PL-04-02

PL-04-02

Plenary PL4: underwent PIB PET imaging. Images were visually inspected and binding quantified by distribution volume ratio (DVR). Results: Neocortical...

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Plenary PL4: underwent PIB PET imaging. Images were visually inspected and binding quantified by distribution volume ratio (DVR). Results: Neocortical A␤ deposition was present in 100% of AD subjects, 89% of DLB subjects, 43% of MCI subjects, 18% of elderly controls and no FTD subjects. PIB distribution was similar in AD and DLB, being greatest in medial frontal, precuneus, parietal and lateral temporal cortex, and caudate nuclei. Occipital, sensori-motor and mesial temporal cortex were less affected. Neocortical DVR measured 2.0 ⫾0.3 in AD, 1.6 ⫾0.3 in DLB, 1.5 ⫾0.4 in MCI, 1.2 ⫾0.2 in control and 1.1 ⫾0.1 in FTD subjects (p ⬍ 0.01 for all differences). Five of the NC had cortical binding predominantly in frontal cortex with one progressing to MCI at 12-month follow-up. DVR correlated with MMSE and memory impairment across all subjects (r ⫽ 0.7, p ⬍ 0.0001) but not within groups (in AD group p ⫽ 0.16), and with a shorter interval from onset of cognitive impairment to diagnosis in DLB (r ⫽ 0.9, p ⬍ 0.002). Conclusions: PIB PET will permit earlier diagnosis of AD and improve differential diagnosis of dementia. Longitudinal follow-up is required to determine the significance of the PIB binding in the normal elderly controls and MCI subjects. Our findings suggest that PIB PET will detect AD before demonstrable cognitive decline and therefore be a useful tool for early intervention trials. O3-06-08

PATTERN OF AMYLOID PLAQUE DEPOSITION WITH PITTSBURGH COMPOUND-B (PIB) IN MILD COGNITIVE IMPAIRMENT

Steven Trent DeKosky1, Chester A. Mathis1, Julie C. Price1, Brian J. Lopresti1, Carolyn C. Meltzer2, Scott K. Ziolko1, Jessica A. Hoge1, Nicholas Tsopelas1, William E. Klunk1, 1University of Pittsburgh, Pittsburgh, PA, USA; 2Emory University, Atlanta, GA, USA. Contact e-mail: [email protected] Background: Mild cognitive impairment (MCI) is a probabilistic transition state to Alzheimer’s disease (AD). Understanding the pathological changes in MCI will aid in diagnosis, disease-risk status, developing treatments, and strategizing disease prevention. PIB is an amyloid-specific PET ligand that visualizes amyloid plaque deposits. Objective(s): To determine the presence, quantity and distribution of PIB binding/retention in MCI compared to normal subjects and patients with AD. Methods: PIB PET imaging (⬃15 mCi, 90 min) was performed in 47 subjects: 13 MCI (70⫾9 yrs; MMSE range: 23-29; both MCI-amnestic and MCI-multiple cognitive domain), 22 normal age-equivalent controls (76⫾7 yrs; MMSE range: 26-30), and 12 AD subjects (69⫾9yrs; MMSE range: 18-28) from the University of Pittsburgh ADRC. MR images were acquired for region definition [e.g., posterior cingulate/precuneus (PRC) & parietal (PAR) cortex] and partial volume correction. Data were analyzed using the Logan graphical analysis with cerebellar (CER) values as reference, since CER does not contain amyloid plaques. The measure of PIB was distribution volume (DV) ratio (DVR), reported as mean⫾1SD. Results: Controls had low DVRs across all regions (range: 1.07-1.32), while AD patients all had higher DVRs about 2-fold greater in these regions (PRC⫽2.4⫾0.3; PAR⫽2.0⫾0.2). MCI subjects had DVRs that spanned the entire range of control and AD values, and both MCI-amnestic and MCI-MCD were in both control-like and AD-like ranges. Non-specific PIB retention in white matter and cerebellum was similar for all groups. Conclusions: Amyloid deposition (as reflected by PIB retention) in MCI was indistinguishable from controls in some MCI subjects, elevated to the level of AD in other MCI subjects, and more rarely, at intermediate levels. The results suggest that PIB retention may identify cases that will progress to AD by identification of PIB binding equivalent to AD; however this must be verified by continued clinical follow-up. This will be especially helpful with MCIMCD, an entity currently under intense study. Absence of PIB retention in MCI may indicate that the subject will not progress to AD, or that some cases develop clinical symptoms before PIB-detectable levels are present. Longitudinal follow-up of these cases is ongoing.

S67 WEDNESDAY, JULY 19, 2006 PLENARY PL4

PL-04-01

CALORIC RESTRICTION

Mary Sano, Mount Sinai School of Medicine, Bronx, NY, USA. Contact e-mail: [email protected] Background: Understanding how to translate findings from caloric restriction (CR) in animal studies to human conditions is complex. More recent literature from animal studies supports the notion that CR may prevent Alzheimer disease pathology. In human studies cognitive benefits have been difficult to observe and much depends on the starting point of the population. Further designing studies to assess the cognitive and disease modifying effects of CR in humans is fraught with practical and ethical dilemmas. Objective(s): This presentation will summarize existing data, identify reasonable manipulations to assess CR in human and clinical trials. Methods: This presentation will review mechanisms proposed from animal studies which suggest that CR may increase longevity by decreased glucose, attenuated free radical generation, alteration of vasculature and reduction of glial activation. Also recent literature will be presented that describes work which supports the notion that CR may prevent Alzheimer disease pathology via activation of SIRT1. In a transgenic mouse model, increases in this protein predict changes in A-beta peptide and decreases and amyloid precursor protein via increases in alpha secretase activity. However, human studies show no systematic benefit on cognition with some positive effects in highly selective populations. Trial designs which may address some of the complexity of CR as an intervention will be presented. Conclusions: CR provides an example of the challenges faced in translation of results from animal studies to clinically useful treatment approaches. PL-04-02

BIOCHEMISTRY OF ␥-SECRETASE AND ITS POTENTIAL AS A THERAPEUTIC TARGET

Michael S. Wolfe, Harvard Medical School, Boston, MA, USA. Contact e-mail: [email protected] Background: ␥-Secretase catalyzes proteolysis within the boundaries of the lipid bilayer as the last step in the formation of A␤, the major protein component of the cerebral plaques of Alzheimer’s disease, from its precursor protein (APP). This enzyme is comprised of four different membrane proteins, with presenilin ostensibly as the catalytic component of an unusual intramembranous aspartyl protease. Objective(s): To understand the biochemistry of this protease and its potential as a therapeutic target for Alzheimer’s disease. Methods: Small molecule probes have been essential for characterizing and identifying this protease as well as advancing the understanding of its catalytic mechanism. Transition-state analogue inhibitors helped identify presenilin as the catalytic component, and immobilization of such compounds onto matrices provided a key step in the purification of the entire enzyme complex. Another type of inhibitor, conformationally constrained peptides that mimic the helical transmembrane domain of APP have been employed to identify an initial substrate docking site and reveal a pathway by which substrate moves from docking site to active site. ␥-Secretase also cleaves other membrane proteins besides APP, the most notorious being the Notch receptor. Because Notch signaling is critical for cell differentiation, ␥-secretase inhibitors that block both APP and Notch proteolysis can cause severe toxicities by interfering with essential processes. However, compounds have recently been identified that modulate the ␥-secretase complex to reduce A␤ without affecting Notch signaling. Conclusions: Although most ␥-secretase inhibitors block the proteolysis of both APP and Notch, the finding that certain compounds can modulate the enzyme complex and selectively alter A␤ production offers renewed hope in this protease as a therapeutic target.