Dementia: Prevention, Diagnosis, & Management

Hi. Thank you for joining. My name is Elizabeth Murphy Bevins, and I'm an assistant professor in the Department of Neurosciences at the University of California, San Diego. I practice there as a clinical neurologist specializing in the field of dementia. And today, I'm going to speak to you about the prevention, diagnosis and management of dementia. This is a field that I am very fond of myself. It's a patient population that I'm very fond of, and I'm very excited to share some of my knowledge with you. I have no disclosures. This is a photo of our new Brain Health and Memory Disorders Program building at the University of California, San Diego, where we just moved in about a year ago. I will start by defining dementia as a clinical syndrome, propose a diagnostic algorithm to approach a patient who presents with cognitive complaints, highlight any atypical clinical features that warrant further investigation beyond the basic diagnostic workup, propose strategies for prevention of dementia with a focus of lifestyle modifications in the middle aged years. Describe our current evidence based therapeutics and discuss novel biomarkers and potential therapies on the horizon. So first, a bit about what dementia is. As the global population ages, dementia has become a public health priority. The World Health Organization estimates that 50 million people are living with dementia worldwide and there are nearly 10 million new cases each year. The term dementia is often poorly understood, especially among patients. It's not uncommon for patients to have a missed conception that the term dementia refers to just normal age related cognitive decline and that dementia is distinct from Alzheimer's disease. In fact, the term dementia is an umbrella term and it encompasses Alzheimer's disease as well as other diseases. Alzheimer's disease is the most common cause of dementia. But the term dementia itself is just defined as a clinical syndrome of cognitive impairment that interferes with daily activities and represents a significant decline from previous levels of functioning. The clinical presentation of all cause dementia is diverse, with variable involvement of different cognitive domains, including memory, language, executive function, attention, visual spatial functions and behaviors. And the underlying pathology is also diverse. So as I mentioned, the most common disease causing dementia is Alzheimer's disease. Alzheimer's disease is thought to account for 60 to 70% of dementia cases, and it is defined pathologically by amyloid beta plaques and tau positive neurofibrillary tangles. And classically, Alzheimer's disease presents as an amnestic syndrome. However, there is increasing awareness for atypical Alzheimer's syndromes in which memory might be relatively well preserved, and these other cognitive domains are preferentially affected. And this is especially true in young onset Alzheimer's disease, which is defined as Alzheimer's disease with symptom onset prior to the age of 65. It's more common that we see these atypical non-amnestic variants of Alzheimer's disease. Conversely, amnestic presentations are classically attributed to Alzheimer's disease. However, postmortem studies show that a substantial portion of amnestic syndromes may be due to non Alzheimer's pathologies, such as the second most common neurodegenerative disease causing dementia, which is Lewy body disease. The core clinical features of Lewy body disease include permanent visual spatial dysfunction and significant cognitive fluctuations, REM behavior disorder, visual hallucinations and Parkinsonism. However, not all Lewy body disease manifests with these core features. And in fact, this diagram becomes exceedingly complicated when we consider even rarer forms of neurodegenerative disease such as frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration and limbic predominant age related TDP 43 encephalopathy known as late. So this this model here really highlights a significant diagnostic challenge in our field, and that is clinical syndrome is nonspecific for underlying disease pathology and vice versa. Underlying disease pathology is nonspecific for clinical syndrome. And then to complicate things even further. Alzheimer's disease very often occurs concomitantly with other dementia pathologies. And specifically we see it very often with both Lewy body disease and with vascular disease. And so this makes clinical diagnosis even more challenging when we are presented with a clinical syndrome and we are trying to decipher what the underlying pathology might be. The ability to accurately identify which disease is the primary cause of a patient's clinical syndrome is increasingly relevant to the clinician. So currently accurate clinical diagnosis is useful in guiding symptomatic management and in enrolling patients appropriately in clinical trials. However, once disease modifying treatments become available and it seems like within the next five years, we likely will have a disease modifying treatment, then accurate diagnosis is going to become very important, especially if these treatments are costly and carry significant risk of adverse events. So this brings us to a discussion on diagnosis. There is really increasing attention to the use of biomarkers to improve diagnostic accuracy, to measure disease progression, and to assess response to potential disease modifying treatments. Definitive diagnosis of Alzheimer's disease and these other neurodegenerative diseases still requires histopathologic confirmation, which typically occurs at autopsy or very often not at all. Over the past decade, we've increasingly incorporated biomarkers such as MRI, pet, cerebral spinal fluid proteins to assist in our pre mortem clinical diagnosis. So this is a diagram to show how I approach a patient who presents with cognitive complaints. And I spend an inordinate, inordinate amount of time taking a very thorough history. And I do rely on the help of either a caregiver or partner or someone who can provide some collateral information in the history. It's very important to identify when the first onset of cognitive decline seemed to be and whether this onset was gradual and insidious, or whether there was an acute onset of cognitive dysfunction. It's also important to really try to assess what the first cognitive difficulties were and how things have progressed over time. I go through a very thorough cognitive review of systems, so I ask questions about each specific cognitive domain, including, and as I showed you before, a memory visual, spatial function, language, executive function, attention. I spend a lot of time asking about mood and any behavioral changes. I ask a lot about sleep as well. I do a review of how people are performing. Patients are performing in their activities of daily living in more moderate or advanced cases, how they're doing with their basic activities of daily living, such as getting dressed, showering, etc. And then in patients with milder complaints, how they're doing in their instrumental activities of daily living. If there's been any change in their ability to manage finances, to manage medications, to prepare food for themselves. Take a very thorough past medical history with a specific attention to any cardiovascular risk factors. I do a very thorough medication reconciliation, and I'll talk more about this later of why this is very important. And that includes a reconciliation of any medications that are used over the counter, supplements, etc.. Social history. I focus quite a bit on on lifestyle. So diet, exercise and substance use, alcohol use and family history. If there is the positive family history for dementia, it's important to identify who in the family has had dementia, how old that person was at symptom onset, and how old the patient was when they passed away. And so someone who has even a first degree family member, a mother or father who develop dementia in their eighties, that does not confer significant increased risk for the patient. However, when there is a family history of young onset dementia, that significantly raises the possibility that you are dealing with a genetic syndrome. After my history moving onto physical exam. So in all patients who present with cognitive complaints, I do a narrow a brief neurocognitive screen on my initial visit. So this is either the mini mental state exam, the MMSE or the MOCA, the Montreal Cognitive Assessment. With regard to which of these I choose, I default toward the MOCA. It's definitely the more thorough of the two and does a better job at representing all of the cognitive domains that we discussed. However, it's also a challenging test. It's far more challenging than the MMSE. And so if I get the sense in taking my clinical history that the patient is in the more moderate or advanced stages of dementia, I will just go to the MMSE because it would simply be too difficult and too time consuming to try to get through a MOCA. On my general neurologic exam I focus again to see if there's any evidence of Parkinsonism. And so then after the history in the physical exam, we come to the part of diagnostic workup. And so I have a pretty low threshold to refer patients for formal neuropsychological screening with one of our neuropsychologists. So this is like the MMSE or the MOCA, but the nurse psychologist works with the patients for a few hours, and this is really helpful, especially in patients who perform very well, who perform in the normal range on the MOCA. If someone gets a normal score in the MOCA, there are really two possibilities. Either there there is not any objective cognitive impairment and the cognitive difficulties that the patient has been noticing is simply age related, normal difficulties, so sometimes we refer to these patients as the worried well. Where it's also possible that there is in fact an objective cognitive decline from prior level of functioning. But maybe that patient was very high level functioning before and they simply maxed out what we're able to detect with the MOCA. So in these patients, getting formal neuropsychological testing can be very helpful to really tease out if there is an objective cognitive impairment and if so, the pattern of impairments, the pattern of cognitive domains that are involved, which helps point to an underlying etiology. In general, neuropsychological testing is very helpful until you get to the moderate or advanced stages of of disease and in which case it becomes less helpful. In addition to neuropsychological testing, most all patients are recommended to have a basic lab screen, so this includes a complete blood count, a comprehensive metabolic panel, vitamin B12, thyroid function tests in high risk populations for patients, men who have sex with men, IV drug users. We should screen for syphilis and HIV as well. And then all patients who present with a cognitive complaint should get some sort of structural head imaging. This is considered standard of care to rule out a non degenerative cause for the cognitive decline. And so this is looking, you know, standard of care is to make sure that there's not a stroke, a bleed, a tumor that's causing the cognitive decline. But beyond that, we use the structural imaging to help us with our differential diagnosis. And again, we we preferentially order an MRI if possible. And that's because it it helps us see whether or not there's atrophy, brain shrinkage more than we would expect for the patient's age. And if so, we look at at what pattern of shrinkage there is. So in Alzheimer's disease, it's characterized typically by a lot of shrinkage in the posterior parietal regions and also the medial temporal lobes, specifically the hippocampus. So this is really the basic workup for most patients. And very often we stop at this point and we have a fairly confident answer as to what's going on. There are some patients in which we do more diagnostic workup. So specifically, if someone has a lot of cognitive changes, but also significant behavioral changes and change in personality, apathy, loss of empathy, disinhibition, impulsivity, changes that point to more of a frontal localization. For differential diagnosis is between Alzheimer's disease and frontotemporal dementia, we very often get an FDG PET scan and that scan is only clinically reimbursed for that's specific indication right now. If the question clinically is FTD versus Alzheimer's disease. And that can be very helpful, we're looking for, again, patterns of hypometabolism. So in Alzheimer's disease, you tend to see hypometabolism in the parietal areas and the temporal areas. In FTD, we see it in the frontal and the temporal areas. And the FDG PET very often starts to change before we see the changes on the MRI and so if our differential is FTD versus AD and we're not seeing a clear answer on MRI one way or the other or the FDG PET scan can be very helpful. And then the other tests that we sometimes turn to is a lumbar puncture. And this is especially helpful in patients who present with with a little bit of an atypical presentation. So maybe if they're young onset and they're presenting in a nonamnestic fashion, but we're still thinking that Alzheimer's disease might be the underlying pathology. We do a lumbar puncture and we measure amyloid beta and total tau and phospho tau in the CSF and we look at the ratio for among them, and that can be very helpful, either in support of or against the diagnosis of Alzheimer's disease. So here I show you the sensitivities, the specificity, specificities and the cost of these various tests and so you can see cognitive testing, this is quite cheap and it performs decently well compared to these other more expensive biomarkers we see here. MRI is in the 80% sensitivity and specificity. FDG PET a little bit more sensitive and specific. We looked down here at the CSF biomarkers. When you combine measures of A beta and Tau you get close to 90% sensitivity and specificity. Of note, the amyloid PET and Tau PET are currently only used on a research basis because they're not reimbursed clinically and you can see they're quite expensive if patients are wanting to pay out of pocket for these tests. But the amyloid PET and the Tau PET are very often included as part of the enrollment criteria for clinical trials. All right. And so certain clinical features suggest a potentially reversible that is a non neurodegenerative etiology and should prompt further investigation beyond the diagnostic workup that I just discussed. These features include acute onset of symptoms, a rapid deterioration younger than expected age for neurodegenerative disease, prominent fluctuations, any high risk exposures, focal findings on the neurologic exam, and an incongruence between neurocognitive testing and clinical history. Although an estimated less than 1% of patients with dementia are thought to have a fully reversible etiology, the potential to cure those cases demands heightened awareness of this, and further dementia is often multifactorial, with both reversible and irreversible contributors. And in this case, these cases might not be curable. But there remains a substantial opportunity to temper the overall disease trajectory and to improve quality of life. There is a wide differential of entities that can contribute to cognitive impairment or dementia in a way that is at least partially reversible. On the spans metabolic, infectious, autoimmune, toxic, structural, epileptic, psychiatric, disease. So here is a graph of when we would consider further diagnostic workup. So any patients who have a history of an autoimmune disorder or suspected autoimmune disorder should undergo further lab test with ESR, ANA, rheumatoid factor for their antibodies. Patients who present with a subacute or rapidly progressive dementia should be tested with anti thyroid globulin and anti thyroid peroxidase antibodies. Serum and urine heavy metals should be ordered in patients who have a history of workplace or recreational exposure. We touched on lumbar puncture before briefly in the context of its diagnostic use for Alzheimer's disease. Additionally, lumbar puncture is indicated in patients with suspected normal pressure hydrocephalus, in patients who have any rapid progression of symptoms, and in patients who have a suggestion of an infectious or inflammatory disease evaluating for normal pressure hydrocephalus, you want to do a large volume lumbar puncture, which means at least 30 ccs of cerebrospinal fluid should be removed and you want to take quantitative measures of gates before you do the lumbar puncture. And within 30 minutes after you do the lumbar puncture, you do want to do it fairly quickly. After the lumbar puncture, after you give the patient a little bit of time to rest because you want to do it before that CSF is replenished. Additionally, in our clinic we very often do pre and post cognitive testing use as digit span, fluency, either an MMSE or a MOCA, because this can be useful in determining whether a patient's cognitive deficits might respond to shunting. In all patients who undergo a lumbar puncture, we send the CSF for basic cell counts. Inflammatory markers in patients again with a concern for an infectious process, we choose various infectious studies and then auto immune and paraneoplastic panel should be considered if there's any suspicion for autoimmune encephalitis. An often overlooked diagnostic tool in the workup with dementia is the electroencephalogram, and it should be obtained in patients who have prominent fluctuations in attention and memory or any other features that might be suggestive of seizures. And so specifically, if you go to report that there are times when there is repetitive speech or any rhythmic movements and any tongue biting, etc., EEG might be very helpful and EEG is also useful if you're concerned about a toxometabolic or inflammatory process in the brain. It can be useful to see if there are any diffuse, nonspecific electrical abnormalities that might support that diagnosis. In recent years, there's really been a paradigm shift from thinking of dementia as an inevitable outcome of aging to seeing it as a potentially preventable entity with a focus specifically on addressing risk factors in the middle aged years. So specifically certain chronic diseases such as hypertension, obstructive sleep apnea, lifestyle factors, diet exercise and exposure to medications, mood disturbances have been shown to potentially play a role in the pathogenesis of neurodegenerative disease, which again really is is a paradigm shift. It was previously thought that the cognitive impairment caused by these entities was transient, fully reversible and independent of, though often concomitant to neurodegeneration. But there's been accumulating data supporting a more direct association with neurodegenerative pathogenesis. And so these factors have really gained new relevance as potentially modifiable targets in dementia prevention. And so here are you you see a table again potentially for factors that you could address specifically in the middle aged years that might help in preventing dementia. Among risk factors for dementia, of all things, it's actually hearing loss that has the highest population attributable factor. And hearing loss is associated with both faster rates of brain atrophy and increased risk of clinical dementia. Fortunately, the use of hearing aids does seem to be protective, and so is as part of the history of someone presenting with a cognitive complaint, we recommend asking every single patient about hearing loss, have a very low threshold to refer for audiology testing, and if there is objective hearing loss on testing and if hearing aids are recommended and received by the patient, make sure that the patient is actually wearing their hearing aids. It's very often the case that patients get hearing aids but don't wear them. So we always recommend that whenever the patient is awake, they're hearing aids should be in. Midlife hypertension has also been associated with an increased risk for all cause dementia and for Alzheimer's disease specifically. A 2020 systematic review and meta analysis showed that midlife hypertension conferred an increased risk of cognitive dysfunction. And fortunately, treatment with antihypertensives reduced dementia risk by 21%. There have been four meta analyzes of antihypertensives that have suggested reduced dementia in the intervention arms. Obstructive sleep apnea has long been recognized as an important cause of cognitive complaint, but there has been recent attention on the potential role of sleep disturbance in Alzheimer's pathology specifically. So prospective cohort studies of incident dementia have shown that people with sleep complaints in the middle aged years have an increased risk of developing Alzheimer's, and meta analyses have confirmed that the potential role for sleep disorders as predictors of Alzheimer's development. At least two recent studies have shown that sleep disruption increases soluble amyloid beta in CSF, which suggests a potential mechanism. The link between obstructive sleep apnea and Alzheimer's is further supported by treatment trials. A large, randomized controlled trial showed a mild but significant improvement of executive function in patients with both Alzheimer's disease and obstructive sleep apnea, who were treated with CPAP for six months. A smaller, randomized controlled trial showed that CPAP treatment improved verbal learning, memory and executive functions in mild to moderate AD subjects with obstructive sleep apnea. And a three year pilot study showed that patients with Alzheimer's disease and obstructive sleep apnea were again were treated with CPAP showed significantly slower decline than the non CPAP group. Questions about sleep should specifically address whether there are any symptoms concerning for obstructive sleep apnea, such as snoring, apnic events, trouble waking up in the morning, excessive daytime somnolence. In patients who report these symptoms and in patients with physical attributes that place them at increased risk for sleep apnea, so having an increased neck circumference, having a body mass index greater than 35, we have a very low threshold to refer for a sleep study. And if someone has already been diagnosed with sleep apnea, again, it's very important to ask about CPAP complaints. With regard to exercise. So longitudinal observational studies have shown exercise to be associated with a reduced risk of dementia. However, randomized controlled trials have failed to show a consistent effect. The World Health Organization guidelines do suggest that physical activity and specifically aerobic exercise, seems to have a small beneficial effect on normal cognition, a possible effect in mild cognitive impairment. And of course, there's very limited downside to talking to patients and recommending exercise. At the UC San Diego Memory Disorders Clinic we generally encourage patients to incorporate 20 to 30 minutes of aerobic exercise daily. And for patients who are limited by pain, by musculoskeletal issues, by severe deconditioning or frailty, we very quickly involve physical therapists to help safely develop an exercise plan and build endurance. With regard to diet, the World Health Organization recommends a mediterranean diet as two randomized controlled trials have shown that improvements in global cognition with this diet. We very often get questions about the ketogenic diet. There is support in animal studies and there's also some benefit seen in human studies. However, on a logistical level, ketogenic diets and ketones supplementation is very challenging to implement and there are also significant potential adverse effects, especially in the elderly population who are already at risk for malnourishment and weight loss. And so in our clinic we go along with the World Health Organization in that we encourage the Mediterranean diet with an emphasis on vegetables. And I generally very strongly discourage frail and elderly patients from attempting a strict diet, a strict ketogenic diet. Although if you have a young, otherwise healthy patient, that's a possibility. Of note there is currently no evidence based data supporting the use of any dietary supplementation in the prevention or treatment of dementia. And we really caution patients against spending exorbitant amounts of money on these products. Unfortunately, patients with dementia and their caregivers represent a very vulnerable population, often a population very desperate to try anything that might help. So I always caution my patients to be very leery of anyone who promises a cure for these diseases because we don't currently have a cure, and especially to be leery if the promise of a cure comes at a very high cost to the patient. For alcohol, there appears to be a U-shaped curve. It seems clear that excessive alcohol consumption is associated with an increased risk of dementia, specifically young onset dementia. However light to moderate drinking, which has not been clearly defined in the literature, what exactly that constitutes may be beneficial. Now a very important word on anticholinergic medications, and this has been quite new in the literature of dementia, and it's an issue that we're just beginning to understand. And again, this is one of those factors that was traditionally thought to only cause a transient and reversible cognitive impairment. But more recently, exposure to anticholinergic medications has been linked to an elevated risk of Alzheimer's disease. In 2015, a prospective cohort study was published with more than 3400 adults, and it showed that higher cumulative anticholinergic use associated with an increased risk of both all cause dementia and Alzheimer's disease. The most commonly used anticholinergic medications in the study were bladder, anti muscarinic, tricyclic antidepressants and first generation antihistamines. That includes diphenhydramine. A subsequent case control study of nearly 300,000 older adults was published in June 2019, and that's hit mainstream news because it showed a nearly 50% increased risk of dementia with exposure equivalent to three years daily use of a single strong anticholinergic medication. So this is someone who has used diphenhydramine to help them fall asleep for the past couple of years. So we recommend, again, a very thorough medication reconciliation in all patients, including over-the-counter medications. We strongly encourage avoidance of any medications with anticholinergic properties, and if a medication is needed for overactive bladder, we recommend Myrbetriq Due to its lack of anticholinergic properties. There is an expanding body of literature on the association between depression and Alzheimer's disease. It is commonly known that depression often accompanies Alzheimer's disease, even in individuals with no prior history of depression. Several studies have shown that depression symptoms associated with changes in Alzheimer's biomarkers. A 2019 longitudinal study showed that worsening depression symptoms significantly associated with cognitive decline over 2 to 7 years in patients who were cognitively unimpaired. But amyloid positive by PET at baseline. The authors of the study proposed a model by which cortical amyloid might underlie both dementia, sorry, both depression and the cognitive decline in early Alzheimer's disease. However, a causal association was not demonstrated, so it remains unclear whether treatment of depression symptoms might improve cognitive impairment due to amyloid burden. We do recommend screening for depression in all patients with cognitive complaints. It's important to keep in mind that depression very often presents atypically in the elderly population. Patients very often deny feeling sad or hopeless, but they express considerable frustration and irritability instead and again, this often goes very much hand-in-hand with cognitive decline as well. Patients who have awareness into their cognitive decline are understandably very frustrated by it. And unfortunately it's a bit of a feedback mechanism. So the more frustrated the patient gets when they can't think of a word, the harder it is for them to access that word. And and so so we talk about this as a very important component of overall brain health. And in our clinic we have a very low threshold to start, specifically selective serotonin reuptake inhibitors. I, I like yes, citalopram and sertraline a lot for this component of frustration and irritability. And then the other antidepressant that I use very commonly, especially when I see the triad of low mood, poor sleep and decline in weight is Mirtazapine. So this graphic is from the 2020 report of the Lancet Commission on Dementia Prevention, Intervention and Care. And it shows very nicely that all of these modifiable risk factors here, so we see hearing loss, hypertension, alcohol, depression, physical inactivity, etc., is not to account for 40% of dementia risk, which is not an insignificant component. And so this is really something to to talk to your patients about. Again, especially in the midlife years, we think these factors start to play a role in the pathogenesis of neurodegenerative disease. It's important to note that we continue to emphasize the importance of these modifiable risk factors, even after patient has been diagnosed with dementia. So there's still a substantial opportunity to improve quality of life in patients with dementia by addressing these factors such as removing exposure to toxic medications, making sure they're getting a good night's sleep at night, incorporating daily exercise, treating underlying mood symptoms and encouraging a healthy diet. And that brings us to the management of dementia. So beyond the lifestyle factors we just discussed, we do have some evidence based therapeutics, although nothing currently that is disease modifying. The mainstay here are the cholinesterase inhibitors. And so this is donepezil, rivastigmine, galantamine and they have been shown to have a useful but modest role in improving cognition and function in patients with mild to moderate Alzheimer's disease and Lewy body disease. We do encourage the use of cholinesterase inhibitors, and I regularly see them benefit my patients. Patients with Lewy body disease in particular, tend to have a very robust response to cholinesterase inhibitors, but I also see a good response in Alzheimer's disease,. But it's really critical that if you are going to prescribe one of these medications, that you prescribe it correctly. So first of all, you have to set expectations with the patient and their caregivers. These are not miracle drugs. These are not going to make the patient normal again. They will likely not have any effect on short term memory. However, they do tend to improve clarity of thinking, and they do tend to increase functionality from a day to day basis. So in addition to setting expectations, it's also very important that you discuss potential side effects of these medications, the main side effects being stomach upset, nausea, diarrhea and and we we try to mitigate these side effects a few different ways. First of all, we recommend starting at half the normal dose of Donepezil, 5 mg for a full month prior to increasing to the full 10 milligrams daily dose. We recommend that this medication be taken in the morning because if it's given at night, it can cause vivid dreams and be disruptive to sleep. And it's critical that patients take it on a full stomach. If a patient wakes up and, takes this medication on an empty stomach, it will make them sick. So we always I always ask my patients, first of all, if they eat breakfast. If not, I recommend that they take it after the first meal of their day. Even in patients who are giving these very specific instructions about 1/3 will still have some side effects. These side effects tend to be mild and they tend to go away within a week. So we ask patients if it's tolerable for them to grin and bear it and that it will likely get better in a week. If the side effects are intolerable or if they're not going away, then sometimes our next attempt is that Rivastigmine patch and this is a bypasses the GI system and so it avoids some of the GI side effects, but not completely. And again, it's important to start at a low dose and slowly increase after at least one month of tolerating the low dose. Memantine is indicated in moderate to severe Alzheimer's disease. And so it's not actually FDA approved currently in mild cognitive impairment, and it's very often added once a patient has already been established on a cholinesterase inhibitor. As a general rule, we make only one medication change at a time in dementia patients because these patients can be very sensitive to medications and if there is either a beneficial response or if there are side effects, we want to know which medication is the culprit. Again, we recommend a slow taper to therapeutic dose over the course of a month. And this is showing you the dosing schedule for the twice daily version. There is also an extended release version with once daily dosing, although that's not always covered by insurance. Lastly, I'm going to briefly touched on future directions in Alzheimer's disease, specifically. So it would be amiss to not recognize the elephant in the room with in terms of failed clinical trials thus far in Alzheimer disease. And in looking back retrospectively over the clinical trials that have failed, it has become apparent that many mistakes were made. Many of these trials tested their drugs in the symptomatic disease stage when it was likely too late to have any benefit. So possibly the right drug, but simply given at the wrong time. Another big problem in the field is that many of these trials were done prior to the use of biomarkers as part of the enrollment criteria and retro retrospective analyses have estimated that in several phase 3 studies of Alzheimer's drugs, around 20% of patients enrolled in these trials did not actually have Alzheimer's pathology when they were later assessed with biomarkers. So possibly the right drug but tested in the wrong subjects. And then in many cases we likely just had the wrong drug. So to address this the second point now, we're very hopeful that the rigorous use of biomarkers drain enrollment in clinical trials is helping to mitigate this problem. There are many, many people working on a drug for Alzheimer's disease. So these are the 2020 numbers for the Alzheimer's disease drug development pipeline to see. There are currently 100 or as of 2020, 121 agents in clinical trials and 29 of which were in phase 3 trials. And there has been a progressive emphasis on non-amyloid targets. Here you can see a graphic representation of drugs in phase 1 the outer rim, phase 2 the middle rim, and phase 3 up top in green. These are the disease modifying biologics. And you can see here in phase 3, all of these are focused on amyloid targets. I'm sure you've heard of Aducanumab, which has was in the news a couple of months ago. In purple here we have the disease modifying small molecules and then in in green or in orange here these are the symptom reducing small molecules and many of these are our compounds that are already FDA approved for other other conditions. And we see here venlafaxine, citalopram, for example. So as new therapies might emerge, there is considerable interest in blood based markers and it makes a lot of sense as a less invasive, more convenient, more cost effective means of evaluating for Alzheimer's pathology, certainly compared to more expensive imaging studies or invasive lumbar puncture. There have been many articles in mainstream news touting a potential blood test for Alzheimer's, and this is understandably very exciting. Three plasma molecules have been most heavily investigated with mixed results, amyloid beta, tau and neurofilament light. Nothing is available yet, but it's anticipated that some of these will be available in the near future. And as these tests do become available, it's important to really remain vigilant about their proper use and specifically to understand the potential positive and negative predictive values. So to help you visualize this, this is a model for the positive predictive value of a theoretical blood based test. And here we are modeling that this blood based test is 80% sensitive and specific. So right now, the plasma biomarkers do not seem to be performing quite as well as the imaging and the CSF biomarkers. And so here in comparison, we just put in FDG PET with a 90% sensitivity and specificity. So our theoretical biomarker here, 80% sensitive and specimen specific. So you think of that as being a fairly good test and then we look at positive predictive value. So again, positive predictive value, just as a reminder, is the probability that a patient actually has the disease if the test is positive. And we break this down here by the these dashed lines here are all comers, all patients, and then up here in the solid lines, these are patients who have been screened with a basic neurocognitive screen, whether that's the MMSE or the MOCA and have been found to have objective cognitive impairment. So that's the positive predictive value in that specific patient population up here. So we see on, say, a 50 year old patient comes to you scores normal on the MOCA but ask you and asks you for the Alzheimer's blood test because they want to be sure. And we see that if you were to get a positive result, it means practically nothing in this patient because the prevalence of dementia is so low in this population. And so then you have to decide if you do offer this patient an Alzheimer's blood test, seems harmless enough. Probably won't cost too much. It's an easy thing to do. How are you going to interpret that positive result? How are you going to explain it to the patient and force your hand into doing further diagnostic workup that might not be clinically indicated? We see that if instead you you first screen the patients and you only focus on those patients who have some objective cognitive impairment, an abnormal score on the MMSE or the MOCA. And then if you really are looking in the age range where dementia is becoming more prevalent, then a positive predictive value becomes um becomes, it's a better test. So a positive result here in an 80 year old who has an abnormal score on the MMSE or MOCA is is meaningful clinically. So this is just it's something to keep in mind when patients start asking you for the Alzheimer's blood test. In conclusion, dementia is a diverse clinical syndrome. It's caused by a number of underlying pathologies, and that makes our accurate diagnosis very challenging. Most common pathology again being Alzheimer's disease. But even in in straightforward Alzheimer's disease, dementia is very often multifactorial, with both reversible and irreversible factors. And even in patients who present with the classic features of neurodegenerative disease, it's important that we evaluate for potentially reversible contributors. There is increasing evidence to support the role of preventative measures in midlife, and although there are no disease modifying therapies currently available, the potential benefit of lifestyle modifications, cholinesterase inhibitors and Memantine should not be negated. And as new diagnostics are developed, we must be very cautious in our use and their interpretation. So that is all. I thank you for attending. I would like to acknowledge Nicholas Bevins, who is a clinical pathologist in lab medicine. He works in diagnostics. He produced that model of a positive predictive value for the theoretical blood test. He's also my husband and father of children. And then my two fantastic mentors at the University of California, San Diego, Dr. Galasko and Dr. Léger. I am indebted to them both. If you have any questions, I would love to hear from you. Please feel free to reach out to me. And this is my email address here. Thank you very much.