They say their study, published online May 10 in Human Molecular Genetics, offers a unique and exciting strategy to treat neurodegenerative diseases that feature abnormal buildup of proteins in Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Huntington disease and Lewy body dementia, among others.

“This drug, in very low doses, turns on the garbage disposal machinery inside neurons to clear toxic proteins from the cell. By clearing intracellular proteins, the drug prevents their accumulation in pathological inclusions called Lewy bodies and/or tangles, and also prevents amyloid secretion into the extracellular space between neurons, so proteins do not form toxic clumps or plaques in the brain,” says the study’s senior investigator, neuroscientist Charbel E-H Moussa, MB, PhD. Moussa heads the laboratory of dementia and Parkinsonism at Georgetown.

When the drug, nilotinib, is used to treat chronic myelogenous leukemia (CML), it forces cancer cells into autophagy - a biological process that leads to death of tumor cells in cancer.

Parkinson’s disease is a movement disorder caused by a loss of brain cells that produce dopamine. Symptoms include facial, hand, arm, and leg tremors, stiffness in the limbs, loss of balance, and slower overall movement. Nearly one million Americans have Parkinson’s, with 60,000 new cases diagnosed in the U.S. each year, and up to ten million individuals worldwide live with this disease according to the Parkinson’s Disease Foundation. Currently, there is no cure for Parkinson’s, but symptoms are treated with medications and procedures such as deep brain stimulation.

Previous studies have found that cigarette smoking and other forms of tobacco, also a Solanaceae plant, reduced relative risk of Parkinson’s disease. However, experts have not confirmed if nicotine or other components in tobacco provide a protective effect, or if people who develop Parkinson’s disease are simply less apt to use tobacco because of differences in the brain that occur early in the disease process, long before diagnosis.

For the present population-based study Dr. Susan Searles Nielsen and colleagues from the University of Washington in Seattle recruited 490 patients newly diagnosed with Parkinson’s disease at the university’s Neurology Clinic or a regional health maintenance organization, Group Health Cooperative. Another 644 unrelated individuals without neurological conditions were used as controls. Questionnaires were used to assess participants’ lifetime diets and tobacco use, which researchers defined as ever smoking more than 100 cigarettes or regularly using cigars, pipes or smokeless tobacco.

The company says that people who received 18 months of infusions with its drug, Gammagard, fared no better than others given infusions of a dummy solution.

Gammagard is immune globulin, natural antibodies culled from donated blood. Researchers thought these antibodies might help remove amyloid, the sticky plaque that clogs patients’ brains, sapping memory and ability to think.

Patients with moderate disease and those with a gene that raises risk of Alzheimer’s who were taking the higher of two doses in the study seemed to benefit, although the study was not big enough to say for sure.

Researchers know that some elderly patients have problems with cognitive function for weeks, sometimes months, following surgical procedures, says senior author David Warner, M.D., a pediatric anesthesiologist at the Mayo Clinic Children’s Center.

There has been concern that exposure to anesthesia may be associated with long-term cognitive changes including dementia, he says. The concern stems in part from a series of studies in which animals were exposed to anesthesia and lesions similar to those observed in Alzheimer’s disease appeared in the brain - including accumulation of amyloid, a protein associated with Alzheimer’s disease.

“It’s reassuring we’re adding to the body of knowledge that there is not an association of anesthesia and surgery with Alzheimer’s,” Dr. Warner says. “There are a lot of things to worry about when an elderly person has surgery, but it seems that developing Alzheimer’s isn’t one of them.”

Blast-induced traumatic brain injury (TBI) has become an important issue in combat casualty care, said senior investigator Patrick Kochanek, M.D., professor and vice chair of critical care medicine and director of the Safar Center for Resuscitation Research at Pitt. In many cases of mild TBI, MRI scans and other conventional imaging technology do not show overt damage to the brain.

“Our research reveals that despite the lack of a lot of obvious neuronal death, there is a lot of molecular madness going on in the brain after a blast exposure,” Dr. Kochanek said. “Even subtle injuries resulted in significant alterations of brain chemistry.”

The research team developed a rat model to examine whether mild blast exposure in a device called a shock tube caused any changes in the brain even if there was no indication of direct cell death, such as bleeding. Brain tissues of rats exposed to blast and to a sham procedure were tested two and 24 hours after the injury.

“We know that cardiovascular disease is an important risk factor for dementia. The suggested decrease in dementia risk coincides with the general reduction in cardiovascular disease over recent decades”, says Associate Professor Chengxuan Qiu of the Aging Research Center, established by Karolinska Institutet and Stockholm University. “Health check-ups and cardiovascular disease prevention have improved significantly in Sweden, and we now see results of this improvement reflected in the risk of developing dementia.”

Dementia is a constellation of symptoms characterized by impaired memory and other mental functions. After age 75, dementia is commonly due to multiple causes, mainly Alzheimers disease and vascular dementia. In the current study, more than 3000 persons 75 years and older living in the central Stockholm neighborhood of Kungsholmen participated. Of the participants, 523 were diagnosed with some form of dementia. The key members of the research group have been essentially the same since 1987, including the neurologist responsible for the clinical diagnoses of dementia. All study participants were assessed by a nurse, a physician, and a psychologist.

The study, published April 10 in The Journal of the American Medical Association, was the first to look at the genetics of a large number of African-Americans diagnosed with this common form of Alzheimer’s disease (1,968 patients) compared to 3,928 normal elderly African-American control participants.

The Alzheimer’s Disease Genetics Consortium conducted the study, which included Mayo Clinic in Florida investigators Neill R. Graff-Radford, M.D., and Nilufer Ertekin-Taner, M.D., Ph.D. They provided genetic samples and data from their Alzheimer’s disease databank.

The study found that the most common risk factor in these African-American patients was the APOE gene, which is also true for Caucasians with the disorder. In addition, another gene, ABCA7, which was discovered to be a risk locus for Caucasians, was also a significant risk factor in African-American patients.

The findings, reported in the April 10, 2013 issue of the journal Neuron, show that brain damage in Alzheimer’s disease is linked to the overactivation of an enzyme called AMPK. When the scientists blocked this enzyme in mouse models of the disease, neurons were protected from loss of synapses- neuron-to-neuron connection points- typical of the early phase of Alzheimer’s disease.

“These findings open up many new avenues of investigation, including the possibility of developing therapies that target the upstream mechanisms leading to AMPK overactivation in the brain,” said TSRI Professor Franck Polleux, who led the new study.

Alzheimer’s disease, a fatal neurodegenerative disorder afflicting more than 25 million people worldwide, currently has no cure or even disease-delaying therapy.

The findings, reported in the April 10, 2013 issue of the journal Neuron, show that brain damage in Alzheimer’s disease is linked to the overactivation of an enzyme called AMPK. When the scientists blocked this enzyme in mouse models of the disease, neurons were protected from loss of synapses - neuron-to-neuron connection points - typical of the early phase of Alzheimer’s disease.

“These findings open up many new avenues of investigation, including the possibility of developing therapies that target the upstream mechanisms leading to AMPK overactivation in the brain,” said TSRI Professor Franck Polleux, who led the new study.

Alzheimer’s disease, a fatal neurodegenerative disorder afflicting more than 25 million people worldwide, currently has no cure or even disease-delaying therapy.

The research in Neuron identifies mutations that affect the build-up of certain proteins in the brain.

High levels of these tau proteins increase the chance of having the disease.

UK experts said the study could help understand the changes that occur in the brains of Alzheimer’s patients.

“The most intriguing finding of our study was the lack of a significant decrease of TH levels in the SN of the low-dose MPTP-treated mice, suggesting that this treatment does not induce a direct loss of nigral dopaminergic neurons,” says Joost Verhaagen PhD, lead investigator of the study. “These findings appear to support the ‘dying back’ hypothesis of PD, which proposes that the TH-positive terminal loss in the striatum is the first neurodegenerative event in PD, which later induces neuronal degeneration in the SN.” Dr. Verhaagen is Head of the Workgroup on Neuroregeneration at the Netherlands Institute for Neuroscience and Professor at the Free University in Amsterdam.

The neurotoxin MPTP (1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine) was used to induce the degenerative changes. Chronic 5 week administration of 25 mg/kg MPTP combined with probenecid (250 mg/kg), which inhibits MPTP clearance and promotes its crossing of the blood-brain barrier, is known to cause dopaminergic neuron degeneration in the SN and decrease striatal dopaminergic nerve terminals. In the current study, 7 mice were treated with 25 mg/kg MPTP plus probenecid, 6 mice received a lower dose of MPTP (15 mg/kg) plus probenecid, and 8 control mice received saline plus probenecid. A grid test, known to be sensitive to striatal dopaminergic input, was used to detect motor deficits.

“No one has been able to determine if Lewy bodies and Lewy neurites, hallmark pathologies in Parkinson’s disease can be degraded,” says Virginia Lee, PhD, director of the Center for Neurodegenerative Disease Research, at the Perelman School of Medicine, University of Pennsylvania.

“With the new neuron model system of Parkinson’s disease pathologies our lab has developed recently, we demonstrated that these aberrant clumps in cells resist degradation as well as impair the function of the macroautophagy system, one of the major garbage disposal systems within the cell.”

Macroautophagy, literally self eating, is the degradation of unnecessary or dysfunctional cellular bits and pieces by a compartment in the cell called the lysosome.

A month after the medicine, Cogane, failed in a clinical trial, Phytopharm said it would not commit any more money to further research and development and would cut staff.
The company said it had held exploratory merger talks with a number of parties.

Cogane’s failure - the latest in a line that include Renovo, Minster and Antisoma - highlighted the all-or-nothing bet that small biotechs need to make to develop and launch drugs on their own.

This Alzheimer’s research, along with additional Parkinson’s research from Penn and beyond, further demonstrates the cell-to-cell transmission of neurodegenerative proteins. John Q. Trojanowski, MD, PhD, co-director of the Center for Neurodegenerative Disease Research (CNDR) and professor of Pathology and Laboratory Medicine at the Perelman School of Medicine, University of Pennsylvania, will present the research in the Hot Topics plenary session on Tuesday, March 19 starting at 5:15pm.

“The transmission model better explains the spread of disease within neurodegenerative disease, and has uncovered new therapeutic opportunities which we are exploring vigorously,” said Dr. Trojanowski. “However, it is important to emphasize that the spread of Alzheimer’s and Parkinson’s pathology does not mean these diseases are infectious, like Mad Cow disease, based on data from another recent study from our group.”
For supplemental information on the transmission of tau pathology, the laboratory of senior author Virginia M.-Y. Lee, Ph.D., MBA, director of CNDR and professor of Pathology and Laboratory Medicine at the Perelman School of Medicine, University of Pennsylvania, published additional findings in the Journal of Neuroscience.

Frontotemporal degeneration, the most common dementia in people under 60, can be hereditary or sporadic in nature and caused by one of two different mutated proteins (tau or TDP-43). The disease results in damage to the anterior temporal and/or frontal lobes of the brain. As the disease progresses, it becomes increasingly difficult for people to plan or organize activities, behave appropriately in social or work settings, interact with others, and care for oneself, resulting in increasing dependency.

In one study, the team confirmed that a novel multimodal imaging approach was more accurate (88 percent) than using either MRI (72 percent) or DTI (81 percent) alone to detect FTD versus Alzheimer’s disease. The two imaging techniques integrate measures of white matter and grey matter, providing a statistically powerful method for predicting underlying pathology in order to screen patients for clinical trials.

“We are moving forward on our biomarker work to optimize our ability to identify the specific cause of an individual’s difficulties during life, said senior author Murray Grossman, MD, EdD, professor of Neurology and director of the Penn FTLD Center. “We use a novel multi-modality approach involving behavioral, imaging and biofluid biomarker measures.”