Neuroscience

Next-generation drugs designed to fight Alzheimer’s disease look very promising. Scientists have unveiled the mechanisms behind two classes of compound currently being tested in clinical trials. They have also identified a likely cause of early-onset hereditary forms of the disease.

The future is looking good for drugs designed to combat Alzheimer’s disease. EPFL scientists have unveiled how two classes of drug compounds currently in clinical trials work to fight the disease. Their research suggests that these compounds target the disease-causing peptides with high precision and with minimal side-effects. At the same time, the scientists offer a molecular explanation for early-onset hereditary forms of Alzheimer’s, which can strike as early as thirty years of age. The conclusions of their research, which has been published in the journal Nature Communications, are very encouraging regarding the future of therapeutic means that could keep Alzheimer’s disease in check.

Alzheimer’s disease is characterized by an aggregation of small biological molecules known as amyloid peptides. We all produce these molecules; they play an essential antioxidant role. But in people with Alzheimer’s disease, these peptides aggregate in the brain into toxic plaques – called “amyloid plaques” – that destroy the surrounding neurons.

The process starts with a long protein, “APP”, which is located across the neuron’s membrane. This protein is cut into several pieces by an enzyme, much like a ribbon is cut by scissors. The initial cut generates a smaller intracellular protein that plays a useful role in the neuron. Another cut releases the rest of APP outside the cell – this part is the amyloid peptide.

For reasons not yet well understood, APP protein can be cut in several different places, producing amyloid peptides that are of varying lengths. Only the longer forms of the amyloid peptide carry the risk of aggregating into plaques, and people with Alzheimer’s disease produce an abnormally high number of these.

A favorite Alzheimer’s target: gamma secretase

The two next-generation classes of compound that are currently in clinical trials target an enzyme that cuts APP, known as gamma secretase. Until now, our understanding of the mechanism involved has been lacking. But with this work, the EPFL researchers were able to shed some more light on it by determining how the drug compounds affect gamma secretase and its cutting activity.

In most forms of Alzheimer’s, abnormally large quantities of the long amyloid peptide 42 – named like that because it contains 42 amino acids – are formed. The drug compounds change the location where gamma secretase cuts the APP protein, thus producing amyloid peptide 38 instead of 42, which is shorter and does not aggregate into neurotoxic plaques.

Compared to previous therapeutic efforts, this is considerable progress. In 2010, Phase III clinical trials had to be abandoned, because the compound being tested inhibited gamma-secretase’s function across the board, meaning that the enzyme was also deactivated in essential cellular differentiation processes, resulting to side-effects like in gastrointestinal bleeding and skin cancer.

“Scientists have been trying to target gamma secretase to treat Alzheimer’s for over a decade,” explains Patrick Fraering, senior author on the study and Merck Serono Chair of Neurosciences at EPFL. “Our work suggests that next-generation molecules, by modulating rather than inhibiting the enzyme, could have few, if any, side-effects. It is tremendously encouraging.”

New insights into hereditary forms of the disease

During their investigation, the scientists also identified possible causes behind some hereditary forms of Alzheimer’s disease. Early-onset Alzheimer’s can appear as early as thirty years of age, with a life expectancy of only a few years. In vitro experiments and numerical simulations show that in early-onset patients, mutations in the APP protein gene modify the way by which APP is cut by the gamma-secretase enzyme. This results in overproduction of amyloid peptide 42, which then aggregates into amyloid plaques.

This research illuminates much that is unknown about Alzheimer’s disease. “We have obtained extraordinary knowledge about how gamma secretase can be modulated,” explains co-author Dirk Beher, scientific chief officer of Asceneuron, a spin-off of Merck Serono, the biopharmaceutical division of Merck KGaA, Darmstadt, Germany. “This knowledge will be invaluable for developing even better targeted drugs to fight the disease.”

Scientists from the Florida campus of The Scripps Research Institute have described findings that could enable the development of more effective drugs for addiction with fewer side effects.

The study, published in the August 2, 2013 issue of the Journal of Biological Chemistry, showed in a combination of cell and animal studies that one active compound maintains a strong bias towards a single biological pathway, providing insight into what future drugs could look like.

The compound examined in the study, known as 6’- guanidinonaltrindole (6’-GNTI), targets the kappa opioid receptor (KOR). Located on nerve cells, KOR plays a role in the release of dopamine, a neurotransmitter that plays a key role in drug addiction. Drugs of abuse often cause the brain to release large amounts of dopamine, flooding the brain’s reward system and reinforcing the addictive cycle.

“There are a number of drug discovery efforts ongoing for KOR,” said Laura Bohn, a TSRI associate professor, who led the study. “The ultimate question is how this receptor should be acted upon to achieve the best therapeutic effects. Our study identifies a marker that shows how things normally happen in live neurons—a critically important secondary test to evaluate potential compounds.”

While KOR has become the focus for drug discovery efforts aimed at treating addiction and mood disorders, KOR can react to signals that originate independently from multiple biological pathways, so current drug candidates targeting KOR often produce unwanted side effects. Compounds that activate KOR can decrease the rewarding effects of abused drugs, but also induce sedation and depression.

The new findings, from studies of nerve cells in the striatum (an area of the brain involved in motor activity and higher brain function), reveal a point on the KOR signaling pathway that may prove to be an important indicator of whether drug candidates can produce effects similar to the natural biological effects.

“Standard screening assays can catch differences but those differences may not play out in live tissue,” Bohn noted. “Essentially, we have shown an important link between cell-based screening assays and what occurs naturally in animal models.”

Those vulnerable to alcoholism may experience an unusually large response in the brain’s reward-seeking pathway when they take a drink

Research from McGill University suggests that people who are vulnerable to developing alcoholism exhibit a distinctive brain response when drinking alcohol, according to a new study by Prof. Marco Leyton, of McGill University’s Department of Psychiatry. Compared to people at low risk for alcohol-use problems, those at high risk showed a greater dopamine response in a brain pathway that increases desire for rewards. These findings, published in the journal Alcoholism: Clinical & Experimental Research, could help shed light on why some people are more at risk of suffering from alcoholism and could mark an important step toward the development of treatment options.

“There is accumulating evidence that there are multiple pathways to alcoholism, each associated with a distinct set of personality traits and neurobiological features”, said Prof. Leyton, a researcher in the Mental Illness and Addiction axis at the Research Institute of the McGill University Health Centre (RI-MUHC). “These individual differences likely influence a wide range of behaviors, both positive and problematic. Our study suggests that a tendency to experience a large dopamine response when drinking alcohol might contribute to one (or more) of these pathways.”

For the study, researchers recruited 26 healthy social drinkers (18 men, 8 women), 18 to 30 years of age, from the Montreal area. The higher-risk subjects were then identified based on personality traits and having a lower intoxication response to alcohol (they did not feel as drunk despite having drunk the same amount). Finally, each participant underwent two positron emission tomography (PET) brain scan exams after drinking either juice or alcohol (about 3 drinks in 15 minutes).

“We found that people vulnerable to developing alcoholism experienced an unusually large brain dopamine response when they took a drink,” said Leyton. “This large response might energize reward-seeking behaviors and counteract the sedative effects of alcohol. Conversely, people who experience minimal dopamine release when they drink might find the sedative effects of alcohol especially pronounced.”

“Although preliminary, the results are compelling,” said Dr. Leyton. “A much larger body of research has identified a role for dopamine in reward-seeking behaviors in general. For example, in both laboratory animals and people, increased dopamine transmission seems to enhance the attractiveness of reward-related stimuli. This effect likely contributes to why having one drink increases the probability of getting a second one – the alcohol-induced dopamine response makes the second drink look all the more desirable. If some people are experiencing unusually large dopamine responses to alcohol, this might put them at risk.”

“People with loved ones struggling with alcoholism often want to know two things: How did they develop this problem? And what can be done to help? Our study helps us answer the first question by furthering our understanding of the causes of addictions. This is an important step toward developing treatments and preventing the disorder in others.”

Physicists and neuroscientists from The University of Nottingham and University of Birmingham have unlocked one of the mysteries of the human brain, thanks to new research using functional Magnetic Resonance Imaging (fMRI) and electroencephalography (EEG).

The work will enable neuroscientists to map a kind of brain function that up to now could not be studied, allowing a more accurate exploration of how both healthy and diseased brains work.

Functional MRI is commonly used to study how the brain works, by providing spatial maps of where in the brain external stimuli, such as pictures and sounds, are processed. The fMRI scan does this by detecting indirect changes in the brain’s blood flow in response to changes in electrical signalling during the stimulus.

Combining techniques

A signal change that happens after the stimulus has stopped is also observed with the fMRI scan. This is called the post-stimulus signal and up until now it has not been used to study how the brain works because its origin was uncertain.

In novel experiments, the research team has now combined fMRI techniques with EEG, which measures electrical activity in the brain, to show that the post-stimulus signal also actually reflects changes in brain signalling.

18 healthy volunteers were monitored by using EEG to measure the electrical activity generated by their brains’ neurons (the signalling cells) while simultaneously recording fMRI measurements. A stimulus of electrical pulses was used to activate the part of the brain that controls movement in the right thumb.

The scientists then compared the EEG and fMRI signals and found that they both vary in the same way after the stimulus stops. This provides compelling evidence that the post-stimulus fMRI signal is a measure of neuronal activity rather than just changes in the brain’s blood flow. Curiously, the team also found the post-stimulus fMRI signal was not consistent, even though the stimulus input to the brain was the same each time. This natural variability in the brain response was also reflected by the EEG activity and the researchers suggest that this signal might help the brain make the transition from processing stimuli back to their internal thoughts in different ways.

New window

Dr Karen Mullinger from The University of Nottingham’s Sir Peter Mansfield Magnetic Resonance Centre said: “This work opens a new window of time in the fMRI signal in which we can look at what the brain is doing. It may also open up new research avenues in exploring the function of the healthy brain and the study of neurological diseases.”

Dr Stephen Mayhew from Birmingham University Imaging Centre said “We do not know what the exact role of the post-stimulus activity is or why this response is not always consistent when the stimulus input to the brain is the same. We have already secured funding through the Birmingham-Nottingham Strategic Collaboration Fund to continue this research into further understanding of human brain function using combinations of neuroimaging methods.”

Director of the Sir Peter Mansfield Magnetic Resonance Centre, Professor Peter Morris, said: “Functional magnetic resonance imaging is the main tool available to cognitive neuroscientists for the investigation of human brain function. The demonstration in this paper, that the secondary fMRI response (the post-stimulus undershoot) is not simply a passive blood flow response, but is directly related to synchronous neural activity, as measured with EEG, heralds an exciting new chapter in our understanding of the workings of the human mind.”

The work has been funded by the Medical Research Council (MRC), Engineering and Physical Science Research Council (EPSRC), The University of Nottingham Anne McLaren Fellowships and University of Birmingham Fellowship and is published in the Proceedings of the National Academy of Sciences (PNAS).

A boost in the speed of brain scans is unveiling new insights into how brain regions work with each other in cooperative groups called networks.

Scientists at Washington University School of Medicine in St. Louis and the Institute of Technology and Advanced Biomedical Imaging at the University of Chieti, Italy, used the quicker scans to track brain activity in volunteers at rest and while they watched a movie.

“Brain activity occurs in waves that repeat as slowly as once every 10 seconds or as rapidly as once every 50 milliseconds,” said senior researcher Maurizio Corbetta, MD, the Norman J. Stupp Professor of Neurology. “This is our first look at these networks where we could sample activity every 50 milliseconds, as well as track slower activity fluctuations that are more similar to those observed with functional magnetic resonance imaging (fMRI). This analysis performed at rest and while watching a movie provides some interesting and novel insights into how these networks are configured in resting and active brains.”

Understanding how brain networks function is important for better diagnosis and treatment of brain injuries, according to Corbetta.

The study appears online in Neuron.

Researchers know of several resting-state brain networks, which are groups of different brain regions whose activity levels rise and fall in sync when the brain is at rest. Scientists used fMRI to locate and characterize these networks, but the relative slowness of this approach limited their observations to activity that changes every 10 seconds or so. A surprising result from fMRI was that the spatial pattern of activity (or topography) of these brain networks is similar at rest and during tasks.

In contrast, a faster technology called magnetoencephalography (MEG) can detect activity at the millisecond level, letting scientists examine waves of activity in frequencies from slow (0.1-4 cycles per second) to fast (greater than 50 cycles per second).

“Interestingly, even when we looked at much higher temporal resolution, brain networks appear to fluctuate on a relatively slow time scale,” said first author Viviana Betti, PhD, a postdoctoral researcher at Chieti. “However, when the subjects went from resting to watching a movie, the networks appeared to shift the frequency channels in which they operate, suggesting that the brain uses different frequencies for rest and task, much like a radio.”

In the study, the scientists asked one group of volunteers to either rest or watch the movie during brain scans. A second group was asked to watch the movie and look for event boundaries, moments when the plot or  characters or other elements of the story changed. They pushed a button when they noticed these changes.

As in previous studies, most subjects recognized similar event boundaries in the movie. The MEG scans showed that the communication between regions in the visual cortex was altered near the movie boundaries, especially in networks in the visual cortex.

“This gives us a hint of how cognitive activity dynamically changes the resting-state networks,” Corbetta said. “Activity locks and unlocks in these networks depending on how the task unfolds. Future studies will need to track resting-state networks in different tasks to see how correlated activity is dynamically coordinated across the brain.”

Anemia, or low levels of red blood cells, may increase the risk of dementia, according to a study published in the July 31, 2013, online issue of Neurology®, the medical journal of the American Academy of Neurology.

“Anemia is common in the elderly and occurs in up to 23 percent of adults ages 65 and older,” said study author Kristine Yaffe, MD, with the University of California – San Francisco and a member of the American Academy of Neurology. “The condition has also been linked in studies to an increased risk of early death.”

For the study, 2,552 older adults between the ages of 70-79 were tested for anemia and also underwent memory and thinking tests over 11 years. Of those, 393 had anemia at the start of the study. At the end of the study, 445, or about 18 percent of participants, developed dementia.

The research found that people who had anemia at the start of the study had a nearly 41 percent higher risk of developing dementia than those who were not anemic. The link remained after considering other factors, such as age, race, sex and education. Of the 393 people with anemia, 89 people, or 23 percent, developed dementia, compared to 366 of the 2,159 people who did not have anemia, or 17 percent.

“There are several explanations for why anemia may be linked to dementia. For example, anemia may be a marker for poor health in general, or low oxygen levels resulting from anemia may play a role in the connection. Reductions in oxygen to the brain have been shown to reduce memory and thinking abilities and may contribute to damage to neurons,” said Yaffe.

New projects will target Fragile X syndrome, nicotine addiction, and age-related macular degeneration

The National Institutes of Health has launched three innovative projects that will focus on development of therapeutics for Fragile X syndrome, nicotine addiction, and age-related macular degeneration (AMD). These projects are funded through the NIH Blueprint Neurotherapeutics Network which provides access to a variety of drug development resources.

“We are excited about the opportunity to apply cutting-edge science to the pursuit of novel treatments for these debilitating disorders” said Rebecca Farkas, Ph.D., program director at NIH’s National Institute of Neurological Disorders and Stroke (NINDS), Office of Translational Research.

The purpose of the NIH Blueprint is to provide in-depth research capabilities to increase the success rate of innovative drug discovery efforts. The program uses a virtual pharma model to provide researchers with access to support and resources that have been traditionally available to large pharmaceutical companies.

Partnerships between NIH program staff and awarded research teams are designed to bridge the funding gap between ground-breaking laboratory research and industry adoption. NIH staff helps investigators work with veteran industry drug development consultants and contract research organization capabilities from the discovery stage through preliminary clinical trials. In addition, each investigator maintains sole ownership of intellectual property associated with his or her project

NIH launched the Blueprint Neurotherapeutics Network in 2011. Including these three awards, 14 drug discovery programs have been funded as part of the program and 10 are currently active (see: http://neuroscienceblueprint.nih.gov/bpdrugs/bpn.htm).

The newly-funded investigators and their organizations are:

• Sage Therapeutics, Cambridge, Mass.
  Principal Investigator: Al Robichaud, Ph.D.
  Disorder: Fragile X syndrome
  Project Summary: Fragile X syndrome is a genetic disorder linked to a range of neurodevelopmental disorders including learning disabilities and cognitive impairment. Many patients experience general and social anxiety yet benzodiazepines, which are drugs typically used to treat anxiety disorders, provide little relief. Their anxiety has been linked to reduced activity in the brain by a protein called, the GABA A receptor. Sage Therapeutics is developing positive allosteric modulators, designed to enhance the receptor’s activity and possibly relieve the anxiety.

• The Scripps Research Institute, Jupiter, Fla.
  Principal Investigator: Paul J. Kenny, Ph.D.
  Disorder: nicotine addiction
  Project Summary: Nicotine addiction has been attributed to the stimulatory effects of nicotine binding to brain proteins called orexin 1 receptors. Dr. Kenny and colleagues will develop selective receptor antagonists as potential smoking cessation aids to treat people who have attempted to quit smoking but faced high relapse rates and significant side effects.

•  University of Utah, Salt Lake City
  Principal Investigator: Dean Yaw Li, Ph.D.
  Disorder: age-related macular degeneration
  Project Summary: Age-related macular degeneration is a leading cause of blindness in the United States. One form, called wet AMD, is associated with inflammation and blood vessel leakage in the retina, the eye’s light-sensitive tissue. Dean Li and his colleagues are developing small molecules that inhibit the activity of Arf6, a molecule known to help control inflammation and blood vessel leakage. This novel approach may lead to effective therapies for treating patients who do not respond to current wet AMD therapies.

The work of two University of Alberta researchers and their teams has contributed to an important next step in finding a cure for deadly prion-folding diseases in humans and animals.

Professor Michael James of the Department of Biochemistry, professor Nat Kav of the Department of Agricultural, Food and Nutritional Science and their labs collaborated to produce mini-antibodies and antibody fragments, using data provided by principal researchers in Switzerland.

The fragments were then used by the lead researchers at the Institute of Neuropathology in Zurich to study interactions between the antibodies and the prion protein and how it results in cell death.

The work conducted at the U of A helps to open the door to designing a molecule that would block prion infection.

“We hope to design a chemical compound that would bind to some part of the prion molecule to prevent the conversion of the normal form of the protein to the disease-causing form,” said James.

Prion protein infections, caused by structural misfolding within the prion protein, lead to fatal neurodegenerative disorders such as Creutzfeldt-Jakob Disease in humans, Bovine Spongiform Encephalopathy (BSE) in cattle and Chronic Wasting Disease in deer. There is currently no cure.

Using recombinant DNA technology, Kav and his lab produced the mini-antibodies and antibody fragments that were then used by James and ultimately studied biologically in the Zurich lab. Using a process called X-ray crystallography, James’s lab was able to identify the three-dimensional structure of where antibodies and antibody fragments bind to the prion molecule, pinpointing regions that are susceptible to changing to a diseased state.

The discovery now makes it possible to begin designing ways to prevent prion disease, in everything from developing treatment for human victims to creating a preventative additive for livestock feed.

The work done by the U of A teams was crucial to the overall research conducted in Zurich, and reflects the high calibre of quality research conducted on campus, Kav noted.

“The U of A collaborated with one of the leading labs in the world, which demonstrates our own level of excellence.”

It also reinforces the U of A’s standing as a leading site of prion research through such institutions as the university’s Centre for Prions and Protein Folding Diseases, James said.

“This latest work advances that.”

The U of A portion of the research was supported by the Alberta Prion Research Institute and PrioNet Canada. The research appears in Nature.

About nine months after suffering a stroke, the patient noticed that words written in a certain shade of blue evoked a strong feeling of disgust. Yellow was only slightly better. Raspberries, which he never used to eat very often, now tasted like blue – and blue tasted like raspberries.

High-pitched brass instruments—specifically the brass theme from James Bond movies—elicited feelings of ecstasy and light blue flashes in his peripheral vision and caused large parts of his brain to light up on an MRI. Music played by a euphonium, a tenor-pitched brass instrument, shut down those sensations.

The patient said he was initially frightened by the mixed messages his brain was sending him and the conflicting senses he was experiencing. He was so worried that something was seriously wrong with him that he raised it with a nurse only as he was leaving an appointment at St. Michael’s Hospital in downtown Toronto.

Physicians and researchers immediately recognized he had synesthesia, a neurological condition in which people experience more than one sense at the same time. They may “see” words or numbers as colours, hear sounds in response to smells or feel something in response to sight.

Most synesthetes are born with the condition, and include some of the world’s most famous authors and artists, including author Vladimir Nabakov, composer Franz Liszt, painter Vasily Kandinsky and singer-songwriter Billy Joel.

The Toronto patient is only the second known person to have acquired synesthesia as a result of a brain injury, in this case a stroke. His case was described in the August issue of the journal Neurology by Dr. Tom Schweizer, a neuroscientist and director of the Neuroscience Research Program at St. Michael’s Li Ka Shing Knowledge Institute.

Dr. Schweizer examined the patient’s brain activity in a functional MRI and compared it to six men of similar age (45) and education (18 years) as each listened to the James Bond Theme and a euphonium solo.

When the James Bond Theme was played, large areas of the patient’s brain lit up including the thalamus (the brain’s information switchboard), the hippocampus (which deals with memory and spatial navigation) and the auditory cortex (which processes sound).

"The areas of the brain that lit up when he heard the James Bond Theme are completely different from the areas we would expect to see light up when people listen to music," Dr. Schweizer said. "Huge areas on both sides of the brain were activated that were not activated when he listened to other music or other auditory stimuli and were not activated in the control group."

The patient and members of the control group also viewed 10-second blocks of words presented in black (which elicits no emotional response in the patient), yellow (mild disgust response) and blue (intense disgust response).

Reading blue letters produced extensive activity in the parts of the patient’s brain responsible for sensory information and processing emotional stimuli and similar but less intense responses for yellow letters. Control groups showed no heightened brain activity in response to the different coloured letters.

Dr. Schweizer said the fact that the patient had very targeted and specific responses to certain stimuli – and that these responses were not experienced by the control group – suggests that his synesthesia was caused as his brain tried to repair itself after his stroke and got cross-wired.

The patient’s stroke occurred in the thalamus, the brain’s central relay station. That’s the same part of the brain affected by the only other reported case of acquired synesthesia.

Higher variability in visit-to-visit blood pressure readings, independent of average blood pressure, could be related to impaired cognitive function in old age in those already at high risk of cardiovascular disease, suggests a paper published today on BMJ.

There is increasing evidence that vascular factors contribute in development and progression of dementia. This is of special interest as cardiovascular factors may be amendable and thus potential targets to reduce cognitive decline and the incidence of dementia. Visit-to-visit blood pressure variability has been linked to cerebrovascular damage (relating to the brain and its blood vessels). It has also been shown that this variability can increase the risk of stroke.

It has been suggested that higher blood pressure variability might potentially lead to cognitive impairment through changes in the brain structures.

Researchers from the Leiden University Medical Center (Netherlands), University College Cork (Ireland) and the Glasgow University (UK) therefore investigated the association of visit-to-visit blood pressure variability (independent of average blood pressure) with cognitive function in older subjects at high risk of cardiovascular disease.

All data were obtained from the PROSPER study, which investigated the effect of statins in prevention of vascular events in older men and women. This study took data on 5,461 individuals aged 70-82 years old in Ireland, Scotland and the Netherlands. Average follow-up was three years.

Both systolic (peak pressure) and diastolic (minimum pressure) blood pressures were measured every three months in the same clinical setting. The variability between these measurements were calculated and used in the analyses.

The study used data on cognitive function where the following was tested: selective attention and reaction time; general cognitive speed; immediate and delayed memory performance.

Results showed that visit-to-visit blood pressure variability was associated with worse performance on all cognitive tests. The results were consistent after adjusting for cardiovascular disease and other risk factors.

The main findings of the study were: higher visit-to-visit blood pressure variability is associated with worse performance in different cognitive tests; higher variability is associated with higher risk of stroke and both these associations are independent of various cardiovascular risk factors, in particular, average blood pressure.

Researcher Simon Mooijaart, (Leiden University Medical Centre, Leiden, the Netherlands) says that by using a population of “over five thousand participants and over three years of blood pressure measurements, we showed that high visit-to-visit systolic and diastolic blood pressure variability associates with worse performance in different domains of cognitive function including selection attention, processing speed, immediate verbal memory and delayed verbal memory”. The researchers do add though that it is still unclear whether higher blood pressure variability is a cause or consequence of impaired cognitive function.

They suggest several explanations for their findings: firstly that blood pressure variability and cognitive impairment could stem from a common cause, with cardiovascular risk factors being the most likely candidate; secondly that variability might reflect a long term instability in the regulation of blood pressure and blood flow to the key organs in the body; thirdly that exaggerated fluctuations in blood pressure could result in the brain not receiving enough blood, which can cause brain injury, leading to impairment of cognitive function.

The researchers conclude that “higher visit-to-visit blood pressure variability independent of average blood pressure might be a potential risk factor with worse cognitive performance in older subjects at high risk of cardiovascular disease”. Given that dementia is a major public health issue, they say that further interventional studies are warranted to establish whether reducing blood pressure variability can decrease the risk of cognitive impairment in old age.

Small study could lead to identification of treatable diseases for some with chronic pain syndrome

About half of a small group of patients with fibromyalgia – a common syndrome that causes chronic pain and other symptoms – was found to have damage to nerve fibers in their skin and other evidence of a disease called small-fiber polyneuropathy (SFPN). Unlike fibromyalgia, which has had no known causes and few effective treatments, SFPN has a clear pathology and is known to be caused by specific medical conditions, some of which can be treated and sometimes cured. The study from Massachusetts General Hospital (MGH) researchers will appear in the journal PAIN and has been released online.

"This provides some of the first objective evidence of a mechanism behind some cases of fibromyalgia, and identifying an underlying cause is the first step towards finding better treatments," says Anne Louise Oaklander, MD, PhD, director of the Nerve Injury Unit in the MGH Department of Neurology and corresponding author of the Pain paper.

The term fibromyalgia describes a set of symptoms – including chronic widespread pain, increased sensitivity to pressure, and fatigue – that is believed to affect 1 to 5 percent of individuals in Western countries, more frequently women. While a diagnosis of fibromyalgia has been recognized by the National Institutes of Health and the American College of Rheumatology, its biologic basis has remained unknown. Fibromyalgia shares many symptoms with SFPN, a recognized cause of chronic widespread pain for which there are accepted, objective tests.

Designed to investigate possible connections between the two conditions, the current study enrolled 27 adult patients with fibromyalgia diagnoses and 30 healthy volunteers. Participants went through a battery of tests used to diagnose SFPN, including assessments of neuropathy based on a physical examination and responses to a questionnaire, skin biopsies to evaluate the number of nerve fibers in their lower legs, and tests of autonomic functions such as heart rate, blood pressure and sweating.

The questionnaires, exam assessments, and skin biopsies all found significant levels of neuropathy in the fibromyalgia patients but not in the control group. Of the 27 fibromyalgia patients, 13 had a marked reduction in nerve fiber density, abnormal autonomic function tests or both, indicating the presence of SFPN. Participants who met criteria for SFPN also underwent blood tests for known causes of the disorder, and while none of them had results suggestive of diabetes, a common cause of SFPN, two were found to have hepatitis C virus infection, which can be successfully treated, and more than half had evidence of some type of immune system dysfunction.

"Until now, there has been no good idea about what causes fibromyalgia, but now we have evidence for some but not all patients. Fibromyalgia is too complex for a ‘one size fits all’ explanation," says Oaklander, an associate professor of Neurology at Harvard Medical School. "The next step of independent confirmation of our findings from other laboratories is already happening, and we also need to follow those patients who didn’t meet SFPN criteria to see if we can find other causes. Helping any of these people receive definitive diagnoses and better treatment would be a great accomplishment."

More study is needed, but isoflurane might provide alternative to electroconvulsive therapy

Although electroconvulsive therapy (ECT) has long been considered the most effective treatment of medication-resistant depression, millions of people who could benefit don’t take advantage of it because of the treatment’s side effects and public misperception of the procedure.

If the results of a campus-wide collaboration of University of Utah researchers are borne out by larger studies and trials, patients with refractory depression might one day have an alternative that is as effective as ECT but without the side effects – the surgical anesthetic drug isoflurane. 

“We need to expand our research into a larger, multicenter trial, but if the results of our pilot study pan out, it would change the face of treating depression,” says Howard R. Weeks, M.D., assistant professor of psychiatry and first author on a study published July 26, 2013, in PLOS ONE online.

Also known as shock therapy, ECT is effective in 55 percent to 90 percent of depression cases, with significant reductions in symptoms typically occurring within two to four weeks. When medications work, they can take six to eight weeks to become effective. But ECT is associated with side effects including amnesia, concentration and attention problems, and other cognitive issues. Many people also mistakenly believe ECT is painful and causes brain damage, which has given the treatment a social stigma that makes millions of patients reluctant to have it. Isoflurane potentially offers an alternative to ECT that could help many of those people, according to Weeks and his colleagues from eight University of Utah departments and programs. 

In a pilot study with 20 patients who received ECT treatments compared to eight patients who received the isoflurane treatments, the researchers found that both therapies provided significant reduction in symptoms of depression. Immediately following the treatments, ECT patients showed declines in areas of memory, verbal fluency, and processing speed. Most of these ECT-related deficits resolved by four weeks. However, autobiographical memory, or recall of personal life events, remained below pretreatment levels for ECT patients four weeks after the treatment. In contrast, the patients treated with isoflurane showed no real impairment but instead had greater improvements in cognitive testing than ECT patients both immediately and four weeks after the treatments. 

In the mid-1980’s, researchers in Europe studied isoflurane as a potential depression therapy. Later studies by other scientists failed to confirm the results of the original work and isoflurane research fell out of favor. But these later studies didn’t adhere to the first study’s protocol regarding type of anesthetic, dosing size and number of treatments, according to Weeks, and he believes that’s why isoflurane’s antidepressant effects weren’t confirmed in subsequent trials. For their research, Weeks and his University of Utah colleagues followed the original study’s protocol. 

“Our data reconfirm that isoflurane had an antidepressant effect approaching ECT with less adverse neurocognitive effects, and reinforce the need for a larger clinical trial,” the researchers wrote. 

Researchers don’t know what produces the relief of depression symptoms from ECT or isoflurane. Weeks believes further research might identify a molecular pathway that both therapies target and is responsible for the improvement in depression. One common effect of both ECT and isoflurane treatments is a brief state of low electrical activity in which the brain becomes unusually quiet. ECT induces a seizure to reach that state, but isoflurane does not. After inhaling the anesthesia, patients are “under” for about 45 minutes, with 15 minutes of that time being a deep state of unconsciousness, according to Weeks. This period of electrical rest for the brain may be a potential explanation for why ECT and isoflurane improve depression. 

If isoflurane proves to be a viable alternative to ECT, a device invented by three University of Utah anesthesiology faculty members can make the anesthetic an even more attractive therapy. The Aneclear™ device (Anecare, Salt Lake City, UT) invented by Dwayne R. Westenskow, Ph.D., Derek J. Sakata, M.D., and Joseph A. Orr, Ph.D., from the University of Utah Department of Anesthesiology, uses hyperventilation and allows patients to rebreathe their own carbon dioxide (C02). Hyperventilation removes anesthesia from the lungs and C02 encourages blood flow to the brain, which encourages quicker removal of anesthetic. The Aneclear™ also minimizes or even eliminates vomiting, nausea, and extreme fatigue that some patients experience from anesthesia. 

“With the Aneclear™, we can wake people up from the anesthesia much quicker,” Weeks says. “This makes the treatment a potentially viable clinical treatment by reducing the time required in an operating room.” 

Weeks and his co-researchers now are looking for grants to fund a larger study that will include several U.S. centers.

Statins, a class of cholesterol-lowering drugs found in millions of medicine cabinets, may help treat Rett Syndrome, according to a study published today in Nature Genetics. The Rett Syndrome Research Trust (RSRT) funded this work with generous support from the Rett Syndrome Research Trust UK and Rett Syndrome Research & Treatment Foundation.

Rett Syndrome is a neurological disorder that affects girls. A seemingly typical toddler begins to miss developmental milestones. A regression follows as young girls lose speech, mobility, and hand use. Many girls have seizures, orthopedic and severe digestive problems, as well as breathing and other autonomic impairments. Most live into adulthood and require total, round-the-clock care. Rett Syndrome affects about 1 in 10,000 girls born in the U.S. each year.

The new study screened for randomly induced mutations in genes that modify the effect of the Rett gene, MECP2 (methyl-CpG-binding protein 2), in a mouse model. MECP2 turns other genes on or off by disrupting chromatin, the DNA-protein mix that makes up chromosomes.

The challenge of treating Rett Syndrome is what drove senior author Monica Justice, Ph.D., Professor in the Departments of Molecular and Human Genetics and Molecular Physiology and Biophysics at the Baylor College of Medicine, to look beyond MECP2, hoping to find new drug targets that might improve symptoms or even reverse the course of the disease. In 2007, Adrian Bird, Ph.D., Buchanan Professor of Genetics at the Wellcome Trust Centre for Cell Biology at the University of Edinburgh, showed that symptoms in mice are reversible regardless of the age of the animal.

Exploring cholesterol metabolism in neurological diseases is an emerging area, with statin drugs being tested in fragile X syndrome, neurofibromatosis, amyotrophic lateral sclerosis, and other conditions. But it hadn’t been on the radar for Rett Syndrome. “Our screen was to see if we could suppress the symptoms to reveal alternative pathways to treatment. The cholesterol hit was a big one,” Dr. Justice said. The screen was unbiased – the researchers were looking for any gene that would interact with MECP2 in a useful way, rather than employing a candidate gene approach based on hypotheses.

Dr. Justice and her team injected healthy male mice with a chemical called ENU (a form of nitrosourea) that mutates sperm stem cells randomly, then mated the males to Rett females. The researchers then looked for offspring that should have developed the syndrome (according to their genes), but didn’t (according to their good health).

Key to the investigation was being able to tell sick mice from healthy ones. Fortunately this turned out to be easy. The rescued mice didn’t develop the characteristic tremor, trouble breathing, poor limb-clasping, and general scruffiness of their affected cage-mates. They moved around more, performed better on mobility tests and lived longer.

Once the rescued mice had been identified the random gene mutations from the 24,000 genes that make up the mouse genome had to be pinpointed. “With next generation DNA sequencing, we are finding mutations so easily and quickly. It’s amazing,” said Dr. Justice, compared to the old days of setting up many more generations of crosses to narrow down a part of the genome harboring a gene of interest.

“We are only15% of the way through the screen, and so far we have identified 5 modifiers. The most drug-targetable is a gene called squalene epoxidase (Sqle), which encodes a rate-limiting enzyme in the cholesterol biosynthetic pathway. Frankly, this discovery was a surprise,” Dr. Justice said.  It’s important to note that this enzyme is different from the rate-limiting enzyme (HMG CoA reductase) influenced by statin drugs.

Cholesterol is of course best known for its negative effects on the cardiovascular system, but the lipid has multiple roles in the brain: it helps to form the myelin insulation on neurons and takes part in membrane trafficking, dendrite remodeling, synapse formation, signal transduction, and neuropeptide synthesis.

The next step was to test several statins (fluvastatin and lovastatin) on Rett mice. Like the Sqle mutation, the drugs improved symptoms. Treated mice performed well on mobility and gross motor tests, had better overall health scores and lived longer. The drugs didn’t, however, improve breathing.

“When we saw the mutation in a cholesterol pathway enzyme, we immediately thought of statin drugs. Now that our eyes have opened to what is going on, we have a multitude of drugs that modulate lipid metabolism that we can try in addition to statins,” said first author Christie Buchovecky, graduate student in the Justice lab.

With additional RSRT funding, pediatric neurologist and Director of the Tri-State Rett Syndrome Center in the Bronx Dr. Sasha Djukic undertook a detailed review of lipid data in girls with Rett Syndrome. She found that a subset have elevated cholesterol levels which normalize as they age. These data are not included in the Nature Genetics publication but will be part of a subsequent paper. Dr. Djukic is now planning a clinical trial.

Drs. Justice and Djukic caution that carefully designed and rigorously executed clinical trials are essential to test whether what works in mice will also work in girls with Rett Syndrome. Clinical trials should also determine the most effective timeframe for treatment, ways to identify which girls are most likely to respond, (for example, will statins help girls with Rett who do not have elevated cholesterol?), which drugs to trial and what dosages are effective but not toxic.

“Although statins are blockbuster drugs taken by a large percentage of the population they are not without risks and side-effects, and data on statins in the general pediatric population are quite limited. One of the key objectives of the clinical trial will be to determine correct dosages for Rett symptoms. It’s important to note that the mice in Dr. Justice’s study received very low doses of statins. I urge parents to resist any temptation to medicate their children with off-label statins,” cautions Dr Djukic. “The only way to know if this class of drugs will be efficacious in Rett is through controlled trials. Working with Dr. Justice and RSRT we will be bringing families additional information as soon as possible.”

“The biggest finding is the discovery that this pathway is so important to the pathology of the disorder; it suggests new directions for trying to learn more about Rett Syndrome,” Dr. Justice explains. “Emerging evidence from both mice and humans suggest that Rett Syndrome may have a component of disease that is metabolic. Certainly, this study will further clarify our data, and may suggest avenues for treatment that were previously unexplored.”

Neuroscientist Sarah Laszlo wants to understand what’s going on in children’s brains when they’re reading. Her research may untangle some of the mysteries surrounding dyslexia and lead to new methods of treating America’s most common learning disorder.

“The brain can reveal things that aren’t necessarily visible on the surface,” she says. “It can tell you things about what’s going wrong that you can’t find out by giving a kid a test or asking him to read out loud.”

Laszlo, who joined Binghamton’s psychology department in 2011, recently received a five-year, $400,763grant from the National Science Foundation’s Early Career Development (CAREER) Program, the agency’s most prestigious award for young researchers. The funding will enable her to conduct a five-year brain activity study of 150 children with and without dyslexia.

Rather than lumping all children with dyslexia into one group, as many previous brain-imaging studies have done, Laszlo’s project will help to establish types and degrees of the disorder.

Her lab uses electroencephalography, or EEG, as a non-invasive way to measure the electrical signals sent between brain cells when they’re communicating with each other. Study participants — kids in kindergarten through fourth grade — wear a cap outfitted with special sensors while playing a computerized reading game.

These scans produce massive amounts of data: The cap’s 10 sensors collect readings 500 times per second for 45 minutes. That’s one reason that brain activity studies are expensive and time-consuming. It’s also the reason that a study of just 150 children is the largest study of its kind.

Kara Federmeier, a professor of psychology at the University of Illinois, says it’s not just the scale of the study that’s impressive; it’s also the project’s duration. “Sarah will be able to assess how the brain transitions from immature reading processes to mature reading processes,” Federmeier says. “Her project promises to provide important, novel data that may be critical for informing educational practices about teaching reading and clinical practices for assessing reading-related difficulties.”

Why study this disorder in particular? Laszlo notes that there are significant, sometimes lifelong consequences of growing up with dyslexia. Many dyslexic children don’t do as well in school as they might otherwise, which limits their career opportunities. Some also encounter social problems. “This has the potential to help a lot of people,” she says.

Laszlo hopes to identify the brain signatures of people with dyslexia and have a clear idea of how to help them. “Once you understand what’s going on in the brain,” she says, “you can do a better job of designing treatments.”

Today, the best-case scenario is that children with dyslexia receive interventions that enable them to get up to speed on reading aloud. But they may continue to lag behind their peers when it comes to comprehension, fluency and speed. “The treatments we have now don’t always fix the underlying problem,” Laszlo says. “They just put a Band-Aid on it. And when you go to do more complicated things, like reading larger passages, the Band-Aid doesn’t help.”

How to Participate

Participants in Sarah Laszlo’s Reading Brain Project play a computerized reading game while researchers measure their brain activity. Children in kindergarten through fourth grade are eligible for the Binghamton University study and will receive $50 or an equivalent gift for their time. To sign up your child, call 607-269-7271 or e-mail readingbrain@binghamton.edu. For more details, visit www.binghamton.edu/reading-brain.

Researchers at McMaster University have discovered a solution to a long-standing medical mystery in Huntington’s disease (HD).

HD is a brain disease that can affect 1 in about 7,000 people in mid-life, causing an increasing loss of brain cells at the centre of the brain. HD researchers have known what the exact DNA change is that causes Huntington’s disease since 1993, but what is typically seen in patients does not lead to disease in animal models. This has made drug discovery difficult.

In this week’s issue of the science journal, the Proceedings of the National Academy of Sciences, professor Ray Truant’s laboratory at McMaster University’s Department of Biochemistry and Biomedical Sciences of the Michael G. DeGroote School of Medicine reveal how they developed a way to measure the shape of the huntingtin protein, inside of cell, while still alive. They then discovered was that the mutant huntingtin protein that causes disease was changing shape. This is the first time anyone has been able to see differences in normal and disease huntingtin with DNA defects that are typical in HD patients.

They went on to show that they can measure this shape change in cells derived from the skin cells of living Huntington’s disease patients.

“With mouse models, we know that some drugs can stop, and even reverse Huntington’s disease, but now we know exactly why,” said Truant. “The huntingtin protein has to take on a precise shape, in order to do its job in the cell. In Huntington’s disease, the right parts of the protein can’t line up to work properly. It’s like trying to use a paperclip after someone has bent it out of shape.”

The research also shows that the shape of disease huntingtin protein can be changed back to normal with chemicals that are in development as drugs for HD.  “We can refold the paper clip,” said Truant.

The methods they developed have been scaled up and used for large scale robotic drug screening, which is now ongoing with a pharmaceutical company. They are looking for drugs that can enter the brain more easily. Furthermore, they can tell if the shape of huntingtin has been corrected in patients undergoing drug trials, without relying on years to know if the HD is affected yet.

This research was a concerted effort from many sources: funding from the Canadian Foundation Institute and the Ontario Innovation Trust for an $11M microscopy centre at McMaster in 2006, ongoing support from the Canadian Institutes of Health Research, and important funding from the Toronto-based Krembil Foundation. The project was initiated with charity grant support from the Huntington Society of Canada, which allowed them to show this method was promising for further support.

The last piece of the puzzle was from the Huntington’s disease patient community, with skin cell donations from living patients and unaffected spouses that allowed the team to look at real human disease.

More information about Huntington’s Disease can be found at HDBuzz.net, a global website in eleven languages that takes primary published research articles and explains them to plain language to more than 300,000 non-scientists per month.

There are eight other diseases that have a similar DNA defects as Huntington’s disease, Truant’s group is now using similar tools to develop assays to measure shape changes in those diseases, to see if this shapeshifting is common in other diseases.

It happens to all of us at least once each winter in Montreal. You’re walking on the sidewalk and before you know it you are slipping on a patch of ice hidden under a dusting of snow. Sometimes you fall. Surprisingly often you manage to recover your balance and walk away unscathed. McGill researchers now understand what’s going on in the brain when you manage to recover your balance in these situations. And it is not just a matter of good luck.

Prof. Kathleen Cullen and her PhD student Jess Brooks of the Dept of Physiology have been able to identify a distinct and surprisingly small cluster of cells deep within the brain that react within milliseconds to readjust our movements when something unexpected happens, whether it is slipping on ice or hitting a rock when skiing. What is astounding is that each individual neuron in this tiny region that is smaller than a pin’s head displays the ability to predict and selectively respond to unexpected motion.

This finding both overturns current theories about how we learn to maintain our balance as we move through the world, and also has significant implications for understanding the neural basis of motion sickness.

Scientists have theorized for some time that we fine-tune our movements and maintain our balance, thanks to a neural library of expected motions that we gain through “sensory conflicts” and errors. “Sensory conflicts” occur when there is a mismatch between what we think will happen as we move through the world and the sometimes contradictory information that our senses provide to us about our movements.

This kind of “sensory conflict” may occur when our bodies detect motion that our eyes cannot see (such as during plane, ocean or car travel), or when our eyes perceive motion that our bodies cannot detect (such as during an IMAX film, when the camera swoops at high speed over the edge of steep cliffs and deep into gorges and valleys while our bodies remain sitting still). These “sensory conflicts” are also responsible for the feelings of vertigo and nausea that are associated with motion sickness.

But while the areas of the brain involved in estimating spatial orientation have been identified for some time, until now, no one has been able to either show that distinct neurons signaling “sensory conflicts” existed, nor demonstrate exactly how they work. “We’ve known for some time that the cerebellum is the part of the brain that takes in sensory information and then causes us to move or react in appropriate ways,” says Prof. Cullen. “But what’s really exciting is that for the first time we show very clearly how the cerebellum selectively encodes unexpected motion, to then send our body messages that help us maintain our balance. That it is such a very exact neural calculation is exciting and unexpected.”

By demonstrating that these “sensory conflict” neurons both exist and function by making choices “on the fly” about which sensory information to respond to, Cullen and her team have made a significant advance in our understanding of how the brain works to keep our bodies in balance as we move about.

The research was done by recording brain activity in macaque monkeys who were engaged in performing specific tasks while at the same time being unexpectedly moved around by flight-simulator style equipment.

A small percentage of people diagnosed with a mysterious neurological condition may only experience psychiatric changes - such as delusional thinking, hallucinations, and aggressive behavior - according to a new study by researchers in the Perelman School of Medicine at the University of Pennsylvania. In addition, people who had previously been diagnosed with this disease, called anti-NMDA receptor (anti-NMDAR) encephalitis, had relapses that only involved psychiatric behavior. In an article published Online First in JAMA Neurology, researchers suggest that, while isolated psychiatric episodes are rare in anti-NMDAR encephalitis cases, abnormal test findings or subtle neurological symptoms should prompt screening for the condition, as it is treatable with immunotherapies.

Within a large group of 571 patients with confirmed Anti-NMDAR Encephalitis, only 23 patients (4 percent) had isolated psychiatric episodes. Of the 23, 5 patients experienced the onset of behavior changes as their only symptoms, without neurological changes, while 18 patients had psychiatric symptoms emerge at the outset of a relapse of Anti-NMDAR Encephalitis in which no neurological changes were identified. After being treated for the condition, 83 percent of these patients recovered substantially or completely.

"While many patients with Anti-NMDAR Encephalitis present with isolated psychiatric symptoms, most of these patients subsequently develop, in a matter of days, additional neurological symptoms which help to make the diagnosis of the disease. In the current study, we find out that a small percentage of patients do not develop neurological symptoms, or sometimes these are very subtle and transitory. Studies using brain MRI and analysis of the cerebrospinal fluid may help to demonstrate signs of inflammation," said Josep Dalmau, MD, PhD, adjunct professor of Neurology. "For patients who have been previously diagnosed with Anti-NMDAR Encephalitis and are in remission, any behavior change may present a relapse and should be tested quickly and treated aggressively."

Anti-NMDAR Encephalitis is one of the most common forms of autoimmune encephalitis, and symptoms can include psychiatric symptoms, memory issues, speech disorders, seizures, involuntary movements, and loss of consciousness. In an earlier Penn Medicine study, 38 percent of all patients (and 46 percent of females with the condition) were found to have a tumor, most commonly it was an ovarian tumor. When correctly diagnosed and treated early, Anti-NMDAR Encephalitis can be effectively treated.

"For patients with new psychotic symptoms that are evaluated in centers where an MRI, EEG or spinal fluid test may not have been administered, there is a chance that Anti-NMDAR Encephalitis may be missed,” said lead author Matthew Kayser, MD, PhD, postdoctoral fellow and attending physician in Psychiatry at Penn. "However, the likelihood of pure or isolated new-onset psychosis to be anti-NMDAR encephalitis gradually decreases if no other symptoms emerge during the first 4 weeks of psychosis."

Anti-NMDAR Encephalitis was first characterized by Penn’s Josep Dalmau, MD, PhD, adjunct professor of Neurology, and David R. Lynch, MD, PhD, associate professor of Neurology and Pediatrics, in 2007. One year later, the same investigators, in collaboration with Rita Balice-Gordon, PhD, professor of Neuroscience, characterized the main syndrome and provided preliminary evidence that the antibodies have a pathogenic effect on the NR1 subunit of the NMDA receptor in the Lancet Neurology in December 2008. The disease can be diagnosed using a test developed at the University of Pennsylvania and currently available worldwide. With appropriate treatment, approximately 81 percent of patients significantly improve and, with a recovery process that takes an average of 2 years, can fully recover.

Princeton University researchers have created “souped up” versions of the calcium-sensitive proteins that for the past decade or so have given scientists an unparalleled view and understanding of brain-cell communication.

Reported July 18 in the journal Nature Communications, the enhanced proteins developed at Princeton respond more quickly to changes in neuron activity, and can be customized to react to different, faster rates of neuron activity. Together, these characteristics would give scientists a more precise and comprehensive view of neuron activity.

The researchers sought to improve the function of proteins known as green fluorescent protein/calmodulin protein (GCaMP) sensors, an amalgam of various natural proteins that are a popular form of sensor proteins known as genetically encoded calcium indicators, or GECIs. Once introduced into the brain via the bloodstream, GCaMPs react to the various calcium ions involved in cell activity by glowing fluorescent green. Scientists use this fluorescence to trace the path of neural signals throughout the brain as they happen.

GCaMPs and other GECIs have been invaluable to neuroscience, said corresponding author Samuel Wang, a Princeton associate professor of molecular biology and the Princeton Neuroscience Institute. Scientists have used the sensors to observe brain signals in real time, and to delve into previously obscure neural networks such as those in the cerebellum. GECIs are necessary for the BRAIN Initiative President Barack Obama announced in April, Wang said. The estimated $3 billion project to map the activity of every neuron in the human brain cannot be done with traditional methods, such as probes that attach to the surface of the brain. “There is no possible way to complete that project with electrodes, so you have to do it with other tools — GECIs are those tools,” he said.

Despite their value, however, the proteins are still limited when it comes to keeping up with the fast-paced, high-voltage ways of brain cells, and various research groups have attempted to address these limitations over the years, Wang said.

“GCaMPs have made significant contributions to neuroscience so far, but there have been some limits and researchers are running up against those limits,” Wang said.

One shortcoming is that GCaMPs are about one-tenth of a second slower than neurons, which can fire hundreds of times per second, Wang said. The proteins activate after neural signals begin, and mark the end of a signal when brain cells have (by neuronal terms) long since moved on to something else, Wang said. A second current limitation is that GCaMPs can only bind to four calcium ions at a time. Higher rates of cell activity cannot be fully explored because GCaMPs fill up quickly on the accompanying rush of calcium.

The Princeton GCaMPs respond more quickly to changes in calcium so that changes in neural activity are seen more immediately, Wang said. By making the sensors a bit more sensitive and fragile — the proteins bond more quickly with calcium and come apart more readily to stop glowing when calcium is removed — the researchers whittled down the roughly 20 millisecond response time of existing GCaMPs to about 10 milliseconds, Wang said.

The researchers also tweaked certain GCaMPs to be sensitive to different types of calcium ion concentrations, meaning that high rates of neural activity can be better explored. “Each probe is sensitive to one range or another, but when we put them together they make a nice choir,” Wang said.

The researchers’ work also revealed the location of a “bottleneck” in GCaMPs that occurs when calcium concentration is high, which poses a third limitation of the existing sensors, Wang said. “Now that we know where that bottle neck is, we think we can design the next generation of proteins to get around it,” Wang said. “We think if we open up that bottleneck, we can get a probe that responds to neuronal signals in one millisecond.”

The faster protein that the Princeton researchers developed could pair with work in other laboratories to improve other areas of GCaMP function, Wang said. For instance, a research group out of the Howard Hughes Medical Institute reported in Nature July 17 that it developed a GCaMP with a brighter fluorescence. Such improvements on existing sensors gradually open up more of the brain to exploration and understanding, said Wang, adding that the Princeton researchers will soon introduce their sensor into fly and mammalian brains.

“At some level, what we’ve done is like taking apart an engine, lubing up the parts and putting it back together. We took what was the best version of the protein at the time and made changes to the letter code of the protein,” Wang said. “We want to watch the whole symphony of thousands of neurons do their thing, and we think this variant of GCaMPs will help us do that better than anyone else has.”

A class of drug, called ACE inhibitors, which are used to lower blood pressure, slow the rate of cognitive decline typical of dementia, suggests research published in the online journal BMJ Open.

Furthermore, these drugs may even boost brain power, the research indicates.

The researchers compared the rates of cognitive decline in 361 patients who had either been diagnosed with Alzheimer’s disease, vascular dementia, or a mix of both. 

Eighty five of the patients were already taking ACE inhibitors; the rest were not.

The researchers also assessed the impact of ACE inhibitors on the brain power of 30 patients newly prescribed these drugs, during their first six months of treatment. The average age of all the participants was 77.

Between 1999 and 2010, the cognitive decline of each patient was assessed using either the Standardised Mini Mental State Examination (SMMSE) or the Quick Mild Cognitive Impairment (Qmci) screen on two separate occasions, six months apart.

Compared with those not taking ACE inhibitors, those on these drugs experienced marginally slower rates of cognitive decline. 

In those whose brain power had been assessed by Qmci, which is a more sensitive screen than the SMMSE, the difference was small, but significant.

And the brain power of those patients newly prescribed ACE inhibitors actually improved over the six month period, compared with those already taking them, and those not taking them at all.

This might be because these patients stuck to their medication regimen better, or it might be a by-product of better blood pressure control, or improved blood flow to the brain, suggest the authors.

But it is the first time that there has been any evidence to suggest that blood pressure lowering drugs may not only halt cognitive decline, but may actually improve brain power.

“This [study] supports the growing body of evidence for the use of ACE inhibitors and other [blood pressure lowering] agents in the management of dementia,” write the authors. 

“Although the differences were small and of uncertain clinical significance, if sustained over years, the compounding effects may well have significant clinical benefits,” they add.

They caution, however, that recent evidence indicates that ACE inhibitors may be harmful in some cases, so if larger studies confirm that they work well in dementia, it may be only certain groups of patients with the condition who stand to benefit.

The results of a new study by neurological researchers at Rush University Medical Center show that a sudden decrease of testosterone, the male sex hormone, may cause Parkinson’s like symptoms in male mice. The findings were recently published in the Journal of Biological Chemistry.

(Image credit)

One of the major roadblocks for discovering drugs against Parkinson’s disease is the unavailability of a reliable animal model for this disease.

“While scientists use different toxins and a number of complex genetic approaches to model Parkinson’s disease in mice, we have found that the sudden drop in the levels of testosterone following castration is sufficient to cause persistent Parkinson’s like pathology and symptoms in male mice,” said Dr. Kalipada Pahan, lead author of the study and the Floyd A. Davis endowed professor of neurology at Rush. “We found that the supplementation of testosterone in the form of 5-alpha dihydrotestosterone (DHT) pellets reverses Parkinson’s pathology in male mice.”

“In men, testosterone levels are intimately coupled to many disease processes,” said Pahan. Typically, in healthy males, testosterone level is the maximum in the mid-30s, which then drop about one percent each year. However, testosterone levels may dip drastically due to stress or sudden turn of other life events, which may make somebody more vulnerable to Parkinson’s disease.

“Therefore, preservation of testosterone in males may be an important step to become resistant to Parkinson’s disease,” said Pahan.

Understanding how the disease works is important to developing effective drugs that protect the brain and stop the progression of Parkinson’s disease. Nitric oxide is an important molecule for our brain and the body.

"However, when nitric oxide is produced within the brain in excess by a protein called inducible nitric oxide synthase, neurons start dying,” said Pahan.

“This study has become more fascinating than we thought,” said Pahan.  “After castration, levels of inducible nitric oxide synthase (iNOS) and nitric oxide go up in the brain dramatically. Interestingly, castration does not cause Parkinson’s like symptoms in male mice deficient in iNOS gene, indicating that loss of testosterone causes symptoms via increased nitric oxide production.”

“Further research must be conducted to see how we could potentially target testosterone levels in human males in order to find a viable treatment,” said Pahan.

Other researchers at Rush involved in this study were Saurabh Khasnavis, PhD, student, Anamitra Ghosh, PhD, student, and Avik Roy, PhD, research assistant professor.

This research was supported by a grant from the National Institutes of Health that received the highest score for its scientific merit in the particular cycle it was reviewed.

Parkinson’s is a slowly progressive disease that affects a small area of cells within the mid-brain known as the substantia nigra. Gradual degeneration of these cells causes a reduction in a vital chemical neurotransmitter, dopamine. The decrease in dopamine results in one or more of the classic signs of Parkinson’s disease that includes resting tremor on one side of the body; generalized slowness of movement; stiffness of limbs and gait or balance problems. The cause of the disease is unknown. Both environmental and genetic causes of the disease have been postulated.

Parkinson’s disease affects about 1.2 million patients in the United States and Canada. Although 15 percent of patients are diagnosed before age 50, it is generally considered a disease that targets older adults, affecting one of every 100 persons over the age of 60. This disease appears to be slightly more common in men than women.