Amongst neuropsychiatric disorders and disease, we are going to be talking about Alzheimer disease and related disorders which means dementia in general. And we try and give an example and a contextualization of what screening may mean with respect to this disease. So what is dementia? Well, first of all dementia is not a normal part of aging and this is a very important message that the World Health Organization is been launching in the past few years. And that's because some of the diseases are progressive in nature and some of the changes that are observable or perceived by the subject are somewhat similar to what happens physiologically with increasing age. Some of these are classically a progressive impairment of cognitive functions. Amongst these, memory. So, the difficulty in learning new stuff, new information, retain these new information and use it in the future is one of the major feature. But in fact, other cognitive domains and truly old cognitive domains later in the disease will be affected which includes attention, language, executive functions and all other forms of superior cognitive abilities. Now, these are not all the story. To receive a diagnosis of dementia, these cognitive impairments should be sufficient in their severity to cause troubles in everyday life, in activities of daily living. Whether it may be complex or not complex and at the beginning of the disease, the impact of these mild disorders would not be sufficient to cause these impacts. So, this functional impairment is a core component of the diagnosis of dementia. Later on in the disease, more psychiatric and behavioral symptoms become prominent and these includes aggression, but at the beginning of disease, apathy, depression and others of these and may or not be used for the diagnosis of dementia because sometimes or most commonly they're not apparent at the beginning of the disease itself. In fact, dementia is a syndrome, which means that can be caused by a number of diseases. The most famous one is Alzheimer's disease and you may see in this slide from the Alzheimer's Society that essentially we do know that Alzheimer's disease explain the great majority of cases of dementia but vascular dementia is also a cause of the syndrome that is quite prevalent in general population. And, there are others that are less prevalent but many may argue that these slides in terms of how the proportion of original causes of dementia are divided is not accurate or correct eventually. The truth is probably that mixed forms in which Alzheimer's component, vascular's component are present at the same time explain or are or do exist and at the same time in a dementia case. Overall, we do know a great deal about the neurobiology and the damage in the brain that occurs at a molecular level for Alzheimer's disease and other forms of dementia. But, put it simple, what we know is that as you see here in a comparison between a normal and a brain of a person with Alzheimer's disease, the latter is simply smaller and that's because it shrunk progressively. So, dementia is always an acquired deficit, is a form of acquired cognitive problems and is an acquired form of this smaller brain because the neurons within the brain are dying and they are reducing in number and this reflects in the reduction and impact on its function overall. Now, from an epidemiological point of view, in the past 10 years there have been a huge effort at international level to enumerate the cases of dementia in the world. And we now have a very good evidence base that shows us that first of all the prevalence of disease doesn't change when it is calculated age specific and education standardized in all world regions. That there are not major geographic variations. This in essence means in this dynamic picture that in 2015 the numbers of people with dementia by world regions were in order of millions, 8.2 in Europe and 4.7 in Northern America. But you can see already now, the majority of people with dementia live in Asia, in eastern countries. What will happen in the next decades is essentially dictated by the fact that population is aging in all world region which is a good news because more people will reach older ages, is a form of success of health in the past century. But because dementia is strictly related to aging and because the risk of dementia increases exponentially with increasing age after the age of 65, it means the fact that it will be more people aged 80 years and more, 90 years and more and 100 and more will essentially lead to an important increment in the number of people that prevalence of the disease in all world regions. So you see here in these dynamics that these will translate from the current 45, 46 million at a global scale in grey at a bottom right to actually the more than 78 million people affected and progressively by 2050 to the astonishing number in the total amount in the world of 135 millions. These calculations of course, projections because we're talking about a future. But the evidence based on which they are grounded is absolutely solid and it counts on epidemiological studies that have been conducted in most of these world regions using highly standardized instruments and tools. So that we have the guarantee that we can make comparisons. Now, the second notion is what are dementia's impact on patients and families in general and therefore, community and society to tell that the disease matters in the first place or not. Well, this is a paper we published few years ago in the Lancet that essentially demonstrates that amongst older people in developing countries dementia is nowadays already the first and most important predictor of disability. In other terms, if we'd reverse the logic of this phrase, amongst older adults who are disabled and need care most of the time, one in four of them have dementia. And, the fact that they have dementia is also explaining why the impact on caregivers is an important component of the disease itself. The caregiver are in most cases family members, the spouse or children of the person affected. You can imagine that a disease has an impact that goes very much beyond the health aspect of it and to name just about a few, you can think about the cost, whether they are direct or health expenditure but also indirect because the caregivers have to attend continuously if the person affected. So, the implications from a public health perspective are enormous. Now, this has been largely neglected in the past few years. It's been called an elephant in the room and that's because the aging of population is a major component as we said but also because we have still a limited understanding of the relationship of the disease itself as we know it in terms of neurobiology in late age. So, why we know the least about the disease is really about that part of the population that will be most affected that is those aged 85 years and more and these will be relevant for what we'll say in a minute about screening. So, this is where we stand right now in terms of diagnosis in population. You see here the list of the five main components on which we base our diagnosis these days and essentially related to the preexisting and the underlying neuropathology. So the damage in the brain and also the fact that these may be monitored or observed with biomarkers. Whether they are hot peripheral or central neuro-imaging or other sorts, which are currently under development. And the fact that the cognitive symptoms that characterize dementia can be and should be measured or subjectively perceived with neuropsychological testing. And again, on the disability as we said dementia is characterized by a major impact on the ability to carry out everyday activities like dressing up or bathing and things like this but also instrumental, more complicated activity like dealing with finance and a lot of things. But of course the subjective impairment and health seeking is crucial because we're not talking about a screening instrument in the general population. We are sitting in our clinics and people have to come to us in the first place. And this is an important element. So the fact the subject perceive that something has changed and that they have a problem is part of the definition of dementia. We argue that with these five elements in place and well-known, we now make a diagnosis of dementia. Which is too late. And the reason why essentially dementia is under-diagnoses in population is, first of all, because there is still no awareness about the disease itself. And it's attached to an important stigmatization of the person and the family itself. And also because there are false beliefs about the fact that nothing can be done to treat dementia. And as you can imagine, this would prevent people to seek help, importantly because they may think, "Well, first of all it's not a disease. It's a normal part of aging. Second, there's nothing that can be done so why should I go to the doctor." All these is rightly wrong but as you can see the numbers on the top right. This is a problem in these settings. Well, these settings in developed countries, Western countries but also this is a more serious aspect in the lower middle income countries where the large majority of people with dementia currently live. So, we argued that early dementia should actually be termed at timely diagnosis because it's based on the five elements that we went through it right now. And that of course in the near future we all would like and wish to have the possibility to make a diagnosis early enough so that something that has not occurred can be predicted, which is the principle of screening as well. And, maybe the course of the disease itself can be altered. And that's where it comes into play the aspect of screening. Are we at a stage where screening for dementia can be recommended in populations? No, we are not. And the reason for that is the combination and the fact that there are not out there disease modifying therapies that can be recommended after the diagnosis is made but particularly because our ability to recognize the disease in its very early stages which is by definition what we do by screening, is essentially too much in its infancy and we are not able to predict a disease in the future. That would cause strain and psychological consequence of people who are announced a disease which is tremendous and most feared. That may be more important of disease itself and in most cases some of these people may never develop the disease itself.
