Changes in the eye might predict onset of frontotemporal dementia
The researchers studied a group of individuals who had a certain genetic mutation that is known to result in FTD. They discovered that, before any cognitive signs of dementia were present, these individuals showed a significant thinning of the retina compared with people who did not have the gene mutation.
“This finding suggests that the retina acts as a type of window to the brain,” said Erik Roberson, M.D., Ph.D., associate professor in the Department of Neurology at UAB and a study co-author.
Roberson and Timothy Kraft, Ph.D., associate professor in the UAB Department of Vision Sciences, collaborated with the lead investigators, Li Gan, Ph.D., from Gladstone and Ari Green, M.D., associate professor of neurology at UCSF.
“Retinal degeneration was detectable in mutation carriers prior to the onset of cognitive symptoms, establishing retinal thinning as one of the earliest observable signs of familial FTD,” Gan said. “This means that retinal thinning could be an easily measured outcome for clinical trials.”
Although it is located in the eye, the retina is made up of neurons with direct connections to the brain. This means that studying the retina is one of the easiest and most accessible ways to examine and track changes in neurons.
This electroretinogram image shows photoreceptor activity from two mice. The gray line represents the animal model that has frontotemporal dementia, the black line is the control or healthy mouse. The large negative spike in the diagram indicates a reduction of ganglion cells in the retina of the mouse model that mirrors human dementia.Roberson’s laboratory has been studying an animal model for FTD. Using a process called ERG, or electroretinogram — similar to an EKG — Roberson and Kraft showed that the retinas in mice with FTD had a loss of ganglion cell function; these cells are responsible for transmitting signals from eye to brain. That data, along with additional ERG studies that Kraft performed in California, aligned well with comparable human studies conducted by Gladstone and UCSF.
“We have a more complete understanding about how the retina functions as opposed to the operations of the complex brain,” said Kraft. “That makes it much easier to use the retina as a tool for better understanding FTD.”
The researchers also discovered new mechanisms by which cell death occurs in FTD. As with most complex neurological disorders, there are several changes in the brain that contribute to the development of FTD. In the inherited form researched in the current study, this includes a deficiency of the protein progranulin, which is tied to the mislocalization of another crucial protein, TDP-43, from the nucleus of the cell out to the cytoplasm.
However, the relationship between neurodegeneration, progranulin and TDP-43 was previously unclear. Using the UAB mouse model of FTD, the scientists were able to investigate this connection for the first time in neurons from the retina. They identified a depletion of TDP-43 from the cell nuclei before any signs of neurodegeneration occurred, signifying that this loss may be a direct cause of the cell death associated with FTD.
TDP-43 levels were shown to be regulated by a third cellular protein called Ran. By increasing expression of Ran, the researchers were able to elevate TDP-43 levels in the nucleus of progranulin-deficient neurons and prevent their death.
“The results of this study have shown that we can use the thinning of retinal cells as a marker for this type of dementia,” said Roberson. “Further studies may also help determine whether the changes in the retina can be utilized as a marker of disease progression. We may also be able to use the retina as a means of gauging the effectiveness of new therapies.”
Researchers from the University of Texas Southwestern also collaborated on this study. It was funded by the Consortium for Frontotemporal Dementia Research, Bluefield Project to Cure FTD, National Institutes of Health, UCSF Resource Allocation Program, UCSF Alzheimer’s Disease Research Center, Chartrand Foundation and Clinical & Science Translational Institute, Howard Hughes Medical Institute, Alzheimer’s Association, Welch Foundation, and Alzheimer’s Drug Discovery Foundation
By: Bob Shephard
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UAB Specialties Gain Ground on U.S. News Ranking
UAB Specialties Gain Ground on U.S. News RankingU.S. News & World Report on July 15 released its 2014-2015 Best Hospitals list, and UAB Hospital continues to rank No. 1 in both Alabama and Birmingham.
Looking more deeply, eight specialties at UAB ranked nationally, including five that improved their classification from high-performing in 2013 to nationally ranked in 2014, meaning they placed among the top 50 facilities.
Those specialties and their 2014 ranks are:
- Diabetes & Endocrinology – No. 39 (up from high-performing in 2013)
- Ear, Nose & Throat – No. 46 (up from high-performing in 2013)
- Gynecology – No. 20 (up from high-performing in 2013)
- Neurology & Neurosurgery – No. 30 (up from high-performing in 2013)
- Orthopedics - No. 31 (up from high-performing in 2013)
- Rheumatology – No. 11 (unchanged from 2013)
- Nephrology – No. 26 (up from No. 46 in 2013)
- Urology – No. 28 (up from No. 36 in 2013)
- Cardiology & Heart Surgery
- Gastroenterology & GI Surgery
Details for all 2014-2015 Best Hospitals ranking can be accessed at health.usnews.com/best-hospitals.
A Parkinson's therapy makes its way through the "valley of death
|Andrew West is pursuing a compound to inhibit LRRK2, an enzyme that appears to be a central enabler of the brain cell death seen in Parkinson's disease.|
"The government is good at funding basic research to identify drug targets, and Big Pharma is good at taking drugs and putting them through clinical trials," says Andrew West, Ph.D., John A. and Ruth R. Jurenko Endowed Professor in Neurology at UAB. "But all of the in-between work, the pre-clinical and drug development components, is called the 'valley of death' for research, because nobody funds it, nobody pays attention to it. That's a big part of the lack of new drugs."
In fact, less than 10 percent of drugs that make it into preclinical testing will end up getting FDA approval, according to the agency's figures. But West is part of a new approach to the drug-discovery process designed to upend those odds: a partnership between UAB and Birmingham-based Southern Research Institute known as the Alabama Drug Discovery Alliance (ADDA).
The partnership is built around the strengths of each institution. UAB labs identify molecular targets that play a key role in disease. In West's case, that's the enzyme LRRK2 (pronounced "lark two"), which appears to be a central enabler of the brain cell death seen in Parkinson's disease.
Southern Research has decades of experience in drug discovery and testing. It employs a host of researchers who are adept at the chemical tweaking needed to make a drug work in humans. Southern Research scientists are also experts at proving a drug's safety and efficacy to the FDA and to large pharmaceutical companies. Big Pharma is often willing to step in and fund new drug projects—but only after they have demonstrated initial success.
Thanks to several years of work, "we're most of the way through the valley of death now," West says. "We have dozens of compounds that are fantastic drugs. We just have a little bit left to go—sometimes the last mile of the marathon can be the most painful."
On the MoveThis month, West's lab published a new study in the Proceedings of the National Academy of Sciences that suggests LRRK2 inhibitors could play a wide role in slowing the progression of Parkinson's disease, or even preventing it altogether.
"This is a critical first step showing that inhibition of LRRK2 may be beneficial to protect against the cell loss and degeneration that occurs in Parkinson's disease," says West. It's another sign that the team's approach is taking it in the right direction across the valley of death—and a welcome oasis to recharge their efforts.
|Robotic systems at Southern Research Institute allow UAB investigators such as Andrew West to screen hundreds of thousands of potential compounds to find the best candidates for new therapeutics.|
Screen TeamThe LRRK2 project's first step was high-throughput screening—using the advanced robotic testing machines at Southern Research to analyze hundreds of thousands of potential compounds and find candidates capable of slowing down LRRK2.
They emerged with hundreds of potential compounds. Further analysis has whittled that down to the best candidates. What makes a "drug great in a tissue culture dish may not be a great thing for a preclinical candidate," West says. "We want to know how well it crosses the blood-brain barrier, if it interacts with any other protein besides LRRK2, how fast it metabolizes, if it collects anywhere abnormally in the body, and if it causes toxicity."
Medicinal chemists at Southern Research specialize in taking promising chemicals and tweaking them to make them even better. "We make very small changes," says West. "We'll put a nitrogen here, a carbon there, and look at the effects in a hypothesis-driven way."
The collective knowledge of the Southern Research scientists is an extremely valuable resource, West emphasizes. "Most of the time you only see these people at big pharmaceutical companies. The relationship between UAB and Southern Research in the ADDA is unique. I haven't seen it built anywhere else in the country, where we get a high-throughput group, drug development group, and biologists sitting at the same table every two weeks discussing the issues."
Getting CloseIn the next few months, West's lab will evaluate each remaining compound in its animal models of Parkinson's disease. The best ones will then move into toxicology studies, "and hopefully next year we'll begin first-in-man studies," West says.
The team has already come very close. "We had a great candidate last year that passed all of the key measures," West says. "It went to the brain perfectly, had good potency, seemed to only interact with LRRK2, no side effects, no toxicity." But when the drug got to living models, "we discovered that the metabolism was way off the charts," says West. "It only survived 15-20 minutes in the body before it was destroyed by the liver. We were close—if we could just have slowed what the liver did by a little bit, we'd be in humans now. But it turns out that was not the right molecular scaffold."
The good news, says West, is that "we have two or three other series that are getting to that same point now." Even more important, he says, "we have a clear pipeline to go to a phase 1 clinical trial," the first evaluation of a potential new drug in humans.
Strong Local SupportIt's important to note that these advances have been accelerated significantly "through local philanthropic support," says West. "There are many people in this area who are disappointed to see that the government doesn't fund a lot of research into Parkinson's disease cures. I think patients are frustrated. You get a diagnosis of Parkinson's disease and there is nothing you can do to stop it. The best advance we have, L-dopa, was developed 50 years ago. There’s really been no breakthrough like that since."
But West is convinced that is about to change. "As soon as I found during post-doctoral work in 2006 that all mutations we know about that cause Parkinson's disease increase LRRK2 activity, the next step in my career was finding somewhere I could do something about that," he says. "And the only place I found in the country was Birmingham, so I moved here immediately."
Now, eight years later, the end may be in sight. "We have to take these drugs to the next level and make them suitable for use in humans," West says. "It's a formidable trek, but I think we have some really good compounds, and more important, the right people that will get us there."