standaart 2016David Standaert, M.D., Ph.D., the John N. Whitaker Professor and chair of the UAB Department of NeurologThough the drug levodopa can dramatically improve Parkinson’s disease symptoms, within five years one-half of the patients using L-DOPA develop an irreversible condition — involuntary repetitive, rapid and jerky movements. This abnormal motor behavior appears only while taking L-DOPA, and it stops if the drug is stopped. However, if L-DOPA is taken again, even many months later, it quickly re-emerges.

In research to prevent this side effect and extend the usefulness of L-DOPA — which is the most effective drug treatment for Parkinson’s disease — University of Alabama at Birmingham researchers have uncovered an essential mechanism of this long-term memory for L-DOPA-induced-dyskinesia, or LID.

They report a widespread reorganization of DNA methylation — a process in which the function of DNA is modified — in brain cells caused by L-DOPA. They also found that treatments that increase or decrease DNA methylation can alter dyskinesia symptoms in an animal model.

Thus, modification of DNA methylation may be a novel therapeutic target to prevent or reverse LID behavior.

“L-DOPA is a very valuable treatment for Parkinson’s, but in many patients its use is limited by dyskinesia,” said David Standaert, M.D., Ph.D., the John N. Whitaker Professor and chair of the Department of Neurology at UAB. “Better means of preventing or reversing LID could greatly extend the use of L-DOPA without inducing intolerable side effects. The treatments we have used here, methionine supplementation or RG-108, are not practical for human use; but they point to the opportunity to develop methylation-based epigenetic therapeutics in Parkinson’s disease.”

The research by David Figge, Karen Eskow Jaunarajs, Ph.D., and corresponding author David Standaert, Center for Neurodegeneration and Experimental TherapeuticsUAB Department of Neurology, was recently published in The Journal of Neuroscience.

Research details

Although studies of LID in animal models have shown changes in gene expression and cell signaling, a key unanswered question still remained: Why is the neural sensitization seen in LID persistent when delivery of L-DOPA is transient?

The UAB researchers suspected DNA methylation changes — the attachment of a methyl group onto nucleotides in DNA — because methylation is known to stably alter gene expression in cells as they grow and differentiate. Furthermore, methylation changes in neurons have been shown to be involved during the formation of place memory and the development of addictive behavior after cocaine use.

In general, increased DNA methylation has a silencing effect on nearby gene expression, while removal of the methyl groups enhances gene expression.

Figge and colleagues found that:

  • L-DOPA treatment of parkinsonian rodents enhanced the expression of two DNA demethylases.
  • Cells in the dorsal striatum in the LID model showed extensive, location-specific changes in DNA methylation, mostly seen as demethylation.
  • The changes in DNA methylation were near many genes with established functional importance in LID.
  • Modulating global DNA methylation — either by injecting methionine to increase methylation or applying RG-108, an inhibitor of methylation, to the striatum — modified the dyskinetic behavior of LID, down or up, respectively.
“Together,” the researchers wrote, “these findings demonstrate that L-DOPA induces widespread changes to striatal DNA methylation and that these modifications are required for the development and maintenance of LID.”

Funding for this work came from the Alacare Mary Sue Beard Predoctoral Fellowship, the Jurenko family, the American Parkinson Disease Association, and National Institute of Neurological Disorders and Stroke grant F31NS090641.
Is Alzheimer’s contagious?

July 11, 2016

By Matt Windsor

What if Alzheimer’s disease is caused, at least in part, by infections? An intriguing study in Science Translational Medicine, from researchers at Harvard University, led to provocative speculation in the New York Times and other major news outlets this summer. “I got asked more questions about this paper than probably anything in the last couple of years,” says Erik Roberson, M.D., Ph.D., co-director of the UAB Center for Neurodegeneration and Experimental Therapeutics in the UAB School of Medicine, associate professor of neurology and neurobiology, and Virginia B. Spencer Scholar in Neuroscience at UAB. “It has gotten a lot of people thinking and talking and asking questions.”

First, Roberson says, a little backstory is in order. In 1906, when Dr. Alois Alzheimer reported the first case of the disease that made him famous, he described a mass of “plaques” and “tangles” in the brain of an afflicted patient, known as Auguste D. But it wasn’t until the 1980s, Roberson explains, that researchers discovered that the main component of those plaques was a protein fragment called amyloid beta; the tangles were made up of a protein called tau.

“The idea that amyloid beta is the main cause of Alzheimer’s disease, what’s known as the ‘amyloid hypothesis,’ has been the main driver in the field” ever since, Roberson says. “There’s lots of evidence that it is part of the disease. That led to lots of trials of drugs to reduce amyloid beta production and inhibitors of aggregation of amyloid beta, but none of those have gone particularly well.”

mix alz bact quote lg2

A new narrative for Alzheimer’s

There are many reasons why that may be the case, Roberson says. For instance, the drugs might not have been able to infiltrate the blood-brain barrier. “But there has been a camp that argues that maybe amyloid beta isn’t the problem,” he says. “Maybe it’s a good thing; part of the brain’s attempt to respond to what is really happening in Alzheimer’s disease.”

Erik RobersonErik RobersonThe Science Translational Medicine paper explores a correlate of that idea — demonstrating that amyloid beta has antibacterial effects. “The main message of the paper is that amyloid beta coats yeast and fungi to prevent them from growing,” says Roberson. That finding “feeds a bigger narrative that has been cropping up over the past year,” he adds: “that infections are the cause of Alzheimer’s disease.”

These wouldn’t need to be life-threatening attacks. The theory, Roberson says, is that “maybe even a mild infection, the kind that many of us are exposed to, could do it. In the course of fighting off that infection, the brain makes amyloid beta to seal the microbes off in plaques, and that ends up having toxic effects.”

This is a “completely different potential cause of Alzheimer’s disease that has not been high on the radar,” Roberson says. In March, a group of about 30 researchers published an editorial in the Journal of Alzheimer’s Disease that summarized the available evidence that microbes could be an Alzheimer’s trigger. “There has been a lot of indirect evidence,” Roberson says. “For example, people with Alzheimer’s disease are more likely to have antibodies against the herpes virus. But that’s not the same thing as proving that herpes is the cause.” Still, the March editorial “got discussion going in the field,” says Roberson, “and I think that is why this subsequent Science Translational Medicine paper attracted so much attention.”

“An interesting idea worthy of more study”

It is a “good paper,” Roberson says. “No one paper generally nails down a question in science; it needs to be reproduced and tried in different species, with different types of amyloid beta and other infectious agents, but this is a good start.” And it helps point to the broader question of the ultimate cause of Alzheimer’s disease, Roberson adds.

About 1 percent of people have a genetic mutation that leads to Alzheimer’s, and there are genes that are risk factors in others, “but we don’t really know what is the cause,” Roberson says. The contention that amyloid beta is actually an “antimicrobial peptide is an interesting idea worthy of more study,” but it will be difficult to replicate the research in humans, Roberson points out. “It’s fairly easy to look at this question in animal models, but not in humans. We can only study someone’s brain after they have died, at a much later stage of the disease.”

mix brain tangles

Investigating a promising therapy

Meanwhile, Roberson’s lab is pursuing another longstanding Alzheimer’s question: What is the relationship between amyloid and tau, the protein responsible for the tangles in Alzheimer’s disease? “If you make a mouse without tau, amyloid beta doesn’t have its toxic effects,” Roberson says. “They require the presence of tau to have a full effect. In people, there are questions about that interaction as well. The amyloid beta accumulates in a different part of the brain than the tau accumulates. So maybe you need both of those hits, or maybe one is causing or enabling the other. We still don’t know.”

While they study that very question, Roberson’s team is also moving forward with tests of a compound that blocks the interaction between tau and another protein, fyn, that is important in these processes of Alzheimer’s. “If you get rid of one or the other, it’s a good thing,” Roberson says. “That is easy in mice, but difficult in patients.” Working with drug chemistry experts at Southern Research, Roberson’s lab has found several compounds that could block the tau-fyn linkup. They are now sifting these “hits” to find the most appropriate candidate compounds, Roberson says. “If we can prevent them from interacting, we believe it will have a beneficial effect.”

laura volpicelliLaura A. Volpicelli-DaleyUsing a robust model for Parkinson’s disease, University of Alabama at Birmingham researchers and colleagues have discovered an interaction in neurons that contributes to Parkinson’s disease, and they have shown that drugs now under development may block the process.

The research team has shown that the most common genetic cause of Parkinson’s disease — a mutant LRRK2 kinase enzyme — contributes to the formation of inclusions in neurons, resembling one of the hallmark pathologies seen in Parkinson’s disease. These inclusions are made up of aggregated alpha synuclein protein, which — the research also shows — can be prevented from forming by using two LRRK2 kinase inhibitor drugs now being developed for clinical use.

The interaction between mutant LRRK2 kinase and alpha-synuclein “may uncover new mechanisms and targets for neuroprotection,” the researchers write in a recent Journal of Neuroscience paper. “These results demonstrate that alpha-synuclein inclusion formation in neurons can be blocked and that novel therapeutic compounds targeting this process by inhibiting LRRK2 kinase activity may slow progression of Parkinson’s disease-associated pathology.”

The potential clinical applications for novel neuroprotection strategies in LRRK2-linked Parkinson’s need to be tested in other preclinical models of Parkinson’s disease, say the researchers, led by corresponding author Laura A. Volpicelli-Daley, Ph.D., and senior author Andrew B. West, Ph.D., Center for Neurodegeneration and Experimental Therapeutics, UAB Department of Neurology.

“These data give us hope for the clinical potential of LRRK2 kinase inhibitors as effective therapies for Parkinson’s disease,” Volpicelli-Daley said. “The LRRK2 kinase inhibitors may inhibit the spread of pathologic alpha-synuclein, not only in patients with LRRK2 mutations, but in all Parkinson’s disease patients. Future studies to validate the safety and efficacy of the LRRK2 inhibitors will be necessary before testing the inhibitors in human clinical trials.”

Besides Parkinson’s disease, alpha-synuclein also plays a central role in development of dementia with Lewy bodies and multiple system atrophy, and it is associated with Alzheimer’s disease and other neurodegenerative disorders.

parkinsons andy westPrimary hippocampal neurons from mice expressing G2019S-LRRK2. The neurons were treated with alpha-synuclein fibrils, and 18 days later immunofluorescence was performed. The magenta shows phospho-alpha-synuclein inclusions in the cell bodies and throughout the axons, which are visualized as green.Research details

The Parkinson’s disease model developed by Volpicelli-Daley applies very low concentrations of pre-formed fibrils of alpha-synuclein to in vitro or in vivo neurons. This causes formation of modified alpha-synuclein inclusions that share morphology with those found in the Parkinson’s disease brain after death.

They used this model to test the effects of neuron expression of the mutant LRRK2 (“lark two”) kinase, G2019S-LRRK2, on the formation of the inclusion pathology.

They found that:

  • G2019S-LRRK2 enhanced alpha-synuclein inclusions in primary hippocampal neurons from the hippocampus region of the brain, 18 days after fibril exposure, as compared with neurons that over-expressed normal LRRK2.
  • The effects of G2019S-LRRK2 expression in the fibril-exposed neurons were lessened by very low concentrations of potent and selective preclinical drugs that inhibit LRRK2 kinase. This suggested that the kinase activity of G2019S-LRRK2, which adds a phosphate onto target proteins, underlies the faster formation of pathologic alpha-synuclein inclusions.
  • G2019S-LRRK2 expression enhanced alpha-synuclein inclusion formation in dopamine neurons from the region of the brain called the substantia nigra pars compacta. The substantia nigra pars compacta is the area of the brain that dies in Parkinson’s disease, so this experiment further supports a link between the G2019S-LRRK2 mutation and Parkinson’s pathogenesis.
As a control, they used anti-sense oligonucleotides to knock down the expression endogenous alpha-synuclein in neurons that expressed G2019S-LRRK2, and this prevented formation of inclusions.

andy westAndrew B. WestIn fluorescence-recovery-after-photobleaching experiments, they found there was a larger pool of mobile alpha-synuclein, as opposed to membrane-bound alpha-synuclein, in neurons that expressed G2019S-LRRK2. Recent work by others has shown that mobile alpha-synuclein is prone to misfolding and aggregation, so the researchers hypothesize that the G2019S-LRRK2 mutation may contribute to Parkinson’s susceptibility by boosting the amounts of mobile alpha-synuclein in neurons.

Besides Volpicelli-Daley and West, co-authors of the paper “G2019S-LRRK2 expression augments alpha-synuclein sequestration into inclusions in neurons” are Hisham Abdelmotilib, Zhiyong Liu, Lindsay Stoyka, João Paulo Lima Daher and Kyle Fraser, all of the Center for Neurodegeneration and Experimental Therapeutics, UAB Department of Neurology; Austen J. Milnerwood, Centre for Applied Neurogenetics, University of British Columbia; Vivek K. Unni, Jungers Center for Neurosciences Research and Parkinson Center of Oregon, Oregon Health & Science University; Warren D. Hirst, Pfizer Neuroscience and Pain Research Unit, Cambridge, Massachusetts; Zhenyu Yue, Departments of Neurology and Neuroscience, Icahn School of Medicine at Mount Sinai; Hien T. Zhao, Ionis Pharmaceuticals, Carlsbad, California; and Richard E. Kennedy, Comprehensive Center for Healthy Aging and Division of Gerontology, Geriatrics, and Palliative Care, UAB Department of Medicine.

Grants to fund this work came from the American Parkinson’s Disease Association, the Michael J. Fox Foundation LEAPS Award and the National Institutes of Health NS064934.

Volpicelli-Daley is an assistant professor in the Department of Neurology.

West is co-director of the Center for Neurodegeneration and Experimental Therapeutics, and the John A. and Ruth R. Jurenko Professor of Neurology at UAB.
Older adults are all too often easy targets for financial abuse, and those with Alzheimer’s disease and other cognitive disorders are especially vulnerable. To learn more about seniors’ financial skills, NIA-funded scientists are using brain scans to explore the regions and connectivity in the brain associated with the ability to manage money.

dollar signs of many colors inside aerial view of brainRecent studies used magnetic resonance imaging (MRI) to identify brain areas that might be associated with a reduced ability to handle financial affairs. The findings offer researchers new insights into changes in the aging brain that may be tied to faulty—and even risky—financial decisions.

“It’s the $18.1 trillion problem,” said Daniel Marson, J.D., Ph.D., professor of neurology at the University of Alabama at Birmingham, citing an estimate of household wealth (PDF, 6.8M) held by U.S. adults age 65 and older. “That money is at risk in part because of the cognitive disorders of aging.”

Older adults lose at least $2.9 billion per year to scams, fraud, theft, and other misdeeds, according to a 2011 MetLife study (PDF, 855K). A 2016 survey by Investor Protection Trust (PDF, 382K), a nonprofit devoted to investor education, shows that 17 percent of people age 65 or older have been taken advantage of financially.

To better understand how age- and Alzheimer’s-related changes in brain structure and function may influence behavior, learning, and decision making, including financial decisions, NIA-supported scientists are using brain imaging.

“Novel neuroimaging studies, along with studies involving cognitive measures, are providing intriguing data on why older adults—even those who were previously quite savvy about finances—may lose their money-managing abilities,” said Nina Silverberg, Ph.D., program director of the Alzheimer’s Disease Centers at NIA’s Division of Neuroscience.

She added, “These new insights add to our growing understanding of the basic biological changes involved in dementia onset and progression and inform our efforts to find effective interventions. These types of studies also help us learn more about the general cognitive changes associated with aging.”

Assessing financial capacity

Financial capacity is necessary for living independently. It encompasses relatively simple tasks, such as counting change and paying bills, and more complex activities, such as balancing a checkbook and making investment decisions. These tasks require cognitive functions that include math skills, memory, attention, executive function, and judgment.

Not surprisingly, people with Alzheimer’s disease and related dementias have poor financial capacity and may not be able to manage money on their own. In fact, trouble managing money is often an early sign of the disease. Like other functional skills, financial capacity is not lost all at once, but declines gradually as Alzheimer’s progresses and cognition—the ability to think, learn, and remember—erodes.

Scientists in recent years have studied older adults without dementia to identify and measure the brain’s role in various aspects of financial ability—and possibly to predict who may be on the path to reduced capacity. Results suggest that even cognitively normal older adults may be at risk for poor financial decision-making in some circumstances.

Researchers commonly use laboratory tasks, such as those that assess reward processing and risk taking, or neuropsychological measures such as the Financial Capacity Instrument (FCI) to assess decision-making abilities in older adults. The FCI tests abilities such as reading a bank statement, paying bills, and using financial judgment. Now researchers are using structural MRIs to look for brain areas that may be involved in diminished financial capacity, how these develop over time, and how they differ in older adults across the cognitive spectrum.

“Imaging is increasing the depth of our scientific understanding of the brain,” Dr. Marson said. “MRI helps us understand how changes in brain structure and connectivity drive downstream functional changes” in everyday life. For example, when a person has trouble reading a bank statement, an MRI may reveal aspects of brain structure associated with that specific trouble.

“Just as neuroimaging is used as a biomarker for early Alzheimer’s disease, one could imagine researchers using MRIs to develop biomarkers for impaired financial decision making,” said Duke Han, Ph.D., an associate professor of family medicine, neurology, and psychology at the University of Southern California, Los Angeles. “Ideally, scientists could find ways to strengthen the brain to keep seniors functioning better so they are less likely to become victims of financial abuse.”

Linking MRI results to financial capacity

two men looking at computer screenResearchers have used different types of MRI to see if brain structure, function, and connectivity relate to financial capacity. So far, no one brain region or activity stands out.

In one early study, Dr. Marson and colleagues found that older adults with mild cognitive impairment (MCI) performed worse than controls on cognitive tests and the FCI. Their performance was moderately associated with the volume of the angular gyrus, a brain structure involved in number processing, calculation, and other processes. Volume changes in the angular gyrus may predict financial-skill deficits in people with memory-related MCI, they concluded (Griffith et al., 2010).

In a follow-up study, Dr. Marson and his team found that reduced volume of the medial frontal cortex, a region of the brain involved in attention and cognitively demanding tasks, was associated with diminished FCI performance in people with mild Alzheimer's disease (Stoeckel et al., 2013). 

Building on these studies, a team at Rush University  Medical Center, Chicago, found that greater financial literacy—conceptual knowledge and numeracy abilities that may support financial capacity—was associated with greater functional connectivity between the posterior cingulate cortex and three other brain regions in older adults without dementia (Han et al., 2014). They used resting-state functional MRI, which shows functional connectivity between brain regions. The researchers could not discern whether better financial literacy strengthened these brain connections, or whether subjects with strong brain connections were somehow more financially literate than those with weaker connections.

In other research, the same team found that seniors without dementia who were susceptible to financial scams—as determined by a short questionnaire, not actual scams—had lower total gray-matter volume and less gray matter in the frontal and temporal lobes (Han et al., 2016). “Further research is needed to determine whether gray-matter reductions in these regions may be a biomarker for susceptibility to scams in old age,” the authors wrote.

What’s ahead?

Use of neuroimaging to better understand brain changes related to decline in financial capacity is a promising area of research. It is too soon to know whether and how such measures may be applied in a clinical setting, but researchers are eager to explore their potential.

“Can we develop a neuroscience of financial capacity? What are the brain regions and networks that support different kinds of financial skills?” asked Dr. Marson.

Dr. Han said he hopes new knowledge will help in efforts to better maintain and improve financial capacity with age and cognitive challenges, not just predict decline. Ultimately, interventions to strengthen or protect certain brain regions might provide much-needed support for functional skills such as financial decision making.


Griffith HR, et al. Magnetic resonance imaging volume of the angular gyri predicts financial skill deficits in people with amnestic cognitive impairment. Journal of the American Geriatrics Society 2010;58:265-274.

Han SD, et al. Financial literacy is associated with medial brain region functional connectivity in old age. Archives of Gerontology and Geriatrics 2014;59(2):429-438.

Han SD, et al. Grey matter correlates of susceptibility to scams in community-dwelling older adults. Brain Imaging and Behavior 2016;10(2):524-532.

Stoeckel LE, et al. MRI volume of the medial frontal cortex predicts financial capacity in patients with mild Alzheimer's disease. Brain Imaging and Behavior 2013;7(3):282-292.

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Page last updated: July 14, 2016