Matthew Schrag
@schrag_matthew
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Neurologist focused on Alzheimer's disease, cerebral amyloid angiopathy and stroke. Principal investigator for SchragLab.
Joined August 2019
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New preprint from our group, led by
@AntunesLissa
, explores structural changes in arterioles with cerebral amyloid angiopathy. Lissa is a master of quantitative 3D microscopy. In this clip, healthy tissue is first, then two cases with CAA.
@VUMCneurology
@VUMCDiscoveries
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We can now say with confidence that β-amyloid is a small part of a complicated disease process, not the singular cause of Alzheimer's disease. It is time to close the book on the amyloid hypothesis.
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In Feb 2022, I sent a letter to editors at the journal Nature raising concerns about the integrity of a 2006 study describing the role of β-amyloid oligomers in Alzheimer's disease and a key assembly the authors termed Aβ*56.
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Donanemab headlines: "Beginning of the end" - "Turning point" - "Brink of wonder" - "Beats disease" - "New era"
Treatment group was three points better on a 144 point scale than the placebo - a roughly 2% difference.
You've heard this story before. This isn't the one.
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The much trumpeted "27% slowing" is a relative value - the absolute difference on this test was 2.5%. In this image, I have re-scaled the result from the NEJM paper to include the absolute difference. [Values approximated using a graph extractor.]
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This "positive" result is paradoxically a blow to the amyloid-cascade hypothesis which claims β-amyloid is the major driver of Alzheimer's disease. Twenty+ years of clinical trials showed amyloid-lowering therapy at best produces a barely detectable clinical effect.
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I want to show you what microhemorrhages and brain swelling from anti-amyloid immunotherapies look like under a microscope. In this severe case, many of the vessels simply disintegrated - see the bleeding and numerous aneurysms in this striking image.
#Alzheimer
#lecanemab
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The Alzheimer's Association wants you to believe there is a "consensus" that Biogen/Eisai's drug Lecanemab is a breakthrough. They are circulating a letter signed by ~200 physicians/scientists to support this claim. BUT - most work for/with Biogen/Eisai.
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We have had the incredible privilege of studying the brain of a patient who died after three doses of Lecanemab/Lequembi. This striking case has intense cerebrovascular inflammation/degeneration. We are so grateful to her family for sharing her story w the scientific community.
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4) Safety is still a huge problem - 44% of patients had treatment-related adverse events, 21% developed brain swelling and/or bleeding, a few of which were severe. Two cases of fatal bleeding occurred when lecanemab was combined with blood thinners.
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Important reporting from Charles Piller
@cpiller
putting the spotlight on research integrity in Alzheimer’s research.
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3) I am not convinced the treatment is "disease modifying." Almost all of the benefit of treatment occurred in the first year, after which the trajectories were more-or-less parallel. With disease modifying treatments, the differences continue to become bigger over time.
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The primary outcome, the CDR-SB, scores patients' level of function on a 0-3 range in six different areas like memory and problem solving for a total score of 0-18 (smaller numbers are better). The benefit of lecanemab was less than 1/2 of a point. This is tiny.
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Third patient death in lecanemab Alzheimer's disease trial described in new reporting from
@cpiller
a Science Magazine. This treatment-related death was not disclosed at the recent CTAD meeting, despite occuring in mid-September.
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Alzheimer's drug Lecanemab from Biogen/Eisai will have its day with the FDA in the near future. Most think approval is a forgone conclusion (they are probably right), but to be clear - I believe it should not be approved. The benefits are too small and dangers are too high.
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As a field, we neuroscientists working on Alzheimer’s disease and related diseases need to have a candid dialogue about research integrity.
Important reporting from
@cpiller
.
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Important article from scientific integrity all-star Elizabeth Bik. Is this why effective treatments for Alzheimer’s disease have been so elusive? Opinion | Science Has a Nasty Photoshopping Problem - The New York Times
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2) The clinical benefit, which seems like a homerun at first glance, is a bit of a mirage. The statistical result is strong, but we need to look beyond p-values. For most individual patients in clinic, the benefits will probably not be detectable.
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As with aducanumab, I do not think the benefits seen in this trial clearly outweigh the risks and despite the general excitement around a possible new treatment, I will be advising my patients to keep waiting.
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Severe bleeding occurred in 3.6% of patients taking anticoagulants in the lecanemab trials. This could be higher in the real world with less rigorous screening and monitoring. Patients with cerebral amyloid angiopathy or who require blood thinners should not take this medication.
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There is no acceptable excuse for this behavior. I propose a very simple new approach to this problem. If you are a journal editor and you see this behavior, retract it. If you are a co-author, insist that the paper is retracted. Zero tolerance.
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1) This trial is much better than the frustrating data associated with Aducanumab. Demographics are well balanced between groups and are (somewhat) more representative, the protocol is coherent and there aren’t major technical problems.
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The drug clearly engaged its target, massively lowering β-amyloid levels in the first year of treatment based on amyloid PET scans.
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Topline results from
@EliLillyandCo
's anti-amyloid Alzheimer's treatment, donanemab. Need to wait for full data release to draw final conclusions. Preliminarily, this is a statistically strong effect, but probably marginal clinical importance. Safety issues may outweigh benefit.
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It is time to retract this paper.
@Nature
, what are you waiting for?
@NaturePortfolio
@NIH
@stribjo
@Thatsregrettab1
@MicrobiomDigest
@megynkelly
@WCRIFoundation
@arwaM
@hervenirom
@howard_gleckman
@wilcocklab
@alzassociation
@PeoplesPharmacy
@jackiefmogensen
@lauriemcginley2
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When you see stuff like this, it shouldn’t be investigated for years. Retract it.
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“These drugs have serious side effects, are difficult to administer and I fear they over-promise outcomes related to memory. The fight for an effective therapy is not over — patients with Alzheimer’s need better treatments than this.”
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Marc Tessier-Lavigne steps down as President of Stanford University over research integrity concerns coming from his lab.
The report release today is fair and rigorous and the plan to address the problematic papers is reasonable.
A couple thoughts:
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As the FDA considers approval of lecanemab, they should prioritize the safety of Alzheimer's patients. Iatrogenic cerebral amyloid related encephalitis (iCARE) can be serious and life-threatening and calls into question whether the minor benefits of this drug outweigh the risks.
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Exaggerated, manipulated, massaged, and sometimes just plain made up data is frustratingly not that rare in our business. It’s time to get serious about research integrity.
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Talking shop with Megyn Kelly today — discussing Alzheimer’s disease research and what needs to happen to
#endalz
.
TODAY: A deep dive into the issue of Alzheimer's ... and some alarming findings about Alzheimer's research.
with:
-
@DrDaleBredesen
-
@schrag_matthew
-
@CPiller
LIVE on
@SIRIUSXM
ch. 111 at NoonET, and all platforms after:
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The key to extraordinary longevity is …… bad record keeping?
Re-evaluating “blue zones.”
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We are incredibly grateful to this patient's family for allowing us to study her brain. They tell their story here:
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First author Sylvain Lesne and senior author Karen Ashe argued that a specific oligomer of β-amyloid induced memory deficits. But some methods didn't make sense and some of the images looked manipulated, as reported by
@cpiller
.
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Integrity concerns in this J Neurosci paper led by Sylvain Lesne were identified ten years ago. Cited over 300 times. It’s time to retract.
@JNeurosci
Do you care?
David and Julie
@rushalzheimers
, do you care?
Adriano
@AdrianoAguzzi
, do you care?
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This is a piece of human brain from a patient who died from a side effect of the Alzheimer's drug lecanemab. The tissue is about 2.5 x 2.5 x 1cm and has been "cleared", allowing us to see the vessels in three dimensions using a type of microscope called a lightsheet.
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Remarkable initial reporting by (then freshman) Theo Baker brought this to light - congratulations.
@tab_delete
Will be watching your career. Early forensic work was from
@MicrobiomDigest
,
@Thatsregrettab1
and others at
@pubpeer
.
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This reaction is not always a benign “imaging abnormality.” It will be important to re-evaluate the approach to screening for CAA prior to anti-amyloid immunotherapy. Patients/families need to know there are real risks.
@VUMCneurology
@VanderbiltBrain
@VanderbiltAlz
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We are introducing the term iatrogenic cerebral amyloid related encephalitis (iCARE) to more accurately describe symptomatic or radiographically serious cases of ARIA. You can see the details of a fatal case in the lecanemab trial in our preprint here.
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If this feels manipulative to you, you aren't alone. Conflicts and adverse events need to be candidly disclosed. Peer-review must be thorough and honest. Failing to respect these basic expectations understandably leads to speculation about the fairness and openness of the field.
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It gets worse -- Dr. Bik discovers that the "sham" condition might be more of a sham than we initially thought.
#FigcheckClass
: One paper published in Neurosurgery(2011).
Unfortunately, Dr. Berislav V. Zlokovic is being questioned. Figcheck discovered the malicious editing and reuse of images in his 2011 paper through image recognition technology. Any comments？
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Tim Hohman talks about leveraging harmonized “big data” sources to understand mechanisms of neuro-resilience. Incredible promise in this work.
@VUMCneurology
@VanderbiltBrain
@VanderbiltAlz
#vumcneuro
#VandyADday
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The letter feels self-congratulatory and makes no pretense of balance. Apparently it was written by Dennis Selkoe and twelve colleagues, all seemingly with connections to Biogen/Eisai or the trials. Importantly, not all bothered to disclose this connection (a recurring problem).
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I believe the frequency with which we are seeing major, field distorting, integrity lapses in Alzheimer's research and neuroscience has as much to do with leading scientists, journals and institutions turning a blind eye as it does with the bad actors themselves.
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Second reported fatality associated with lecanumab treatment and blood thinners. This seems like a dangerous combination.
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On an MRI we can see swelling and some of the larger areas of bleeding, but these pictures show how extensive the vascular degeneration can be. You can see more details from this important case in our preprint here:
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We need to create a laboratory culture where trainees are not overly pressured to produce specific outcomes, but rather focus on rigor and reproducibility. And there is no substitute for a Principal Investigator being physically present in the lab ... a lot.
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The article was one of the five most cited primary basic science papers in the field in the last 20 years, but in July 2022 Nature flagged the article asking readers to use caution in interpreting the results.
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The video shows a 3D rendering of the tissue block with vessels false-colored pink. The hazy background around some of the vessels (see yellow arrows) is from bleeding (the ruptured ends of the vessel are at the red arrows). Blood propagates in perivascular spaces some distance.
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Incredible work going on to defeat Alzheimer’s disease at Vanderbilt, thanks to the incredible people willing to join a clinical study.
@VanderbiltAlz
@VanderbiltBrain
@VUMCneurology
#vumcneuro
One major study is tracking how good heart health may slow or even stop Alzheimer’s from developing in the brain.
@mariashriver
shares more.
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This past March, senior author Karen Ashe released a pre-print article attempting to replicate key aspects of the 2006 study. This was an important step, and I appreciate the effort Dr. Ashe's team spent producing this.
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Example: Dr. Jeffrey Cummings disclosed no conflicts of interest, yet in a 2021 paper in the Journal of Prevention of Alzheimer's Disease (where he is an editor) he had a long list of relevant conflicts (the small print in the image), including connections to Eisai and Biogen.
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I recently got to talk shop with Daniel Claassen
@claassendoc
about the clinical management of cerebral amyloid angiopathy. Listen here:
@VUMCneurology
#vumcneurology
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Dr. Ashe’s concurrence that this approach to tissue fractionation is unacceptable should prompt a retraction of the article, as several conclusions rely on it. It calls into question Figure 1c, Figure 2, and Figure 3, as well as supplementary figures 1a, 2, 3, 4, 5e/f.
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The authors were able to detect a band potentially consistent with Aβ*56 in less than 15% of the animals, and this after considerable technical improvements which were not present in the original study.
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A new example of probable embellishment is shown here from sfig1. The bands look the same, including an air bubble (red arrows). Transforming the image using a lookup table enables visualization of subtle internal details in the bands (lower image) where several details align.
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There are also lots of aneurysms (a couple marked in green arrows in the last image). The vessels should be smooth and gently tapering and branching. Twisted, kinked or distended vessels are not normal. See this video in 4k on YouTube:
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Comparing the new blot with Figure 1c of the 2006 paper shows an important difference – the “Aβ*56” band in the pre-print runs closer to the “non-specific” 50kDa band and is lower intensity than the comparable blot from 2006. Is that the same protein? (See red arrows below).
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If Eisai and Biogen will not acknowledge that this case has an extremely high probability of being treatment related, how can you trust remainder of their safety data for lecanemab?
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Eisai's perfunctory response to
@cpiller
's recent report on the third death in the Lecanemab trials as "provided by sources...who may not have all the information necessary to make an accurate conclusion" raises a major red flag for me.
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Good scientists should retract a paper once in a while. We should destigmatize this. The probability of getting through a career (100 or 200 papers) and never having a problem manuscript is unrealistic, let's not pretend otherwise.
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Treating people with earlier stages of tau accumulation was a thoughtful strategy. Based on my back-of-the-envelope estimates, earlier tau status didn't result in better cognitive response (0.68 points on the CDR-SB in the intermediate tau group, 0.74 in the high tau group).
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We need to understand ARIA and iCARE better. We are particularly grateful to the special family of this patient who allowed us to study her brain and share this information (photos with permission). They tell their story here:
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Donanemab, lecanemab and aducanumab seem to be very similar in terms of efficacy and safety. In the upcoming full data release, I'm looking for clear evidence that the benefits outweigh the risks.
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Long term anticoagulation is dangerous in patients with cerebral amyloid angiopathy, especially with prior ICH. But that doesn’t mean their A fib can’t be treated. Left atrial appendage closure is an alternative that needs to be included in the trials.
1/6 🧵
Are you involved in the management of patients with
#Afib
or intracranial hemorrhage? Important recently published information contained in the following thread.
#neurotwitter
#cardiotwitter
#stroke
#medtwitter
#MedEd
@McmasterStroke
#stroke
@PHRIresearch
@MacDeptMed
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The scale to which donanemab slows cognitive decline is very small (an absolute difference of about 4% on the CDR-SB test). Most patients and families won't notice the difference after 18 months of intravenous injections every two weeks. It doesn't give people their memory back.
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"ARIA" is euphemistically named an “amyloid related imaging abnormality” as if it doesn’t cause important clinical symptoms. Most clinical trials programs present it as a minor concern, usually transient and asymptomatic. It can be very dangerous, and sometimes lethal.
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Thoughtful comments in this thread. Was the placebo adequate in the donanemab and lecanemab Alzheimer’s disease trials?
The main limitation of the
#donanemab
#lecanemab
trials is not mentioned & overlooked in circulating commentary: use of saline placebo. While common, but it is a particularly weak placebo for this drug class, introducing concern of bias that is enhanced by reading the data. /1
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We will share much more about this case in a peer reviewed setting, but a few photos to start the conversation. She had severe cerebral amyloid angiopathy and frequent microhemorrhages with intense perivascular inflammation.
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3. They say: “Comparing banding patterns in our current western blots with those in the literature, ... the Aβ*56 entity we describe here ... may not correspond exactly to the ~56-kDa entities that have been identified using other protocols.”
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2. Dr. Ashe re-evaluated tissue from her prior studies, including a supplementary table indicating whether Aβ*56 was present in individual mice. This included 48 transgenic mice between the ages of 6 and 9 months (a range where the 2006 paper argued that all the mice had Aβ*56).
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Both trials were published in a single manuscript in the obscure, low-tier outlet JPAD, co-authored by two of the lead editors of the journal. Remarkably for one of the most controversial datasets our field has ever seen, the study was "peer reviewed" in less than a month.
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Initial report from trial of lecanemab: statistically met endpoints, but clinically the effect is very small and toxicity is still an issue. Be careful of the hype before we see the data in full. There is a long history here.
#endalz
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Deaths and serious adverse events in clinical trials need to be thoroughly and openly addressed. The failure of Eisai/Biogen to disclose this case when reporting the clinical trial results is concerning and undermines my confidence that the reported safety data is complete.
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That 2021 paper? It was an "expert panel" paper providing "appropriate use recommendations" for aducanumab mere weeks after its approval. The consequential paper was "peer reviewed" in 8 days (over a holiday) and 5/6 authors had connections to Biogen/Eisai.
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Congratulations to
@brianmacgrory
on being elected a Fellow of the American Heart Association (FAHA). That’s part of a string of big accomplishments this year and it’s only March!
@Duke_Neurology
@StrokeAHA_ASA
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The editor is simply wrong here — context is important. 1) Scientific work often spans papers, and should be seen as a whole. 2) It can clarify the issue of intentionality. 3) It can exonerate uninvolved co-authors. This “see no evil” mindset from journal editors needs to stop.
Here is a first for me:
Journal editor reprimands me for sending list of 25 papers by same author, published in different journals, because that introduces "bias into the process." They told me I should send concerns "without mention of unvalidated concerns at other journals."
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I sent an analysis of this pre-print to Nature recently and shared it on PubPeer. There are three important conclusion from this new analysis.
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As we wrestle with the appropriate use of these drugs, we need all of the data. This episode undermines my trust in Eisai and Biogen and falls into the same pattern of frustrating behavior we witnessed around the approval and post-approval marketing of aducanumab.
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1. Dr. Ashe did not replicate the tissue fractionation used in the 2006 paper. “We adjusted the buffers used to extract proteins, because we found that extracts containing detergents form irreversible, insoluble precipitates and may contain membrane-associated proteins.”
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Image credit to
@AntunesLissa
from the SchragLAB (
@LABSchrag
) and Jose Maldonado (Vanderbilt Neurovisualization Lab).
@VUCellImaging
@VUMCneurology
@VUMCDiscoveries
@VanderbiltAlz
@US_FDA
@nvillain_alz
@ProfRobHoward
@a_charidimou
@MadhavThambiset
@cpiller
@ApostolovaLiana
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Three more surprises from the FDA decision on aducanumab:
1) Approved for Alzheimer’s disease, no restriction on disease stage.
2) No requirement for amyloid-PET, CSF analysis or APOE testing.
3) OK to continue, even after severe ARIA-H if imaging looks stable.
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It’s Alzheimer’s Disease Research Day at Vanderbilt. Great line-up of talks today!
@VanderbiltAlz
@VUMCneurology
@VanderbiltBrain
#VandyADday
#vumcneuro
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The company downplayed the death in a communication to Fierce Pharma saying that “The rates of deaths and causes of deaths that we are observing in the lecanemab studies are consistent with those expected in people this age.”
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I reviewed hundreds of pages of medical records and multiple scans when
@cpiller
asked me to review the case. The article was deeply researched, and the concern is very real. This appears to be a highly unusual cause of death and should not be dismissed as expected or common.
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Patient safety is paramount, and I am not convinced this treatment is safe. Rushing this drug to market would be a mistake.
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A Renaissance for Alzheimer’s and Dementia Science Brings Vigorous Debate: thoughtful comments from
@DrMariaALZ
. “We all must agree on the crucial importance of scientific integrity. It is the coin of the realm.”
#AAIC2022
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When vessels with cerebral amyloid angiopathy rupture, the organized rings of amyloid shatter and only shards remain (red). Outstanding microscopy from Lissa.
Here's a dramatic picture of an artery that ruptured due to cerebral amyloid angiopathy; residual, fractured beta-amyloid shards are stained red. Credit:
@AntunesLissa
.
@vumcneurology
#vumcneuro
@VanderbiltAlz
@VanderbiltBrain
@VUCellImaging
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Current issues aside, Marc Tessier-Lavigne is a superb neuroscientist whose many other accomplishments have stood the test of time. It is entirely appropriate that he will continue his research at Stanford.
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Co-authors on papers are not responsible for someone else's research misconduct.
However, when (especially senior) co-authors become aware of manipulation or a data quality breach, they have an obligation to correct the record and actively maintain a culture of integrity.
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