Team describes step-by-step progress in battling toxoplasmosis

July 15, 2016

Toxoplasma gondii parasite up close. Credit: University of Melbourne

In the July 14 edition of Scientific Reports, 39 researchers from 14 leading institutions in the United States, United Kingdom and France suggest novel approaches that could hasten the development of better medications for people suffering from toxoplasmosis. This chronic, currently incurable infection, caused by the parasite Toxoplasma gondii, infects the brain and eye of as many as 2 billion people worldwide.

Their findings provide conceptual and practical roadmaps for improving the efficacy and reducing toxicity of available medicines. They also offer insights into the biology of T. gondii, suggest critical molecular targets for new medicines, and offer renewed hope for the speedy development of much-needed curative medicines for those with toxoplasmosis—and potentially malaria.

The researchers describe three significant steps forward:

• They characterized a new experimental model, a Brazilian strain of T. gondii, called EGS, which behaves in tissue culture much like the dormant cystic parasites that live in human brain cells. This is "an immensely useful and important advance for medicine development," said the study's corresponding author Rima McLeod, professor of ophthalmology and visual sciences and of pediatrics at the University of Chicago. "It allows us to define its genotype and phenotype in depth and to identify what it does to its human host's blood and primary brain stem cells. Remarkably, this encysted parasite turns on host cell pathways in ways that can alter ribosomal function and cause mis-splicing of transcripts as well as other flaws associated with Alzheimer's and Parkinson's disease."
• The researchers found targets critical for the parasite's various life stages. Especially appealing was the parasite's mitochondrial protein, cytochrome b. The team was able to develop compounds more soluble than existing cytochrome b inhibiting quinolones. These can limit parasite survival, and have physiochemical properties commensurate with crossing the blood-brain barrier to treat central nervous system infections. This work emphasizes that the cytochrome bc 1 complex is a critical target. Co-crystallography of the enzyme with the inhibitor provides information to optimize inhibitory compounds.
• They show that greater understanding of T. gondii could have significant implications for anti-malarial research. Compounds they developed were highly effective against Plasmodium falciparum, the parasite that causes malaria, including all tested drug-resistant strains. Malaria, McLeod emphasized, "kills a child every eleven seconds."

The team's findings matter because T. gondii is the most frequent cause of infection leading to destruction of the back of the eye for persons in most countries in the world. It is most damaging for infants and children who acquire infection from their mothers during gestation, but it can also cause life-threatening infections in those with compromised immune systems, such as those with cancer, autoimmune disease or AIDS. Highly virulent strains of Toxoplasma are also now known to cause lethal disease, especially in South America.

A large data analysis by researchers at the University of Chicago, published June 26, 2016, in Clinical Infectious Diseases, found that the estimated annual incidence of toxoplasmosis over the last ten years in the US was 6,137 people, based on diagnostic codes for the disease. An editorial in that journal notes that these data "are the strongest to date to indicate that toxoplasmosis represents a significant disease burden in the United States."

More information: Martin McPhillie et al, New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections, Scientific Reports (2016).  DOI: 10.1038/srep29179 

http://medicalxpress.com/news/2016-07-team-step-by-step-toxoplasmosis.html

Progress in world's first Alzheimer's vaccine

July 14, 2016

Dr Nikolai Petrovsky and a 3D protein model being used in the development of a possible Alzheimer’s disease vaccine. Credit: Flinders University

With more than 7.5 million new cases of Alzheimer's disease a year, the race to find a vaccine and effective treatment for dementia is growing by the day.

Now, researchers in the U.S. and Australia have made a breakthrough discovery in the international quest to discover a new and potentially effective vaccine targeting the pathological proteins associated with Alzheimer's disease (AD), the most common cause of dementia in the elderly.

In research findings just released in Nature's Scientific Reports journal, Flinders University experts, as part of a high-level U.S. research team at the Institute of Molecular Medicine (IMM) and University of California, Irvine (UCI), have made a successful vaccine formulation that targets the abnormal beta-amyloid and tau proteins that signal Alzheimer's disease.

With more than 48 million dementia cases in 2015, Alzheimer's is emerging as one of the costliest to the world's health care systems, especially in mature economies in Western countries.

The World Health Organisation has projected the total global societal cost of dementia-related illnesses and care at more than $US600 billion a year.

"If we are successful in pre-clinical trials, in three to five years, we could be well on the way to one of the most important developments in recent medical history," says Flinders University School of Medicine Professor Nikolai Petrovsky, director of South Australian vaccine research company Vaxine Pty Ltd.

"Along with our rapidly aging populations, we now know that the explosion in type 2 diabetes in the West is likely to further dramatically fuel the projected rise in the number of cases of dementia globally, with diabetes being the major risk factor for Alzheimer's disease," Professor Petrovsky says.

The scale of the dementia problem has seen the U.S. Congress commit a further $US350 million to the National Institutes of Health (NIH) for research into Alzheimer's disease, taking research funding in the US to more than $US1.3 billion this year.

With NIH and Alzheimer's Association funding, the U.S. researchers say they have developed an "exceptional" universal vaccine platform, called MultiTEP, to target the hallmark proteins, aberrant forms of AB and tau proteins.

β-amyloid (AB) is a protein found to be prominent in driving Alzheimer's disease, but the accumulation of pathological tau also correlates with the formation of dementia in Alzheimer's patients.

Using a combination of anti-amyloid-beta and anti-tau vaccines with powerful and safe adjuvant technology called Advax developed by Vaxine Pty Ltd "shows promise for both preventive and therapeutic approaches in AD," Professor David Cribbs told Bloomberg news agency in the U.S.

Professor Michael Agadjanyan, head of IMM Department of Molecular Immunology, says the MultiTEP platform-based vaccines "do not induce potentially harmful auto-reactive cellular immune responses, while still generating antibodies that bind strongly to the amyloid and tau pathological molecules in brain tissue from AD patients."

Co-author of the latest paper, IMM Department of Molecular Immunology, Associate Professor Anahit Ghochikyan, says, "This study suggests that we can immunise patients at the early stages of AD, or even healthy people at risk for AD, using our anti-amyloid-beta vaccine, and, if the disease progresses, then vaccinate with another anti-tau vaccine to increase effectiveness."

She says the cooperative studies with National Institute of Aging IMM scientists and collaborators from UCI and the University of Southern California are working with experts from four companies to conduct non-clinical safety-toxicology studies to fulfil US Government safety standards for the Investigational New Drug application.

After completion of these pre-clinical studies, they plan to test the immunogenicity and efficacy of the new vaccines in human trials.

Cutting-edge research company Vaxine Pty Ltd is internationally renowned for developing the world's first swine flu vaccine during the 2009 pandemic and is active on other fronts including Ebola and Zika virus research.

The vaxine is funded by the U.S. NIH to develop novel compounds called adjuvants that play a critical role in maximising vaccine effectiveness. The Vaxine Advax adjuvant technology is a key component in the development of IMM's Alzheimer's vaccine.

More information: Hayk Davtyan et al. Alzheimer's disease AdvaxCpG- adjuvanted MultiTEP-based dual and single vaccines induce high-titer antibodies against various forms of tau and Aβ pathological molecules, Scientific Reports (2016). DOI: 10.1038/srep28912

http://medicalxpress.com/news/2016-07-world-alzheimer-vaccine.html

Grant to Fund Purdue Study on Parkinson's

July 15, 2016

Jason Cannon

WEST LAFAYETTE -

The National Institute of Environmental Health Sciences has awarded a five-year, nearly $1.7 million grant to a Purdue University health sciences professor. Jason Cannon will use the funds to determine if dietary factors have a role in Parkinson's Disease.

Cannon is an associate professor of toxicology in Purdue's School of Health Sciences. The study seeks to determine if heterocyclic aromatic animes, a possible carcinogen that is formed when grilling meat at high temperatures, is also a neurotoxin linked to the disease.

"Other researchers have found that the class of compounds heterocyclic aromatic animes are probable carcinogens, and one of these cancer scientists shared with me that while the animals in their study were exposed to the carcinogen, they also experienced neurological problems," said Cannon. "My lab's work has found that when we isolate neurons in cultures and expose cells to reasonable doses of these compounds, yes, we see the same types of neurons lost in Parkinson's disease."

Purdue says Cannon will study the compound's effect more in-depth. Cannon says he is interested in looking at factors that cause Parkinson's which people could potentially encounter every day.

The study is being done in collaboration with other researchers from Purdue, as well as researchers from the University of Minnesota, the Defense Threat Reduction Agency in Virginia and the Biosciences and Biotechnology Division at Lawrence Livermore National Laboratory in California.

http://www.insideindianabusiness.com/story/32454399/grant-to-fund-purdue-study-on-parkinsons

Parkinson's Study Showing Increased Death Risk with Antipsychotic Drugs Fuels Debate Among Experts

Magdalena Kegel

July 15, 2016

This week, a more than decade-old debate concerning the use of antipsychotic drugs in the elderly with dementia flared up after a study showing that these drugs also increased the risk of death in patients with Parkinson’s disease was published in the journal JAMA Neurology.

Authored by Dr. Daniel Weintraub, an expert on geriatric psychiatry at the Veterans Affairs Parkinson’s Disease Research, Education and Clinical Center in Pennsylvania, the study, “Association of Antipsychotic Use With Mortality Risk in Patients With Parkinson Disease,” echoed earlier findings.

But Weintraub also highlighted the difficult trade-off physicians face when deciding on psychosis treatment in Parkinson’s patients, especially in the face of ambiguous evidence.

Reports published years ago demonstrated that the use of antipsychotic drugs in elderly patients with dementia increased the likelihood of death. This led the U.S. FDA to require a black box warning adjoining the label on antipsychotic drugs. The label states the drugs are not approved for treatment of psychosis in elderly patients with dementia, since such treatment is linked to an increased risk of death.

A 2005 warning including newer generation drugs, generally referred to as atypical antipsychotics, was extended in 2008 to also include older generation, so-called typical drugs.

In Parkinson’s disease, dementia affects up to 80 percent of patients, and 60 percent also experience psychotic symptoms, making the new study especially appropriate.

Although a smaller study published last year reported similar findings, the new report adds significantly to the evidence by its sheer size. Exploring differences in survival in 7,877 treated, and 7,877 untreated, Parkinson’s patients registered in the Veterans Health Administration database from 1999 to 2010, there was plenty of data from which to draw conclusions.

For the retrospective analysis, each patient taking antipsychotic medication was paired with an untreated patient matched by age, sex, and a range of clinical characteristics.

The study showed that antipsychotic use increased the risk of death twice as much after 180 days of treatment, with patients using typical antipsychotics experiencing the highest risk — almost four times more than untreated patients. Those on atypical medication were more than twice at risk (2.3 times) compared to untreated participants.

The findings send a clear message to physicians: Use extreme caution when treating Parkinson’s patients with antipsychotic drugs. The debate the article prompted, however, shows a more nuanced picture of the situation.

In a comment to the article, published by a trio from the University of Florida — Irene Malaty, Michael Okun, and Michael Jaffee, all experts in the field — it became clear the findings warrant additional discussion, particularly of the interpretation of the data.

Unlike the earlier study, the report did not compare untreated psychotic Parkinson’s patients with those receiving antipsychotic medication; there is only a comparison of drug use. Earlier studies, they point out, have shown that psychosis itself is linked to a greater risk of death, independent of drug use.

Parkinson’s is a disease characterized by the death of neurons producing the signaling factor dopamine, and treatment aims to improve dopamine signaling in the brain. Unfortunately, all antipsychotic drugs on the market work in the opposite direction, by decreasing dopamine signaling. This often leads to Parkinson’s-like side effects in psychotic patients without a Parkinson’s diagnosis.

The main cause of death in the study was Parkinson’s disease, and the authors argue that the drugs, by virtue of their actions on dopamine neurons, might have worsened the disease, hastening death.

The idea is supported by the observation that untreated Parkinson’s patients most often died of cardiovascular disease, which is emphasized in an editorial in the same journal that also attempts to bring a more nuanced view to the discussion.

Titled “Antipsychotics and Increased Mortality — Are We Sure?” the editorial, authored by Mark Baron — yet another long-time expert on Parkinson’s disease — points out that the available data can by no means distinguish whether the increased death risk is a result of the underlying psychosis, or caused by its treatment.

Baron, director of the Southeast Veterans Affairs Parkinson’s Disease Research, Education, and Clinical Center in Virginia, also noted that the study likely included a large number of patients where a Parkinson’s diagnosis might have been questionable, since detailed information on diagnostic procedures were lacking. This would make it difficult to conclude if any findings were really influenced by the diagnosis of Parkinson’s disease.

Another study exploring antipsychotic use in elderly Parkinson’s patients and elderly people without a neurological disorder, suggested that such drug use was linked to death independent of diagnosis — a finding supported by other data showing that antipsychotic use in the elderly is a risky practice.

Baron also underscored another crucial point in the editorial — the scarcity of other options. Weighing a possible risk of death against any potential benefits the treatment might have is a dilemma physicians deal with every day, particularly when faced with a severely psychotic patient and the reactions of family members to the black box warning label accompanying such drugs.

Malaty and her colleagues seem to have made up their minds on this point, stating they suspect that a risk-benefit trade-off would likely favor treatment in most patients.

A new drug, Nuplazid (pimavanserin), particularly tailored to treat psychosis in Parkinson’s, was approved earlier this year by the FDA, but its hefty price tag is likely to limit its use. In addition, all studies so far have shown that newer, atypical antipsychotics such as quetiapine pose a smaller risk than older drugs. The drug Clozapin stands out as an option with the least impact on motor symptoms. Less risky options are unavailable, and would need more exploration.

Weintraub, who also serves as an associate professor of psychiatry at Perelman School of Medicine at the University of Pennsylvania, replied swiftly to the comments. He said that while the study could not compare treated and untreated psychotic Parkinson’s patients, statistical tools, adjusting the analysis for the presence of psychosis, did not indicate that it was the psychotic disease itself that was responsible for the increased death rate.

Given that the study suffers an equal lack of certainty of psychiatric diagnosis as Baron pointed out for the diagnosis of Parkinson’s in the first place, this does not seem to be a convincing argument.

Stating that only about half of psychotic patients are treated with antipsychotics, and therefore it is not evident that these patients need antipsychotics, he also rebuked Malaty’s statement of a risk-benefit analysis favoring treatment.

Although Weintraub admits that the study presents no final statement about the risk of antipsychotic drugs in Parkinson’s disease patients, he concurred with the others that more research is needed to understand the risks of the treatment — with clinical trials following patients over time as the most sensible option to get more decisive answers on this sensitive subject.

http://parkinsonsnewstoday.com/2016/07/15/parkinsons-study-showing-increased-death-risk-with-antipsychotic-drugs-fuels-debate/

Parkinson's MCI Has Distinct Subtypes

Kristina Fiore 
Associate Editor, MedPage 

July 15, 2016

Most common was non-amnestic with executive dysfunction

In the observational LANDSCAPE study, the most common subtype of PD-MCI was non-amnestic single domain (39.4%), Elke Kalbe, MD, of University Hospital Cologne in Germany, and colleagues reported online in the Journal of Neurology, Neurosurgery and Psychiatry.

They also found that age, gender, and global cognition predicted disease subtype -- and they noted that additional longitudinal research is needed to determine whether these specific MCI profiles predict the development of dementia in Parkinson's patients.

About a quarter of patients with Parkinson's have MCI, and higher rates have been reported with more advanced disease severity. Some work has suggested that PD-MCI also predicts conversion to dementia.

Researchers also believe the MCI seen in Parkinson's is different from that involved in Alzheimer's disease: it appears to affect executive function rather than memory.

However, the jury is still out on PD-MCI, as results regarding the cognitive profile of patients with Parkinson's have been variable and have come from small studies. Indeed, the Movement Disorders Society's most recent (2012) guidelines on diagnosing MCI in patients with Parkinson's caution that its criteria will require validation and will likely be refined with additional research.

To further clarify the issue, Kalbe and colleagues conducted the LANDSCAPE Study, a multicenter, prospective observational trial of 269 patients with PD-MCI -- the largest number of prospectively recruited patients with PD-MCI to date, the researchers said.

About two-thirds of patients with PD-MCI had executive impairment (65.3%), followed by visuospatial (36.3%), memory (33.5%), attention (25.8%), and language impairment (6.5%).

After non-amnestic single domain MCI, the largest subtypes of participants were amnestic multiple domain (30.5%), non-amnestic multiple domain (23.4%), and amnestic single domain (6.7%).

The tests most frequently impaired were the Modified Card Scoring Test (MCST) (number of categories 43.5%), the digit span backwards (36.1%), and the word list direct recall (31.2%).

Regression analyses showed that lower global cognition, female gender, and higher age predicted PD-MCI subtypes -- but education and disease-related parameters did not.

"Our finding that executive dysfunctions are the most typical cognitive symptom in PD-MCI is in line with recent reviews and original studies and reflects the fact that the 'cognitive' frontostriatal loop projecting from the dorsal striatum to the dorsolateral prefrontal cortex, which is related to executive functions, is affected early in patients with PD," the researchers wrote. "Likewise, executive dysfunctions are most typical in newly diagnosed, drug-naïve patients with PD."

Kalbe and co-authors did acknowledge, however, that some studies have shown memory to be most frequently impacted in Parkinson's, and this could be due to methodological differences in studies, or it may reflect different neuropathological pathways that suggest different subtypes of Parkinson's disease.

The team also noted that patients with the amnestic multiple domains subtype had the lowest performance in global cognitive scores, suggesting that these patients may be the most likely to go on to develop dementia.

"Predicting the [amnestic multiple domains PD-MCI subtype] with variables that are easily available in clinical routine could be useful, as this subtype scored lowest on global cognition and ... may thus be 'closest' to dementia." The researchers cautioned, however, that commonly used cognitive tests vary greatly in their sensitivity to detect dysfunction.

The study was limited because PD-MCI diagnosis was not based on the Movement Disorders Society criteria since those were not available when the study started, and because the small size of the amnestic single domain subtype may have confounded statistical comparisons between this and other subtypes.

Kalbe et al concluded that additional longitudinal data are needed to test the hypothesis that patients with PD-MCI with specific cognitive profiles have different risks for developing dementia.

The study was supported by Novartis, the International Parkinson Fonds, and the German Ministry for Education and Research.

http://www.medpagetoday.com/Neurology/ParkinsonsDisease/59094?