parkison's

Is Parkinson’s an Autoimmune Disease?

This is a new, and likely controversial, idea in Parkinson’s disease; but if true, it could lead to new ways to prevent neuronal death in Parkinson’s that resemble treatments for autoimmune diseases,” said the study’s senior author, David Sulzer, PhD, professor of neurobiology in the departments of psychiatry, neurology, and pharmacology at Columbia University College of Physicians & Surgeons.

The new hypothesis about Parkinson’s emerges from other findings in the study that overturn a deep-seated assumption about neurons and the immune system.

For decades, neurobiologists have thought that neurons are protected from attacks from the immune system, in part, because they do not display antigens on their cell surfaces. Most cells, if infected by virus or bacteria, will display bits of the microbe (antigens) on their outer surface. When the immune system recognizes the foreign antigens, T cells attack and kill the cells. Because scientists thought that neurons did not display antigens, they also thought that the neurons were exempt from T-cell attacks.

“That idea made sense because, except in rare circumstances, our brains cannot make new neurons to replenish ones killed by the immune system,” Dr. Sulzer says. “But, unexpectedly, we found that some types of neurons can display antigens.”

Cells display antigens with special proteins called MHCs. Using postmortem brain tissue donated to the Columbia Brain Bank by healthy donors, Dr. Sulzer and his postdoc Carolina Cebrián, PhD, first noticed—to their surprise—that MHC-1 proteins were present in two types of neurons. These two types of neurons—one of which is dopamine neurons in a brain region called the substantia nigra—degenerate during Parkinson’s disease.

To see if living neurons use MHC-1 to display antigens (and not for some other purpose), Drs. Sulzer and Cebrián conducted in vitro experiments with mouse neurons and human neurons created from embryonic stem cells. The studies showed that under certain circumstances—including conditions known to occur in Parkinson’s—the neurons use MHC-1 to display antigens. Among the different types of neurons tested, the two types affected in Parkinson’s were far more responsive than other neurons to signals that triggered antigen display.

The researchers then confirmed that T cells recognized and attacked neurons displaying specific antigens.

The results raise the possibility that Parkinson’s is partly an autoimmune disease, Dr. Sulzer says, but more research is needed to confirm the idea.

“Right now, we’ve showed that certain neurons display antigens and that T cells can recognize these antigens and kill neurons,” Dr. Sulzer says, “but we still need to determine whether this is actually happening in people. We need to show that there are certain T cells in Parkinson’s patients that can attack their neurons.”

If the immune system does kill neurons in Parkinson’s disease, Dr. Sulzer cautions that it is not the only thing going awry in the disease. “This idea may explain the final step,” he says. “We don’t know if preventing the death of neurons at this point will leave people with sick cells and no change in their symptoms, or not.”

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Neurodegeneration’s Spread

Aggregates of the Huntington’s disease-associated protein, huntingtin, can spread among neurons, according to a study published last month  in Nature Neuroscience, giving credence, experts suggest, to the idea that the propagation of mutant proteins may be a unifying feature of neurodegenerative diseases.

Huntington’s disease, a progressive neurodegenerative disorder that impairs both movement and cognition, is caused by dominant mutations in the huntingtin gene that lead to abnormally long stretches of the amino acid glutamine in the huntingtin protein. These proteins tend to clump in affected neurons, although whether the aggregates are a cause of neurodegeneration or perhaps some kind of cellular response to the mutant protein is still a matter of debate.

The huntingtin gene is expressed throughout the nervous system, so it is hard to tell whether huntingtin aggregates originate within the cells in which they are observed.

To answer this question, researchers from the Novartis Institutes for Biomedical Research in Basel, Switzerland, and their academic colleagues introduced neurons with the wild-type huntingtin gene into mutant brain tissue—both in cell culture and in a mouse model. After several weeks, they observed that aggregates of mutant huntingtin protein had appeared in the wild-type neurons, indicating that the protein from the mutant neurons had spread.

“This paper reports for the first time that mutant huntingtin can spread between neurons,” lead author F. Paolo Di Giorgio, who studies Huntington’s and other neurodegenerative diseases at the Novartis Institutes, told The Scientist.

Neurodegenerative diseases including Parkinson’s, Alzheimer’s, amyotrophic lateral sclerosis (ALS), and frontotemporal lobar degeneration have been shown to involve the propagation of aggregate pathology from cell to cell. Evidence is mounting that neurodegenerative diseases share mechanisms with prion diseases—exemplified by mad cow disease and its human counterpart, Creutzfeldt-Jakob disease, in which misfolded, deleterious proteins propagate over long distances and cause other molecules to misfold.

“This is the first time that diseases involving what are called polyglutamine-expanded proteins have been found to involve a process of transneuronal propagation,” said Albert La Spada, who studies neurodegenerative disease at the University of California, San Diego, School of Medicine and penned a companion article about the study but was not involved in the work. Polyglutamine expansion is a feature of eight neurodegenerative diseases, including Huntington’s, La Spada said. “That’s significant because it extends the scope of this mechanism more broadly across potentially all neurodegenerative diseases. That’s what makes this study particularly exciting.”

To see if huntingtin aggregates could propagate, the researchers first grew human embryonic stem cells alongside brain slices from either mice with a Huntington’s-like disease or wild-type mice. The stem cells differentiated into neurons and formed connections with the mutant neurons of the brain slices.  By six weeks of this co-culture, the introduced wild-type neurons exhibited mutant huntingtin aggregates. They also had shorter and fewer appendages than did neurons co-cultured with wild-type brain slices. Further, introduced neurons that exhibited huntingtin aggregates had significantly narrower cell bodies and fewer projections than those that did not.

“Cells that bear these aggregates show abnormal pathology that is more pronounced [with] respect to cells that don’t bear the aggregates,” said Di Giorgio, “so it seems that when the neurons uptake mutant huntingtin—wild-type neurons that don’t carry any mutation—they will start to show signs of cellular atrophy.”

Huntington’s disease typically begins in the striatum, a brain region involved in movement control, and progresses to the cortex. To examine the way Huntington’s disease might affect this neuronal pathway, the researchers co-cultured striatal and cortical brain slices from wild-type and mutant mice. They found that when mutant cortical neurons and wild-type striatal brain slices were cultured together, functional neuronal connections formed between the brain slices, and mutant huntingtin spread to the wild-type neurons.

When researchers tried the reverse approach—linking mutant striatum and wild-type cortex—the two regions did not form neuronal connections, suggesting that mutant huntingtin within the striatum could disrupt corticostriatal connections.

To explore the corticostriatal pathway in vivo, the researchers used a virus to introduce the polyglutamine-repeat-encoding part of the huntingtin gene into the cortical neurons of wild-type mice. The neurons that were infected with the virus developed aggregates as expected, as did the striatal neurons with which the infected cells made connections.

Finally, in order to probe the mechanism of mutant huntingtin spreading, the researchers returned to their original experimental setup—co-cultures of wild-type human neurons and mutant mouse brain slices—and inhibited the synaptic vesicle pathway using botulinum toxin. Blocking the synaptic transmission reduced the spread of the huntingtin aggregates.  

Taken together, these results lend support to the idea that Huntington’s disease shares features with other neurodegenerative diseases, and with prion diseases.

“If neurodegenerative diseases have a unifying feature,” neurobehavioral geneticist X. William Yang from the University of California, Los Angeles, told The Scientist in an e-mail, “then understand[ing] the mechanisms or developing therapies against such common features may have more general implications/utility for all such disorders.” 

“If spreading occurs and drives disease progression, then blocking the spreading process could be a viable treatment approach,” added La Spada. “If the spreading process occurs extracellularly … then immunizing patients against a disease protein could be explored as a therapy.”

Neutron Beams Reveal How Two Potential Pieces of Parkinson’s Puzzle Fit

To understand diseases like Parkinson’s, the tiniest of puzzles may hold big answers. That’s why a team including scientists from the National Institute of Standards and Technology (NIST) have determined* how two potentially key pieces of the Parkinson’s puzzle fit together, in an effort to reveal how the still poorly understood illness develops and affects its victims.

This puzzle is a tough one because its pieces are not only microscopic but three-dimensional, and can even change shape. The pieces are protein molecules whose lengthy names are abbreviated as GCase and α-syn. The two proteins wrap around each other and take on a complicated shape before attaching themselves to the membrane surface inside a neural cell in a victim’s brain.

While much remains unknown about Parkinson’s, clues abound that the proteins’ behavior is somehow important. Parkinson’s victims have a buildup of α-syn in their cells, a possible factor in the dementia that the disease often brings. They also are far more likely to have a mutation in the gene that instructs cells to create GCase. Low levels of GCase cause another disease, Gaucher, and in some individuals suffering from both Parkinson’s and Gaucher simultaneously, Parkinson’s may appear at a younger age.

To get a better handle on how these proteins operate in the body, the team—which also included scientists from the National Institutes of Health (NIH) and Carnegie Mellon University—came to the NIST Center for Neutron Research (NCNR) to get a picture of how the two proteins combine into a single unit called a complex that interacts with cell membranes. Using techniques including neutron reflectometry, the team teased out the first-ever structural picture of the GCase/α-syn complex, including their shape change, which NIH’s Jennifer Lee says would not have been detectable by any other methods.

“It gives us a potential interaction model of the two and structural insights in how α-syn may interfere with activity on a cell membrane,” Lee says. “An equally important contribution here is that this is the first, I believe, to look at complex formation at the membrane interface using neutron science.”

The study still leaves many mysteries about the complex—notably how it attaches to and interacts with the membrane inside a part of the cell called the lysosome where α-syn is broken-down. The team plans to follow up with additional investigations, especially once an improved reflectometer that could offer greater resolution arrives at the NCNR in about 2017. Meanwhile, the results of the current study—and the tools that provided them—will give the team other options to explore.

“It lays the groundwork for exploring the complex relationship between proteins that are involved in the causes of disease,” Lee says. “This will also offer a way for us to investigate other substances that would affect the interaction.”

Image: The proteins GCase (in pink) and α-syn (blue) forms a complex in cellular membrane. Neutron reflectometry (suggested by the yellow beam) revealed the structure of the complex. α-Syn shifts GCase slightly away from membrane, possibly contributing to effects related to Parkinson’s disease.Credit: Alan Hoofring/NIH Medical Arts

Improper protein digestion in neurons identified as a cause of familial Parkinson’s.

Findings point to potential targets for preventing or treating the neurodegenerative disease

Researchers at Columbia University Medical Center (CUMC), with collaborators at the Albert Einstein College of Medicine of Yeshiva University, have discovered how the most common genetic mutations in familial Parkinson’s disease damage brain cells. The mutations block an intracellular system that normally prevents a protein called alpha-synuclein from reaching toxic levels in dopamine-producing neurons. The findings suggest that interventions aimed at enhancing this digestive system, or preventing its disruption, may prove valuable in the prevention or treatment of Parkinson’s. The study was published March 3 in the online edition of the journal Nature Neuroscience.

Parkinson’s disease is characterized by the formation of Lewy bodies (which are largely composed of alpha-synuclein) in dopamine neurons. In 1997, scientists discovered that a mutation in alpha-synuclein can lead to Lewy body formation. “But alpha-synuclein mutations occur in only a tiny percentage of Parkinson’s patients,” said co-lead author David L. Sulzer, PhD, professor of neurology, pharmacology, and psychiatry at CUMC. “This meant that there must be something else that interfered with alpha-synuclein in people with Parkinson’s.”

Dr. Sulzer and his colleagues suspected that a gene called leucine-rich repeat kinase-2 (LRRK2) might be involved. LRRK2 mutations are the most common mutations to have been linked to Parkinson’s. The current study aimed to determine how these mutations might lead to the accumulation of alpha-synuclein.

“We found that abnormal forms of LRRK2 protein disrupt a critical protein-degradation process in cells called chaperone-mediated autophagy,” said Dr. Sulzer. “One of the proteins affected by this disruption is alpha-synuclein. As this protein starts to accumulate, it becomes toxic to neurons.” Delving deeper, the researchers found that LRRK2 mutations interfere with LAMP-2A, a lysosome membrane receptor that plays a key role in lysosome function.

(Chaperone-mediated autophagy, or CMA, is responsible for transporting old or damaged proteins from the cell body to the lysosomes, where they are digested into amino acids and then recycled. In 2004, Dr. Sulzer and the current paper’s other co-lead author, Ana Maria Cuervo, MD, PhD, professor of developmental & molecular biology, of anatomy & structural biology, and of medicine at Albert Einstein College of Medicine of Yeshiva University, showed that alpha-synuclein is degraded by the CMA pathway.)

“Now that we know this step that may be causing the disease in many patients, we can begin to develop drug treatments or genetic treatments that can enhance the digestion of these disease-triggering proteins, alpha-synuclein and LRRK2, or that remove alpha-synuclein,” said Dr. Sulzer.

While LRRK2 mutations are the most common genetic cause of Parkinson’s, it is too early to tell whether these findings, and therapies that might stem from them, would apply to patients with non-familial Parkinson’s, the more common form of the disease. “Right now, all we can say is that it looks as though we’ve found a fundamental pathway that causes the buildup of alpha-synuclein in people with LRRK2 mutations and links these mutations to a common cause of the disease. We suspect that this pathway may be involved in many other Parkinson’s patients,” said Dr. Sulzer.

The study involved mouse neurons in tissue culture from four different animal models, neurons from the brains of patients with Parkinson’s with LRRK2 mutations, and neurons derived from the skin cells of Parkinson’s patients via induced pluripotent stem (iPS) cell technology. All the lines of research confirmed the researchers’ discovery.

Parkinson’s Disease-like sleep and motor problems observed in α-synuclein mutant mice

The presence of Lewy bodies in nerve cells, formed by intracellular deposits of the protein α-synuclein, is a characteristic pathologic feature of Parkinson’s Disease (PD). In the quest for an animal model of PD that mimics motor and non-motor symptoms of human PD, scientists have developed strains of mice that overexpress α-synuclein. By studying a strain of mice bred to overexpress α-synuclein via the Thy-1 promoter, scientists have found these mice develop many of the age-related progressive motor symptoms of PD and demonstrate changes in sleep and anxiety. Their results are published in the latest issue of Journal of Parkinson’s Disease.

PD is the second most common neurodegenerative disorder in the United States, affecting approximately one million Americans and five million people worldwide. Its prevalence is projected to double by 2030. The most obvious symptoms are movement-related, such as involuntary shaking and muscle stiffness; non-motor symptoms, such as increases in anxiety and sleep disturbances, can appear prior to the onset of motor symptoms. Although the drug levodopa can relieve some symptoms, there is no cure – intensifying the pressure to find an animal model that can help clarify the pathological processes underlying human PD and find new medications to treat the pathology and/or relieve symptoms.

Investigators at the National Institute on Aging compared wild type mice with specially bred mice that were transgenic for the A53T mutation of the human α-synuclein (SNCA) gene under the control of a human thymus cell antigen 1, theta (THY-1) promoter. As the mice aged, their motor performance on a rotarod test (which measures how long the mouse can remain on a rotating rod) became impaired and the length of their strides were significantly shorter than the wild type control mice.

The study also found that SNCA mice displayed fragmented nighttime activity patterns compared to wild type controls and appeared to have a reduced overall sleep time. “Despite the prevalence of abnormal sleep patterns in PD, very few studies to date have outlined sleep disturbances in animal models of PD,” says Sarah M. Rothman, PhD, a researcher with the National Institute on Aging, in Baltimore, MD.

Many PD patients typically show an increase in anxiety and depression, and in this respect the SNCA mouse model did not replicate the human condition. SNCA mice displayed an early and significant decrease in anxiety-like behavior that persisted throughout their lifespan, as shown by both open field and elevated plus maze tests (in which mice have the choice of spending time in open or closed arms of a maze). Other rodent models that utilize changes in expression of α-synuclein have also reported lower anxiety levels. The authors suggest that higher levels of serotonin found in the hypothalamus of the SNCA mice may be associated with the reduced anxiety observed.

The authors say it is important to remember that the SNCA “model utilizes the presence of a mutation that only occurs very rarely in PD. While all PD patients display α-synuclein pathology, they do not all express the mutated form of the protein,” says Dr. Rothman.

Sorting out the structure of a Parkinson’s protein

Computer modeling may resolve conflicting results and offer hints for new drug-design strategies.

Clumps of proteins that accumulate in brain cells are a hallmark of neurological diseases such as dementia, Parkinson’s disease and Alzheimer’s disease. Over the past several years, there has been much controversy over the structure of one of those proteins, known as alpha synuclein.

MIT computational scientists have now modeled the structure of that protein, most commonly associated with Parkinson’s, and found that it can take on either of two proposed states — floppy or rigid. The findings suggest that forcing the protein to switch to the rigid structure, which does not aggregate, could offer a new way to treat Parkinson’s, says Collin Stultz, an associate professor of electrical engineering and computer science at MIT.

“If alpha synuclein can really adopt this ordered structure that does not aggregate, you could imagine a drug-design strategy that stabilizes these ordered structures to prevent them from aggregating,” says Stultz, who is the senior author of a paper describing the findings in a recent issue of the Journal of the American Chemical Society.

For decades, scientists have believed that alpha synuclein, which forms clumps known as Lewy bodies in brain cells and other neurons, is inherently disordered and floppy. However, in 2011 Harvard University neurologist Dennis Selkoe and colleagues reported that after carefully extracting alpha synuclein from cells, they found it to have a very well-defined, folded structure.

That surprising finding set off a scientific controversy. Some tried and failed to replicate the finding, but scientists at Brandeis University, led by Thomas Pochapsky and Gregory Petsko, also found folded (or ordered) structures in the alpha synuclein protein.

Stultz and his group decided to jump into the fray, working with Pochapsky’s lab, and developed a computer-modeling approach to predict what kind of structures the protein might take. Working with the structural data obtained by the Brandeis researchers, Stultz created a model that calculates the probabilities of many different possible structures, to determine what set of structures would best explain the experimental data.

The calculations suggest that the protein can rapidly switch among many different conformations. At any given time, about 70 percent of individual proteins will be in one of the many possible disordered states, which exist as single molecules of the alpha synuclein protein. When three or four of the proteins join together, they can assume a mix of possible rigid structures, including helices and beta strands (protein chains that can link together to form sheets).

“On the one hand, the people who say it’s disordered are right, because a majority of the protein is disordered,” Stultz says. “And the people who would say that it’s ordered are not wrong; it’s just a very small fraction of the protein that is ordered.”

The MIT researchers also found that when alpha synuclein adopts an ordered structure, similar to that described by Selkoe and co-workers, the portions of the protein that tend to aggregate with other molecules are buried deep within the structure, explaining why those ordered forms do not clump together.

Stultz is now working to figure out what controls the protein’s configuration. There is some evidence that other molecules in the cell can modify alpha synuclein, forcing it to assume one conformation or another.

“If this structure really does exist, we have a new way now of potentially designing drugs that will prevent aggregation of alpha synuclein,” he says.

Mild cognitive impairment at Parkinson’s disease diagnosis linked with higher risk for early dementia

Mild cognitive impairment at the time of Parkinson disease (PD) diagnosis appears to be associated with an increased risk for early dementia in a Norwegian study, according to a report published Online First by JAMA Neurology, a JAMA Network publication.

Patients with PD have an increased risk for dementia (PDD) compared with healthy individuals and researchers sought to examine the course of mild cognitive impairment (MCI) and its progression to dementia in a group of patients with PD. The Norwegian ParkWest study is an ongoing population-based study of the incidence, neurobiology and prognosis of PD in western and southern Norway, according to the study background.

The study by Kenn Freddy Pedersen, M.D., Ph.D., of Stavanger University Hospital, Norway, included 182 patients with PD monitored for three years. More patients with MCI than without MCI at baseline (10 of 37 [27 percent] vs. 1 of 145 [0.7 percent]) progressed to dementia during follow-up. Of those with MCI at baseline, 8 of 37 (21.6 percent) had MCI that reverted to normal cognition during follow-up, according to the study results.

The results also show that mild cognitive impairment at the one-year visit was associated with a similar progression rate to dementia (10 of 36 patients [27.8 percent] and reversion rate to normal cognition (7 of 36 [19.4 percent]). Of the 22 patients with persistent MCI at baseline and the one-year visit, 10 (45.5 percent) developed dementia and only two (9.1 percent) had MCI that reverted to normal cognition by the end of the study.

“This prospective population-based study of an incident PD cohort demonstrates that MCI within the first year of PD diagnosis signals a highly increased risk for early incident dementia. More than 25 percent of patients with MCI at diagnosis of PD developed dementia within three years of follow-up compared with less than 1 percent of patients without MCI at PD diagnosis. Among patients with MCI at baseline and one year of follow-up, almost half progressed to dementia. These findings support the validity of the MCI concept in patients with early PD,” the study authors conclude.

(JAMA Neurol. Published online March 25, 2013. doi:10.1001/jamaneurol.2013.2110. Available pre-embargo to the media athttp://media.jamanetwork.com.)

STUDY: ‘VIRTUAL’ HOUSE CALLS COMPARABLE TO IN-PERSON CARE FOR PEOPLE WITH PARKINSON’S DISEASE

A small study of 20 people with Parkinson’s disease suggests that “virtual house calls” using Web-based video conferencing provide clinical benefits comparable to in-person physician office visits, while saving patients and their caregivers time and travel.

“It appears we can use the same technology Grandma uses to chat with her grandson to provide her with valuable medical care in her home,” says study leader Ray Dorsey, M.D., M.B.A., an associate professor of neurology at the Johns Hopkins University School of Medicine. “If this proof-of-concept study is affirmed, the findings open the door to a new era where anyone anywhere can receive the care she needs.”

A report on the study, conducted by researchers at Johns Hopkins and the University of Rochester Medical Center is being published online in JAMA Neurology.

Dorsey cautions that wider use of virtual house calls is not without hurdles. For example, under current Medicare rules, physicians are not reimbursed for providing remote care directly into the home. There are also licensing issues.

Doctors may not treat patients in states in which they are not licensed, so that means a patient from, say, Delaware, could come to Johns Hopkins in Baltimore for treatment, but a Johns Hopkins physician could not conduct a virtual house call with that same patient without a Delaware medical license.

“Reimbursement and licensure issues are trailing innovation and, if anything, act as a hindrance,” Dorsey says. “There’s really a disconnect.”

For the study, Dorsey and his colleagues at Johns Hopkins and the University of Rochester Medical Center enrolled 20 of their Parkinson’s disease (PD) patients who had home Internet access. Nine were randomly selected to receive three virtual house calls, while 11 were scheduled for three in-person visits to a physician’s office over the course of seven months.

Roughly the same number of patients made their scheduled visits (one in-person patient missed a visit because of a car accident on the way to the appointment), and quality-of-life changes did not differ between the two groups. The researchers also found that the care was no better – but no worse–for those seen “virtually” or in person.

They also found that, compared to in-person visits, each telemedicine visit saved participants and their caregivers on average 100 miles of travel and three hours of time.

PD is a disorder of the brain that leads to shaking (tremors), slowness of movement, stiffness and difficulty walking. PD usually develops after age 50 and is one of the most common nervous system disorders of the elderly, affecting an estimated 500,000 Americans. That number is expected to nearly double over the next generation, Dorsey notes.

Research has shown that 42 percent of Medicare beneficiaries with PD did not receive care from a neurologist in the first four years after diagnosis, and that patients who don’t see a neurologist are 20 percent more likely to die in the first six years after diagnosis. In addition, Dorsey notes, such patients are 14 percent more likely to fracture a hip and 21 percent more likely to be placed in a nursing home in the first year after diagnosis. And he says money saved by preventing the need for hospitalization and skilled nursing care would more than make up for the small reimbursement costs to neurologists who conduct virtual house calls.

“Physician visits are a rounding error to Medicare in the economic scheme of things,” says Dorsey, director of the Johns Hopkins Parkinson’s Disease and Movement Disorders Center.

Dorsey says that virtual house calls may be especially important for people who live far from large medical centers where specialists are more likely to practice.

Over the Web, neurologists can perform nearly all of the tests that would be done in a regular office visit for a Parkinson’s patient, he says. The physician can watch the patient walk, observe tremors, check the rate at which the patient blinks and assess facial expressions – all measures of the slowing of movement. The principal test that cannot be done is one that assesses stiffness in the arms.

Only larger studies can affirm the comparability and effectiveness of telemedicine, Dorsey says, along with the value to people with other diseases.

Parkinsons’ drug helps older people to make decisions

A drug widely used to treat Parkinson’s Disease can help to reverse age-related impairments in decision making in some older people, a study from researchers at the Wellcome Trust Centre for Neuroimaging has shown.

The study, published today in the journal Nature Neuroscience, also describes changes in the patterns of brain activity of adults in their seventies that help to explain why they are worse at making decisions than younger people.

Poorer decision-making is a natural part of the ageing process that stems from a decline in our brains’ ability to learn from our experiences. Part of the decision-making process involves learning to predict the likelihood of getting a reward from the choices that we make.

An area of the brain called the nucleus accumbens is responsible for interpreting the difference between the reward that we’re expecting to get from a decision and the reward that is actually received. These so called ‘prediction errors’, reported by a brain chemical called dopamine, help us to learn from our actions and modify our behaviour to make better choices the next time.

Dr Rumana Chowdhury, who led the study at the Wellcome Trust Centre for Neuroimaging at UCL, said: “We know that dopamine decline is part of the normal aging process so we wanted to see whether it had any effect on reward-based decision making. We found that when we treated older people who were particularly bad at making decisions with a drug that increases dopamine in the brain, their ability to learn from rewards improved to a level comparable to somebody in their twenties and enabled them to make better decisions.”

The team used a combination of behavioural testing and brain imaging techniques, to investigate the decision-making process in 32 healthy volunteers aged in their early seventies compared with 22 volunteers in their mid-twenties. Older participants were tested on and off L-DOPA, a drug that increases levels of dopamine in the brain. L-DOPA, more commonly known as Levodopa, is widely used in the clinic to treat Parkinson’s.

The participants were asked to complete a behavioural learning task called the two-arm bandit, which mimics the decisions that gamblers make while playing slot machines. Players were shown two images and had to choose the one that they thought would give them the biggest reward. Their performance before and after drug treatment was assessed by the amount of money they won in the task.

“The older volunteers who were less able to predict the likelihood of a reward from their decisions, and so performed worst in the task, showed a significant improvement following drug treatment,” Dr Chowdhury explains.

The team then looked at brain activity in the participants as they played the game using functional Magnetic Resonance Imaging (fMRI), and measured connections between areas of the brain that are involved in reward prediction using a technique called Diffusor Tensor Imaging (DTI).

The findings reveal that the older adults who performed best in the gambling game before drug treatment had greater integrity of their dopamine pathways. Older adults who performed poorly before drug treatment were not able to adequately signal reward expectation in the brain – this was corrected by L-DOPA and their performance improved on the drug.

Dr John Williams, Head of Neuroscience and Mental Health at the Wellcome Trust, said: “This careful investigation into the subtle cognitive changes that take place as we age offers important insights into what may happen at both a functional and anatomical level in older people who have problems with making decisions. That the team were able to reverse these changes by manipulating dopamine levels offers the hope of therapeutic approaches that could allow older people to function more effectively in the wider community.”