Naftali Raz - US grants

DESCRIPTION: These studies extend and expand those conduct previously. These previous studies showed that age-related los in vortical volume is not uniform but differential and selective. Age-related loss in the prefrontal cortex if pronounced and associated with age-related deficits in executive functions. In contrast, age-related loss in the hippocampal formation is mild and not generally associated with memory deficits. In a subgroup of elderly adults, however, there was a significant association between hippocampal volume and explicit memory. It is hypothesized that prefrontal atrophy is associated with healthy aging, whereas limbic atrophy is associated with the beginning of cognitive pathology. The proposed studies have three goals: 1) Investigate the longitudinal course of cerebral and cognitive aging: 2) Expand the study of the relation between age-related atrophy in the prefrontal cortex and age-related decline in executive functions; and 3) Examine more closely the relation between age-related hippocampal atrophy and deficits in declarative memory after 60 years of age.

[unreadable] DESCRIPTION (provided by applicant): This research project is proposed in response to the small grants program announcement of the National Institute on Aging (PAR-03-056). Specifically, we respond to the aims #2 (Cardiovascular and Cerebrovascular Aging), and #16 (Executive Function) on the list of objectives in that announcement. The main goal of the proposed research is to explore the feasibility of using Transcranial Doppler Sonography (TCD) for assessment of the influence exerted by hemodynamic factors on differential age related changes in brain and cognition. We are specifically interested in exploring the links between age-related slowing of cerebral arterial blood velocity (CBF-V) in anterior and middle cerebral arteries, as a marker for cerebral hypoperfusion, and regional increase in white matter hyperintensities (WMH) burden as well as shrinkage of the cortex and the underlying white matter. In cognitive domain we will focus in the executive functions which are differentially sensitive to aging and prefrontal pathology. Our hypotheses are based on the body of clinical and preclinical studies that suggested CBF-V slowing as risk factor for developing WMH, our own studies that support the plausibility of modifying influence of cerebrovascular risk factors on age-related brain shrinkage and on the studies that suggest differential vulnerability of executive functions to mild hypertension. While a preliminary report [5] indicates that reduced CBF-V may be associated with structural brain pathology (global WMH burden), neither regional specificity, nor cognitive relationship nor longitudinal course of that index have been established. We have conducted research on a cohort of healthy adults (age 18-85) and obtained cognitive and MRI-based structural brain measures on more than 100 individuals. In this project, we propose to use these data as baseline measures in a two-year longitudinal study and to relate hemodynamic variables to the rate of neuroanatomical and cognitive change. Thus, the proposed research fits the announced goals of the program in that it represents a pilot study that will examine feasibility of application of a technique widely used in the clinic to research on healthy aging, and it will benefit from statistical analysis of existing data. [unreadable] [unreadable]

The goals of this continuing project are 1. Aim 1. To describe the course of differential brain aging vyith a focus on the best-case-scenario naturalistic study of successful aging. With that focus, the study will complement existing large-scale longitudinal investigations of typical geriatric samples. Our objective is to examine the closest approximation to successful physiological aging to be found in an unselected human population. 2. Aim 2, To gain insights into mechanisms of age-related differential brain shrinkage by examining changes in microstructure of the white matter and indirect indices of regional brain iron content. 3. Aim 3. To evaluate the links between age-related regional brain changes (volume, diffusion and magnetization properties, and iron content) and performance in three cognitive domains with known vulnerability to aging: episodic memory, executive functions, and speed of processing. 4. Aim 4. To examine the effect of vascular risk factors (physiological and genetic) as modifiers of brain and cognitive aging. We will continue our investigation into the effects of sub-clinical levels of vascular risk conveyed by elevated blood pressure, circulating cardiac risk factors (homocysteine, C-reactive protein), elevated insulin, and genetic variants associated with vascular and metabolic risk (MTHFR C677T, IL1-p C511T, BDNF Val66Met, ACE l/D, ApoEpound4, diabetes risk genes, and polymorphisms related to specific neurotransmitters - acetylcholine, serotonin, dopamine). Aim 5. Common to all listed aims is a longitudinal approach to study of biological and cognitive change with Latent Growth Curves models that allow estimation of the shape of the trajectories of aging. Aim 6. Methodological contributions. During the proposed extension award period, we plan to initiate several methodological investigations, in which we will compared manual volumetry and ROI-based evaluation of white matter integrity with various semi-automated methods, with a hope to improve those methods to the level comparable with the golden standard.

PROJECT SUMMARY/ABSTRACT Dramatic increases in longevity observed in the past century have come with an added price: increased prevalence of age-related cognitive disorders, such as Alzheimer's' disease (AD), that impose significant burden on individual and societal resources. There is no cure for AD or other dementias, and shifting the investigation beyond the framework of ?-amyloid accumulation and focus on identifying the harbingers of disease at the earliest possible time is critical. As AD is diagnosed clinically by examining primarily declines in episodic memory, investigation of neural functions that are associated with that cognitive domain and that may change before behavioral deficits are apparent, is a highly plausible choice for discovery of a prospective early biomarker of disease. A key candidate is glutamate (Glu) because of its ubiquity in the cerebral neurotransmission mechanisms and its fundamental role in mnemonic processes leading to a highly plausible target in this search. Although the notion of glutamatergic dysfunction associated with memory declines in AD and normal aging has garnered empirical support, no direct in vivo evidence of changes in memory-related Glu modulation among older adults is available. Examining age difference and age-related changes in task-related Glu modulation is the main aim of this study. To advance this goal, we introduce, with compelling preliminary data, the application of in vivo ¹H fMRS, a highly novel method for quantifying in real-time the task-related modulation of Glu. We will assess Glu modulation within the hippocampus (HC), while older and younger participants engage in an associative learning and memory task that we have established as a robust, specific hippocampal challenge in preciously published work. ¹H fMRS provides real-time task-related changes in Glu that is independent of vascular confounds as is with BOLD fMRI and at a temporal resolution of under a minute. The task, the brain location, and the choice of the neurotransmitter (Glu) are highly relevant to aging and AD. We will acquire a structural MRI of the whole brain, a high-resolution scan of the hippocampal body that allows measurement of the HC subfields, and a 1H fMRS of the HC during encoding and retrieval of object-location associations in 36 healthy young (21-30-year-old) and 36 healthy older (60-70-year-old) participants. The procedure will be repeated after one year. This high-risk high-yield study aims to establish Glu modulation changes as a viable early marker of cognitive decline in the context of structural HC changes and decline in memory performance. The knowledge advancement from this study will be demonstration of a link between changes in task-related Glu modulation in the older adults, HC volume and memory over time. This study will provide important foundations for future multi-occasion longitudinal studies that will advance understanding of individual differences in cognitive development in the late part of the lifespan without misleading inferences from cross-sectional studies and provide a foundation for intervention aimed at mitigating cognitive declines.