With your extra risk of Parkinsons post stroke; DOES YOUR DOCTOR HAVE EXACT PREVENTION PROTOCOLS? NO? So, your doctor is incompetent?
Parkinson’s Disease May Have Link to Stroke March 2017
Over 8 years and nothing was done about preventing Parkinsons; there is NO excuse for such fucking incompetence!
Like, just maybe something in here? Oh, your doctor is so incompetent s/he doesn't know any of this stuff?
The latest here:
New Imaging Tech Spots Hidden Protein Predicting Parkinson’s Disease
Researchers have been chasing the causes of Parkinson’s disease for more than a century, yet its hallmark feature — microscopic protein clumps called Lewy bodies — remains enigmatic: Patients with just a few Lewy bodies can be devastatingly ill, while others with neurons packed full of them sometimes show milder symptoms.
Another culprit has emerged. Nanoscale protein assemblies called alpha-synuclein oligomers had been hiding in plain sight, too small to detect with conventional microscopy. A group of researchers can now look more closely at oligomers — literally — because they developed a way to see them in postmortem brain tissue for the first time. They detail the discovery in a recent paper published in Nature Biomedical Engineering.
When the team captured their first clear images, the reaction was immediate.
“We said, wow, isn’t this fantastic,” said Steven Lee, PhD, a microscopy specialist at the University of Cambridge in Cambridge, England, and co-lead author of the study. “We can see these small clumps; they have all different sizes, and they appear to be everywhere.”
It had been a long road. Despite extensive in vitro data suggesting oligomers existed, many researchers remained skeptical that they were actually present in the brain.
Lee recalls Professor Sir John Hardy, FRS, an eventual co-author on the study and a geneticist who’d been working on Parkinson’s his whole career, standing up at an internal funder conference for the Aligning Science Across Parkinson’s initiative. “He said, ‘We have been looking for [these] oligomers for 30 years, and we haven’t found them.’”
By that point, Lee’s team had already been working on imaging. He chimed in. “I said, ‘I think the reason you haven’t is not biological; it’s technological.’”
Seeing Stars in Daylight
Lewy bodies don’t appear out of nowhere — they are an end product of a progressive assembly line.
The process starts when single misfolded units of the alpha-synuclein protein begin sticking together, forming tiny intermediate clumps, acting like bridges between solitary proteins and the massive fibrils that eventually become Lewy bodies.
In countless experiments across cell cultures and animal models, researchers demonstrated that these small, soluble oligomers kill neurons with ruthless efficiency, while their larger cousins — the fully formed Lewy bodies — leave cells relatively unharmed.
This disease-associated subpopulation of alpha-synuclein oligomers is much more common than the Lewy bodies traditionally used to diagnose Parkinson’s, making them the faint stars of a hidden galaxy of Parkinson’s pathology, while the Lewy bodies were merely the handful of planets visible to the naked eye.
The challenge in visualizing them, Lee explained, wasn’t building a more powerful microscope. It was more fundamental than that.
“If you look up at the blue sky, you know that starlight is there, right?” he said. “You can’t see stars in the daytime because the Rayleigh scatter — the blue sky — raises the background to a point where they’re invisible. The same thing is true in brain tissue.”
Human brains are, to put it technically, extremely messy at the molecular level. Tissue autofluorescence — the natural glow from cellular components like lipids and other biological matter under laser light — creates a high background intensity, or “noise floor,” that obscures faint signals. The oligomers, being nanoscale, can only bind to a few of the fluorescent antibodies that scientists use to tag and visualize them under a microscope, making their signal incredibly dim. It’s like trying to spot a candle flame during a firework show.
The solution, which the team calls Advanced Sensing of Aggregates-Parkinson’s Disease, involved a two-part strategy analogous to stargazing: Make the background “night sky” in the brain darker and use a more powerful microscope to capture the lighter, toxic aggregates in the foreground.
The research team used Sudan Black B, a fat-soluble dye, to quench much of this obfuscating autofluorescence. An optimized 10-minute incubation with the dye suppressed an incredible 93% of the tissue’s background glow, effectively switching off the lights and turning day into night.
That wasn’t enough. To achieve the sensitivity to detect the faint light from the oligomers, the team used a high numerical aperture objective lens, a piece of advanced optics typically used for imaging single molecules. A higher numerical aperture allows the microscope to gather light from a much wider angle, dramatically increasing the signal collected from the sample.
The combination dropped the noise floor low enough that the oligomers, faint as they were, finally became visible.
The Twist: Alpha-Synuclein Oligomers in Healthy Brains
What started as a 5-year project sometimes involved the team working around the clock to collect images in the lab of Sonia Gandhi, BMBCh, PhD, professor of neurology at the University College London, London, England, and co-lead author of the study. This eventually generated 12,028 high-resolution images and a dataset of 1.2 million individual protein aggregates, all of which are now online for researchers to search through. For their next paper, currently in review, the dataset was even bigger, equivalent to 6 months of continuous imaging, 24 hours a day, capturing 4.5 billion aggregates.
Science at this scale requires a certain obsessiveness.
“We always ask ourselves if what we see could be due to random chance,” explained Lucien Weiss, PhD, associate professor of engineering physics at Polytechnique Montreal, Montreal, Canada, and co-lead author of the study. “In this project, once we knew more about what to look for, we asked if the same signatures show up using other methods.”
The team reran experiments with different methods and compared adjacent tissue slices, compared different reagents, and even sourced samples from a different brain bank. “Because we image many oligomers across many samples to get significant numbers," Weiss said, “we started to see really strong reproducibility.”
The findings broke down into three key discoveries, and the first one was a surprise. Yes, Parkinson’s brains were loaded with nanoscale alpha-synuclein assemblies — hundreds per cell. But so were healthy control brains.
“They’re there in healthy controls as well, which is really surprising and interesting,” Lee said. “We hadn’t quite expected that.” This wasn’t noise or artifact. The assemblies were there, reliably, in people who’d never had a tremor in their lives. But why do they turn toxic?
The second finding provided a clue. When the computational analysis parsed through the brightness distributions — a proxy for size — a distinct subpopulation emerged in the Parkinson’s samples. These assemblies were brighter, larger, and had chemical properties suggesting structural differences. They resisted enzymatic breakdown and showed “seed competence,” meaning they may act as a template to trigger a chain reaction, causing healthy proteins to misfold and join the unhealthy clump. And they clustered around neurons, astrocytes, and microglia in patterns never seen in healthy tissue.
The numbers were stark: These disease-specific assemblies made up about 10% of all oligomers in Parkinson’s brains but only 0.26% in healthy control brains.
Why Every Drug Has Failed
The implications ripple outward in uncomfortable directions. Said Lee, “So far, all attempts to develop disease-targeting drugs in Parkinson’s disease have failed. This tells us the standard model for drug discovery simply doesn’t work.”
Going forward, Lee’s team will use automated microscopy to screen drug libraries from a Japanese pharmaceutical company, testing whether compounds can disassemble, prevent, or accelerate the formation of the toxic alpha-synuclein oligomeric aggregates. He argued previous drug trials failed because they measured the average behavior of all proteins in the brain, most of which aren’t in this problematic oligomeric state.
There’s another problem, and it’s arguably worse. “There’s a massive misdiagnosis rate, about 20% both ways,” Lee revealed. Parkinson’s is diagnosed clinically, but the only definitive diagnosis comes from a postmortem brain biopsy. So roughly 1 in 5 patients enrolled in clinical trials doesn’t actually have Parkinson’s disease.
“You have to wait for them to pass away, check the brain, and go, ‘Oh, he didn’t have Parkinson’s, he had PSP [progressive supranuclear palsy],’” said Lee. “And all that data you’ve been collecting is difficult to make meaningful conclusions from.”
Meanwhile, they’re also working to detect these assemblies in living patients — in cerebrospinal fluid, blood, and even saliva. Early data suggest it’s possible. “We’ve shown there’s an increased aggregate load in cerebrospinal fluid of people with Parkinson’s,” Lee said. “We didn’t know whether they were present in the brain at that time. Now we know.”
This matters for two reasons. Firstly, a test that detects disease-specific oligomers could identify Parkinson’s before symptoms appear, when neurons are still salvageable. Secondly, clinical trials could track whether treatments reduce oligomer levels rather than waiting years to see if symptoms slow.
The Cure Question
On whether Parkinson’s could be cured in our lifetime, Weiss was cautious, pointing to the practical challenges of treating a disease of aging. “You don’t start treating someone until you have a reason to treat them. For people who have a genetic predisposition, you have a chance to intervene and do something about it and prolong the good years. But can it be cured forever? I’m not sure when you would know to start giving treatments to someone that may or may not develop the disease.”
Lee, however, was adamant. “I respectfully disagree completely, 100%,” he said. “Things that historically seemed incredibly difficult have been chipped at by incremental developments. It’s complex and difficult, but it’s not unsolvable.”
Funding will certainly play a part. This research itself was only possible because of funding by Aligning Science Across Parkinson’s, a philanthropic initiative supported by Sergey Brin, co-founder of Google, who has committed nearly half a billion dollars to Parkinson’s research. “We’re extremely lucky to be involved with a fantastic initiative,” Lee said.
Weiss added, “I get excited about solving challenges. We’re motivated by the idea that, if this works, we’re able to understand something that we couldn’t before. Ultimately, that knowledge grows and goes back into helping our communities. The public investment in science and understanding diseases is a long-term effort, but it’s really the best way we know of to solve these very complex problems. You have to put in this legwork now to solve the problem down the road.”
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