Shifted focus for target oriented basic research in Alzheimer disease

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  • yet evaluated the effect of aerobic exercise on cognition in MCI or mild AD.

    ALZHEIMER DISEASE

    ALZHEIMER THERAPY?

    of AKeywords. Alzheimers disease, Risk factors, Mortality

    MRI MARKERS OF MICROVASCULAR PATHOLOGY ANDHEMORRHAGIC RISK

    David J. Werring. UCL Institute of Neurology, National Hospital, Queen SquareCity, London, GB.E-mail: d.werring@ucl.ac.uk

    Neurodegenerative diseases, including sporadic Alzheimers disease (AD),almost invariably coexistwith cerebrovascular disease inolder people. Cerebralsmall vessel disease (SVD) is the most important vascular contribution to de-mentia, causes about a fth of all ischaemic strokes, and most cases of spon-taneous intracerebral haemorrhage.Developments inneuroimaging, especiallymagnetic resonance imaging (MRI) now detect an increasing number of po-tential biomarkers of SVD. These include small subcortical infarcts, whitematter magnetic resonance (MR) hyperintensities, lacunes, prominent peri-Keywords. Alzheimers disease, Dementia, Physical exercise

    FACTORS THAT AFFECT LIFESPAN IN MILD VERSUS MODERATEALZHEIMERS DISEASE

    Carina Wattmo, E. Londos, L. Minthon. Clinical Memory Research Unit, Dept. ofClinical Sciences, Malm, Lund University, Malm, Sweden.E-mail: carina.wattmo@skane.se

    Background/objectives. Increased knowledge of the factors that mightaffect lifespan in Alzheimers disease (AD) patients treated with cholines-terase inhibitors (ChEIs) is important for clinicians and for the health ser-vices. Moreover, future disease-modifying therapies might affect survival.We aimed to identify factors that inuence life expectancy in the mild vs.moderate stage of ChEI-treated AD.Methods. The Swedish Alzheimer Treatment Study (SATS) is a prospective,observational, multicentre study for the assessment of ChEI treatment in aroutine clinical setting. This presentation included 791 deceased participantswith a clinical diagnosis of AD. Of those, 538 were dened as mild (Mini-Mental State Examination (MMSE) score, 20e26) and 253 as moderate(MMSE score, 10e19) AD at the start of ChEI therapy (shortly after the time ofdiagnosis). The patients date of death was recorded and their survival wasindividually compared with the sex- and age-matched general population.Results. Themean standard deviation time from AD diagnosis to death was5.93 2.88 years in the mild and 5.32 2.44 years in themoderate stage (p0.002). This differencewas not observed in theyoungest and oldest age groups,in thosewithmoreyearsofeducation, or in the sex-orapolipoproteinE (APOE)-specic subgroups. Compared with the general population, a decrease in ex-pected lifespanwas found in themild andmoderate ADpatients (40% vs. 47%, p 0.002). Highly educated individuals or carriers of two APOE e4 alleles in themoderate stage exhibited great reductions in life expectancy (57%).Conclusion. The survival time after diagnosis in the mild vs. moderate stagemight be similar in subgroups of AD, suggesting that genetic and socio-de-mographic factors have a strong impact on lifespan, even among AD patients.Higher education or carrying two APOE e4 alleles were risk factors forincreased mortality in the more advanced stage.diminishing the detrimental effects of the cascade reaction. Thus, based onexperimental studies, there is a theoretical rationale for an effect fromphysical exercise on cognitive performance and function in AD. In humansboth short term and long term exercise is associated with improved learningand memory and with the induction of Brain Derived Neurotrophic Factor(BDNF), an important plasticity-related neurotrophin. Although some clinicaltrials on various forms of physical activity have been performed onmoderateto severe AD subjects, there is insufcient evidence for an effect of physicalexercise in subjects with dementia, primarily due to lack of appropriatelydesigned studies. Thus, to which extent moderate to high intensity physicalexercisemay prevent dementia or slow down the disease process in AD is notyet clear. Several large randomized controlled trials on the effect of physicalexercise on prevention of dementia and functional outcome in healthyelderly subjects or subjects with subjective cognitive symptoms, recruitedfrom population studies, are now ongoing. However, only few studies have as

    Abstracts / Neurobiologyvascular spaces, cerebralmicrobleeds (CMBs), cortical supercial siderosis, andManfred Windisch. NeuroScios GmbH, St. Radegund/Graz, Austria.E-mail: mwindisch@neuroscios.com

    The fact that there are no naturally occurring animal models of Alzheimersdisease (AD) available, makes it necessary to create articial systems, eitherby induction of lesions or by genectic manipulation. Majority of AD modelsdifferent transgenic rodents, over-expressing disease relevant proteins likeAPP or tau that are believed to be involved in the pathogenesis. In spite ofenormous efforts no real complete model could be established so far, thatreally replicates the proposed disease cascade. High levels of over productionof different mutated proteins that do never exist in a single patient questionalready any translational value. On the other hand it is a fact that treatmenteffects on different disease targets like beta-secretase could be reproduced inhuman clinical trial, but biochemical changes did not result in functionalimprovements. It seems obvious that cognitive changes that were shown inrats and mice as a consequence of the genetic manipulation or the lesion aremost likely not the cause of cognitive disturbance in humans. This lack ofBengt Winblad. Karolinska Institutet Alzheimer Disease Research Cente,Stockholm, Sweden.E-mail: bengt-winblad-swedishbrainpower@ki.se

    Research into AD has been partly successful in terms of developing symp-tomatic treatments, but has also had several failures in terms of developingdisease-modifying therapies. The last drug to enter the market was in 2002.Since then, many products in different development phases have failed.Why? Wrong target, wrong molecules, inappropriate animal models, inap-propriate proof-of-concept studies, heterogeneous patient groups, tooadvanced disease, non-relevant outcome measures, inter-centre variabilityin increasingly globalised multi-centre trials? Many clinical and experi-mental studies are ongoing, mainly based on anti-amyloid-b (Ab) strategies,but the exact role played by Ab in AD pathogenesis is not yet clear. We needto acknowledge that a single cure for AD is unlikely to be found and that theapproach to drug development for this disorder needs to be reconsidered.Preclinical research is constantly providing us with new information of thecomplex AD puzzle, and an analysis of this information might reveal patternsof pharmacological interactions instead of single potential drug targets.Increased collaboration between pharmaceutical companies, basic andclinical researchers will bring us closer to developing an optimal pharma-ceutical approach for the treatment of AD. A better understanding of thedisease pathogenesis will hopefully be the way forward to nding relevanttargets in order to optimize treatment for AD.

    Keywords. Alzheimer disease, Drug targets, Treatment strategies

    WHY DID ANIMAL MODELS FAIL TO SHOW THE RIGHT WAY TOatrophy. Some SVDmarkersmay have a particularly valuable role in identifyingthe underlying small vessel arteriopathy; for example, a strictly lobar pattern ofCMBs is suggestive of CAA, while deep CMBs more likely reect hypertensivearteriopathy. Of the small vessel diseases, cerebral amyloid angiopathy (CAA) isof particular interest in dementia research because of the overlap and potentialinteraction with AD. Detecting CAA has potential importance in the followingways: for theprediction andmonitoringofAD treatment-related complications(especially from immunotherapy); understanding disease mechanisms andclinical features; and in assessing bleeding risk. In this presentation recentprogress indevelopingdiagnostic andprognostic neuroimagingbiomarkers forCAA will be reviewed, highlighting the relevance to dementia research wher-ever possible. In addition to CMBs, we will consider the topography of MRI-visible perivascular spaces and cortical supercial siderosis as characteristicneuroimagingmarkers of CAAwith relevance for diagnosis, understanding andmonitoring CAA.

    Keywords. MRI, Small vessel disease, Cerebral amyloid Angiopathy

    SHIFTED FOCUS FOR TARGET ORIENTED BASIC RESEARCH IN

    ging 35 (2014) S1eS27 S25correlation leads to wrong conclusions in selection of new treatments forclinical testing. So the selection of models was already critical, but in addition

    Outline placeholderKeywords

    Factors that affect lifespan in mild versus moderate Alzheimer's diseaseBackground/objectivesMethodsResultsConclusionKeywords

    MRI Markers of microvascular pathology and hemorrhagic riskKeywords

    Shifted focus for target oriented basic research in Alzheimer diseaseKeywords

    Why did animal models fail to show the right way to Alzheimer Therapy?

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