Alberto Espay
@albertoespay.bsky.social
Neurology professor at the University of Cincinnati, an advocate of precision and rescue medicines for Parkinson's & Alzheimer's. Author #BrainFables.
The words of the Parkinson's literature: “Accumulation” “Replication” "Prion-like" “Propagation” “Strains” "Seeding" They shape what we believe and do. Our patients’ lives depend on the language we adopt. With Andrew Lees (@ajlees), in @GreenJournal: doi.org/10.1212/WNL....
The “too late” defense of anti-amyloid trials has been tested in 6 preclinical #Alzheimer's trials (amyloid-positive, cognitively normal people). They range from futility to worsening. When does “early is better” become unfalsifiable? lnkd.in/p/gYsFkWW5
The “Early is Better” Alzheimer’s mantra is challenged by the evidence. For years, a standard explanation for failed anti-amyloid trials has been: “We treated patients too late.” The reasoning was… ...
The “Early is Better” Alzheimer’s mantra is challenged by the evidence. For years, a standard explanation for failed anti-amyloid trials has been: “We treated patients too late.” The reasoning was t...
lnkd.in
With lecanemab, the real-world harms are clearly observed and include death; the cognitive benefit is counterfactual. Here is the latest real-world report exemplifying this mismatch. www.linkedin.com/posts/albert...
#alzheimers #lecanemab | Alberto Espay
A mismatch is emerging in the real-world evidence for anti-amyloid Alzheimer treatments. These infusions are administered with the intention of preserving cognition. Yet real-world reports quantify AR...
linkedin.com
Less tau accumulation yet more clinical deterioration. PROSPECT-ALZ offers a striking test of what happens when biomarkers move in the “right” direction but patients don't quite follow. What does it take to falsify the tau-toxicity hypothesis? www.linkedin.com/posts/albert...
Less tau accumulation. More clinical deterioration. The PROSPECT-ALZ trial of the OGA* inhibitor ceperognastat offers another striking example of biomarker–clinical dissociation in Alzheimer’s… | Alb...
Less tau accumulation. More clinical deterioration. The PROSPECT-ALZ trial of the OGA* inhibitor ceperognastat offers another striking example of biomarker–clinical dissociation in Alzheimer’s diseas...
linkedin.com
What is p-tau217 accurate for? Detecting amyloid/tau pathology is not the same as predicting who will develop Alzheimer’s dementia. My take on Jeanne Lenzer’s newest investigation. www.linkedin.com/posts/albert...
In the new world of blood-based biomarkers, what is a positive p-tau217 accurate for? A positive p-tau217 is highly accurate for identifying the presence of amyloid and tau pathology in the brain… | ...
In the new world of blood-based biomarkers, what is a positive p-tau217 accurate for? A positive p-tau217 is highly accurate for identifying the presence of amyloid and tau pathology in the brain. In...
linkedin.com
Is the post–18-month steepening in the lecanemab and donanemab trials simply #Alzheimers natural “waterfall”? Unlikely, but let's assume it is true. What does that imply for claims of disease modification? lnkd.in/p/gzErdGEB
#alzheimersdisease #lecanemab #donanemab | Alberto Espay
𝐒𝐡𝐨𝐮𝐥𝐝 𝐭𝐡𝐞 𝐬𝐭𝐞𝐞𝐩𝐞𝐧𝐢𝐧𝐠 𝐨𝐟 𝐝𝐞𝐜𝐥𝐢𝐧𝐞 𝐚𝐟𝐭𝐞𝐫 𝐦𝐨𝐧𝐭𝐡 𝟏𝟖 𝐢𝐧 𝐥𝐞𝐜𝐚𝐧𝐞𝐦𝐚𝐛 𝐚𝐧𝐝 𝐝𝐨𝐧𝐚𝐧𝐞𝐦𝐚𝐛 𝐭𝐫𝐢𝐚𝐥𝐬 𝐨𝐟 𝐞𝐚𝐫𝐥𝐲 𝐀𝐥𝐳𝐡𝐞𝐢𝐦𝐞𝐫’𝐬 𝐝𝐢𝐬𝐞𝐚𝐬𝐞 𝐜𝐨𝐧𝐜𝐞𝐫𝐧 𝐮𝐬? The Öhman models have been cited as evidence that this observation simply re...
lnkd.in
After 18 months, the curves got steeper—not flatter. Our analysis of long-term lecanemab and donanemab data challenges the “longer is better” narrative in @Alzheimers treatment and underscores the need for access to participant-level trial data. www.linkedin.com/posts/albert...
#alzheimersdisease #lecanemab #donanemab | Alberto Espay
It is visible to the naked eye: After 18 months, the slopes of decline got steeper in the treated Alzheimer’s trial cohorts. But we put it to the statistical test. Our analysis of the published long...
linkedin.com
A provocative thought from a Sunday conversation: What if amyloid is to dementia what gastric acid was to ulcers? A real risk, mistaken for the cause. Are we living through the Billroth stage of Alzheimer’s therapeutics? lnkd.in/p/ghn8Pv6d
A perfect Sunday conversation. One enlightened colleague earlier today brought up one of the greatest dramas in the history of medicine: the once crazy suggestion that gastric ulcers might be caused… ...
A perfect Sunday conversation. One enlightened colleague earlier today brought up one of the greatest dramas in the history of medicine: the once crazy suggestion that gastric ulcers might be caused b...
lnkd.in
Research for the sake of research: sophisticated analytics to show that patients differ from one another. By publishing such papers, we fuel an academic culture that rewards paper counts over knowledge that ultimately matters to patients. movementdisorders.onlinelibrary.wiley.com/doi/10.1002/...
Clinical Heterogeneity in Orthostatic Movement Disorders: Insights from Latent Class Analysis and Disease Burden Scoring
Background Orthostatic tremor (OT) and orthostatic myoclonus (OM) are rare hyperkinetic disorders characterized by unsteadiness during stance. Substantial clinical overlap limits the prognostic and ...
movementdisorders.onlinelibrary.wiley.com
What Does α-Syn-SAA-Negative Parkinson's Disease Reveal About the Proposed “Biological Definition” of Parkinson's Disease? www.linkedin.com/posts/albert...
What Does α-Syn-SAA-Negative Parkinson's Disease Reveal About the Proposed “Biological Definition” of Parkinson's Disease? An analysis of the PPMI cohort found remarkably few differences betw...
What Does α-Syn-SAA-Negative Parkinson's Disease Reveal About the Proposed “Biological Definition” of Parkinson's Disease? An analysis of the PPMI cohort found remarkably few differences between peop...
linkedin.com
Today in history (1633): Galileo gives the thumbs-up to geocentrism and saves his life. I, too, am confident that pathology is the center of the neurodegenerative disease universe, and everything else revolves around it. (More thoughts on LinkedIn.) www.linkedin.com/posts/albert...
On this day in 1633, Galileo was forced to recant his support for the Copernican view that the Earth was not the center of the universe. For his heresy, the church sentenced him to life imprisonment… ...
On this day in 1633, Galileo was forced to recant his support for the Copernican view that the Earth was not the center of the universe. For his heresy, the church sentenced him to life imprisonment u...
linkedin.com
#Parkinsons with and without detectable pathological α-synuclein (αSyn-SAA) are remarkably similar. What does that mean for the idea that α-syn aggregates "biologically define" PD? My take on a new #PPMI analysis: www.linkedin.com/posts/albert...
The house of cards we built around α-synuclein as the biological definition and toxic driver of Parkinson’s disease is unraveling from the inside, suggests a new analysis from the PPMI study, just… | ...
The house of cards we built around α-synuclein as the biological definition and toxic driver of Parkinson’s disease is unraveling from the inside, suggests a new analysis from the PPMI study, just pub...
linkedin.com
A community-recruited cohort provides evidence against the “positive AD biomarker = Alzheimer's disease” equivalence. www.linkedin.com/posts/albert...
#alzheimers | Alberto Espay
Biomarkers of Alzheimer’s pathology may identify aging biology, not necessarily Alzheimer’s disease. By conflating the two, a biomarker-centered framework of Alzheimer’s disease risks harm rather than...
linkedin.com
Another negative anti-tau trial, another positive corporate report. www.linkedin.com/posts/albert...
Topline Results from Phase 2 CELIA Study of Diranersen (BIIB080): First Study to Show Reduction in Tau Pathology and Cognitive Benefit in Patients with Early Alzheimer’s Disease | Biogen | Alberto Esp...
Positive biotech messaging after failed endpoints is becoming a genre of its own. Notice the wording of the Biogen press release about the Phase 2 CELIA study evaluating diranersen (#BIIB080), an ant...
linkedin.com
𝐀𝐥𝐳𝐡𝐞𝐢𝐦𝐞𝐫'𝐬 𝐭𝐚𝐮 𝐛𝐢𝐨𝐦𝐚𝐫𝐤𝐞𝐫𝐬 𝐜𝐨𝐫𝐫𝐞𝐜𝐭𝐞𝐝. 𝐀𝐥𝐳𝐡𝐞𝐢𝐦𝐞𝐫'𝐬 𝐝𝐢𝐬𝐞𝐚𝐬𝐞 𝐮𝐧𝐜𝐡𝐚𝐧𝐠𝐞𝐝. ~10 anti-tau monoclonal antibodies tested to date in #Alzheimers. They change tau, not the disease. www.linkedin.com/posts/albert...
#alzheimers #tau | Alberto Espay | 23 comments
𝐀𝐥𝐳𝐡𝐞𝐢𝐦𝐞𝐫'𝐬 𝐭𝐚𝐮 𝐛𝐢𝐨𝐦𝐚𝐫𝐤𝐞𝐫𝐬 𝐜𝐨𝐫𝐫𝐞𝐜𝐭𝐞𝐝. 𝐀𝐥𝐳𝐡𝐞𝐢𝐦𝐞𝐫'𝐬 𝐝𝐢𝐬𝐞𝐚𝐬𝐞 𝐮𝐧𝐜𝐡𝐚𝐧𝐠𝐞𝐝. Over the past decade in Alzheimer’s disease, ~10–12 anti-tau monoclonal antibodies have been tested across ~6–8 Phase 2 programs, ...
linkedin.com
I now understand why we can look at the same data on studies of tests of pathology and come to very different conclusions. My thoughts here. www.linkedin.com/posts/albert...
I now understand why we can look at the same data on tests of pathology and come to very different conclusions. Some see blood-based biomarkers like high pTau217 and conclude: “We can now detect… | A...
I now understand why we can look at the same data on tests of pathology and come to very different conclusions. Some see blood-based biomarkers like high pTau217 and conclude: “We can now detect Alzh...
linkedin.com
A faux vignette illustrates a flawed causal inference in Parkinson's research: pathology ('calcification') is mistaken for a pathogenic mechanism ('toxicity') rather than a marker of protein dyshomeostasis ('calcium metabolism'). @ajlees.bsky.social www.linkedin.com/posts/albert...
A 56-year-old man presents with parkinsonism. Brain imaging reveals basal ganglia calcifications. His clinician, concluding that the calcifications triggered his symptoms, prescribes calcium… | Albert...
A 56-year-old man presents with parkinsonism. Brain imaging reveals basal ganglia calcifications. His clinician, concluding that the calcifications triggered his symptoms, prescribes calcium chelation...
linkedin.com
Time to reconsider use of statins for primary cardiovascular prophylaxis in Parkinson's disease? www.linkedin.com/posts/albert...
Statins for primary cardiovascular prevention in Parkinson’s disease: is it time to rethink the balance of risk and benefit? A new study adds to the concern that statins may not be benign in PD. In… ...
Statins for primary cardiovascular prevention in Parkinson’s disease: is it time to rethink the balance of risk and benefit? A new study adds to the concern that statins may not be benign in PD. In 3...
linkedin.com
If Parkinson’s is “biologically defined” by a positive α-synuclein test, what do we do with the 10% who are negative? Can we distinguish between detecting pathology and defining disease? www.linkedin.com/posts/albert...
If Parkinson’s is “biologically defined” by a positive α-synuclein test, what do we do with the 10% who are negative? The α-synuclein seed amplification assay (αsyn-SAA) sensitively detects… | Alberto...
If Parkinson’s is “biologically defined” by a positive α-synuclein test, what do we do with the 10% who are negative? The α-synuclein seed amplification assay (αsyn-SAA) sensitively detects aggregated...
linkedin.com
𝐓𝐡𝐢𝐬 𝐭𝐫𝐞𝐚𝐭𝐦𝐞𝐧𝐭 𝐜𝐚𝐧 𝐤𝐢𝐥𝐥. 𝐂𝐨𝐮𝐧𝐭𝐢𝐧𝐠 𝐢𝐬 𝐥𝐞𝐠𝐚𝐥𝐥𝐲 𝐩𝐫𝐨𝐡𝐢𝐛𝐢𝐭𝐞𝐝 (*until 2036–2037). Deaths occur with lecanemab & donanemab, but excess mortality can’t be estimated: it is proprietary data and can be withheld for a decade. www.linkedin.com/posts/albert...
Science For Sale: How Drugmakers Captured The FDA | Alberto Espay
𝐓𝐡𝐢𝐬 𝐭𝐫𝐞𝐚𝐭𝐦𝐞𝐧𝐭 𝐜𝐚𝐧 𝐤𝐢𝐥𝐥. 𝐂𝐨𝐮𝐧𝐭𝐢𝐧𝐠 𝐢𝐬 𝐥𝐞𝐠𝐚𝐥𝐥𝐲 𝐩𝐫𝐨𝐡𝐢𝐛𝐢𝐭𝐞𝐝.* (*until 2036–2037) 𝐃𝐞𝐚𝐭𝐡𝐬 𝐚𝐬 𝐩𝐫𝐨𝐩𝐫𝐢𝐞𝐭𝐚𝐫𝐲 𝐝𝐚𝐭𝐚. It has now been 15 months since I retracted my first and only paper, which sought to estimate ...
linkedin.com
𝐘𝐨𝐮𝐫 𝐛𝐫𝐚𝐢𝐧 𝐰𝐢𝐥𝐥 𝐬𝐡𝐫𝐢𝐧𝐤 𝐛𝐮𝐭 𝐭𝐡𝐢𝐬 𝐢𝐬 “𝐩𝐬𝐞𝐮𝐝𝐨-𝐚𝐭𝐫𝐨𝐩𝐡𝐲,” 𝐭𝐫𝐮𝐬𝐭 𝐮𝐬. We need independent analysis, not trust. The dry weight of Aβ accounts for <1/1,000 of the observed volume change in #Alzheimers with treatment. www.linkedin.com/posts/albert...
𝐓𝐡𝐢𝐬 𝐭𝐫𝐞𝐚𝐭𝐦𝐞𝐧𝐭 𝐰𝐢𝐥𝐥 𝐬𝐡𝐫𝐢𝐧𝐤 𝐲𝐨𝐮𝐫 𝐛𝐫𝐚𝐢𝐧. 𝐘𝐨𝐮'𝐫𝐞 𝐰𝐞𝐥𝐜𝐨𝐦𝐞. That statement is not rhetorical. We are told that reduced brain volume is the mechanism by which… | Alberto Espay
𝐓𝐡𝐢𝐬 𝐭𝐫𝐞𝐚𝐭𝐦𝐞𝐧𝐭 𝐰𝐢𝐥𝐥 𝐬𝐡𝐫𝐢𝐧𝐤 𝐲𝐨𝐮𝐫 𝐛𝐫𝐚𝐢𝐧. 𝐘𝐨𝐮'𝐫𝐞 𝐰𝐞𝐥𝐜𝐨𝐦𝐞. That statement is not rhetorical. We are told that reduced brain volume is the mechanism by which anti-amyloid (Aβ) monoclonal antibodies benefi...
linkedin.com
In Parkinson’s, we obsess over what α-synuclein becomes when aggregated, and ignore what neurons lose when its normal form disappears. New data in α-syn KO mice: hyposmia, apoptosis, impaired autophagy. Depletion may matter more than we think. www.linkedin.com/posts/albert...
Parkinson’s disease is often framed as a disorder of 'toxic accumulation' of pathological α-synuclein. Yet the reciprocal process, the depletion of soluble, functional α-synuclein, has receive...
Parkinson’s disease is often framed as a disorder of 'toxic accumulation' of pathological α-synuclein. Yet the reciprocal process, the depletion of soluble, functional α-synuclein, has received far le...
linkedin.com
“Alzheimer’s is caused by pathology decades before symptoms.” If so, removing pathology in preclinical AD should prevent decline. It didn't—most preclinical AD trials (4/6) worsened outcomes in treated vs placebo. Pathology ≠ disease. www.youtube.com/watch?v=_Z_Z...
Alzheimer’s Isn’t Inevitable - What Top Harvard Scientist Now Knows About Prevention
YouTube video by The HumanWare Project
youtube.com
Detecting Alzheimer’s, or Detecting Age? A new @Nature study shows the wide gap between #Alzheimers pathology (Tau217) and disease. Pathology and disease prevalence diverge across adulthood. Is pathology a marker of successful aging? www.linkedin.com/pulse/detect... via @LinkedIn
Detecting Alzheimer’s — or Detecting Age?
A blood-based biomarker of Alzheimer’s quintuples the population prevalence of Alzheimer’s. This is in the newly created world, where a pathology test trumps clinical symptoms.
linkedin.com
Resolving the Biomarker-Clinical “Mismatch” in Alzheimer's Disease www.linkedin.com/pulse/resolv...
Resolving the Biomarker-Clinical “Mismatch” in Alzheimer's Disease
A recent JAMA Neurology paper assesses the extent to which a measure of the tau protein in plasma known as p-tau217, drives the severity of Alzheimer’s disease, as measured by the Clinical Dementia Ra...
linkedin.com
Antivirals treat active viral infections. Using HSV-1 IgG/IgM to enroll #Alzheimers patients does not mean the virus is actively driving dementia. Without viral replication, there is no target. Thus, placebo outperforming valacyclovir is unsurprising. jamanetwork.com/journals/jam...
Valacyclovir Treatment of Early Symptomatic Alzheimer Disease
This randomized clinical trial compares the efficacy and adverse effects of valacyclovir vs placebo in patients with early symptomatic Alzheimer disease and seropositivity to herpes simplex viruses.
jamanetwork.com
Can high LRRK2 kinase activity be compensatory in LRRK2-#Parkinsons? We collect evidence suggesting we may be undermining cellular restoration in ongoing kinase inhibitor trials (e.g., BIIB122) & outline precision-medicine strategies in G2019S LRRK2-PD www.sciencedirect.com/science/arti...
On why the α-Syn SAA test cannot inform on #Parkinsons severity, biology, risk, or prognosis. In this article, I reflect on why "seeding activity" extracted from "kinetic parameters" can never reflect disease activity. linkedin.com/pulse/why-la... via @linkedin.com
Why the latest test for Parkinson’s cannot be quantitative –only binary (yes/no)
The α-Synuclein Seed Amplification Assay (α-Syn SAA) In response to many biological exposures, monomeric (normal) α-synuclein transforms into fibrillar (abnormal) aggregates, which we call Lewy pathol...
linkedin.com
For decades, we have tried to suppress γ-secretase, lower Aβ42 levels, or remove amyloid from the brain. We show that PSEN1 mutations already reduce γ-secretase activity and lower Aβ42. Why restoring Aβ42 is the way forward for #Alzheimers, via @Brain1878 academic.oup.com/brain/articl...
Restoring amyloid-β42 and γ-secretase function in Alzheimer’s disease
Espay et al. challenge the view that Alzheimer’s disease is caused by increased gamma-secretase activity and overproduction of Aβ42. Instead, they suggest
academic.oup.com
Increasing synuclein pathology as a treatment for corticobasal syndrome? Facetious, yes ... but that’s one logical takeaway when learning that CBS patients positive for αSyn-SAA show milder disease, slower progression, and lower NfL. movementdisorders.onlinelibrary.wiley.com/doi/10.1002/...
A Biomarker‐Based Classification of Corticobasal Syndrome
Background Corticobasal syndrome (CBS) is a clinically defined syndrome with progressive movement and cortical dysfunction, caused by various underlying pathologies, most commonly tau-predominant pa...
movementdisorders.onlinelibrary.wiley.com