Parkinson's and Alzheimer's: The solution in sight | Dr. Alberto Espay | TEDxWrigleyville
The speaker, a neurologist studying neurodegenerative diseases, argues that the focus on removing abnormal proteins as the source of disease is flawed because normal proteins are more critical, suggesting future therapies should focus on increasing the levels of normal proteins to restore brain function regardless of protein clumps. He details how diagnosis relies on observation and how current anti-protein therapies have failed, citing data that shows protein reduction correlates with further decline in patients. The most promising intervention involves elevating normal protein levels to a functional threshold, offering a pathway toward individualized "rescue medicine."
## Speakers & Context
- Unnamed neurologist who specializes in diseases of brain proteins.
- Diagnoses conditions like Parkinson's or Alzheimer's by observing physical symptoms:
* Parkinson's: slow movement, tremor in one hand, shuffling feet while walking.
* Diagnosis relies on applying criteria developed by expert forebears; cannot be proven without a biopsy or autopsy.
- The field faces a challenge in establishing diagnosis and building trust in clinical recommendations.
## Theses & Positions
- The narrative surrounding neurodegenerative diseases must shift: the problem may not be the abnormal proteins, but the lack of normal proteins.
- Normal proteins are inherently soluble and flexible, allowing them to perform critical functions throughout the brain.
- The process of protein change is universal across all neurodegenerative diseases.
- The core function of proteins is that they only operate when they are in a normal, soluble state; clumping renders them non-functional.
- The paradox in the field is that successful removal of abnormal proteins has not led to recovery; in fact, some trials showed worsening with reduction.
- The most promising approach is not to remove the villains, but to increase the levels of normal proteins in the brain to a certain threshold, allowing the brain to operate normally even if abnormal proteins are present.
## Concepts & Definitions
- **Proteinopathies:** Diseases caused by abnormal proteins.
- **Solubility:** The ability of normal proteins to dissolve in water, allowing quantification via spinal tap.
- **Protein Transformation:** The process where normal, soluble proteins clump into compact, insoluble structures.
- **Protein Aggregation:** The accumulation of these abnormal protein clumps.
- **Rescue Medicine:** An individualized approach aiming to raise the levels of normal proteins to restore brain function, irrespective of existing protein clumps.
- **Syndrome vs. Disease:** The speaker cautions that treating conditions should be viewed as a syndrome, not a definitive disease, due to diagnostic limitations.
## Mechanisms & Processes
- **Diagnosis (Historical):** Early 1900s neuroleptologists used microscopes on post-mortem brain tissue to find abnormal protein clumps, assuming these clumps were the *cause* of degeneration.
- **Normal Protein Function:** Critical for brain structure and maintaining neuronal communication; genes coding for these proteins are preserved since prehistoric genomes.
- **Pathogenesis (Current Theory):** When encountering a foreign element (like a virus), normal soluble proteins transform, clumping into structures (like amyloids) that are "too compact so tight that they are almost impossible to be toxic."
- **Milk Analogy:** Soluble-to-insoluble phase transformation (like milk curdling) illustrates that once aggregated, the structure cannot return to its original functional state.
- **Therapeutic Goal:** Shifting from *removal* (clearing clumps) to *elevation* (increasing normal proteins).
## Timeline & Sequence
- **Early 1900s:** Beginning of the current diagnostic narrative, using microscopes to find abnormal proteins in deceased patients.
- **Past Two Decades:** Testing anti-protein treatments for amyloid, synuclein, and Tau proteins.
- **Recent Findings:** Studies on 600 people with known amyloid levels via PET scans revealed that individual status (normal vs. demented) correlated with normal protein levels, not just amyloid load.
## Named Entities
- **Parkinson's disease, Alzheimer's:** Examples of neurodegenerative diseases.
- **Amyloid, Synuclein, Tau:** Specific types of proteins implicated in neurodegeneration.
## Numbers & Data
- Number of abnormal proteins studied: **Proteinopathies**.
- Number of trials testing amyloid clearance: **Over 40 trials**.
- Number of interventions tested: **Approximately 20 interventions**.
- Number of trials showing no benefit: **75** (reduction in amyloid did not lead to recovery).
- Number of people studied in the latest research: **600 people**.
- Correlation finding: When normal protein levels are high, the individual remains normal, regardless of the amount of abnormal protein found.
## Examples & Cases
- **Diagnosis via observation:** Assessing movement (slow, tremor, shuffling) or speech patterns.
- **Clinical Failure Example:** In 40 of the amyloid trials, patients in the experimental arm with the greatest amyloid reduction showed worsening and further brain shrinkage.
- **The Milk Analogy:** Leaving milk outside the refrigerator demonstrates soluble-to-insoluble phase transformation; curd cannot become milk again.
## Counterarguments & Caveats
- The initial narrative wrongly assumed that the abnormal protein clumps were the necessary and sufficient cause of the disease.
- The idea that removing the toxic element will restore health is flawed, as evidenced by clinical trials and the concept of necessary background proteins.
## Conclusions & Recommendations
- The focus must shift from *removing* aggregated proteins to *increasing* the functional levels of normal proteins in the brain.
- Precision medicine should aim to elevate normal protein levels to a threshold where the brain can function normally, even if the underlying cause is not yet fully understood.
- This approach, termed "rescue medicine," allows for proactive restoration of lost neural function.
## Implications & Consequences
- If the normal protein threshold can be reached, the mechanism preventing the pathogenic clumping can be restored, making the process reversible or manageable.
- The ability to measure the normal protein level provides a metric for treatment efficacy beyond mere aggregation reduction.
## Verbatim Moments
- *"It holds our attention and it galvanizes us it gains a common enemy."*
- *"It may be that it is not about how much of these villains we have these abnormal proteins but rather how feel the normal proteins we have left."*
- *"I do it by asking questions and observing patients."*
- *"The part of the narrative that began at that point was in assuming that what they had encountered was the cause of the problem."*
- *"The solubility of it allows us to quantify in the liquid that surrounds the brain and we can measure that through a spinal tap."*
- *"proteins are only able to function when they are normal when they are in this soluble functional state."*
- *"if they are the villains somehow then our brains should return to normal and people should get back to state of normalcy."*
- *"if we are able to bring the brain the levels of these normal proteins to elevate the levels to normal then it won't matter if we don't yet know what that is now."*