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PL2. Changing practice – Medical and clinical aspects

Detailed Programme, abstracts and presentations

PL2. Changing practice – Medical and clinical aspects (Friday, 5 October, 10.30–12.00, Europa 4)

PL2.1. Changing the criteria for the diagnosis of Alzheimer’s disease

Bruno Dubois, Olga Uspenskaya, Leonardo Cruz de Souza, Marie Sarazin

Alzheimer’s disease (AD) has traditionally been defined as a type of dementia, a concept reified with the publication of the National Institute of Neurological and Communicative Disorders and Stroke – Alzheimer’s Disease and Related Disorders (NINCDS-ADRDA) criteria in 1984. Three major tenets of these criteria were that: i) the clinical diagnosis of AD cannot be made with certainty and requires post-mortem confirmation; ii) accordingly, the clinical diagnosis of AD can only be ‘probable’; and iii) the diagnosis can be made only when the disease is advanced and reaches the threshold of dementia.

The discovery of biomarkers, considered as surrogate markers of the underlying neuropathological changes, led an international work group (IWG) to propose a new conceptual framework for AD in 2007 (IWG/Dubois Criteria). According to the IWG, AD is now defined as a dual clinico-biological entity that can be recognised in vivo, prior to the onset of the dementia syndrome, on the basis of: i) a specific core clinical phenotype comprised of an amnestic syndrome of the hippocampal type; and ii) supportive evidence from biomarkers reflecting the location or the nature of Alzheimer-type changes. Therefore, AD is diagnosed with the same criteria throughout all symptomatic phases of the disease based on the biologically-based approach to diagnosis, independent of clinical expression of disease severity. The definitions were further clarified in 2010.

The major advance of the IWG/Dubois Criteria and of the subsequent National Institute on Aging/Alzheimer’s Association (NIA/AA) criteria was to integrate biomarkers of Alzheimer pathology into a diagnostic framework for earlier clinical diagnosis. The use of biomarkers in research will assist with clinical trials and possibly with regulatory decisions. They will set the stage for primary and secondary prevention. The emphasis on biomarkers builds on an increasingly robust scientific basis, but the data are still emerging and verification of the type of changes, correlations with clinical outcomes, order of appearance, and consistency across populations is required. The IWG/Dubois Criteria embrace the entire continuum of symptomatic AD, from the prodromal to the dementia forms, in a single diagnostic framework by integrating biomarkers into all phases of the diagnostic approach. They emphasise episodic memory impairment as the key AD phenotype but acknowledge the existence and importance of atypical forms. The 2007 criteria have already shown their utility for research studies and clinical trials: they were successfully implemented in the current Phase 2 clinical trials for prodromal AD with a gamma secretase inhibitor, two immunotherapies, and the LipiDiDiet study, and they have been accepted by the European Medicine Agency (EMA) for use in AD clinical trials. Moreover, data have accumulated since 2007 that confirm the added value of biomarkers for the diagnosis of AD: although not intended for this purpose, expert clinical centres have started to use the criteria in specific (young onset AD) or complex cases.

PL2.2. Prospects for prevention of dementia in our increasingly ageing society: Good news on the horizon?

Eric B. Larson

Unprecedented numbers of people are living to advanced old age. These changes have profound effects on society and are challenging social policies, social services and medical care throughout the world. One striking feature is the vast increase in numbers of persons with Alzheimer’s disease and other dementias. This increase is driven not by an overall increase in the incidence of these conditions but by the vast numbers of persons surviving to ‘old-old’ age. Demographic research shows that postponement of mortality is widespread in countries with expanding older populations. In addition, rather than senescence being inevitable, biodemography research suggests widespread variations in patterns of ageing. Research advances suggest that cardiovascular disease and some cancers are being prevented or treated more effectively, contributing to a postponement of mortality and compression of morbidity. What are the prospects for prevention of dementia?

Primary prevention trials of antioxidants, estrogen, ginkgo and NSAIDs have been disappointing. Other studies of single agents like aspirin, DHEA, and cholinesterase inhibitors do not suggest prospects for prevention. By contrast, recent evidence from at least three epidemiologic studies describe delayed onset of dementia over recent decades and that a compression of cognitive morbidity may be occurring as onset of dementia occurs closer to the time of death. These studies suggest that better education, more favourable socio-economic conditions and better control of cardiovascular risk may be contributing to the postponement, or even prevention, of dementia. Another important finding is the complex ‘ecology’ of the ageing human brain. Recent data using neuropathologic studies of brains obtained from four large population-based studies show an individually varying complex convergence of subclinical diseases in the brains of cognitively normal very old adults, as indicated by widespread degenerative changes of Alzheimer’s disease, Lewy Body disease and vascular disease.

Multiple risk factors for dementia have been established: cardiovascular disease risk factors (hypertension, lipids, smoking, etc) along with depression, physical activity, intellectual activity and obesity/metabolic dysregulation. There may be modifiable risk factors for dementia similar to modifiable risk factors for cardiovascular disease and stroke. One group has estimated that up to half of Alzheimer’s disease cases may be attributable to modifiable risk factors. Recent work on exercise has shown striking evidence of neuroprotective effects.

The good news on the horizon related to prevention of dementia is that there may already be some postponement of cognitive morbidity and dementia, consequent to overall better health in our ageing populations, and the emergence of multiple risk factors that, if modifiable, may reduce the burden of these diseases. Widespread prevention trials are needed to better establish whether this ‘possible’ good news is indeed going to be realised.

PL2.3. Treating people with Alzheimer’s disease – An overview of the latest research

Achim Schneeberger

Half a decade ago, researches around Dubois proposed to change the concept of diagnosing Alzheimer’s disease (AD). The 1984 NINCDS-ADRDA criteria neither integrated specific clinical features nor biomarker data. As a result, definitive diagnosis was only possible late in the disease process and would require pathological confirmation. The new concept is based on clinical-biological grounds. When originally put forward it was based on a multitude of small studies of rather short duration. During the last few years, large research initiatives were established to unravel the natural course of the disease. Starting with US ADNI (AD neuroimaging initiative), comparable initiatives were formed in Europe, Japan and Australia. These initiatives now provided data confirming the new concept of AD diagnosis. These days, AD is perceived as a disease that starts years to decades before the appearance of clinically detectable symptoms. The earliest change detectable with modern methods is the one in the amyloid pathway. Amyloid pathology, as defined by positive amyloid imaging or decline in CSF Aβ42 levels, precedes tau pathology as well as structural brain changes (e.g. hippocampal atrophy). These changes are followed by typical or atypical clinical manifestations, which are gradually worsening and ultimately reach the dementia threshold. Defining the disease on specific clinical and biological features allows a (relatively) early and specific diagnosis and, thus, the development of disease-modifying (DM) therapies. DM therapies are expected to exert their activity best at a disease stage when neurodegeneration is still limited. Most new therapeutic approaches currently in clinical development target the amyloid pathway, while much fewer approaches target tau pathology or other mechanisms such as mitochondrial dysfunction or oxidative stress. For late summer 2012, we expect Phase III results on Bapineuzumab and Solanezumab, two monoclonal antibodies. While both target Aβ, they differ substantially (e.g. exact target structure, isotype). These differences do not only impact their side effects but will also determine their clinical activity. This obviously extends to all other Aβ immunotherapeutics. IVIG represents another drug currently in Phase III. Active vaccines offer a couple of advantages over passive immunotherapy including the route of administration (s.c./i.m. vs. i.v.) and manufacturing costs. Currently, three candidates are in Phase II: ACC001, CAD106 and AD02. AD02 stands out as the only immunotherapeutic that targets early AD (all others are tested in mild to moderate AD). In addition, it yielded promising clinical Phase I data. Testing DM strategies in early, prodromal disease is one of the biggest moves in AD research over the last 1–2 years. It is about to start in a prevention setting in cohorts of familial AD (Alzheimer’s prevention initiative, A4 trial, DIAN).

In conclusion, our increasing understanding of the pathology underlying AD is being translated into better diagnostic algorithms, and is helping to develop new drug candidates with DM properties as well as their rationale and appropriate clinical evaluation.

PL2.4. Imaging for diagnosis of Alzheimer’s disease – New insights from EU-funded and international research

Giovanni Frisoni

Imaging techniques have advanced to provide in vivo neuropathology of Alzheimer’s disease and other neurodegenerative diseases at the molecular, cellular, tissue, and organ level. They have allowed us to outline the progression of changes that take place at each level in the brain of persons who are about to develop the disease, show the very earliest symptoms of the disease, or have the full-blown disease. This conceptual model has allowed us to identify disease stages where appropriate imaging markers can be used to diagnose the disease early in the disease course. These advances have found ample space in research settings, but some are slowly being implemented in clinical practice. Research and development efforts are being carried out in Europe and elsewhere to extend the model to non-Alzheimer’s neurodegenerative dementias, standardise imaging markers for routine clinical use, understand advantages and disadvantages over fluid (CSF) markers, and develop efficient and effective diagnostic protocols.






Last Updated: Wednesday 14 November 2012