Alberto Espay

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...

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/...

Beyond Pathology: α‐Synuclein Homeostasis and Three Principles to Guide Research Click on the article title to read more.

Proposing three principles to guide #Parkinson research:
1. Quantify monomeric & pathological α-synuclein
2. Prioritize human evidence over animal models
3. Use clinical trials to test hypotheses, not just molecules
@ajlees.bsky.social
movementdisorders.onlinelibrary.wiley.com/doi/10.1002/...

Future models will hopefully stop misleading about “timed gained” with anti-amyloid monoclonal antibodies.

Yes. The biophysical framework is better at distinguishing between normal and accelerated aging than the clinicopathologic framework. In normal aging, there is plenty of pathology 'accumulation'. Degeneration may only happen when the precipitation of monomeric peptides exceeds their replacement.

That's my hope, Elaine.

Clinical and MRI Correlates of β‐Amyloid Load Inconsistent With Its Presumed Neurotoxicity in Cognitively Healthy Ageing At low levels, β-amyloid—a protein commonly present in brains of patients with Alzheimer's disease – appears to actually support overall tissue integrity, blood flow, brain function and cognitive abi....

Can #Alzheimers happen when β-amyloid protection fails? This is one conclusion drawn by the authors of a new Human Connectome Project study, which shows that higher β-amyloid load is associated with better cognition, fitness, tissue integrity & perfusion.
onlinelibrary.wiley.com/doi/10.1111/...

I have submitted it for publication as a viewpoint, but will be thinking of other strategies too.

Thank you, Emilia. So far, the reaction is relatively subdued. I am unsure how far this view on the open-label extension has gotten.

‘Pathology is disease’ Parkinson's mythology: The ‘brain-first-body-first’ case study - Alberto J. Espay, Andrew J. Lees, 2025

Remember kids: "Pathology does not mean disease. Most individuals with pathology will never have disease"

Wonderful letter from @albertoespay.bsky.social
"In the reality we inhabit, we have made Lewy pathology not just a marker of PD, but its very maker!
journals.sagepub.com/doi/10.1177/...

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We neurologists fall in love with our hypotheses: they never die. The latest: Depending on where Lewy pathology is first found, one of 2 #Parkinsons types exists. @ajlees and I explain the newest inconsistency in this “brain-first/body-first” hypothesis.
journals.sagepub.com/doi/10.1177/...

(5/5) Bottom line: The 40% ‘slower decline’ holds only if we compare the results to a historic cohort (link to earlier post below). But compared to the model, patients decline 40% faster than anticipated. We expected larger benefits, but they instead shrink rapidly.
bsky.app/profile/albe...

(4/9) Why does lecanemab look better? It is compared to a steeper-than-modeled slope from ADNI. Whereas the newly modeled decline is 0.05/mo ((1.5-0.6)/18), the observed decline is 0.07/mo ((1.8-0.5)/18), which means an actual 40% acceleration of decline ((0.07-0.05)/0.05)* 100).

(3/9) 2025 𝐥𝐞𝐜𝐚𝐧𝐞𝐦𝐚𝐛 𝐝𝐚𝐭𝐚: At 18 months (0.8-0.5 = 0.3) and 36 months (2.0-1.8 = 0.2), lecanemab slowed the CDR-SB decline by 37.5% vs placebo in the first period (0.3 / 0.8) \* 100). That difference narrowed to 10% in the second (0.2 / 2.0) \* 100).

(2/9) 2024 𝐬𝐢𝐦𝐮𝐥𝐚𝐭𝐢𝐨𝐧: At 18 months (0.8-0.6 = 0.2) and 36 months (2.0-1.5 = 0.5), lecanemab 𝐬𝐥𝐨𝐰𝐞𝐝 𝐭𝐡𝐞 𝐂𝐃𝐑-𝐒𝐁 𝐝𝐞𝐜𝐥𝐢𝐧𝐞 by 25% vs placebo at both timepoints (0.2 / 0.8) \* 100) & (0.5 / 2.0) \* 100).

Remember the “time saved” modeling for #Alzheimers infusions introduced a year ago? Extrapolating the observed curves, patients would increase their months ‘saved’ to 7.5. The #lecanemab data have shattered the optimistic model prediction—Details on this discrepancy follow (🧵1 of 5).

A mind-reading brain implant that comes with password protection A brain–computer interface decodes in near-real time the imagined speech of people who have difficulty enunciating words.

Losing your mind by forgetting 𝘵𝘩𝘦 password
www.nature.com/articles/d41...

Those are not included, making the slope of treatment look better than it actually is.

15 years (and 12 editions) later, here we are again for our annual 4-day intensive course on the diagnosis and treatment of #movementdisorders.

This year we're in charming Milan, hosted by the conference centre of Humanitas University.

More info here: www.mdscourse.com

(9/9) Bottom line: The illusion of ‘increasing benefit’ driven by survivor bias and historical comparisons masks the accelerated decline on treatment. Open-label extension data are incompatible with disease modification. Clinicians, patients, and policymakers beware!

(8/9) All caveats aside, the steepening (worsening) of the slopes of decline for lecanemab and donanemab suggests that patients deteriorate more rapidly the longer they are on treatment, a pattern inconsistent with an increasing therapeutic effect.

(7/9) Add the survivor bias: By the end of the OLE, only 56% of patients remained on lecanemab, 53% on donanemab. The disproportionate influence of better-tolerating, slower-progressing participants enriching the open-label extension skews the mean CDR-SB changes.

(6/9) Comparing the extrapolated slope of the placebo arm vs the observed donanemab arm, the CDR-SB difference favoring donanemab shrinks from 0.6 at 18 months to 0.3 at 36 months. Versus the ADNI slope used for lecanemab there would be no difference. This ADNI slope is steeper.

(5/9) Comparing the extrapolated slope of the placebo arm vs the observed lecanemab arm, the CDR-SB difference favoring lecanemab does not expand but shrinks: from 0.5 at the end of the double-blind period to 0.2 at month 48 of the open-label extension.

(4/9) So why do the curves shown at AAIC look like the gap widens over time? Because instead of a concurrent placebo group, results were compared to an 𝗲𝘅𝘁𝗲𝗿𝗻𝗮𝗹 𝗵𝗶𝘀𝘁𝗼𝗿𝗶𝗰𝗮𝗹 𝗰𝗼𝗵𝗼𝗿𝘁 (ADNI)—a method riddled with bias (inclusion criteria, dropout rates, etc.).

(3/9) Donanemab: In the 18 double-blind months, the CDR-SB score lowers by 1.6 (vs. 2.2 in placebo); in the subsequent 18 open-label months, the CDR-SB lowers 2.5 (4.1-1.6) –a 𝟱𝟲% 𝗳𝗮𝘀𝘁𝗲𝗿 𝗱𝗲𝗰𝗹𝗶𝗻𝗲 (2.5 -1.6 /1.6 * 100).

(2/9) Lecanemab: In the 18 double-blind months, the CDR-SB score lowers (worsens) by 1.2 (vs. 1.7 in placebo); in the subsequent 18 open-label months, the CDR-SB lowers by 1.8 (3 -1.2) –a 𝟱𝟬% 𝗳𝗮𝘀𝘁𝗲𝗿 𝗱𝗲𝗰𝗹𝗶𝗻𝗲 (1.8 -1.2 /1.2 * 100).

In #Alzheimers news: “4 years on #lecanemab, the benefit tripled” … “3 years on #donanemab, the benefit doubled”, as summed by @Alzforum from #AAIC25 reported data. How the graphical illusion hides the acceleration of cognitive decline (9-part thread).
www.alzforum.org/news/confere...

Amylyx halted the ORION trial in #PSP: no benefit from AMX0035 (sodium phenylbutyrate + taurursodiol).

The question: a false negative trial (inadequate drug) or a true negative (protein aggregation + mitochondrial dysfunction not driving PSP)?

investors.amylyx.com/news-release...

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

"These findings suggest that restoring, not reducing, γ-secretase activity & monomeric Aβ42 levels above a compensation threshold could offer disease-modifying therapeutic benefits"; More data from @albertoespay.bsky.social & colleagues
academic.oup.com/brain/advanc...

Some scholars have become so preoccupied with turning reality into definitions that they have totally lost sight of what Parkinson’s disease and Alzheimer’s disease actually are.
They are so fixated with galaxies they can no longer see the stars