Hello and thank you for joining me today in the neurocognitive disorders talk. My name is Pallavi Joshi and I'm a geriatric psychiatrist at Banner Alzheimer's Institute in Phoenix, Arizona. I have no conflicts and the objectives of the session are to discuss the epidemiology of neurocognitive disorders amongst older adults, to describe the assessment of neurocognitive disorders amongst older adults, and finally to enumerate the evidence-based pharmacological and non-pharmacological treatment for neurocognitive disorders among older adults. So let's begin by describing what neurocognitive disorders are. The DSM-5 has three subcategories of neurocognitive disorders. Delirium, mild neurocognitive disorder, and major neurocognitive disorder. Mild neurocognitive disorder is a decline from a previous level of performance in one or more cognitive domains. What we colloquially call memory has different eyes, different domains including complex attention, executive functioning, learning and memory, language, and perceptual cognition. The evidence is based on the concern of the individual, a knowledgeable informant, or a clinician. There should also be a modest impairment in cognitive performance, preferably documented by standardized neuropsych testing, or if that cannot be done, another quantified clinical assessment. We'll talk in a little bit about what those quantified assessments look like. However, although there is a decline in performance of cognitive functioning, these cognitive deficits do not interfere with the capacity for independence in everyday activities. For example, daily living, such as bill paying, or medication management. They do not occur exclusively in the context of delirium, and they are not better explained by another mental disorder. For example, a major depressive disorder or a psychotic disorder that may impact cognition. Major neurocognitive disorder, which we also refer to as dementia, is the evidence of a significant cognitive decline from a previous level of performance in one or more cognitive domains, and similar cognitive domains to mild neurocognitive disorder. However, in major neurocognitive disorder, the cognitive deficits do interfere with independence in everyday activities. At the very minimum, an individual with major neurocognitive disorder will have difficulty with complex instrumental activities in daily living, such as bill paying or managing medications. Major neurocognitive disorder may occur with or without clinically significant behavioral disturbance. If there is clinically significant behavioral disturbance, then this may be defined by agitation. However, these behavioral disturbances are also not due to a pre-existing psychiatric disorder, such as major depressive disorder, schizophrenia. Now, approximately 8 million individuals in the United States live with dementia, and while Alzheimer's disease is the most common form of dementia, it's not the only cause of dementia. Vascular disease, dementia of the body, and Parkinson's disease may also contribute to the presentation of dementia. The key features are progressive loss of memory and other thinking ability, which eventually cause impairment in daily functioning. But despite the large high prevalence of dementia in the United States, only less than 50% of people with dementia actually get a diagnosis. There are different subtypes of dementia, and Alzheimer's is the most common cause of dementia. However, despite the different subtypes, all dementias usually result in changes. As I mentioned before, Alzheimer's disease is the most common cause of dementia, and the prevalence is increasing. It's predicted to increase to 12.7 million by 2050, and it's the fifth leading cause of death in older adults. The costs to both financial and healthcare are significant. Dementia is estimated to have an annual cost of $1.2 trillion by 2050, and the cost to the non-infected individual, including caregivers, is significant too. Approximately 50% of caregivers will become ill or depressed. But what are the risk factors of dementia? How do we identify those who are at highest risk for developing dementia, and what can we do to prevent it? The greatest risk factor by far is age. Increasing age is an independent risk factor for the development of all types of neurocognitive disorders or dementias. By the age of 65, approximately 5% to 15% of individuals will have underlying Alzheimer's disease pathology. By the age of 85, this increases to between 25% to 30% of individuals who will have underlying Alzheimer's disease pathology. Alzheimer's disease is not the only pathology that contributes to major cognitive disorders. Vascular risk factors, the presence of diabetes, hypertension, hyperlipidemia, can increase the risk of developing and progressing cognitive disorders. Similar to vascular risk factors, obesity is an independent risk factor, and other risk factors are the presence of traumatic brain injury or any kind of insult to the brain, vascular or structural, smoking, and poor sleep. Let's talk about genetics of Alzheimer's disease. Unlike the other dementias, such as vascular dementia, the genetics of Alzheimer's disease are relatively better characterized. Increasingly, we believe that the risk is determined by polygenic risk factors. The single gene or single allele that has been highly correlated with the development of Alzheimer's disease is the APOE gene. There are three versions of APOE, APOE2, APOE3, and APOE4. Alzheimer's disease is associated with one or two APOE4 alleles. However, the APOE2 alleles are associated with a decreased risk of developing Alzheimer's disease. The important thing to remember about APOE4 genes and APOE4 risk factors is that APOE4 is a risk factor for developing Alzheimer's disease. While the APOE4 carriers have a higher risk of developing Alzheimer's disease compared to the general population, the presence of the gene is not deterministic. It does not guarantee that somebody will develop Alzheimer's disease. Conversely, the absence of APOE4 also does not guarantee that somebody will develop Alzheimer's disease. Unlike autosomally dominant neurodegenerative conditions like Huntington's disease, in which the gene definitively predicts the development of the disease, APOE4 is a little bit more complicated in that it is a risk factor, but it is not a risk-determining gene. In fact, most late-onset Alzheimer's disease results from a combination of the genetic factors such as APOE4 and lifestyle and environmental factors such as the ones we reviewed recently. Now, in order to diagnose and assess Alzheimer's disease, it starts with a clinical evaluation. The history is possibly the most important component of a clinical evaluation for any type of major neurocognitive disorder. Starting with the evolution of the illness, what were the primary presenting factors? Was it a cognitive change? Was it change in function, behavior, neurological features, disturbed speech? Has it been progressive? Has it been fluctuating? Has it been developing gradually? Social and developmental features can often inform the history. Has there been a pre-morbid history of episodic or non-episodic cognitive change that helps us see the differential differently? Medical and surgical history as well, so we mentioned that vascular risk factors are independent risk factors for the development of Alzheimer's disease. Obstructive sleep apnea impairs restorative sleep and is an independent risk factor for all-cause dementia. Certainly, medical and poorly treated medical conditions can confound the diagnosis. For example, the presence of hypo or hyperthyroidism or vitamin deficiencies of B12 and folate may mimic a major neurocognitive disorder, but these cognitive changes reverse when the medical condition is appropriately treated. A neurological exam is key in identifying certain non-cognitive features that may guide us towards a diagnosis. For example, focal findings may point towards a focal lesion, presence of a prior stroke or an infarct. Parkinsonism may give clues towards low body dementia. Frontal release signs or normal gates may point towards other neurological conditions that have a major neurocognitive disorder as part of the presentation. Finally, after completing a thorough history and mental status exam, an office-based neuropsychological testing can help objectify these deficits. In addition to understanding the subjective history presented by the patient and a reliable informant, it's also important to quantify the reported deficits using standardized office-based cognitive testing and a lab workup at the very minimum, including CBC with differential, CMP, B12, and TSH. Neuroimaging, as you may have observed earlier, is not part of the diagnostic criteria for major or minor neurocognitive disorder as outlined by the DSM-5. However, even though dementia is a clinical diagnosis and neuroimaging is not part of the criteria, it is important to do it in an office-based setting, and most importantly, to rule out contributing causes such as a stroke, a mass inflammation that may be contributing to the cognitive impairment or structural changes in the brain, such as preferential cortical or hippocampal atrophy that may be indicative of an Alzheimer's disease, or a preferential frontotemporal lobar atrophy that may be indicative of a frontotemporal dementia. Now, these are tests that are not routinely recommended or done. However, there may be certain cases in which the history points towards a need for tests like this. So, syphilis serology used to be a broad question. It used to be presented as uniformly done. It's no longer routinely done. The prevalence of syphilis in this population in 2023 is now so low that the test is not that helpful. If you suspect certain other syndromic or systemic conditions based on the history, so for example, if you suspect vasculitis, an ESR may be helpful. If there's concern for substance use or a prescription drug that can be measured, for example, lithium levels, Depakote, nortriptyline, then a drug level may be helpful in ruling out drug toxicity or drug side effects. HIV, Lyme serology, and heavy metals really only if there is known exposure or if the history suggests a risk. Now, PET or SPECT imaging, FDG-PET helps see areas of relative hypermetabolism in the brain. FDG-PET is covered by Medicare, but it is not FDA approved, and the only indication for FDG-PET is to distinguish frontotemporal dementia from Alzheimer's disease. In other words, if the clinical history is atypical and there's confusion about whether this could be more similar to Alzheimer's disease or frontotemporal dementia, the FDG-PET can help distinguish them with the different patterns. However, FDG-PET is not helpful in diagnosing other types of dementia that are non-FTD or non-Alzheimer's disease. We talked about the APOE for risk for developing dementia, but APOE genotyping is rarely used clinically as it doesn't inform whether or when someone will develop Alzheimer's disease and what to think about it. However, this is now changing as more treatments that are preclinical are being developed. And then finally, a lumbar puncture for CSF A-beta 42 or tau ratio. Again, this was more rarely used in the past, but it's becoming more increasingly used. The approval of new medications such as aducanumab and mecanumab require the presence of amyloid as determined by either lumbar puncture or an amyloid PET scan. And in order to receive the drug, the presence of amyloid is necessary. And so, because of the advent of these new therapies, the use of CSF A-beta 42 to tau ratio is becoming more and more more and more routinely practiced to guide therapeutic need and response. All right, so let's take a quick look at some MRIs. So, this is a comparison of an MRI brain of a normal person, of a normal brain versus a brain with Alzheimer's disease. And as you can see in the B slide, we notice a couple of different things. The first thing is, you know, what we do not see. What we do not see is the presence of a focal infarct or a focal mask. Don't worry, I'm a psychiatrist too, so there's not going to be any MRIs that are hard to read here. But, you know, there are no obvious large lesions or strokes. What we do notice are, number one, there is global atrophy. So, in slide B compared to, in brain B compared to brain A, there's a lot more black space, and that is the presence of global atrophy. Now, the atrophy is in all areas of the cortex. However, it is more pronounced in the temporal lobes. We also notice that the ventricles are significantly more enlarged, and that's, again, because of the cortical atrophy. So, this is a typical presentation of a normal versus atrophy brain. And there may be different MRI findings in other types of dementia. So, in the first slide, the first slide shows a presentation of a multi-infarct dementia, which is dementia caused by the long-term sequelae of multiple large vessel infarctions. And in here, you can see two large areas of infarcts, two areas of MRI hyperintensity, which show the presence of infarcts. The second one is a strategic infarct dementia, which is an area of more, it's not as, it's not a large vessel infarction as compared to the first one. It is more, it's a smaller vessel, but the vessel is in a more strategic location, which causes more significant cognitive deficits. And the third one, finally, is a subcortical vascular dementia. So, compared to the brain on the far left, which has two discrete areas of hypodensity, the brain on the right doesn't have discrete areas. It's just kind of all over the brain, and it is subcortical. So, as you can see, the area, the cortex or the tissue that is most distal is relatively preserved, and the infarcts tend to be throughout, and they tend to be subcortical. All right, well, let's talk briefly about emerging fluid value biomarkers. There's been a lot of chatter about this recently. So, in January 2023, the FDA approved the first in vitro diagnostic test for early detection of amyloid plaques associated with Alzheimer's disease. And in July 2020, there was a newly validated blood test for p-tau-217, and p-tau-217 is the subtype of p-tau, which accurately distinguishes Alzheimer's disease from other neurodegenerative disorders. The p-tau-217 in blood, when collected during life, accurately predicted tau brain changes seen in post-mortem brain tissues in AD patients. And so, this is already a validated test. The blood tau levels are detected up to 20 years before the average age of onset of Alzheimer's disease symptoms, and because of its high predictability and validity, it could eventually become promising blood-based biomarkers for the future detection of Alzheimer's disease. It's not currently used in clinical practice. It is mostly used in research settings, not because it's not, but it is already determined to be accurately predictive, validated, and reliable. All right, now who should be evaluated for cognitive impairment? Should it be everybody who comes into the office? Should it be select people? Well, it's certainly people who present or report memory concerns or other cognitive complaints should be evaluated, as well as individuals whose family members report cognitive impairment or cognitive concerns with or without the patient also reporting them. Oftentimes, the deficits may be subtle enough, there may be lack of insight, and the person who's experiencing cognitive deficits may not be the person who brings up the complaints. It may be a family member. And if a family member reports these concerns, regardless of whether the patient's concern or not, they are an appropriate candidate to evaluate. And in this case, you may liaise with a family member to get them into an appointment and start to do a workup. Medicare beneficiaries also receive a cognitive screening as part of the annual wellness visit. I just want to emphasize that as part of the annual wellness visit, this is a cognitive screening. It's not a thorough or full cognitive workup. The time attributed to a cognitive screening during annual wellness visits tends to be limited. It really tends to be a subjective history of cognitive complaints. And there may be a cognitive testing component, such as three-word recall and orientation, or a minimental state exam as part of the cognitive screening. However, it is not a thorough cognitive assessment that also includes neuroimaging, labs, neurological exam, unless there are significant concerns. Now, we talked about objective cognitive tests or assessments to quantify these deficits. Now, there's no one perfect screening instrument that can be used in every patient population. But in order for a screening tool to be effective, it should at the very least be highly accurate, easy and quick to administer in an office-based setting. It should be suitable for virtual visits. And it should screen across language and other social barriers. So even if an interpreter is used to translate the screen, the cognitive test, it should not be so culturally dependent that the interpretation is not able to overcome that. So these are two commonly used tests, the MOCA and the... Actually, yeah. So this is a MOCA version, one MOCA version. Actually, you know what? They're both the same. They're both the same. So this is a MOCA, a Montreal Cognitive Test. It's much more sensitive and specific than the mini mental state exam. And it also tests different domains of functioning. So at the very top, the visual, spatial and executive functioning, the trails A and the clock drawing tests are both independently validated tests of cognitive function. They're also helpful because they are not language-based or verbally-based tests. And so they are less sensitive to people for whom English is not a first language. It also tests other non-verbal domains of cognition, such as calculation and language. It tests in a few different ways. And this is important because while the most common first presenting symptom of any neurocognitive disorder is memory changes or short-term memory changes, the second most common symptom is language changes, word-finding difficulty, naming issues. And so screening for language is very important. And it can also help identify early and incipient language-based neurocognitive disorders, such as primary progressive aphasia, in which memory is affected significantly down the line, but the first presenting symptom tends to be language-based or aphasia. Those of you who practice in the VA system may be more accustomed to the SLUMS examination. And again, this is similar to the MOCA. This also has different domains of cognition, visual-spatial, clock-drawing, language, calculation. And it's better validated in a veteran population compared to the MOCA. Actually, I see a couple of questions. I'm actually just going to answer them as we go along since we have a little bit of time. So the first question is in the dementia workup, what neuroimaging should be used, MRI or CT scan, and with or without contrast? So in a dementia workup, typically I would recommend using an MRI. Brain, the reason is that CT is really better for seeing the bees, blood, bone, and bullet. And so unless you're concerned about an intracranial bleed, in which case the CT would be a superior choice, the MRI is a better choice. I typically use non-contrast MRI. It is better for seeing structure. The reason for using a contrast MRI would be the presence or the suspicion for a contrast-enhancing lesion or a tumor. And generally, in this case, your friendly radiologist will guide you on the appropriate choice for contrast versus non-contrast. But 99% of the time, I use MRI brain non-contrast. The second question is, do you see MOCA results often affected by education level? Yes, all cognitive testing is affected by education level. And that's why in the MOCA, you give somebody an extra point if they've had less than 12 years of education. So again, these are office-based tests. So they help give us a quantification of somebody's cognition. But the office-based test or the score on the office-based test does not make the diagnosis. You as a clinician make the diagnosis, taking in the comprehensive history, seeing if there has been a change in decline in cognition compared to a prior level, based on the history, the informant. Maybe sometimes you may not know the answer on the first visit because you don't have enough of a baseline or history to go by. That is fine. That's what follow-up visits are for. So six months down the line, you may choose to repeat cognitive testing and see if there now has been a decline in the cognitive testing or if there has been a decline in functioning or cognition reported by the patient or their caregiver. Fall cognitive testing has a floor and ceiling effect. So people who have very low levels of formal literacy, people who have, you know, I mean, less than grade school level will often not do well on these office-based testing. And it's not because they have, it may not be because they have a cognitive impairment. It may be because they never acquired the information in the first place. So for people with very low levels of literacy, these cognitive-based tests, office-based tests may not be that helpful. And the same is true for people with very high levels of education. So people who have over 20 years of education, MD, PhDs, lawyers, doctors, they may have such high levels of crystallized and verbal intelligence that they are able, and they have such higher levels of cognitive reserve that they may be able to perform better on standardized cognitive testing that may mask subtle deficits. So, you know, cognitive testing, yes, it may not be effective for people with very, at extremes of educational spectrums, but it tends to be useful for the majority of the population. All right, so we talked about cognitive testing. So when do you refer people for neuropsychological testing? And by neuropsychological testing, I don't mean office-based cognitive testing like the Mini-Mentalist, Lums, or MOCA. When do you refer them to a neuropsychologist who can dedicate four to six hours with them to do a thorough assessment? It certainly wouldn't be every single person. So in cases where there are clear deficits, in cases there is clear objective and subjective decline in cognition that affects day-to-day functioning, you can make that diagnosis on the office-based visit. Referral to neuropsych testing does not necessarily add much to the picture. The neuropsych tests are helpful when the case presentation is atypical or the diagnosis is unclear. So people who are age 55 or under, the prevalence of a major neurocognitive disorder in this population is statistically very low. They also tend to have more atypical presentations. So in that case, you may refer for neuropsych testing to help elucidate those deficits. Rapid progression and the presence of non-cognitive symptoms such as multiple falls, more than three in one year, visual or auditory hallucinations or delusions. By this, we don't mean multiple falls that are due to an attributable physical or neurological disorder. So not somebody who's falling because we know that they have a known gait instability or not somebody who has visual or auditory hallucinations because of a known history of schizophrenia. This is all new onset in older age that is not due to a known physical or psychiatric disorder. It's really to rule out possible complex dementia. So for example, Parkinson's disease, dementia with Lewy bodies, frontotemporal dementia, Creutzfeldt-Jakob disease, the really uncommon variants that have atypical presentations. Neuropsych testing can often be helpful in differentiating the cognitive deficits due to these dementias. Okay, now once we've diagnosed somebody with major neurocognitive disorder, we need to move towards treatment. The treatment paradigm for all neurocognitive disorders is the combination of pharmacological and non-pharmacological approaches to mitigate the progressive loss of cognitive and functional abilities. Down upstream of any type of cognitive deficit, there are complex and incompletely understood processes that begin decades prior to the manifestation of the actual clinical symptoms. These processes happen at multiple different levels of destruction, molecular, intracellular, network, and systems. The treatment aims, and treatment is almost a misnomer because we don't really treat neurocognitive disorders to remission. We manage the symptoms. The aims are to retain the quality of life, to mitigate the burden of illness, and to reduce the long-term clinical decline, and finally to manage behavioral and psychological symptoms of dementia. I won't talk too much about the management of behavioral and psychological symptoms of dementia as there is another webinar later today by Dr. Raj Tampy devoted to this entire topic. I would definitely encourage you to attend that if you're working with individuals with neurocognitive disorders. For the rest of the webinar today, I'll be talking more about the management of the cognitive and functional symptoms of dementia. Recognizing and identifying neurocognitive disorders is the first and most important step in treatment. Although there are certain treatment guidelines, the treatment itself should always be individualized to the person. If you've seen one patient with dementia, you've seen one patient with dementia because the manifestation is maybe different with every person with dementia based on their underlying personality, environmental and social factors, family structure, and personal goals and values. Once you've ruled out and treated underlying medical conditions, review the neuropsychiatric diagnosis, must now assess and reverse aggravating factors, and educating caregivers is going to be most important. We often talk about behavioral techniques in management of dementia and that's for two reasons. The first is that our pharmacological treatments for dementia don't really work that well. Behavioral techniques and behavioral management is still the mainstay of managing neurocognitive disorders. The second reason is that there is no pharmacological management without non-pharmacological management. As somebody with a neurocognitive disorder starts to lose their ability to self-regulate emotion, as they start to have more difficulty making sense of the world, little things that may not be upsetting to somebody without a cognitive disorder become more and more agitating and frustrating to somebody with a cognitive disorder. And so reassurance is important in making them feel safe and loved. Even for somebody who is agitated because of dementia, it really is a cry for an unmet need, pain, an environmental stressor. Instead of verbalizing and saying I'm cold and I would like a sweater and also the light is too bright and it's hurting my eyes, somebody with dementia may not be able to verbalize those articulately and instead it may manifest as screaming or clawing or pacing or whining. So these manifestations, these behaviors of agitation and dementia are a cry for an unmet need. And I like the Ps of dementia because they really help narrow down what possible environmental factors can be modified. So pain, patty, palate, position, possession. So maybe having a picture of a loved one or a favorite sweater, peaceful environment, protection, the sense of purpose and pleasure. And distractors such as music, chocolate, compliments can mitigate agitation. And while it's important to have a sense of structure and a sense of purpose, it's also important not to be overwhelmed. So reducing, so modifying activities and communication over time so it's not overwhelming, eliminating confusing stimuli such as TV, mirrors, pictures, etc. And communication should be clear, concise, and concrete. We've been told our whole lives that lying is bad, but in the case of dementia, a white lie may not be a bad thing. Therapeutic fibbing can go a long way in redirecting somebody and avoid saying the words no or avoid having an argument. You will never win an argument with somebody with dementia. Use less statements. So instead of saying, mom, don't get up and open the drawer, say let's go outside and take a walk. So distraction and using less statements to redirect. And teaching caregivers this is really the most important part of what we do. They're the ones who spend 24 hours a day with the patients and they're the ones who are having difficulty trying to conceptualize why their loved one is going through these changes. So reassuring them that it's the disease talking, not the patient, teaching them that this is manifestation of the dementia itself and helping them with strategies on how to manage the person is going to go a lot further than the medications that we give them. Cholinesterase inhibitors are the first-line treatment for first-line pharmacological management for dementia. So denepazil, rivastigmine, and galantamine are all cholinesterase inhibitors. Denepazil comes in both an oral tablet as well as a transdermal patch. There's also a newly approved long-term patch called Adalarity. And then adverse effects for all formulations of denepazil. Really the most common ones are gastrointestinal, nausea, vomiting, diarrhea, weight loss, abnormal dreams, and insomnia can be an issue. And so dosing it in the morning can decrease the risk. And similarly, taking the medication with food in the morning can help decrease the risk of the GI side effects. Similar to denepazil, rivastigmine also comes in a capsule as well as a transdermal patch and has very similar side effects. The transdermal patch tends to have less risk of the gastrointestinal side effects as it bypasses the gut and has a greater risk of local skin irritation and reactions. And galantamine is the third cholinesterase inhibitor that's commonly used. Also comes in an immediate release tablet or an extended release capsule. And again, same risks. The three main risks of cholinesterase inhibitors are gastrointestinal, bradycardia, and hypertension. Now how effective is denepazil? So a Cochrane review looking at 30 studies with over 8,000 participants showed that cognition was better with denepazil as measured by the ADCS ADL. However, there were no differences in behavior or quality of life between denepazil and placebo. Similar to denepazil, a Cochrane review of rivastigmine showed that cognition was better with the ADLS-COG. However, again, behavior and quality of life were no different between denepazil and placebo. The second class of medications for Alzheimer's disease is memantine. Memantine is not a cholinesterase inhibitor. It works on the NMDA receptors and memantine comes in an immediate release and extended release formulation. For the immediate release formulation, it is dosed on a titration schedule, five milligrams a day, which increases by, in five milligrams, increments one week apart until the target dose of 10 milligrams twice a day is reached. Unlike cholinesterase inhibitors, diarrhea and nausea are not significant or well, are common side effects of memantine. However, dizziness, confusion and headache and constipation are the most common side effects of memantine to watch out for. Both cholinesterase inhibitors and memantine are FDA approved for Alzheimer's, for dementia, for major neurocognitive disorder of Alzheimer's disease. Rivastigmine is also FDA approved for the treatment of dementia with Lewy bodies. Neither cholinesterase inhibitors nor NMDA agonists are approved for the use of other types of dementia, such as vascular dementia or frontotemporal dementia. So in some cases, not only is it not approved, but in some cases, using cholinesterase inhibitors may actually worsen behaviors in frontotemporal dementia. The combination of cholinesterase inhibitors and memantine is much more effective for cognition, daily function, behavior and global severity as compared to the use of monotherapy of either medication alone. Typically, cholinesterase inhibitors are added in the mild stage and continued generally until the severe stage of Alzheimer's disease. Memantine is FDA approved for the moderate stage. It's added in the moderate stage and the benefit of adding it in the mild stage is not well established. So anti-amyloid therapies are the new class of medications that are gaining a lot of recent approvals. The pathophysiology behind anti-amyloid therapies is that amyloids are a pathological hallmark of Alzheimer's disease. Specifically, they are not a pathological hallmark of non-Alzheimer's disease, such as vascular or frontotemporal dementia, and amyloid buildup can predict future dementia. And so by blocking amyloid, can we prevent Alzheimer's disease downstream? So aducanumab was approved, or aducanumab gained FDA approval in 2022, and the evidence for aducanumab comes from two large trials, the eMERGE and ENGAGE trials. The primary outcome they looked at was the amyloid PET SUVR, and in both eMERGE and ENGAGE, which were two identical trials looking at the change in the amyloid PET over time with the medication, with the drug aducanumab compared to placebo, there was a significant decline in the amyloid PET SUVR over time. So the evidence in these trials showed that the medication was effective in removing amyloid over time. However, the impact on clinical function was not well established. Some of the secondary outcomes involved cognitive testing and CDRs on the boxes, and in these trials, there was not adequate evidence that the study drug modified the clinical functioning. And so while the change in amyloid was established, the change in clinical functioning was not well established. Because of the significant change in amyloid, and because of the significant advancement, the drug aducanumab gained and accelerated FDA approval, and the trials were prematurely concluded. But why is it not routinely given in clinical practice? One of the reasons is that the clinical benefit was not really clear based on the trials. And there are still several other questions about this drug. The first is that the risk of side effects is quite significant. So one of the significant side effects is RER amyloid-related imaging abnormalities. And in every monoclonal antibody clinical trial that's been done to date, the presence of immunotherapy-induced ARIA, either edema or hemorrhage, was present, and it was correlated with both the dose of the medication as well as the presence of APOE4 allele in the patients. And so the risk of ARIA, while statistically low, is quite significant. Not only is it a serious side effect to be aware of, but monitoring for ARIA is very resource-intensive. People who are receiving this drug, either in a research setting or now, or for the past year in a clinical setting, must have routine screening MRIs to be read for the presence of ARIA-E or ARIA-H in order to continue receiving the drug. So these are the appropriate use recommendations for Adjucanumab published in the American Association of Neurology Journal. And as you can see, the clinical trial enrollment criteria are quite strict. It is notably approved for people with MMSC of 24 to 30. So that, yeah, MMSC, sorry, this was a clinical, the appropriate use in clinical practice is MMSC of 21 to 30, which eliminates a lot of folks that we tend to get referred for. So it really only is approved for people who meet clinical criteria for MCI-DV Alzheimer's disease or mild Alzheimer's disease. They're all on one of the Alzheimer's dementia. They must also have an amyloid-positive PET or CSF findings consistent with Alzheimer's disease. So in other words, the amyloid status must be established. And the exclusion of non-Alzheimer's disease neurological disorders, and they cannot be on anticoagulants because being on anticoagulants increases the risk of microhemorrhages. And finally, if there is evidence of acute or subacute hemorrhage or more than four microhemorrhages or cortical infarction, lacunar infarction, or diffuse white matter disease, they are not good. They will not qualify for aducanumab. So I think just looking at these clinical criteria, you can see how few of our patients that we routinely care for in clinical practice would, a very small minority would be able to qualify for aducanumab. And then once they do qualify, it is a very resource-intensive medication to dispense. It's dispensed in an infusion center with escalating doses every four weeks. There needs to be a neuroradiologist who can routinely read MRIs for the presence of emerging aria E or aria H. And so people who are in remote areas, who are in rural areas, who do not have reliable study partners, who do not have reliable caregivers, or whose caregivers have significant other demands, will not be able to get this medication. And finally, it is quite expensive. Other than the direct cost of the study drug, there are significant non-ancillary costs, such as the maintenance of an infusion center, the study staff, the neurologist. And so not everybody can afford this medication. Since aducanumab came out, there's been a second drug that was recently approved. It's also a monoclonal antibody called leucanumab. And the evidence for leucanumab comes from an 18-month double-blind placebo-controlled trial. The difference between the trial data between aducanumab and leucanumab is that in leucanumab, there was a clinical change. So the primary study endpoint was the CDR sum of boxes. And in leucanumab, the participants showed greater reductions in brain amyloid burden, but they also showed an improvement, a clinical improvement, based on the ADAS-CoG and based on the ABCS-ADL. Leucanumab also has the same side effects of ARIA-E and ARIA-H, which are higher in A44 carriers. And it also has the same care delivery and resource considerations as aducanumab does. So having routine MRI reads to screen for ARIA, going to an infusion trial. And so while these therapies are promising, we still need to do a lot of work to establish the safe team efficacy and improve their care delivery. So, you know, as I mentioned earlier, access is a significant issue for all of these. There is still limited CMS coverage. Clinical trials have long had poor minority representation and rural access. And, you know, there, even in large cities or academic centers, there may be a dearth of experts who are proficient in recognizing ARIA on MRI and managing ARIA on an MRI. And so while I think this represents a positive step in drug delivery and drug development, we still need to do a lot of work to make it accessible to individuals with neurocognitive disorders. And I'm going to wrap up soon so we have some time for questions. But, you know, just briefly to talk about dananumab, it's another pipeline. And that's another map in the pipeline development. The clinical trials are ongoing and the readout is expected to be in the coming year. And at this point, it's showing decline on the IADRS by 32% compared with placebo at 18 months. So I think as we continue to work on dananumab and other maps in the clinical trial pipelines, we'll be able to make these drugs more safe and efficacious. So in summary, Alzheimer's disease is a common neurodegenerative disease with age being the greatest risk factor. The precursor is mild cognitive impairment or MCI, of which 85% of people with MCI will progress to frank dementia in approximately five years. History is the most important component of any assessment for neurocognitive disorders, but some form of objective cognitive testing such as many mental or loci is also needed. And structural imaging, functional imaging, PET scans may have a key role in identifying the ideology. And blood-based biomarkers are not currently used in clinical practice, but this may be something that we start seeing more in the next five to 10 years. And once this happens, we'll be able to identify who's at high risk and can diagnose specific dementia subtypes. All right, so I think we answered the neuroimaging question and the MOCA question already. Okay, the next question is, when treating patients routinely for other psychiatric illness who age during their course of treatment, when or at a certain age would you start screening for cognitive problems? So, you know, I think regardless of whether they have a, regardless of whether or not you are seeing them for another psychiatric illness or not, I think that the guidelines still whether when either the patient presents with a cognitive complaint or a caregiver presents with a cognitive complaint, or there is objective change. So in this case, the difference is that even though they have an existing psychiatric disorder, it should still be a change in baseline. And if you're already seeing somebody for a pre-existing psychiatric disorder, then you know their current baseline. And if their cognition starts to change from that baseline, either based on subjective report, informant report, or objective assessment, that's when to start getting concerned. The probability of dementia under the age of 55 is very low, or neurocognitive disorders or neurodegenerative conditions under the age of 55 is very low. So under the age of 55, you may not routinely screen people, there may not be that much benefit. But over the age of 60, the routine assessment would start to make sense. The next question is, what would you recommend then in vascular dementia if Aricept and Dementia are not FDA approved? There is no medication that is FDA approved for the treatment of vascular dementia. The only treatment for vascular dementia is to prevent further vascular decline by management of vascular risk factors, and to prevent a stroke by managing the vascular risk factors. Are the MABS contraindicated for vascular dementia, and what are the recommendations for treatments for vascular dementia? The MABS work by removing amyloid from the brain, and so they are only approved for Alzheimer's disease because they are anti-amyloid therapies. They will not work in vascular dementia because there is not a presence of amyloid leading to pathology in vascular dementia. So that's why the current MABS are anti-amyloid therapies, and so they only work for neurodegenerative conditions in which the underlying culprit is amyloid, which is Alzheimer's disease. So there are a couple of questions about behavioral management. In the nursing home setting, what would be the best PRN for agitation and sundowning? So like I said, there's a whole webinar by Dr. Raj Tampy on behavioral and psychological management of dementia, so I would encourage you to attend that because there is really no best PRN, and I think it's behavioral and psychological management of dementia is a whole topic unto itself, so I would encourage you to go to that webinar. So there's a question, when do you consider referring to neurology as opposed to continuing care and psychiatry? So I think those are, when it comes to neurocognitive disorders, I think psychiatry versus neurology are almost arbitrary lines that we draw on. So neuropsych, I mean, neurocognitive disorders are a DSM diagnosis, and so psychiatrists are well qualified to manage them. I think to me, when I consider referring to neurology is when there is the presence of a co-occurring neurological disorder that I am not planning on managing myself. So for example, if it's dementia due to Parkinson's disease, I do not plan to manage the Parkinson's disease myself, and in that case, I would refer to a neurologist who can manage the Parkinson's disease as well as the neurocognitive sequelae of the Parkinson's disease. Okay, at what point, at one point does, I think it's, I think it's, the question is, at what point does one decide not to prescribe any cognitive enhancers? So that's a good question. There are, there are two times that you would not prescribe a cognitive enhancer. The one, the first is if the side effects outweigh the benefits. So some people will not tolerate a cognitive enhancer. They will not tolerate a cholinesterase inhibitor, and this happens in about 10 to 15 percent of the population that the side effects are so severe that they are just miserable, and so their quality of life is worse because of the side effects, then you will stop the cholinesterase inhibitor. The second time is when the dementia is so severe that they are candidates for hospice or palliative care because in that setting, the goal is no longer to prolong cognitive decline or prolong life. The goal is comfort. So when the goal of treatment changes from preventing progression to comfort, that's when the decision to withdraw some of these cholinesterase inhibitors will be made. And the last question is, do you use terms MCI and mild neurocognitive disorder interchangeably? Yes, that is accurate. So in the DSM-5, it's called mild neurocognitive disorder, and we often, we also use it clinically as mild cognitive impairment. Both are, MCI and mild neurocognitive disorder are both terms that describe a change in cognition from a prior level that do not affect day-to-day functioning yet. So the last question is, how do you instill hope in the caregiver when patients do not appear to respond to any of the cholinesterase inhibitors and you are not able to offer any other meds? So unfortunately, this is not an uncommon scenario. A lot of people will not respond to cholinesterase inhibitors, and even when people do respond to cholinesterase inhibitors, cholinesterase inhibitors don't reverse the cognitive progression. They just slow it down. So their loved one will continue to decline. So this is unfortunately a very common scenario in dementia management. I think caregiver support groups and caregiver resources go a long way with this. I think this is really not a one-and-done thing. I don't think you can meet somebody once and instill hope and send them on their way. I think it comes from a longitudinal relationship with the patient and caregiver. The Alzheimer's Association has a lot of great resources for caregivers, webinars, reading materials, support groups, caregiver groups, and a lot of the caregiver groups are really effective in creating this community and sharing resources and offering support and hope to each other. All right, and I think we're at time, so thank you everyone for listening today.

neurocognitive disorders

Alzheimer's disease

DSM-5

dementia

APOE gene

cognitive assessment

cholinesterase inhibitors

memantine

anti-amyloid agents

caregiver support