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by Andrew Schwartz
It’s gut-wrenching to witness someone you love change personality. Patients who suffer from cognitive disorders, such as Alzheimer’s disease and frontotemporal dementia, may lose their memories or social skills; some lose their ability to speak, swallow or move. All eventually die from their disease. And as of yet, there are no effective therapies for most of them.
This agony has researchers at the UCSF Memory and Aging Center (MAC) determined to find cures – or at least therapies that can slow the progression of these diseases.
“This is a huge public health crisis,” said Adam Boxer, MD, PhD, who directs the Alzheimer’s Disease and Frontotemporal Dementia Clinical Trials Program at the MAC. “With many Baby Boomers reaching the age where developing neurodegenerative diseases become common, we urgently need to find effective therapies – now.”
“Now” is precisely the idea behind the new Sandler Neurosciences Center at Mission Bay, which gathers under one roof the MAC’s clinicians and basic scientists, along with many other neurologists and neuroscientists from around UCSF. In a building designed to foster collaborative research among these neuroscience experts, there is revived hope that now is the time for progress to accelerate toward more effective therapies.
Historically, such progress has been slow. Physicians and scientists have struggled to map connections between cognitive loss and the imaging and lab studies that examine the myriad of cellular interactions in brain tissue. When researchers think they understand an important factor, they might test potential therapies in animals, and if they are effective, in animal brains. The researchers then test whether the same target can be reached in human brains.
But because animals don’t speak, tracking the parallel behavioral and cognitive changes between humans and animals is especially challenging, creating an enormous hurdle, made much more complicated when research takes place in disparate locations around a university, a city, a country and the world.
In contrast, at Sandler, clinicians see patients on the first floor and can immediately run samples to labs in the same building, allowing researchers who develop therapies or diagnostic tests to see if their ideas work and understand the reasons why or why not. Similarly, researchers on the top floor – including Nobel Prize winner Stanley Prusiner, MD, who discovered prions, one of the main factors in many neurodegenerative disorders – can use high throughput screening to develop therapies safe enough for patients in clinical trials.
“This streamlines multiple steps and allows a more efficient translation,” said Bruce Miller, MD, the MAC’s director.
Michael Geschwind, MD, PhD, is a neurologist who treats patients with and conducts research on rapidly progressive dementia (RPD), which is often initiated by other neurological disorders, including immunological disorders and neurodegenerative diseases, such as prion disease.
Geschwind is collaborating with Stephen DeArmond, MD, PhD, at the Institute for Neurodegenerative Diseases to map the abnormal areas on brain MRIs of his former patients, while comparing these scans to the pattern of disease in tissue acquired from their brains. The goal is to understand the mechanisms and cellular processes underlying the disease and, ultimately, to use that knowledge for therapy.
“The difference here is I can walk right upstairs, look at the tissue under the microscope, and…begin to understand the pathologies causing the abnormalities,” said Geschwind. “This shortens a process that once took several weeks to just a few days.”
Another example: when RPD is a result of immunological disorders, it can potentially be reversed – though it takes considerable experience and expertise to make the proper diagnosis. Geschwind and his colleague neuroimmunologist Jeffrey Gelfand, MD, both see patients in clinic and collaborate with basic science researchers at Sandler to better identify and characterize what's causing immunological-based RPD.
Such collaborations do more than speed the process from bedside to bench and back again; they also offer the potential for new thinking. Because many of these diseases appear to be related, a breakthrough in one area could theoretically open the door to many others.
For example, mutations in the progranulin molecule have been identified as one of the genetic causes of some frontotemporal dementias. Decreased levels of progranulin also may be an important regulator of brain inflammation, which could influence the onset and course of some forms of Alzheimer’s disease, as well as other neurological disorders.
Adam Boxer is involved with a UCSF-based research consortium that has identified novel progranulin-focused therapies for frontotemporal dementia which they hope will lead to human clinical trials in the next year. They speculate it is easier to demonstrate a drug’s effectiveness in patients with frontotemporal dementia than in Alzheimer’s, because people with frontotemporal dementia tend to have fewer complicating pathologies and thus less excess “noise” that can mask the benefits of an effective drug.
In just the first few months since the building has opened, such “cross-pollination” opportunities have emerged with startling frequency, according to many MAC researchers. Aimee Kao, MD, PhD – who among her many research pursuits also examines progranulin – offers another example.
Recently, she was walking by the lab of William Seeley, MD, whose research on frontotemporal dementias earned him a 2011MacArthur Fellowship, commonly known as a “genius grant.”
Seeley was conducting an autopsy on a frontotemporal dementia patient with a progranulin mutation. The man’s brain atrophy pattern was clearly more pronounced in certain areas than in patients who lack the mutation. Seeley and Kao began speculating about how to connect observations in humans to those in a model organism. Kao said that given the dozens of potential neurons she and others might study for the effect of a progranulin mutation in animals, that conversation could streamline her choices to neurons similar to those affected in patients.
“We need to know we’re making the right analogies as we move promising therapeutic ideas into human trials,” said Kao.
Getting the analogies right is another factor critical to speeding discovery, because it improves the odds of investing in therapies with genuine promise, rather than wasting time on false hope.
“In the Alzheimer’s world, for example, over the past decade there were billions spent on failed drugs and clinical trials,” said Boxer. “In retrospect, many researchers have realized that one frequent problem was that studies failed to demonstrate ‘proof of concept,’ where we validate that the biological effect of a drug in animal models also takes place in human patients.”
To do these studies, researchers need access to advanced technology that can reliably demonstrate how the proposed therapies might affect, for example, a protein known to be an important cause of memory loss. Imaging modalities like PET or MRI, or new types of human physiology tests, such as retinal thickness, eye movement and cerebrospinal fluid measurements all can play a role. “These have been the missing links in many failed programs, and they are what we’re bringing together here,” said Boxer.
Seeley believes that access to both technology and a critical mass of knowledge can be unusually powerful. He describes how in his frontotemporal dementia research, one of the biggest challenges is access to healthy brain tissue that can help researchers better understand areas of the brain affected by the disease. When a colleague in the Center for Integrated Neuroscience completed a neurosurgical operation on an epilepsy patient, Seeley and his team leapt at the chance to examine the tissue, spending from dusk to dawn in the Sandler Center. When they needed a better instrument, they found a junior researcher who helped them examine the tissue with a sophisticated microscope.
“We were seeing things during that week that no one has ever seen before,” said Seeley, who is now involved in multiple collaborations with people within MAC and with other neuroscientists.
“I think it teaches me the most to work with people who have a different set of eyes and head full of other ideas,” he said. “Here, there are new opportunities and collaborations coming into my world just about every two weeks. If it goes any faster, I'll have to put a lock on my door.”
Those who envisioned the Sandler Center could not be more pleased. “We want this to be a place that is open, collaborative, imaginative and where the focus on patients and their diseases is evident,” said Miller.
“It’s helped us think about things, not just from a clinical perspective, but also from immunological, imaging, and basic science perspectives, so we can attack diseases and problems in a more multidisciplinary fashion,” said Geschwind. “It makes me much more optimistic about being able to help my patients.”
For the teams of clinicians, scientists, patients and families weary of human tragedy, such optimism kindles the realistic hope they’ve been waiting to feel for a very long time.