Felicia Goldstein - US grants

[unreadable] DESCRIPTION (provided by applicant): This R21 application is aimed to develop an approach that combines a novel in vivo imaging technique, diffusion tensor imaging (DTI), and physiological and cognitive measures to investigate the relationship between vascular comorbidities and white matter damage in patients with mild-moderate Alzheimer's disease (AD). Vascular comorbidities such as hypertension, hypercholesterolemia, and cardiac disease are common in AD patients, and have been found in studies of normal aging and dementia to be related to both cognitive dysfunction and white matter (WM) damage. Although a handful of studies have examined WM changes in AD patients using DTI, these studies have included relatively healthy patients without vascular comorbidities and/or cerebrovascular changes, and therefore have not yet examined their association. In addition, general measures of overall cognitive functioning have been used as opposed to domain-specific tests that are necessary to evaluate associated deficits. A total of 50 AD patients and 20 cognitively intact controls will be prospectively recruited and will undergo objective measurement of vascular comorbidities, neuroimaging studies using DTI, and neuropsychological evaluations. Innovative aspects of this proposed R21 project are 1) to further develop DTI methodology to quantify WM damage and its relationship to vascular comorbidity in AD patients, and 2) to identify brain regions and corresponding cognitive deficits that are vulnerable to vascular comorbidities. Specific Aims are 1) To investigate the relationship between vascular comorbidities and DTI indices of white matter integrity in patients with mild-moderate AD. 2) To identify specific white matter regions which are vulnerable to the presence and severity of vascular comorbidities in AD patients and 3) To test and validate DTI indices in specific brain regions by correlating them with neurocognitive performance. The findings are anticipated to alert health care professionals to the importance of vascular comorbidities and their control in patients with Alzheimer's disease. An overriding accomplishment will be the delineation of specific DTI parameters which can be used as markers of disease progression and treatment efficacy. Since vascular comorbidities are potentially treatable, the findings of this study will alert clinicians to the importance of measuring and controlling these comorbidities, even in patients who are already diagnosed with Alzheimer's disease. It is anticipated that the findings will help clarify the overlap between AD and vascular dementia, identify at risk patients, and contribute to the development of pharmacologic agents that target specific patient subgroups. [unreadable] [unreadable] [unreadable]

? DESCRIPTION (provided by applicant): Alzheimer's disease - the most common age-related neurodegenerative disorder - is a personal and societal tragedy of immense and growing proportions. Over 5 million Americans currently suffer from Alzheimer's disease (AD), and the number is expected to triple by 2050. Despite recent progress in characterizing AD, therapeutic interventions have been disappointing in large part because we lack a complete understanding of the mechanisms that contribute to this disease. Research suggests that peripheral inflammation is an important and modifiable risk factor for AD, and epidemiologic studies suggest that mid-life metabolic syndrome, obesity, and hypertension are inter-related health care conditions that increase the risk of age-related neurodegenerative disorders, particularly AD. The mechanistic links between these systemic disorders and neurodegeneration are poorly understood, but may be the key to developing effective anti-AD therapeutics. These risk factors are particularly prevalent in African Americans, who are also at increased risk for AD. The novel overarching hypothesis of this proposal is that chronic systemic disorders (i.e. metabolic syndrome and hypertension) are mechanistically linked to AD through a multistage process that involves dysregulation of the renin angiotensin system (RAS), systemic inflammation and a heightened peripheral immune response, followed by increased immune cell trafficking across the blood brain barrier (BBB) and leading to chronic neuroinflammation, CNS dysfunction, and cognitive decline. To test this hypothesis, we have assembled an interdisciplinary team of experts in inflammation, RAS dysfunction and neurodegeneration to address the following questions: 1) What is the relationship between chronic peripheral inflammation and Alzheimer-like pathology in a transgenic mouse model of Alzheimer-like pathology? 2) How is overactivation of the renin-angiotensin system related to brain inflammation, immune function and AD-like pathogenesis in this model? and 3) How is RAS dysfunction related to central inflammation and immune function in humans at risk for AD? In addressing the third question we will focus on African Americans, who are particularly vulnerable to metabolic syndrome and AD yet have received little attention in systematic investigations. Successful completion of the proposed studies will provide new and potentially paradigm- shifting mechanistic information on how diet- and hypertension-induced chronic peripheral inflammation and chronic brain inflammation contribute to the development of AD.

PROJECT SUMMARY Challenges exist in recruiting and retaining minorities in research on Alzheimer?s disease (AD), thereby limiting the ability to elucidate mechanisms for health disparities in AD risk and to adequately measure treatment efficacy in underserved populations. African Americans represent an especially important group to target for research due to their two-fold risk of AD compared to non-Hispanic Caucasians. Advances in technology to evaluate cognitive functioning, particularly the use of mobile applications such as smartphones, offer the promise for overcoming barriers that may limit African American research participation including scheduling difficulties, associated study costs, and examinee/examiner cultural mismatches. Remotely administered neuropsychological measures can be performed at an individual?s convenience, and outcomes can be collected at multiple time points. In the proposed R03 study, we will leverage the resources and volunteers who have signed up for a new community initiative at our institution, the Emory Healthy Aging Study, involving remote engagement of individuals through smartphone technology. The Co-PIs have selected tasks from the cognitive neuroscience literature that are non-proprietary and have strong behavioral and neuroimaging correlates in APOE-?4 carriers, amnestic mild cognitive impairment and AD patients, and healthy aging groups. The proposed grant will pilot these measures when administered via smartphones to middle-aged and older African Americans and Caucasians, with the overall goal of determining whether group differences exist that could have diagnostic relevance in future studies. Sixty African American and 60 non-Hispanic Caucasian adults 45-75 years of age will complete the traditional versions and the smartphone adaptations of the cognitive measures in the clinic setting and will then complete the smartphone applications remotely at 3 and 6 months post-baseline assessment. Specific Aims are to 1) Establish reliability of the smartphone applications (both internal consistency and in comparison to the traditional version (inter-modality reliability)) 2) Establish test- retest reliability of the smartphone measures; and 3) Assess adherence rates of the remotely administered smartphone measures. A secondary Aim is to examine factors (i.e., quality of education, socioeconomic status, and vascular comorbidities) that we expect to be correlated with performance on cognitive measures administered via smartphones and that are underlying factors often associated with cognitive performance differences between African Americans and Caucasians. The long-term goal of a future study is to validate these mobile cognitive measures against neuroimaging, genetic, and CSF biomarkers of central amyloidosis.