Georgetown University

Simple Test May Help Gauge Dopamine Loss in Parkinson’s.

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The Triplets Learning Task (TLT) may help determine the extent of dopamine loss in patients with Parkinson’s disease (PD), results of a pilot study hint.

The TLT tests implicit learning, a type of learning that occurs without awareness or intent and that relies on the caudate nucleus, an area of the brain affected by dopamine loss.

The test is a sequential learning task that doesn’t require complex motor skills, which tend to decline in people with PD. In the TLT, participants see 4 open circles, see 2 red dots appear, and are asked to respond when they see a green dot appear. Unbeknownst to them, the authors note, the location of the first red dot predicts the location of the green target. Participants learn implicitly where the green target will appear, and they become faster and more accurate in their responses.

Katherine R. Gamble, psychology PhD student at Georgetown University in Washington, DC, and colleagues had 27 patients with mild to moderate PD receiving dopaminergic medication and 27 healthy controls matched for age and education take the TLT on several occasions.

Patients with PD implicitly learned the dot pattern with training, as did controls, but a loss of dopamine appeared to “negatively impact” that learning compared with healthy older adults, Gamble noted in an interview with Medscape Medical News.

“Their performance began to decline toward the end of training, suggesting that people with Parkinson’s disease lack the neural resources in the caudate, such as dopamine, to complete the learning task,” she added in a conference statement.

Gamble reported the findings here at Neuroscience 2013, the annual meeting of the Society for Neuroscience.

Implicit Learning

In this study, participants responded to 6 “epochs” of the TLT, for a total of 1500 trials. All patients had been diagnosed with PD by a neurologist, and all were receiving treatment with anti-PD medication when they took the test.

Their results showed “significant implicit sequence learning” on the TLT test, the researchers report. Learning increased over the first 5 epochs of training, they note; patients continued to respond more quickly to high- vs low-probability triplets, but this plateaued between periods 5 and 6.

“We suggest that in people with PD, learning is intact early in training because less affected regions of the brain (eg, the hippocampus) can support learning,” they conclude. “However, PD-related dopamine deficits appear later in training when the caudate becomes more important.”

The TLT “may be a noninvasive way to evaluate the level of dopamine deficiency in PD patients, and which may lead to future ways to improve clinical treatment of PD patients,” said Steven E. Lo, MD, associate professor of neurology at Georgetown University Medical Center and a coauthor of the study, in a statement.

The researchers are now testing how implicit learning may differ by different PD stages and drug doses.

Evaluating Dopamine Deficiency

Asked to comment on this pilot study, Lidia Gardner, PhD, assistant professor, Department of Neurology, University of Tennessee Health Science Center in Memphis, said the “simple implicit learning test might be potentially a useful tool for neuropsychologists. I would like to know if there is any correlation between the disease progression and the time required for TLT training.”

However, she told Medscape Medical News, “Until a strong correlation is established, most physicians would shy away from using it as a diagnostic tool for the loss of dopamine neurons. However, in addition to other clinical tests it could be useful.”

“Currently, the loss of dopamine neurons can be visualized with PET [positron emission tomography] using 18F-DOPA or other radio-tracers. This technique can give a relatively close assessment of dopamine neurons in PD patients. A simple and inexpensive test (in comparison to PET or SPECT [single-photon emission computed tomography]) is always welcome in healthcare administration,” Dr. Gardner said.

Malaria programme gets kiss of death from Global Fund.

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It appears that the Affordable Medicines Facility — Malaria (AMFm) is being scuttled by the Global Fund to Fight AIDS, Tuberculosis and Malaria. The AMFm is a multimillion-dollar programme to get effective drugs — artemisinin-based combination therapies (ACTs) — to remote rural villages, where local stores are often the main providers of medicines.

That’s my first take on the Global Fund’s announcement this afternoon, delivered towards the end of a two-day meeting of its board, which began yesterday in Geneva, Switzerland. The fund intends to end AMFm’s stand-alone status, and instead “integrate” the AMFm into its existing core system of providing grants to countries to purchase drugs, bed nets and other malaria-control measures.

Meanwhile, just in: the Fund announced a few minutes ago that it has nominated as its new executive director Mark Dybul, a former head of the President’s Emergency Program for AIDS Relief (PEPFAR), who now co-directs the Global Health Law Program at the O’Neill Institute for National and Global Health Law at Georgetown University in Washington DC. It follows the resignation of Michel Kazatchkine in February (see ‘Global health hits crisis point‘).  More on that later.

The idea behind the AMFm was to make ACTs the frontline treatment, something which has been badly hindered by their much higher price than older antimalarials. Although these older drugs, such as chloroquine, are cheap, they are often ineffective because the parasite has developed resistance to them.

AMFm’s strategy was to first guarantee a market of large bulk orders, allowing it to negotiate large cuts in the price of the drugs from pharmaceutical companies. It then gave importers in affected countries — both in the public and private sector — a subsidy on their purchases, to bring the final price to the consumer down to a level competitive with older drugs. It was also intended to compete with artemisinin monotherapies, which are a recipe for generating drug resistance against the only drug class that is truly effective against malaria.

A full-blown country-level trial of the AMFm concept in eight countries — Cambodia, Ghana, Kenya, Madagascar, Niger, Nigeria, Tanzania (including Zanzibar) and Uganda — began in July 2010 and runs until December 2012. It has had its critics — see ‘Malaria plan under scrutiny’ — but in anyone’s reasonable terms it has already been remarkably successful in many important ways within a very short period ( see the 31 October Lancet paper ‘Effect of the Affordable Medicines Facility—malaria (AMFm) on the availability, price, and market share of quality-assured artemisinin-based combination therapies in seven countries: a before-and-after analysis of outlet survey data’).

The Global Fund’s press release detailing its plans is entitled ‘Board approves integration of AMFm into core Global Fund grant processes‘, and much of its soothingly reassuring content would perhaps have many thinking that the AMFm’s integration into the Global Fund’s core grants system is good news. But it is in effect being killed. There’s will be no new money ringfenced for the AMFm once it runs through its current funding up to the end of 2013, which means that any countries wanting to set aside cash for the private sector will be required to take this from their country grants from the Global Fund. In reality, that will probably translate into AMFm activities simply being terminated in most countries, leading to local price rises in ACTs, and the drugs disappearing off the shelves of local pharmacies. AMFm’s clout in negotiating bulk pricing deals internationally will also probably be weakened.

Here’s what a group of AMFm’s supporters wrote in the Lancet on 31 October about what ‘integration’ of the AMFm into the Global Fund would mean (from’The Affordable Medicines Facility—malaria: killing it slowly‘):

“In November, 2012, the Board of the Global Fund will vote to either continue AMFm in a modified form after December, 2013, or terminate the programme. There is a strong push from donors (though not from countries) to integrate AMFm into the regular Global Fund model, whereby countries would choose how much of their country budget envelopes, which are already committed to other priorities supporting the public sector, to reallocate to AMFm. We believe that this approach will create instability in artemisinin demand, lower the number of ACT manufacturers, increase ACT prices, and abandon the millions who depend on AMFm-subsidised ACTs. Most importantly, it will kill a programme that, when fully implemented, rapidly met its benchmarks despite the many constraints, expectations, and unrealistic timelines imposed on it. We must acknowledge that an efficient approach to subsidising antimalarial drugs has worked, making them available in the private sector where people go to buy them.”

The Global Fund’s board has decided AMFm’s fate, and there is probably no going back on that. But the world now urgently needs a strategy that works with the private sector to keep down ACT prices, particularly in Africa.

Souce: Nature blog