The loss of dopamine neurons in the substantia nigra is often cited as the defining tragedy of Parkinson’s. However, a newly released meta-analysis examining 60 years of post-mortem evidence across different regions of the brain in people living with PD —the most comprehensive study of its kind—reveals that this narrative may be misleading our attempts to help those in need.
Led by the Skene Lab at the UK Dementia Research Institute, researchers scoured the literature to identify specific patterns of cellular loss in Parkinson’s. The team evaluated 166 case-control post-mortem studies published between 1963 and 2025. Ultimately, they compared patient data against healthy controls across 145 distinct region-cell populations to see exactly where the biological wreckage occurs. The results suggest we may not have the evidence needed to back up our long held claims.
For one, the results revealed that locus coeruleus noradrenergic neurons degenerate at almost the same rate as dopamine neurons in the substantia nigra (“with both populations losing more than 60% of neurons”). These noradrenergic neurons are central regulators of alertness, attention, stress responses, and sleep-wake cycles, each known to be affected in people with PD. They also found significant loss of cholinergic neurons in the forebrain, cells linked to memory and cognition.
What’s more, despite decades of research we still don’t actually know if affected cells die. The vast majority of studies count markers (such as Tyrosine Hydroxylase (TH), melanin, or ChAT) rather than neurons themselves; meaning we cannot distinguish between a cell that has died and a cell that has turned off these identifying features. We have been counting the lights in the windows of a city, not the buildings themselves.
The study also attempted to stratify the data to look for differences between: Body-first vs. Brain-first progression, Genetic variants (LRRK2 vs. GBA) vs. Idiopathic cases, and disease duration and its impact on specific cell loss. Each attempt came up short, not because researchers weren’t diligent, but because the clinical data is too sparse to support the weight of these questions. (“Only 4 of 145 populations are adequately powered, and 82% of Allen Brain Atlas regions have never been quantified in Parkinson’s disease.”)
We are decades into the study of this disease, yet the raw data left behind by previous generations is too thin to build a bridge to personalized medicine. Going forward, we need to consider more than just the dopamine systems into studies of Parkinson’s if we want a more complete picture of this disease.
Finally, I want to commend the authors for doing something that should be standard for all such research. They simplified and translated their work into plain English and even created an interactive website with a great walkthrough for anyone who wants to better understand their work, click the image below to be redirected to that website. I am hopeful that more researchers will follow their lead going forward.
The Vulnerable Parkinson’s Brain
Thank you for sending out this important info.