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Hello. My name is Brad Dickerson and I am presenting a section today on designing individualized treatment plans for early AD. The learning objective is to design individualized treatment plans for early AD that balance patient and caregiver goals with AA risk mitigation strategies, applying shared decision-making principles. Here are my disclosures. So let's start with the case to illustrate these points. This is a 67-year-old woman who's a retired college administrator. She had gradually increasing memory difficulty for about a year and a half, uh, was increasingly reliant on notes and reminders, and would sometimes repeat questions that would happen within a fairly short span. That was out of character for her. She was becoming increasingly disorganized just over the past 6 months or so and would sometimes make mistakes in recipes when hosting friends, which was also out of character for her. Her husband had to talk with her about taking over paying bills after she had made some mistakes. Otherwise, she was independent in her volunteer activities, driving, and instrumental and basic activities of daily living. We asked her husband to complete a couple of validated symptom survey instruments about her day to day functioning. And the quick dementia rating system was rated as a 5 out of 30 with lower scores indicating better function and cognition and mood and behavior. She had a 3.5 in cognitive function and a 1.5 in mood and behavior subdomains, consistent with um mild cognitive impairment or very mild dementia. And her functional activities questionnaire was 15 out of 30, more consistent with mild dementia in terms of impact on her day to day functioning of these cognitive symptoms. Her past medical history was uh pretty um insignificant, primarily notable for depression that had only been present for about 5 years, uh, not long-standing. She was on escitalopram for that, which seemed to be working well. Her family history was negative for anyone in the family with dementia or other neurologic conditions. And on examination, her physical and neurological exam were within normal limits. Her validated symptom and sign assessment with the Montreal cognitive assessment was 18 out of 30 with impairments in the mini trail-making test, clock draw strategy, serial sevens, verbal fluency, and she had poor recall, um, and she was unable to retrieve some of the words for orientation. So this was all put together and felt to be consistent with very mild dementia, with the syndrome being a progressive amnesticdy executive syndrome with depression. Let's review the anti-amyloid therapeutic clinical eligibility criteria. These criteria have been put forth by the committee that developed the appropriate use recommendations, uh, and are consistent with the FDA label with a few additional nuances to go through really as a checklist to figure out if this individual is a good candidate for these new therapies or whether there might be some potential uh contraindications. So are the clinical symptoms consistent with the clinical syndrome associated with Alzheimer's disease neuropathologic changes? Yes, this is a classic prototypical syndrome. Does she have uh early functional impairment at the level of mild cognitive impairment or mild dementia? Yes, she does. Is there a lack of other medical, neurological or psychiatric conditions besides AD that could reasonably be judged as the primary source of the patient's decline? So far, that seems to be the case. We haven't uh gone through the full biological workup yet, but we'll come to that in a moment. Is the patient free of poorly controlled medical or psychiatric conditions that might interfere with her ability to comply with the protocol? That's correct. Is the patient free of social barriers that impact the ability to receive uh safe anti-amyloid uh therapies? As far as we know so far, that's true as well. We haven't explored it in detail yet. Is the current medication regimen, uh, list free of anticoagulation, anticoagulants? Yes. Also free of immunosuppressants, immunoglobulins, or other monoclonal antibodies? Yes. Is the neurologic exam consistent with underlying AD as the cause of the patient's cognitive symptoms? Yes, although we haven't seen uh biomarkers, and we know that the neurologic exam and symptom presentation sometimes can look like AD but not actually be AD. So we need those. Is the cognitive exam consistent with early-stage? Uh, uh, mild cognitive impairment or mild dementia, yes. And does she have the capacity to make and communicate medical decisions and complete a written informed consent process, ensuring that she understands the risks and potential benefits? We haven't gone through that in detail yet, but so far, there's no reason to believe that she doesn't. Uh, next, uh, is she reasonably expected to be able to receive the recommended MRIs? She has no pacemaker or indication of claustrophobia. Uh, we haven't discussed it in detail, but, uh, this looks good. Uh, we don't yet know what her MRI looks like, which we'll get to in a moment, but MRI criteria are that there should be, uh, little evidence of hemorrhage, fewer than 4 microhemorrhages, uh, no more than 1 macro hemorrhage, and, um, uh, no superficial cirrhosis or vasogenic edema, and, uh, white matter signal abnormality is consistent with no greater than a moderate stage white matter disease. And then laboratory and biomarker testing and APOE genotype testing, which we will talk about in a moment. So her routine labs were within normal limits. Her brain MRI showed left frontal and medial temporal lobe atrophy on T1 weighted sequence. Flare showed physicus 1, so, um, really minimal white matter signal abnormalities, and the gradient recall echo sequence was negative for any microhemorrhage or other evidence of blood products. So that looks good. Uh, she had a cerebrospinal fluid AD biomarker panel run, which was completely consistent with, uh, amyloid beta 42, total tau levels and hyperphosphorylated tau levels consistent with AD. So, very classic. And then her APOE genotype was E3E3, which is considered to be low risk for ARA, relatively speaking. So, in an APOE3E3 non-carrier, for our first polling question, what would the level of risk of symptomatic ARIA be with leanimab? So thanks for completing the polls, and uh the risk is really low, 1.4% for uh APOE for non-carriers. Uh, the risk goes up with APOE for um carrier status. So, in thinking about this case, uh, we, we talked about the potential benefits, risks, and logistics of amyloid targeting therapy plans with the patient and the care partner, and they asked appropriate questions, uh, including questions about the potential benefits, which are a slowing of cognitive decline by 25 to 35% at 18 months. No expected improvement. Longer term potential benefits are unclear, although open label extension data have so far been encouraging. We answered questions about potential risks. Uh, there is a, a substantial risk of infusion reactions, although the vast majority of those are mild and are, uh, a brief flu-like illness at the time of infusion or shortly afterward. Aria in 12 to 17% radiographically, and symptomatic aria in APOE4 non-carriers, 1.4%, usually quite mild. We also answered questions about logistics. This therapy plan requires infusions every 2 weeks, regular MRI monitoring, clinical monitoring. And a follow-up amyloid PET scan at 12 to 18 months with the potential to switch to subcutaneous maintenance dosing at the point of amyloid clearance or after 18 months. The patient and care partner expressed understanding and willingness to proceed and were able to indicate that she would be able to express any, um, report any side effects if they were to occur. So, um, a, a little bit of additional detail about the MRI protocol shows the, um, protocol for surveillance, MRI scans. Of course, if someone had symptoms suggestive of Aria, um, that were reported to any of the clinical staff, they would, uh, potentially get a, uh, unscheduled MRI. Uh, to evaluate for AIA if there were concern for that. But the blue squares at the bottom show when the scheduled MRI protocol is with the idea that AIA is most likely to occur, if it's going to occur in about the 1st 6 months or so of treatment. So this patient started therapy, had IV infusions every other week, had 32 without any reactions, no clinical complaints on surveillance interviews. She had her scheduled surveillance MRIs with no evidence of aria and is getting close to the point where she's planning to switch to maintenance dosing soon. She and her husband have reported and the follow-up clinical assessments have indicated some mild progression in the cognitive and functional impairment that she has, but only relatively mild over this period of time. So in thinking about the lessons from this case, uh, more than 75% of patients have a completely uneventful course with regard to safety. Biological efficacy can clearly be shown with a follow-up amyloid PET scan, with most patients showing quite a robust reduction of amyloid over that period of time. And um it may be difficult to evaluate clinical benefits since we are poor at predicting individual patient trajectories of cognitive decline, and we absolutely need better tools to better determine whether there's evidence of clinical efficacy in individual patients, which many groups are pursuing. So let's move now to our second case.