Aging In Arizona, Part 4: Consortium, Brain Bank Make Arizona Center For Research
More Arizonans are living longer because medical advances in heart disease, cancer and diabetes keep their bodies going. But what about their brains? In our five-part series, Aging In Arizona, we explore what researchers are learning about the aging brain, the risks of developing dementia and latest treatments for it.
Arizona is a major player in Alzheimer’s disease research thanks in part to statewide collaboration among different institutions. But what also is advancing research is access to some of the freshest brain tissue on the planet.
Converging at University of Arizona’s College of Medicine in downtown Phoenix, researchers from ten Arizona institutions recently gathered for the annual Arizona Alzheimer's Consortium. Dr. Eric Reiman is director of the Arizona Alzheimer's Consortium.
“So Alzheimer’s is an unacceptable problem,” said Reiman. “With a growing number of people living to older ages, this one age-related disorder is projected to take a financially overwhelming toll on countries around the world by the time today’s 35-year-olds become senior citizens.”
Reiman is reviewing research posters with students and professionals standing next to them. Soon, presentations of work done by universities, hospitals and independent groups will begin.
“And we’re betting that some of these treatments may have a particularly profound benefit if started in healthy individuals before the disease has significantly ravage the brain,” Reiman said.
Reiman said he’s hopeful a new standard of Alzheimer’s patient and family care will be established in the next five years.
“And we think we have a fighting chance to find and support the approval of effective prevention therapies by 2025," Reiman said. "Just a few years ago, there was no chance that we would have an effective therapy by that point. And we’re pleased that Arizona has played a leadership role in the advancement of prevention therapies.”
One of the projects include detecting and tracking pre-existing plaque in the brains of adults with Down syndrome, who now live longer and have an even higher chance of developing dementia. Another is mindcrowd.org, a 10 minute, 20-question memory test from the Translational Genomics Research Institute (TGen). Led by Dr. Matthew Huentelman, the 3-year-old project has been taken by more than 65,000 participants with a goal of 1 million individuals.
“We really are using this approach to better understand the aging brain, how the brain ages differently amongst even healthy individuals, so trying to understand the genetic drivers of the differences in how our memory performs," said Huentelman. "But also our lifestyle choices and how that impacts how our memory performs.”
It’s already the largest memory study ever performed. Huentelman said the researchers will collect small finger-prick blood samples via mail to analyze their DNA. And although DNA information will give some insight to participants, it doesn't provide a complete picture.
“There are two other major important molecules that we care about, RNA, which is a sister chemical to DNA, and proteins, both of those change minute to minute, hour to hour, day to day — and that’s where we can’t get a glimpse into your brain by studying something else," Huentelman said. "We have to actually study the brain.”
Which is possible at the Brain and Body Donation Program at Banner Sun Health Research Institute in Sun City, northwest of Phoenix.
Brian Browne, a spokesman for the program, explained what brain atrophy looks like using a sample abnormal brain.
“This is the left hemisphere of a brain," said Browne. "The brain should be nice and tightly packed like this, the gyri like this. But take a look at the temporal and frontal lobe where you see widespread atrophy here where you’re seeing everything pull away I can stick my fingers between the gyri. So this is one of the tell-tale signs that there’s some stuff going on here."
And it's finding donors that may be showing signs of Alzheimer’s or Parkinson’s that are of interest to the Brain and Body Donation Program along with normal brains from other cadavers. Browne said there is currently a two-year waiting list for normal brains, which serve as the researchers control group. But patients who are exhibiting an active processing of Alzheimer's, Parkinson's or brain cancer are immediately accepted.
Browne said what makes the program stand out is the average time of three hours between a donor’s death and an autopsy, compared to other similar centers where 12 to 24 hours is the norm. This makes the lab highly sought after for the fresh brain tissue. Extracting a brain from a cadaver takes about two to three hours. A full body autopsy takes a bit longer.
“It is like an orchestra in here when we’re doing autopsies," said Browne. "And we’re able to ascertain what we need to do and recover the tissue of both brain and full body. And then we go into the process of one, do the gross examination and note-take every aspect of what we see. And then secondly, we start processing the tissue immediately.”
At the lab is a stand with several slots, resembling an oversized metallic bagel slicer.
“Then we section the brain here," Browne said. "Because, a lot of the areas of the brain we’re interested in are in the interior portion of the brain. And then we prepare them to be frozen or fixed depending on what we’re going to be doing with the brain.”
This step is critical. With every hour that passes, tissue concentration and the presence of RNA, which serves as a tissue quality indicator molecule, diminishes.
Dr. Thomas Beach, director of Brain and Body Donation Program, said to preserve tissue quality, it must be frozen just hours after death. That makes is it the closest to live tissue researchers can study with chemical reactions frozen in place. If not frozen, the brain sample will be placed in formaldehyde for future examination under a microscope.
Down the hall from the morgue is a room full of brains in small containers filled with formaldehyde at room temperature. The brains are organized based on condition. Next to that room are freezers set at -112 degrees Fahrenheit.
“In order to look at molecules, we need to freeze tissue and then analyze it biochemically where we can look at thousands of proteins, all the messenger RNA at once, and we can sort out which of those chemical reactions involved was disturbed very early in the disease,” said Beach."
It is these chemical reactions that start to form the physical alterations in the brain, some of which are natural. Beach said vascular tissue in the brain, which carries blood, steadily breaks down causing mini-strokes mostly unnoticed but that can gradually build over time. This and other changes are some of the physical indicators Beach looks for to find brain disease.
“Alzheimer’s is marked in the brain by microscopic lesions called plaques and tangles," Beach said. "Every single older person has got tangles in a restricted part of the brain by age seventy, so that’s the constant in aging.”
In Alzheimer's patients, the rate of these lesions spreading through the cerebral cortex, or outer layer of the brain, can double every five years. Beach said another constant is loss of brain mass. Natural aging of both male and female means brains can lose nearly 20 percent of their weight.
“If we do statistical analysis of the aging brain, and we use brain atrophy as the outcome, we know that the aging brain shrinks a lot from age fifty to age ninety,” said Beach.
And Beach would much rather have participants and future brain or body donors sign up when healthy. He said the sooner the better, but since Sun City is primarily a retirement community, Beach said volunteers with at least 10 years of projected life left are ideal to gather critical information.
“And see us once a year," said Beach. "We assess their neuropsychological, cognitive abilities, how they move, their coordination of the brain and muscles, and how all of that declines gradually with age and merges in some people into Parkinson’s and Alzheimer’s disease.”
The volunteers get to decide whether to donate just their brain or their whole body. Beach said the majority of patients elect to donate their whole body, which is critical to investigate how other organs and bodily systems both impact and are impacted by brain disease or just normal aging. While many organs have shown to be at different levels of health when compared to the brain, Beach said there is a constant.
“The major relationship between the brain and the body is the heart," said Beach. "So we know from studies where people have been followed middle age into old age that if you have risk factors for cardiovascular disease in middle age, you’re at higher risk of dementia in old age.”
Back at TGen, Huentelman said that early-onset Alzheimer's is relatively easy to detect genetically and can be diagnosed with certainty, but that it only affects less than three percent of Alzheimer's patients. The vast majority are late-onset patients, where the disease takes a long time to develop.
“Alzheimer's disease is a disorder that takes many decades to onset with the memory loss problems," Huentelman said. "So there are molecular changes happening in that Alzheimer’s disease patient’s brain for one, maybe two decades before they show up at their doctor’s office with memory complaints.”
Huentelman noted there are current drug therapies for Alzheimer's, but since many people don’t report concerns until memory problems arise, it may be too late as plaques and tangles are too developed. He said these drugs may be strong enough as is, but early detection techniques need to catch signs of the disease earlier, which his mindcrowd.org project may help with on a larger population scale. Until then, Huentelman suggested what to do in the meantime.
“Part of keeping your brain healthy is making sure you use your brain," said Huentelman. "We do know it’s important to get out and socialize and use your brain whenever you can. I mean, this is also just fun. It’s part of being a human being and navigating your world and solving problems. We get enjoyment from that and we should continue that throughout our life.”