Temporal patterns of change in clinical variables leading to MCI

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Symposium S2-02: MCI Diagnosis and Prediction INSTRUMENTAL ACTIVITIES OF DAILY LIVING PREDICTING MCI

Karine Pe´re`s, Institut National de la Sante´ et de la Recherche Me´dicale, Bordeaux, France. Contact e-mail: [email protected] Background: We can assume that any cognitive deficits assessable by neuropsychological testings must have a measurable impact on abilities in daily living. Consequently, we can hypothesize that subtle restriction in complex Activities of Daily Living (ADL) must be observed early in the course of dementia as observed in neuropsychology and improves the prediction of subsequent dementia. Methods: The Paquid cohort is an epidemiological study of cerebral and functional aging, initiated in 1988 on elderly communitydwellers in southwestern France and still on going after 20 years of follow-up. Restriction, even mild, in four specific Instrumental ADLs (telephone, transportation, medication, finances) was studied as particularly predictive of dementia. Results: First, the IADL-restricted MCI had a greater risk of dementia in the two following years (OR ¼ 7.4, 95%CI ¼ 3.3-16.5) compared with the non-IADL-restricted controls. The risk for the non-restricted MCI was 2.8 (95%CI ¼ 1.3-6.0). IADL-restriction also lowered the chance of reversibility to normal. Another analyses showed that 10 years before the clinical diagnosis of dementia, the future cases had already greater IADL-restrictions, and particularly for handling finances. After controlling for age, gender, and education, IADL-restricted subjects at baseline had a higher risk of dementia 10 years later (OR ¼ 2.6, 95%CI ¼ 1.2-5.4). Finally, recent findings showed that IADL-restriction and Subjective Memory Complaint (SMC) had significant but radically different clinical meanings in women and men. IADL-restriction at baseline was associated with an increased risk of dementia only in men (HR ¼ 2.5, 1.6-4.0), whereas SMC did not (p ¼ 0.97). The reverse was observed in females, in whom SMC almost doubled the risk (1.46 to 2.38), without any association with IADL-restriction once controlled for SMC. Conclusions: Restriction, even subtle, in complex activities of daily appears to be a strong predictor of subsequent dementia. Abilities in daily living as well as their evolution over time may represent a simple and useful screening tool in general population to facilitate an earlier and a more egalitarian access to specialized unit where more sophisticated diagnostic tools are available. However, further researches are necessary to refine this functional assessment to be more sensitive to very early signs of the disease and more specific of the dementia process. S2-02-04

MILD MOTOR IMPAIRMENT: MOTOR CHANGE PRECEDING MILD COGNITIVE IMPAIRMENT AND DEMENTIA

Richard M. Camicioli, University of Alberta, Edmonton, AB, Canada. Contact e-mail: [email protected] Background: Mild cognitive impairment has been established as a precursor to the development of dementia. Dementia is associated with motor changes including parkinsonism (tremor, bradykinesia, rigidity) and gait impairment. Such motor changes can precede the onset of dementia, and differs by subtype of dementia, suggesting that a syndrome of mild motor impairment (MMI) may be useful to identify. Methods: Data from a convenience sample of 50 community volunteers (65 years of age and older) were examined for the association between cognitive impairment based on neuropsychological testing (i.e., without subjective complaints) and motor signs, including items from the Unified Parkinson’s Disease Rating Scale (UPDRS) and measured gait in order to determine if motor signs are associated with preclinical cognitive impairment. A systematic review was performed for studies examining the relationship between motor changes and mild cognitive impairment using the keywords mild cognitive impairment and the following: motor, gait, parkinsonism, parkinsonian, extra-pyramidal, neurological, neurologic, subclinical and signs. Cross-sectional and prospective cohort studies were pulled. Abstracts were culled if were related to specific clinical disease. Results: People with psychometrically defined mild cognitive impairment (less than 1.5 SD below norms) adjusted for cognitive complaints (based on the clinical dementia rating scale) had slower gait, increased number of steps to walk 30 feet (reflecting decreased stride length), and greater decrement in steps during a verbal fluency task. Extra-pyramidal signs based on the UPDRS were

not associated with cognitive impairment. The vast majority of studies examining the association between motor signs and mild cognitive impairment were cross sectional. These indicate that MCI is associated with motor signs. Prospective studies suggest that motor signs are associated with the incidence of questionable dementia, the incidence of dementia and the progression of mild cognitive impairment to dementia. Conclusions: Motor impairment is associated with presymptomatic cognitive decline. The relationship of motor signs to the timing of MCI, its progression to dementia, and its pathological basis requires further study. Along with mild cognitive impairment, mild motor impairment is likely to contribute to functional decline in older people. S2-02-05

ROLE OF BIOMARKERS IN MCI

Prashanthi Vemuri, Mayo Clinic, Rochester, MN, USA. Contact e-mail: [email protected] Background: Both CSF and imaging indicators of disease (biomarkers) that closely reflect the underlying pathology provide an independent measure of pathology based only on biology in contrast to clinical diagnosis done on the basis of clinical examination and neuropsychological tests. The candidate biomarkers corresponding to each of the dominant pathological findings in Alzheimer’s disease (AD) are: 1) low CSF Ab1-42 levels and increased PIB uptake on PIB-PET scans which reflect deposition of Ab in plaques; 2) high CSF t-tau, p-tau levels and decreased FDG uptake on FDG-PET scans which reflects active axonal and neuronal damage and 3) atrophy seen on MRI scans which is the direct result of loss of neurons, synapses and dendritic arborization. The main aim of this talk is to discuss the utility of these key biomarkers in mild cognitive impairment (MCI). Methods: Cross-sectional biomarker measurements serve as measures of disease stage along the cognitively normal to AD continuum and serial biomarker measurements provide information regarding the intensity of the disease i.e. the rate of change in disease related pathology. Results: Measuring biomarkers cross-sectionally and/or longitudinally can aid in answering these four important questions in MCI: 1) early diagnosis of cognitive impairment; 2) prognostic information in MCI including predicting the risk of progression in MCI and differential diagnosis of dementia sub-types; 3) measuring the efficacy of therapeutics and 4) providing mechanistic inferences into the disease process. Conclusions: Both cross-sectional and serial biomarker studies have found that there is an observable change in the candidate biomarkers early in the disease process, these measures correlate well with clinical measures of general cognition and functional status in MCI and are predictive of risk of progression to dementia. In this talk we will discuss the key role played by CSF and imaging biomarkers in the diagnosis, prognosis and disease management of MCI. S2-02-06

TEMPORAL PATTERNS OF CHANGE IN CLINICAL VARIABLES LEADING TO MCI

Hiroko H. Dodge, Oregon Health & Science University, Portland, OR, USA. Contact e-mail: [email protected] Background: For the early detection of pre-clinical stages of dementia, it is critical to distinguish between normal and pathological cognitive aging processes. One approach which could be useful in detecting early pre-clinical stages of dementia is to examine the longitudinal trajectories of various clinical markers among the cognitively healthy and those destined to develop cognitive impairment. Studies have shown that some of these measures may demonstrate decline even a decade before dementia onset. The objective of this study is to identify the timing of acceleration in changes in various clinical markers in relation to the transition to mild cognitive impairment (MCI). Methods: First, change point models were applied to the longitudinal cohort data of the Oregon Brain Aging Study (OBAS) with semi-annual follow-up. Next, as an exploratory analysis, we applied quantile regression models to intra-individual change observed during the follow-up. We explored an approach to examine the order and combinations of the acceleration of change in various clinical markers using reference-frames of annual change derived from quantile regression models. Results: The analysis based on the change point model showed: 1) longitudinal trajectories in clinical variables are different between those whose cognition remained intact and those who transitioned to MCI, and 2) timing of acceleration in changes

Symposium S2-03: Disease Mechanisms-APP/A Beta in relation to MCI conversion differed among clinical variables: Deceleration in gait speed occurred over a decade before the transition to MCI, followed by the acceleration in decline in neuropsychological tests and expansion in ventricular volume, the latter occurring about 3 to 4 years before the transition. Our exploratory analysis using quantile regression models, which focuses on multi-factorial changes within individuals, appears to be a useful and valid method to elucidate potential physiological mechanisms occurring during the pre-symptomatic phase of dementia. Conclusions: Understanding the order and combinations of intra-individual changes associated with transition to MCI is fundamental to recognition of meaningful change and the pathophysiological pathways underlying developing dementia. These data can ultimately be applied over time to help clinicians in the early identification of dementia and to institute early treatment strategies. MONDAY, JULY 12, 2010 SYMPOSIUM S2-03 DISEASE MECHANISMS-APP/A BETA S2-03-01

SPLICING AND DICING IN APP PROCESSING: TARGETING PROTEASES AND MRNAS THAT REGULATE A-BETA PRODUCTION

Michael S. Wolfe, Harvard Medical School, Boston, MA, USA. Contact e-mail: [email protected] Background: Beta- and gamma-secretases catalyze production of A-beta, the major protein component of the cerebral plaques of Alzheimer’s disease, from its precursor protein (APP). While these enzymes are both aspartyl proteases and top therapeutic targets, their biochemical properties are quite different, and each presents different problems for drug discovery. Gammasecretase inhibitors should avoid blocking proteolysis of the Notch receptor, part of an essential signaling pathway in cell differentiation. Beta-secretase (BACE1) inhibitors have poor drug-like properties and do not access the brain well. OBJECTIVES: To develop Notch-sparing gamma-secretase inhibitors and to explore the regulation of mRNA splicing of BACE1 as an alternative strategy toward lowering its activity. Methods: From initial hits, iterative design, synthesis and biochemical evaluation was carried out to identify potent and selective Notch-sparing gamma-secretase inhibitors. Promising compounds were further tested in cell culture for A-beta-lowering effects and evaluated for physiochemical and pharmacokinetic properties. BACE1 alternative splicing was studied using quantitative and semi-quantitative RT-PCR methods and via a mini-gene system that recapitulates endogenous BACE1 splicing. The A-beta-generating activity of BACE1 isoforms was determined as well. Results: Iterative medicinal chemistry has led to gamma-secretase inhibitors that effectively block A-beta production and that are substantially selective with respect to Notch proteolysis. These compounds have promising physicochemical and pharmacokinetic properties, suggesting that further preclinical development is warranted. Alternative splicing of BACE1 results in isoforms with little proteolytic activity, and shunting splicing of BACE1 toward these isoforms with antisense oligonucleotides results in reduced A-beta production in cells. Cis-elements in the BACE1 pre-mRNA that regulate alternative splicing have been identified, raising the prospect of finding small molecule modulators of BACE1 splicing. Conclusions: The discovery of Notch-sparing inhibitors makes gammasecretase a much more promising therapeutic target. Beta-secretase activity can be reduced indirectly, at the level of pre-mRNA splicing, by shunting activity to inactive isoforms. S2-03-02

MOLECULAR MECHANISM OF ACTION OF GAMMA-SECRETASE INHIBITORS AND MODULATORS

Taisuke Tomita, The University of Tokyo, Tokyo, Japan. Contact e-mail: [email protected] Background: Genetic and biological studies provide strong evidence that the production and deposition of amyloid-beta peptides (Abeta) contribute to the etiology of Alzheimer’s disease (AD). Thus, gamma-secretase, that is a responsible protease for the Abeta generation, is a plausible molecular

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target for AD treatment. gamma-Secretase is an unusual aspartic protease that cleaves the scissile bond within the transmembrane domain. This unusual enzyme is composed of a high molecular weight membrane protein complex containing presenilin, nicastrin, Aph-1 and Pen-2. Presenilin, a catalytic subunit for the gamma-secretase, forms a ‘‘catalytic pore’’ structure in which intramembrane cleavage might be occurred. Drugs that regulate the production of Abeta by inhibiting or modulating the gamma-secretase activity could provide a disease-modifying effect on AD, although recent studies suggest that the gamma-secretase plays important roles in cellular signaling including Notch pathway. Thus, much attention is now focused on the understanding the molecular mechanism whereby the gamma-secretase inhibitors and modulators specifically regulate the Abeta-generating gamma-secretase activity. Methods: Using chemical biological technique (i.e., photoaffinity labeling), we have identified direct molecular targets of the gamma-secretase inhibitors and modulators. We have also analyzed the effects of these compounds on the catalytic pore structure using biochemical structural analysis. Results: We found that the Notch-sparing gamma-secretase inhibitor and modulator directly target the presenilin and affect the structure of the catalytic pore. Conclusions: Our results clearly indicate that presenilin is an important molecular target for the Notch-sparing gamma-secretase inhibitors as well as modulators. I will also summarize our recent studies on the gammasecretase complex, and envision the direction for developing the effective and selective gamma-secretase inhibitors as therapeutics for AD. S2-03-03

ROLE OF PRESENILIN 1 IN ADULT NEUROGENESIS

Sangram Sisodia, University of Chicago, Chicago, IL, USA. Contact e-mail: [email protected] Background: Inheritance of mutant genes encoding presenilins (PS1 and PS2) variants cause autosomal dominant, familial Alzheimer’s disease (FAD). We have investigated the influence of expressing these mutant PS1 variants on hippocampal neurogenesis in transgenic mouse models and have shown that expression of mutant PS1 leads to impairments in environmental enrichment (EE)-mediated proliferation and differentiation of hippocampal progenitor cells (NPCs). Methods: Mouse prion promoter-driven transgenes encoding either human wild-type PS1 or FAD-linked M146L and aE9 PS1 variants were exposed to standard housing conditions, or to EE, a setting that is known to induce proliferation of progenitors (NPCs) in the dentate subgranular zone and differentiation of these cells towards a neurogenic fate. In contrast to standard housing conditions, in which NPC proliferation, survival and neuronal differentiation is unaffected by expression of either wtPS1 or PS1 variants, these parameters are markedly attenuated in the hippocampus of mice expressing mutant PS1 following EE. We have shown that the proliferation and neurogenic potential of NPCs expressing either wt or mutant PS1 are indistinguishable in vitro, but that the conditioned media from microglia expressing mutant PS1 impairs the proliferation and neuronal lineage commitment of NPCs expressing wtPS1. Results: Using proteomic and high density microrray strategies, we show that the levels of secreted chemokines in the conditioned medium of microglia expressing mutant PS1 mutant, or in microglia from enriched adult mice are significantly altered and we argue that these factors are, at least in part, responsible for the defects in proliferation and neurogenesis observed in vivo. Conclusions: Current efforts are focused on the purification and molecular analysis of microglia from enriched mice and the development of a conditional transgenic mouse model that will allow us to evaluate the impact of specific cell types in the CNS on mutant PS1-mediated alterations in NPC proliferation and neurogenesis in the hippocampus. These findings support a non-cell-autonomous role for mutant PS1 in hippocampal neurogenesis. S2-03-04

REVERSE CHEMICAL GENETICS APPROACH TO IDENTIFY DRUGGABLE GENE PRODUCTS IN ALZHEIMER’S DISEASE

Tae-Wan Kim, Columbia University, New York, NY, USA. Contact e-mail: [email protected] Background: The amyloid beta-peptide (Abeta) is produced by sequential proteolytic cleavage of beta-amyloid precursor protein (APP) by a set of