Cracking the Code

Cracking the Code

How physiologists are advancing science in neurodegenerative diseases.
By Dara Chadwick

Neurodegenerative diseases have long been a scientific puzzle. What causes these conditions and how can we cure them?

The term includes disorders that cause progressive functional loss and death in neural cells, leading to nervous system dysfunction. Of the more than 600 known neurologic disorders, neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS) and other motor neuron diseases are estimated to affect nearly 7 million people collectively in the U.S.

 

Meredith Hay, PhD, FAPS, professor of physiology at the University of Arizona in Tucson, spent much of her career studying high blood pressure. About a decade ago, she began to study age-related cognitive impairment and how memory changes as we age.

Hay’s research interests came together in a personal way. “My mother suffered from undiagnosed heart failure following chemotherapy for breast cancer,” she says. “She developed significant cognitive impairment and, ultimately, vascular dementia. I knew then that we had to find a way for cardiovascular experts to connect with neuroscientists to help patients.”

Hay says about 70% of people older than 65 have hypertension, diabetes or cardiovascular disease. “The question has always been, what’s the impact of those diseases on our cognitive function?” she says.

There’s much that researchers don’t yet know about neurodegenerative diseases. But we do know that our risk of developing these conditions increases with age. With the Pew Research Center projecting more than 80 million U.S. residents age 65 and older by 2050, we also know that time is of the essence for this work.

Finding the common denominators

One difficult challenge in neurodegenerative disease research is the vast number of unknowns. Bringing scientists together is key to making progress, Hay says.

“Whether it’s clinical science or basic science, our disciplines are deep, but not broad,” she says. “Rarely does a patient have just one disease, and often one disease will impact another. Getting people to think outside their silos is one of the big challenges in science. It will require multiple disciplines to achieve the breakthroughs we’re looking for.”

In studying vascular dementia, Hay looks at the role of brain inflammation and reactive oxygen generation in neurodegenerative disease development. “Reactive oxygen is one of the early signals of too much inflammation,” she says. “It’s damaging to tissues and causes cytokine release. One of our therapeutic targets is decreasing reactive oxygen in endothelial cells and in the brain, which will decrease some of the brain inflammation that results in cognitive impairment.”

Most neurodegenerative diseases, including Alzheimer’s, Parkinson’s and some Lewy body diseases, have both an inflammatory component and a vascular component, Hay notes.

“Different neurodegenerative diseases come from different etiologies,” she says. “We want to find those common denominators across different diseases, whether that’s inflammation, vascular changes or blood flow changes. There’s not going to be one gene you can tweak to cure the disease because there are so many factors that affect prevalence.”

Common denominators are also a research focus for Ana Takakura, PhD, associate professor in the Department of Pharmacology at the Institute of Biomedical Sciences at the University of São Paulo in Brazil. She explores links between respiration and neurodegenerative disease using an animal model to induce Parkinson’s in mice and rats to study changes in neurons associated with respiratory rhythms.

Takakura has observed a reduction in the number of neurons in the pre-Botzinger complex, the region of the brainstem in mammals that controls inspiration (inhalation). She has also seen a reduction in neurons in the ventral aspect of the brain stem, where central chemosensors help the brain detect increases in carbon dioxide. “If you have an increase in CO2, neurons send information to increase ventilation and remove excess CO2 from the body,” she says.

In Parkinson’s disease, neurodegeneration in the substantia nigra—the brain’s dopamine-producing region—is associated with the disease’s classic motor symptoms. While the substantia nigra is not close to brain regions that control respiration, Takakura’s research shows that neural degeneration and breathing are linked, she says.

In her lab, researchers induce neuron death in the substantia nigra and record breathing changes. Rats show observable respiratory changes in about 40 days while mice show changes at about 10 days. “It’s clear that we first have degeneration of the substantia nigra and then we have degeneration of the neurons that control breathing and, consequently, physiological changes,” she says.

In her model and in Parkinson’s disease, there is a decrease in the number of neurons in the substantia nigra. “The question is, can these neurons of the substantia nigra send direct projections to the regions that control breathing?” she says. With fewer neurons, there are fewer projections, so the two regions no longer communicate. “This could be responsible for neurodegeneration in the respiratory regions.”

Respiratory changes in Parkinson’s are usually associated with pneumonia and obstructive sleep apnea, often seen as disease advances. But Takakura sees common denominators between neural degeneration in the substantia nigra and in regions that control respiration happening earlier in the disease’s progression. She’s optimistic that pharmacological intervention can halt respiratory changes.

“We’ve tried pharmacological approaches to reduce oxidative stress and neuroinflammation,” she says. “We start treatment in a phase of our experimental model where we already have degeneration of the substantia nigra, so it’s like Parkinson’s has already started. We already have the physiopathology of the disease. We start our treatment, and it is able to impair the neurodegeneration and respiratory changes.”

Takakura acknowledges that her research is experimental. “It’s not patients,” she says. “We are talking about pharmacological treatments that can have side effects. But usually, people that study neural control of breathing study physiological states not associated with pathology. People that study Parkinson’s disease study cognitive symptoms or dysautonomia that can appear before classical symptoms. Respiratory changes are interesting because they can be related to the morbidity and mortality of the disease.” 

Determining research focus

With so many neurodegenerative diseases, how do physiologists decide where to focus their research efforts? 

“A part of my job I love is that I get a bird’s-eye view of what’s going on in the field,” says Jonathan Hollander, PhD, program director in the Genes, Environment and Health Branch at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina. He manages a research portfolio exploring how environment affects neurological diseases and disorders. While he helps applicants think about their ideas from the early stage through review, “it’s up to the researcher to present why what they’ve proposed to study is important in its potential impact on human health.”

Multiple factors can affect what research is funded by the National Institutes of Health (NIH), including the rigorous peer review process, Hollander says. He also points out that although Congress typically funds NIH programs and operations through annual appropriations, in some instances, Congress can set money aside to study a particular disease, such as Alzheimer’s. “Currently, there is a bypass budget of several million dollars set aside to accelerate Alzheimer’s disease and related dementias research.

“In the context of neurodegenerative disease, we know that the aging population is dramatically going to increase. We know the prevalence of neurodegenerative diseases is going to go up. Certainly, that is a driver of a decision for potential targeted funds for a disease area.”

Jonathan Hollander, PhD

“In the context of neurodegenerative disease, we know that the aging population is dramatically going to increase,” he says. “We know the prevalence of neurodegenerative diseases is going to go up. Certainly, that is a driver of a decision for potential targeted funds for a disease area.”

Hollander encourages physiologists to think big when putting together research proposals. Projects with a strong scientific premise in a particular area may be right for “high risk, high reward” applications in which preliminary data aren’t required. This funding differs from traditional R01 grants, where there may be larger amounts of money but preliminary data are expected, he says.

Neurodegenerative disease research has entered an exciting time, according to Hollander. “There is a lot to understand about genetic and nongenetic risk factors in these diseases,” he says. “Think about an area like Parkinson’s disease where there is a long prodromal phase. Before motor symptoms begin, you might have nonmotor symptoms that could happen decades earlier. This may be a critical window of opportunity for the most effective intervention and prevention strategies.”

Hollander also notes growing interest in biomarkers of neurodegenerative disease. “There’s research looking at exosomes and their role as an early indicator of disease,” he says. “Another area I’m excited about is emerging chemicals research. We have a portfolio of investigators looking at things like pesticides, metal exposure and air pollutants and how they might impact health, but there are so many new emerging chemicals that we know so little about. What environmental exposures can be avoided that might prevent or reduce the risk of disease?”

The common denominators between different neurodegenerative diseases—and between neurodegenerative diseases and other health conditions—remain a strong focus. 

“We think of these as exclusively brain diseases, but there is a growing interest in areas outside the brain that might be affected before we get to brain pathology,” Hollander says. As an example, he cites changes in the gut that could be early indicators of neurodegenerative disease.

Evolutions in treatment

Curing neurodegenerative diseases remains elusive. But emerging therapies that treat symptoms provide hope for many people. Dennis Turner, MD, professor of neurosurgery at Duke University in Durham, North Carolina, is a neurosurgeon who treats tremor and Parkinson’s disease with deep brain stimulation (DBS). 

During his career, he has seen an evolution in thinking around treatments for Parkinson’s. In the mid-1990s, glia-derived neurotrophic factor (GDNF) looked to be a promising treatment in monkey models of Parkinson’s disease. Also studied were embryonic cell transplants, with preliminary data from two large multi-center randomized trials that looked promising.

“By 2005, the field had cleared because the cell transplant trials were negative and it’s very hard to get embryonic cells,” Turner says. “The initial GDF trials caused side effects, and by 2015, all the gene therapy trials with GDNF and similar molecules had not worked well. The only thing left of all the ideas from the 1990s is deep brain stimulation. And it works fabulously well in Parkinson’s.”

In Parkinson’s disease, dopamine is missing. “All the attempts like GDF, standard medical treatment we do now and many of the gene therapies were all focused on enhancing dopamine,” he says. DBS doesn’t involve dopamine; instead, it resets the brain’s circuitry so cells no longer need dopamine and patients don’t need medication.

Potential treatments for other neurodegenerative diseases have generated interest, according to Hollander. “In Alzheimer’s disease, several monoclonal antibodies are undergoing clinical trials,” he says. “While there’s been controversy around aducanumab, there are other therapies in development that show promise in trying to reduce beta-amyloid in the brain. There is controversy about whether that ultimately leads to increased cognitive ability. Can we stop the progression by reducing beta-amyloid in the brain with these drugs?”

Minimal cognitive impairment (MCI) is a predecessor to Alzheimer’s disease, and people with MCI have more plaques that people who are aging normally, Turner says. “Patients with MCI have had enough brain damage that brain metabolism has dropped. Poor metabolism doesn’t cause neurodegenerative disease but can make it worse,” he adds. Starting treatment early in neurodegenerative disease may help keep symptoms from progressing, according to Turner. 

That’s a research goal for Hay. She’s the founder, president and CEO of ProNeurogen, a company working to develop a drug to decrease brain inflammation and reactive oxygen and protect the brain from neurodegeneration. “We’ve taken angiotensin-(1-7), a natural anti-inflammatory peptide in our bodies, and added glucose to it,” she says. “Our drug, PNA5, has a better half-life and has brain penetration.”

Hay encourages physiologists to think outside their own expertise. “We forget that it’s all interconnected,” she says. “But I’m optimistic. I think within the next 10 years, we’ll have some treatments that will help our cognitive lifespan match our physical lifespan. That’s what we all want—healthy cognitive function throughout our lifespan.” 

 

This article was originally published in the May 2023 issue of The Physiologist Magazine.