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Alberto Espay

@albertoespay.bsky.social

1K followers 110 following 460 posts

Neurology professor at the University of Cincinnati, an advocate of precision and rescue medicines for Parkinson's & Alzheimer's. Author #BrainFables.

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Alberto Espay @albertoespay.bsky.social · Jun 27

How does physics inform neurodegeneration? Supersaturation lowers the nucleation barrier for the precipitation of monomeric proteins into their pathological state. In normal aging, replacement matches loss; in accelerated aging, it does not. (1/4)
onlinelibrary.wiley.com/doi/10.1002/...

Physics of Protein Aggregation in Normal and Accelerated Brain Aging

Soluble monomeric proteins precipitate via nucleation into insoluble amyloids in response to age-related exposures (e.g., microbes, nanoparticles). Persistent soluble-to-insoluble phase transition de....

onlinelibrary.wiley.com

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Alberto Espay @albertoespay.bsky.social · 3d

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

Alberto Espay @albertoespay.bsky.social · 7d

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.

Alberto Espay @albertoespay.bsky.social · 7d

That's my hope, Elaine.

Alberto Espay @albertoespay.bsky.social · 10d

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/...

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....

onlinelibrary.wiley.com

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Alberto Espay @albertoespay.bsky.social · 14d

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

Alberto Espay @albertoespay.bsky.social · 16d

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

Reposted by Alberto Espay

The Science of Parkinson's @scienceofpd.bsky.social · 18d

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/...

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

journals.sagepub.com

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Alberto Espay @albertoespay.bsky.social · 19d

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/...

Sage Journals: Discover world-class research

Subscription and open access journals from Sage, the world's leading independent academic publisher.

journals.sagepub.com

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Alberto Espay @albertoespay.bsky.social · Sep 5

(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...

Alberto Espay @albertoespay.bsky.social · Aug 28

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...

Alberto Espay @albertoespay.bsky.social · Sep 5

(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).

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Alberto Espay @albertoespay.bsky.social · Sep 5

(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).

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Alberto Espay @albertoespay.bsky.social · Sep 5

(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).

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Alberto Espay @albertoespay.bsky.social · Sep 5

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).

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Alberto Espay @albertoespay.bsky.social · Sep 3

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

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.

www.nature.com

Alberto Espay @albertoespay.bsky.social · Aug 30

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

Reposted by Alberto Espay

Alfonso Fasano @alfonsofasano.bsky.social · Jul 12

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

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Alberto Espay @albertoespay.bsky.social · Aug 28

(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!

Alberto Espay @albertoespay.bsky.social · Aug 28

(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.

Alberto Espay @albertoespay.bsky.social · Aug 28

(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.

Alberto Espay @albertoespay.bsky.social · Aug 28

(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.

Alberto Espay @albertoespay.bsky.social · Aug 28

(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.

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Alberto Espay @albertoespay.bsky.social · Aug 28

(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.).

Alberto Espay @albertoespay.bsky.social · Aug 28

(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).

Alberto Espay @albertoespay.bsky.social · Aug 28

(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).

Alberto Espay @albertoespay.bsky.social · Aug 28

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