Julie G wrote: ↑Fri Dec 02, 2022 10:53 am
... Given the high prevalence of CAA for E4 carriers, are they giving baseline MRIs prior to lecanamb? If positive, is lecanamab contraindicated given the significant risk of bleeding? If this patient had a baseline MRI and CAA had previously been identified, why in the world would TPA have been given?
All of this is hitting close to home for me. My E4 mother just experienced a hemorrhagic stroke, CAA, the day after Thanksgiving. We're still in the ICU, but hope to be on our way to rehab soon. The likelihood of myself and my brothers having CAA is quite high. Once I'm out of the hospital, I plan to be evaluated.
Julie, my deepest wish is for your mother to be out of the ICU soon and able to heal with her family's love.
My time spent with a loved one in the ICU was a rollercoaster of feeling that he was in the safest and yet scariest place, with the best people and yet with me not knowing how to help. Take care of yourselves during these difficult days.
I think the quickest answer to your final question is that the MRI would likely not have shown diagnostic proof of CAA. Per Karelena's post, the ER doctors may have believed from the MRI that they were treating an ischemic stroke initially, and only upon TpA did she have massive hemorrhagic bleed. Here's a 2018 listing of possible biomarkers of CAA, some of which require highly specialized tests such as diffusion tensor imaging (DTI), but one of which is a positive amyloid beta PET or CSF result. None of these are sufficient to diagnose CAA, I believe.
Diagnosis of Cerebral Amyloid Angiopathy Evolution of the Boston Criteria
The ability to diagnose CAA during life with good specificity is a prerequisite for identifying other biomarkers of the disease’s presence, severity, and future behavior... Among the long (and likely still growing) list of CAA biomarkers made possible by the Boston criteria are (1) white matter T2 hyperintensities, with tendency for posterior predominance or a multiple subcortical spot pattern; (2) altered diffusion tensor imaging parameters such as global mean diffusion or diffusion tensor-derived global efficiency; (3) vascular reactivity to functional stimulation; (4) cortical thickness; (5) punctate diffusion weighted imaging hyperintensities suggestive of acute microinfarcts; (6) enlarged perivascular spaces in the centrum semiovale; (7) positron-emission tomography labeling with the amyloid ligands Pittsburgh compound B and florbetapir; and (8) reduced cerebrospinal fluid concentrations of β-amyloid. These multimodal biomarkers serve as both important windows into the pathogenesis of CAA and candidate outcome markers for clinical trials.
The CLARITY and AHEAD studies require one MRI shortly before baseline randomization, in addition to ECGs, blood and urine tests, physical and soft-sign neurological exams and amyloid and tau PET scans. From what I have heard from researchers, anyone with either one macrohemorrhage (≥ 10mm) or 8 or more "microbleeds" (≤ 5mm) prior to baseline is excluded and anyone who meets that criteria during the study is withdrawn. Doctors at each site have final authority to exclude people when they feel that patient safety may be jeopardized.
An additional MRI is done during the titration period, at about 1 month and again at 6 months, and unscheduled MRIs are done if a trial participant has symptoms that are consistent with possible ARIA-E or ARIA-H (study personnel are of course blinded as to assignment). Blood tests, ECGs and physicals are done every 6 months, with additional consultation from the study site doctor if a participant has an illness. Infusions may be "paused" for a week or more on the decision of the study site doctor and heart rate and blood pressure readings are taken before and after infusions.
The safety issue for lecanemab is important. In the 11/29 CLARITY presentation on safety data, Dr. Marwan Sabbagh, a behavioral neurologist, noted that none of the patients who died after having a macro-hemorrhage had been diagnosed with ARIA-H or ARIA-E, nor had they been excluded due to use of anti-coagulant medications. About 5.7% of patients in both the placebo and lecanemab arms prior to open label extension (OLE) were on such drugs, in hopes of having participation consistent with common comorbidities and medications used in MCI and mild AD patients in communities.
It will be important to learn why these other participants did not experience macro-hemorrhages while on the drug.
- One of 897 participants on the placebo arms of the combined trials died of a macro-hemorrhage during the trials, a rate of 0.1% ; two of 1608 people receiving lecanemab died of macrohemorrhages, also a rate of 0.1%
- The first patient who died while on lecanemab was 87, non-ApoE4, with anti-coagulant medication, prior heart attack, successive falls, and pneumonia before his macrohemorrhage, followed some months later by cardio-respiratory arrest. Given the association of advanced age with CAA even in non-poE 4 populations, and the prior history of heart disease, it seems likely that he should have been excluded from the CLARITY trial.
I heard at least one researcher note that the risk of death appears to be about 1 in 1000 people treated at this stage of disease. If that proves to be an accurate risk ratio for people with MCI/mild AD, it may be less with people in the AHEAD trial, and will be something each participant should have access to transparently to make an informed consent.
"Isolated ARIA-H", defined as one or more microbleeds with or without symptom but without ARIA-E, was seen in 7.8% of placebo participants and 8.9% of lecanemab participants, suggesting that microbleeds in isolation in this population occur with only a slightly higher rate on lecanemab and may be most influence by age and vascular disease. The incidence of ARIA-H in addition to ARIA-E
was 8.4% on the treatment arm vs 1.2 % in the placebo group, suggesting that ARIA-E (edema) may induce stress on the small blood vessels. Study protocol was to withdraw people once they had ≥ 8 macrobleeds or one macro-hemorrhage ≥ 10mm. Neither of the patients who died had that history.
My maternal grandmother died of a massive stroke at age 45, and my mother had multiple microbleeds with uncontrolled high blood pressure in her 70's, leading to mixed dementia in her 80's. I strongly support the need for better and earlier diagnosis of CAA as an independent risk for major brain bleeds for those of us with ApoE 4/4 . Yet, I still believe this drug may be of significant help to those who wish to slow the rate of progression, since the widening curve between placebo and treated patients suggests that the benefit will exceed 27% beyond 18 months, and results presented suggested the biggest change was in perceived burden and perceived functional skills by caregivers of those on the treatment arm--while they were unaware of their loved one' study arm.
I hope that we will learn more from this and other studies. From what I have seen and heard, the most important information may have been presented by Dr. Reisa Sperling, one of the principal co-investigators on the AHEAD studies. She stated in an opening address that we need to recognize that anti-amyloid treatments may be necessary for those who appear highly likely to progress on the path to MCI and AD--AND that researchers need to design combination therapies and multi-modal trials that address vascular, metabolic, inflammatory, toxic, social and age-related contributors to Alzheimer's related dementia.
Sending hope for better news soon for your mother.