Hello, teachers and students! I’m glad to come to Dingxiang Garden to study with you. I am Dr. Han from the Department of Neurology, Xuanwu Hospital, Capital Medical University. Today, we are going to study the progress of preclinical subjective cognitive decline in AD. When we talk about AD, it is inevitable to mention the German psychiatrist Alois Alzheimer. Dr. Alois Alzheimer, who first reported the first case of AD in the world in 1906, was a 51-year-old German woman, whose main manifestations were memory loss, aphasia, and decline in other cognitive domains, and her entire course of the disease was 5 years. She ended up with flexion contractures, diaphoresis and bed rest, ending her life. What later set Dr. Alzheimer above other doctors was that he studied the disease in greater depth. He performed a brain autopsy on this patient after her death and discovered a characteristic pathological change in AD, which is now the gold standard for diagnosing AD – senile plaques and neuronal fiber tangles. It has been more than 100 years since the first case, but we still do not have a clear understanding of the disease, and there are many hypotheses about its pathogenesis. Among the many hypotheses, the more recognized ones are the Aβ cascade waterfall hypothesis and the tau protein hypothesis. We see these two pictures of the great man. This disease can inevitably invade all people, and the main and most irresistible risk factor is age. The incidence increases with age, and the pathophysiological changes associated with Aβ invade the human brain after a number of years of compensation and eventually loss of compensation before the disease develops. We know that AD is a degenerative disease of the central nervous system and it is irreversible, therefore, its early diagnosis and delayed onset become crucial. As the president of the World AD Association said, this disease is like a ticking time bomb that is always threatening our human society and always has the possibility of detonation. Its incidence is also very high. As we can see in authoritative journals, its incidence is 5.2 million people in the United States, and it is expected that by 2040, the number of AD patients worldwide will reach 81.1 million. Let’s first look at the first diagnostic criteria for this disease in the world. It was published in 1984 in the journal NEUROLOGY by the National Institute of Neurological and Communicative Disorders and Stroke – Alzheimer’s Disease and Related Disorders Association was first published. This diagnostic criterion is, in a nutshell, a passive diagnostic criterion. It excludes all diseases that may cause cognitive decline before it is considered clinically as Probable Alzheimer’s disease, if there are also some risk factors, such as abnormal thyroid function, severe anemia, systemic diseases like folic acid and B12 deficiency, general anesthesia for surgery, traumatic brain injury, other degenerative diseases of the nervous system (CBD, CJD, Huntington disease), etc., can all cause cognitive decline. However, when we consider that the cognitive decline is not due to other causes but to AD, we consider it to be Possible AD, and only when post-mortem examination reveals senile plaques and neurofibrillary tangles can we identify Definite Alzheimer disease, and only when it has progressed to the point where it affects the ability to perform daily life can we consider it to be AD dementia. So, limited by the scientific development at that time, by 2007, with the advancement of technology and the improvement of examination tools, with MRI, PET, cerebrospinal fluid, and genetic tests, the understanding of this disease has become more detailed. The diagnostic criteria, relative to the 1984 diagnostic criteria were revised. The most important feature is that the significance of biomarker for the diagnosis of AD was introduced for the first time, so our diagnosis of AD has changed from passive to active, and we can base on the typical clinical symptoms of AD – situational memory loss, plus the assessment of neuropsychological scale, plus any of the auxiliary examinations, for example, hippocampal atrophy on MRI, temporoparietal metabolism on FDG-PET, etc. decreases, etc., or decreases in Aβ1-42, increases in T-tau and p-tau seen in the cerebrospinal fluid, familial AD can be seen with mutations in the APP, PS1, and PS2 genes, and these will allow us to make a diagnosis of AD during the patient’s lifetime. From these we can see that diagnostic imaging and biomarkers occupy half of the world and are very important. By 2011, the NIA-AA, which is the National Institute on Aging-Alzheimer Association Association, revised the diagnostic criteria for AD once again, proposing that AD is a continuous pathophysiologic process. In other words, not only in the dementia stage we can diagnose AD, but also in the pre-dementia MCI stage Mild Cognitive Impairment stage, we can also consider it as AD, and the 2011 NIA-AA diagnostic criteria also proposed that in the pre-clinical stage, that is, in the absence of We can also study AD according to biomarker when there are no clinical symptoms. AD is divided into three different stages, and diagnostic criteria are given for each of the three stages. For diagnostic criteria, in addition to blood and imaging, there are also diagnostic criteria for urine, which is AD7cNTP. we can clearly see from this bar chart that as cognition declines, abnormalities in urine biomarkers can be seen not only in the dementia and MCI stages. By 2014, the revision of the diagnostic criteria for NINCDS-ADRDA was similar to the diagnostic criteria for NIA-AA in 2007 and 2011, with the difference that the diagnostic criteria for atypical AD were proposed. Also according to IWG-2 regarding the diagnostic criteria in 2014, the significance of urine diagnosis was proposed, that is, a: specific clinical symptoms; b: pathological evidence in the body, we use urine to examine AD7cNTP, if both are met, according to the description of IWG-2 it is possible to diagnose a+b met and support a definite diagnosis of AD. If only the urine test is positive and the clinical symptoms are negative, the biomarkers suggest that neuronal damage due to neurodegenerative disease is occurring, probably due to individual compensation without clinical symptoms, and with time, continuous examination and follow-up, clinical symptoms may appear, and when a+b is satisfied, the diagnosis of AD is considered to be supported. Here are the diagnostic applications of the urine biomarker in different situations respectively. Until 2011 the preclinical stage of Alzheimer’s disease diagnostic criteria was proposed by Dr Sperling. She believes that in the course of AD, the attack of AD on the human brain starts many years before the clinical symptoms appear. However, because people have brain and cognitive reserves, they do not exhibit clinical symptoms. If we can detect and intervene in the early stage of the disease, it will be twice as effective and provide a good time for us to intervene in AD early. This is the description of the diagnostic criteria of AD by NIA-AA in 2011. From the graph we can see that the solid line above is the normal aging cognition declining with age. The dashed line is the process of cognitive decline in patients with AD pathological aggression, which is significantly steeper than normal aging, and it declines significantly faster. It is divided into three stages: the dementia stage when it affects the ability to perform daily living, and the MCI stage before it affects the ability to perform daily living or when it is mildly affected. Before MCI, when it does not affect the ability of daily living, or even when the neuropsychological scale does not meet the criteria of mild cognitive impairment, but the patient has subjective complaints, complaints of memory loss or cognitive decline, and the patient compares himself with himself longitudinally is the stage of decline. The preclinical stage is divided into two parts, one is with AD pathological intrusion but without symptoms, and the other is with AD pathological intrusion with symptoms. But not to the extent of objective mild cognitive impairment. The preclinical stage is divided into three main stages. First, there is a pathological deposition of Aβ, which is Amyloidosis without symptoms, and this stage can be seen on PET/CT or Amyloid PET as the deposition of A in the brain. It is also possible to see the decrease of Aβ1-42 by examination of cerebrospinal fluid. In the second stage, with the deposition of βAmyloid, neurons cause degeneration, microglia proliferation, and apoptosis of neurons, which is the second stage. In the image, we can see the thinning of the cerebral cortex, the atrophy of the hippocampus, and the reduced functional connectivity through functional MRI. FDG-PET can see the reduced metabolism, which is what we can see in the second stage. In 2014, German psychiatrist Frank Jessen first proposed the concept of SCD, Subjective Cognitive Decline. Cognitive Decline, which is the mildest stage in the preclinical stage of AD, that is, the mild cognitive decline stage in the three preclinical stages of AD mentioned earlier, considered as the preclinical subjective cognitive decline stage. Generally speaking, subjective cognitive decline is subjective and has no relationship with objective, the patient himself thinks he has a decline, he compares himself with himself, today with yesterday, this year with last year, especially within 5 years, it is a decline, we think he has subjective cognitive decline, and the objective examination does not reach the level of MCI. However, subjective cognitive decline is not enough, objective examination and differential diagnosis are needed because many causes can lead to subjective cognitive decline, not only AD, but also other causes, such as venereal disease, depression and anxiety, personality, cerebrovascular disease, etc., so differential diagnosis is needed. So, at which stage of subjective cognitive decline is it? This graph explains it. The green band shows the band of normal cognitive level after adjustment by age, gender, and education, and the purple, sloping line of decline is a line of decline after cognition is affected, and the intersection of this line and the green band, the vertical coordinate indicates after the objective level of mild cognitive impairment is reached. Before that, although the cognitive level also decreases, the overall cognition is still within the normal range, and this stage is called the subjective cognitive decline stage. This is the line where the subjective cognitive decline begins, and this is a short period of time that can be effectively prevented if we can seize this opportunity to intervene with the patient, such as sunlight, diet, exercise, etc. The evolution of the concept of subjective cognitive decline. In fact, the concept of subjective cognitive impairment was introduced as early as 1982, and as time went on, the technical means advanced, some people studied the disease or symptoms from MRI, some from PET, some from cerebrospinal fluid, in many ways. We can also think of it as the pre-MCI stage pre-MCI, the diagnostic criteria for this stage of SCD, first of all, a relatively sustained decline in one’s own cognition and previous state, and a decline unrelated to the acute event, and within the normal range of age, gender, and education adjusted post-neuropsychological scale examination, and, at the same time, the exclusion of the following conditions, such as dementia, MCI or other conditions such as major depression and anxiety that can cause the symptom. In addition, the main thing to look at is the subjective cognitive decline in the preclinical period of AD that we want to study, that is, the subjective cognitive decline superimposed, which needs to be consistent with, first of all, memory and not other cognitive domains decline, the onset of the disease is in the last 5 years, it cannot be a decline compared to the young (20 years old), that is meaningless, but only a decline compared to the memory and cognitive situation within 5 years, to be meaningful. The age of occurrence of the subjective complaints is meaningful after 60 years of age, 20 and 30 years of age are not meaningful and are mainly differentiated from anxiety and depression. Self-perceived subjective memory decline causes personal or other people’s concern, and this is also meaningful. The other is the horizontal comparison, and other people in the same age group is poor performance, this is also meaningful. The most important is the following three biomarkers, or objective evidence that informed individuals see a problem, or a positive APOE4 gene for sporadic Alzheimer’s susceptibility, and this is more supportive of a subjective cognitive decline consistent with preclinical AD. Of course, this is not absolute, because it is only a risk factor, it is not like a familial genetic gene, APP, PS1, PS2 is stronger evidence. Also a positive PIB-PET, and now tau-PET, a decline in cerebrospinal fluid Aβ1-42, an increase in T-tau and P-tau, any of these biomarkers that are positive are meaningful for the superimposition of SCD. It is epidemiological, with 25%-50% of people over 65 years of age experiencing memory loss, with subjective memory loss increasing with age in people over 85 years of age, with rates as high as 88%. Time is of the essence, so I will not go into detail. In conclusion, subjective cognitive decline is very common in the elderly population and it can serve as a windfall for preclinical AD. Although SCD is only a symptom and a clinical manifestation, it is very helpful to prompt us to pay attention to the preclinical stage of AD. This is a previous study by some experts on this disease, which found abnormalities in gray matter structure, white matter connectivity, etc., compared to normal people. The subjective cognitive decline in this population is not only the subjective complaints of the patients, but also the objective differences we found with the normal cognitive population, such as abnormalities in PET examination of glucose metabolism and fMRI examination of task state. This is our group’s study on people with subjective cognitive decline. Its background is mainly based on the research of others internationally, especially Jessen’s conceptual framework of subjective cognitive decline, which standardized the criteria for everyone’s research. We see this graph showing that abnormalities in biomarkers occur not only at the dementia or MCI stage, but even before the onset of symptoms, and these different colors indicate abnormalities in different biomarkers that can be seen long before MCI. This is a review of our international research on subjective cognitive decline, and from this article, we can see that some people have studied SCD with different methods, structural MRI, functional MRI, PET. This is our scenario, we find two groups of people and compare them, we consider if there is a difference between SCD and NC functionally and structurally, SCD mainly comes from my memory clinic in our hospital, NC is recruited through word of mouth or microsoft advertising among acquaintances, and it turns out that there is a significant difference in functional MRI between these two groups. This is the result of the scale performance of its behavioral psychology, which is the result of its structural performance. We can see from this figure, this blue is where there is a significant difference between these two groups, the ALFF value SCD is significantly lower than NC. Future direction: further expand the sample size and improve the examination means, currently we only pass functional MRI, diffusion tensor imaging (DTI), structural MRI, our hospital can do FDG-PET, we expect to be able to carry out PIB-PET examination next year, genes have been carried out in the clinic, and our laboratory can also do APOEξ4 examination. We have perfected all the relevant biomarkers for the subjects. The most important thing is the longitudinal follow-up, which is planned for these populations once a year, so that we can see how it evolves and clarify in what kind of baseline period changes in brain areas can transform into mild cognitive impairment in how long, into dementia, etc. Since the introduction of Professor Jessen’s conceptual framework in 2014, especially the SCD overlay concept, our understanding of the specificity of SCD has increased, especially with the use of biomarkers, which has made us more proactive and effective in studying these populations. This is this year’s AAIC annual meeting, and the speaker is Petersen, the originator of MCI, and the presenter is Professor Frank Jessen. This is a picture of me with Petersen and Prof. Jessen after the meeting. On October 23rd, we invited Prof. Jessen to our hospital’s education office to have an academic exchange with our group and our partners, and he told us about the progress of research on subjective cognitive decline in SCD, and we introduced our group’s research progress on SCD to Prof. Jessen separately. This is our hospital’s cognitive research team. Welcome everyone, who has related problems, to our hospital for a systematic and comprehensive examination, thank you.