ALZHEIMER'S DISEASE RESEARCH CENTER AT COLUMBIA UNIV
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Project 3: Memory decline is the earliest manifestation of Alzheimer's disease (AD), and can be detected up to 10 years before the diagnosis is fully established by current methods. Numerous investigations indicate that decline in memory performance with advancing age is common and may occur in the absence of AD. It remains uncertain whether this failure in memory performance reflects a prodromal stage of AD or is a normal variation of aging. Early AD targets the hippocampal formation, a structure comprised of distinct anatomical regions. We have recently developed a functional MR protocol that can detect differential activation of these separate hippocampal, and in a series of pilot studies have found that AD patients have dysfunction in all regions compared to age-matched controls. When we employed this fMRI protocol to study elderly individuals with memory decline, but without dementia, two patterns of hippocampal activation emerged: One pattern had predominant dysfunction in the entorhinal region and was indistinguishable to the pattern seen in AD; and a second pattern had dysfunction restricted to single hippocampal region, the subiculum. The primary goal of this proposal is to determine whether this fMRI protocol can detect a regional pattern of hippocampal dysfunction that is associated with AD, and whether it can reliably dissociate healthy elderly with memory decline into those with and or without prodromal AD. 20 patients with probable AD, 40 elderly with normal with normal memory, and 80 elderly with memory decline will be evaluated at baseline. Elderly with and without memory decline will be followed prospectively and some are predicted to progress to AD at follow-up. Analysis will determine whether elderly with an AD-like hippocampal activation pattern at baseline have different clinical courses and a different incidence of AD. The fMRI protocol will also be employed to identify topographical networks within the hippocampus associated with normal memory processing.
The Alzheimer's Disease Research Center (ADRC) at Columbia University was established to courage and integrate research on the causes of Alzheimer's Disease (AD) and related age-related neurodegenerative diseases and to foster the development of improved diagnosis, prevention and treatment of these conditions. The Clinical Core and Neuropathology Core of the ADRC provide the patient and tissue resources for the examination of new diagnostic and treatment modalities and for biological investigation. The population of the Clinical Core is ethnically diverse with substantial numbers of White, Black and Hispanic patients. The integral research projects of the ADRC are focused on the molecular biology of dementia and on early changes in brain function in AD. These research projects are extended by a large number of independently funded projects on the dementias and their underlying biology which have been nucleated by the Center and draw on ADRC resources. The ADRC actively encourages research in all aspects of AD including caregiving, treatment and biology. The ADRC also serves and a source of education and information on AD. Through the efforts of Education and Information Transfer ore we provide a Web Page with both local and general information; training programs in the biology and psychology of aging; and extensive seminar and works- in-progress series; education for primary care physicians in care of AD patients and educational programs to the lay community. The ADRC offers research services for genotyping, DNA storage, cell line production and DNA sequencing and maintains a bank of appropriate tissues, DNA and cell lines to facilitate research in this and other research centers.
The Neuropathology Core and Molecular Diagnostics Core is overseen by a professional staff of Michael L. Shelanski, M.D., Ph.D., and Steven S. Chin, M.D., Ph.D. The core provides "state of the art" neuropathologic examination of patients with various neurodegenerative disorders as well as neurologically normal individuals. These patients are clinically evaluated in detail by the Columbia ADRC and other neurology groups. The core provides detailed reports of findings and diagnoses to patient families and their physicians. Diagnoses are rendered according to presently accepted and recommended neuropathological criteria. In particular, the recently developed NIH-Regan Institute Working Group diagnostic criteria for the neuropathological assessment of Alzheimer's disease is utilized. Standard postmortem handling of brain tissues includes hemisection of the fresh brain, quick freezing of coronally sliced slabs of one half of the brain for banking and eventual distribution to investigators within and outside the ADRC, and fixation of the other half in formalin for histopathological examination and diagnosis. Microscopic examination includes application of H&E, thioflavine S, modified Bieschowsky silver, Gallyas silver, anti-ubiquitin, anti-synuclein, anti- tau, and anti-amyloid stains to selected sections from a standardized set of sample neuroanatomic regions. Collections of formalin-fixed and frozen brain tissue, lymphoblastoid cell lines, DNA from study patients, and their corresponding databases are maintained and distributed to investigators by the core. The core actively educates and trains neuropathology fellows, pathology, neurology, and psychiatry residents, and other health professionals in the importance and practical aspects of post-mortem examination and tissue banking. Clinicopathological correlation conferences are held to review discuss interesting and instructive study cases. The core strongly encourages research collaborations, and providing neuropathological and basic research expertise, access to biologic specimens, and assistance and access to specialized instruments, such as fluorescence, electron and laser capture microscopes as well as high speed DNA sequence analysis.
