center (WCMC) NEXT site will increase the efficiency of clinical research sponsored by NINDS through the creation of a shared infrastructure that will benefit from existing resources, including two CTSAs, to conduct Phase II exploratory trials, some of which may be biomarker-informed, in partnership with industry and foundations. The two neuroscience centers have a long history of collaboration in research; their respective hospitals are combined (New York Presbyterian Hospital); and they both have CTSAs linked in a regional consortium. Our aims are: 1) to develop a neuroscience clinical trials site at CUMC (hub) and WCMC (spoke) that draws from extensive expertise in adult and pediatric neurology, neurosurgery, basic neuroscience, and neuroepidemiology and that is capable of conducting five to seven Phase II clinical trials or biomarker validation studies across its lifespan; 2) to leverage resources from the CTSA and Office of Clinical Trials at each center to efficiently identify and recruit ethnically diverse participants who are expeditiously recruited and followed to trial completion; 3) to train the next generation of clinical and basic neuroscientists to become independent investigators who will design and conduct clinical trials, making use of new technologies and trial methodologies; and 4) to participate in, and contribute to, the NEXT network on a national level. We have identified co-investigators who have experience in NIH-, industry- and foundation-supported clinical trials, demonstrated partnership with foundations, and a commitment to mentorship. We have developed a recruitment strategy for rare and more common neurological diseases, making use of our respective communities, ambulatory care networks, and advanced bioinformatics. Our recruitment efforts will dovetail with our three-pronged goal to: 1) educate families through bilingual (English and Spanish) disease-specific programs, 2) develop a clinical-research learning-institute for advocates, and 3) organize a multifaceted program for faculty career-development. The large SMA population (n=106) and demonstrated successful enrollment in the Biomarker for SMA study provides us with the necessary experience to conduct the anticipated NEXT SMA biomarker validation trial.

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.

The Columbia University Medical Center-Weill Cornell Medical Center NNEXT site has increased the efficiency of clinical research sponsored by NINDS, by creating a shared infrastructure that has benefited from existing resources, including two CTSAs, to conduct seven Phase II exploratory trials and one biomarker study. Four studies are completed, and four are underway. The joint NNEXT site has been led by PIs Karen Marder M.D. MPH and Claudia Chiriboga M.D. MPH at CUMC, and now, emblematic of the increased synergy between CUMC and WCMC, Claire Henchcliffe M.D. DPhil at WCMC will join as PI. The two neuroscience centers have a long history of collaboration in research; their respective hospitals are combined (New York Presbyterian Hospital), and they both have CTSAs linked in a regional consortium, the NYCON. Since 2011 our institutions have strengthened their relationship through an emphasis on Precision Medicine?s ?All of Us? program. Our aims are 1) To build upon the success of our joint neuroscience CUMC-WCMC clinical trials site, capable of conducting the planned five to ten NNEXT trials, by drawing on our extensive expertise in adult and pediatric neurology, neurosurgery, and basic neuroscience. We have developed a recruitment strategy for rare and more common neurological diseases, making use of our respective communities, ambulatory care networks, and advanced bioinformatics. Our recruitment efforts will dovetail with our three-pronged goal to educate families through bilingual (English and Spanish) disease-specific programs. We will be guided by a Recruitment Retention Core composed of individuals with expertise (minority recruitment, epidemiology) providing practical real-time problem-solving to NEXT trialists. 2) To leverage resources from the CTSA, Office of Clinical Trials, IRB, and the Office of Research Compliance and Training, at each center to efficiently identify and expeditiously recruit ethnically diverse participants who are followed to trial completion. 3) To participate in, and contribute to, the NNEXT network by developing our own clinical trials. We have identified a team of co-investigators at both sites who have experience in NIH, industry and foundation supported clinical trials, have demonstrated partnership with foundations, and have a commitment to mentorship. A NEXT Advisory Committee including senior leadership will provide guidance on both current and future projects. 4) To train the next generation of clinical and basic neuroscientists to become independent investigators, able to design and conduct clinical trials, and benefiting from new technologies and trial methodologies. To this end, we will organize a multifaceted program for faculty career-development. 5) To improve dissemination of information to patients, families, and disease-specific advocates about scientific advances and the importance of clinical trials in our community, using educationally and culturally appropriate tools, and innovations including telehealth to reach a broader public.