Posts tagged neuroscience

May 8, 2012

Researchers at the Medical Research Council (MRC) Toxicology Unit at the University of Leicester have identified a major pathway leading to brain cell death in mice with neurodegenerative disease. The team was able to block the pathway, preventing brain cell death and increasing survival in the mice.

In human neurodegenerative diseases, including Alzheimer’s, Parkinson’s and prion diseases, proteins “misfold” in a variety of different ways resulting in the build up of misshapen proteins. These form the plaques found in Alzheimer’s and the Lewy bodies found in Parkinson’s disease. 
  
The researchers studied mice with neurodegeneration caused by prion disease, as these mouse models currently provide the best animal representation of human neurodegenerative disorders, where it is known that the build up of misshapen proteins is linked with brain cell death. 
  
They found that the build up of misfolded proteins in the brains of these mice activates a natural defence mechanism in cells, which switches off the production of new proteins. This would normally switch back ‘on’ again, but in these mice the continued build-up of misshapen protein keeps the switch turned ‘off’. This is the trigger point leading to brain cell death, as those key proteins essential for nerve cell survival are not made. 
  
By injecting a protein that blocks the ‘off’ switch of the pathway, the scientists were able to restore protein production, independently of the build up of misshapen proteins, and halt the neurodegeneration. The brain cells were protected, protein levels and synaptic transmission (the way in which brain cells signal to each other) were restored and the mice lived longer, even though only a very small part of their brain had been treated. 
  
Misshapen proteins in human neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases, also over-activate this fundamental pathway controlling protein synthesis in the brains of patients, which represents a common target underlying these different clinical conditions. The scientists’ results suggest that treatments focused on this pathway could be protective in a range of neurodegenerative disease in which misshapen proteins are building up and causing neurons to die. 
  
Professor Giovanna Mallucci, who led the team, said: “What’s exciting is the emergence of a common mechanism of brain cell death across a range of different neurodegenerative disorders and activated by the different misfolded proteins in each disease. The fact that in mice with prion disease we were able to manipulate this mechanism and protect the brain cells means we may have a way forward in how we treat other disorders. Instead of targeting individual misfolded proteins in different neurodegenerative diseases, we may be able to target the shared pathways and rescue brain cell degeneration irrespective of the underlying disease.” 
  
Professor Hugh Perry, chair of the MRC’s Neuroscience and Mental Health Board, said: “Neurodegenerative diseases such as Alzheimer’s and Parkinson’s are debilitating and largely untreatable conditions. Alzheimer’s disease and related disorders affect over seven million people in Europe, and this figure is expected to double every 20 years as the population ages across Europe. The MRC believes that research such as this, which looks at the fundamental mechanisms of these devastating diseases, is absolutely vital. Understanding the mechanism that leads to neuronal dysfunction prior to neuronal loss is a critical step in finding ways to arrest disease progression.”

Provided by Medical Research Council 

Source: medicalxpress.com

May 8, 2012

(Medical Xpress) — Having a fat head may not be a bad thing, according to new findings at The Johns Hopkins University. As reported in the February 9 issue of Neuron, Hopkins researchers have made a significant discovery as to how adding fat molecules to proteins can influence the brain circuitry controlling cognitive function, including learning and memory.

“When you learn something, you strengthen and inhibit certain transmissions and sculpt a particular circuit. Recall [or memory] is using that circuit again,” says Richard L. Huganir, Ph.D., professor and director of the Solomon H. Snyder Department of Neuroscience at Johns Hopkins. His team’s latest finding describes for the first time how one protein chemically alters another in this circuit strengthening process and represents another step toward understanding a key part of how memories are made and maintained within the brain, something researchers believe could provide a pathway toward treating disorders like Alzheimer’s and schizophrenia.

In studying the molecular underpinnings of learning and memory, Huganir and his team have focused on one of several processes in which a molecule is tagged by another molecule of fat. Tagging sends the molecules to a particular destination within a cell. Specifically, the team has studied DHHC5, which is known to add a fat molecule to other proteins. Until now it was not known which proteins receive this tag.

The scientists suspected a target molecule would need to bind DHHC5, which would then transfer fat onto it. To determine what DHHC5 could bind, they used it as bait in a large pool of rat brain proteins to fish for those that stuck to DHHC5. Within that pool, DHHC5 bound four different proteins, researchers found. Using a computer program, they compared these with other proteins implicated in learning and memory. All four shared similarity with the brain protein known as GRIP1, mutations of which have been linked to disorders such as autism. The scientists then tested GRIP1 and DHHC5 directly and found that they bound each other as well. Next, they put GRIP1 into human kidney cells, either by itself or with DHHC5, and analyzed each group of cells to see what happened. They found that only the GRIP1 proteins that were added to cells with DHHC5 were tagged with fat. From this they concluded that DHHC5 does indeed tag GRIP1 with fat.

The researchers then wanted to know if this process happens in a brain. However, they needed a way to look into a living cell and be able to tell apart GRIP1 that had a fat tag and GRIP1 that didn’t. They designed two distinct GRIP1 proteins: one permanently tagged with fat, and another mutated so that it could never be tagged. They added color markers to both proteins so they could track them under a microscope, and then added one type or the other to living brain cells. The fat-tagged proteins seemed to form clusters extending to the cell’s edges in a pattern resembling that of cellular recycling-center proteins. The untagged proteins, in contrast, seemed to diffuse around the center of the cell. From this, the team concluded that DHHC5 tags proteins like GRIP1 with fat to send them to be recycled.

According to Huganir, protein recycling is critical for strengthening and maintaining memory circuits. Since GRIP1 is involved with recycling, it may be important in this critical aspect of memory formation. Huganir believes some day researchers could learn how to control this mechanism and reverse the disease process for disorders like Alzheimer’s and schizophrenia.

“Some day we may be able to inhibit or activate these molecules,” Huganir says. “These molecules are involved in mediating everything in the brain, all behaviors.”

Provided by Johns Hopkins University

Source: medicalxpress.com

May 7th, 2012

New research provides the strongest evidence to date that psychopathy is linked to specific structural abnormalities in the brain.

The study, published in Archives of General Psychiatry and led by researchers at King’s College London is the first to confirm that psychopathy is a distinct neuro-developmental sub-group of anti-social personality disorder (ASPD).

Most violent crimes are committed by a small group of persistent male offenders with ASPD. Approximately half of male prisoners in England and Wales will meet diagnostic criteria for ASPD. The majority of such men are not true psychopaths (ASPD-P). They are characterised by emotional instability, impulsivity and high levels of mood and anxiety disorders. They typically use aggression in a reactive way in response to a perceived threat or sense of frustration.

However, about one third of such men will meet additional diagnostic criteria for psychopathy (ASPD+P). They are characterised by a lack of empathy and remorse, and use aggression in a planned way to secure what they want (status, money etc.). Previous research has shown that psychopaths’ brains differ structurally from healthy brains, but until now, none have examined these differences within a population of violent offenders with ASPD.

Dr Nigel Blackwood from the Institute of Psychiatry at King’s and lead author of the study says: ‘Using MRI scans we found that psychopaths had structural brain abnormalities in key areas of their ‘social brains’ compared to those who just had ASPD. This adds to behavioural and developmental evidence that psychopathy is an important subgroup of ASPD with a different neurobiological basis and different treatment needs.

‘There is a clear behavioural difference amongst those diagnosed with ASPD depending on whether or not they also have psychopathy. We describe those without psychopathy as ‘hot-headed’ and those with psychopathy as ‘cold-hearted’. The ‘cold-hearted’ psychopathic group begin offending earlier, engage in a broader range and greater density of offending behaviours, and respond less well to treatment programmes in adulthood, compared to the ‘hot-headed’ group. We now know that this behavioural difference corresponds to very specific structural brain abnormalities which underpin psychopathic behaviour, such as profound deficits in empathising with the distress of others.’

The researchers used Magnetic Resonance Imaging (MRI) to scan the brains of 44 violent adult male offenders diagnosed with Anti-Social Personality Disorder (ASPD). Crimes committed included murder, rape, attempted murder and grievous bodily harm. Of these, 17 met the diagnosis for psychopathy (ASPD+P) and 27 did not (ASPD-P). They also scanned the brains of 22 healthy non-offenders.

The study found that ASPD+P offenders displayed significantly reduced grey matter volumes in the anterior rostral prefrontal cortex and temporal poles compared to ASPD-P offenders and healthy non-offenders. These areas are important in understanding other people’s emotions and intentions and are activated when people think about moral behaviour. Damage to these areas is associated with impaired empathising with other people, poor response to fear and distress and a lack of ‘self-conscious’ emotions such as guilt or embarrassment.

Dr Blackwood explains: ‘Identifying and diagnosing this sub-group of violent offenders with brain scans has important implications for treatment. Those without the syndrome of psychopathy, and the associated structural brain damage, will benefit from cognitive and behavioural treatments. Optimal treatment for the group of psychopaths is much less clear at this stage.’

Source: Neuroscience News

ScienceDaily (May 7, 2012) — Greater purpose in life may help stave off the harmful effects of plaques and tangles associated with Alzheimer’s disease, according to a new study by researchers at Rush University Medical Center.

Greater purpose in life may help stave off the harmful effects of plaques and tangles associated with Alzheimer’s disease, according to a new study. (Credit: © Nejron Photo / Fotolia)

The study is published in the May issue of the Archives of General Psychiatry.

"Our study showed that people who reported greater purpose in life exhibited better cognition than those with less purpose in life even as plaques and tangles accumulated in their brains," said Patricia A. Boyle, PhD.

"These findings suggest that purpose in life protects against the harmful effects of plaques and tangles on memory and other thinking abilities. This is encouraging and suggests that engaging in meaningful and purposeful activities promotes cognitive health in old age."

Boyle and her colleagues from the Rush Alzheimer’s Disease Center studied 246 participants from the Rush Memory and Aging Project who did not have dementia and who subsequently died and underwent brain autopsy. Participants received an annual clinical evaluation for up to approximately 10 years, which included detailed cognitive testing and neurological exams.

Participants also answered questions about purpose in life, the degree to which one derives meaning from life’s experiences and is focused and intentional. Brain plaques and tangles were quantified after death. The authors then examined whether purpose in life slowed the rate of cognitive decline even as older persons accumulated plaques and tangles.

While plaques and tangles are very common among persons who develop Alzheimer’s dementia (characterized by prominent memory loss and changes in other thinking abilities), recent data suggest that plaques and tangles accumulate in most older persons, even those without dementia. Plaques and tangles disrupt memory and other cognitive functions.

Boyle and colleagues note that much of the Alzheimer’s research that is ongoing seeks to identify ways to prevent or limit the accumulation of plaques and tangles in the brain, a task that has proven quite difficult. Studies such as the current one are needed because, until effective preventive therapies are discovered, strategies that minimize the impact of plaques and tangles on cognition are urgently needed.

"These studies are challenging because many factors influence cognition and research studies often lack the brain specimen data needed to quantify Alzheimer’s changes in the brain," Boyle said. "Identifying factors that promote cognitive health even as plaques and tangles accumulate will help combat the already large and rapidly increasing public health challenge posed by Alzheimer’s disease."

The Rush Memory and Aging Project, which began in 1997, is a longitudinal clinical-pathological study of common chronic conditions of aging. Participants are older persons recruited from about 40 continuous care retirement communities and senior subsidized housing facilities in and around the Chicago Metropolitan area. More than 1,500 older persons are currently enrolled in the study.

Source: Science Daily

ScienceDaily (May 7, 2012) — Antipsychotic medications are increasingly prescribed in the US, but they can cause serious side effects including rapid weight gain, especially in children. In the first study of its kind, researchers at Zucker Hillside Hospital and the Feinstein Institute for Medical Research identified a gene that increases weight gain in those treated with commonly-used antipsychotic drugs.

These findings were published in the May issue of Archives of General Psychiatry.

Second-generation antipsychotics (SGAs) were used as the treatment in this study. SGAs are commonly used to treat many psychotic and nonpsychotic disorders. However, it is important to note that these SGAs are associated with substantial weight gain, including the development of obesity and other cardiovascular risk factors. The weight gain side effect of SGAs is significant because it often results in a reduced life expectancy of up to 30 years in those who suffer from chronic and severe mental illnesses. The weight gain also prompts some to stop taking the medication, adversely impacting their quality of life.

In this genome-wide association study (GWAS), researchers first evaluated a group of pediatric patients in the US being treated for the first time with antipsychotics. They then replicated the result in three independent groups of patients who were in psychiatric hospitals in the United States and Germany or participating in European antipsychotic drug trials. The gene that was identified to increase weight gain, MC4R or melanocortin 4 receptor, has been previously identified as being linked to obesity and type 2 diabetes. In the new study, it was found that patients gained up to 20 pounds when on treatment.

"This study offers the prospect of being able to identify individuals who are at greatest risk for severe weight gain following antipsychotic treatment," said Anil Malhotra, MD, investigator at the Zucker Hillside Hospital Department of Psychiatry Research and Feinstein Institute for Medical Research. "We hope that those who are at risk could receive more intensive or alternative treatment that would reduce the potential for weight gain and we are currently conducting studies to identify such treatment."

Additional Details About the Study

Researchers conducted the first GWAS of SGA-induced weight gain in patients carefully monitored for medication adherence who were undergoing initial treatment with SGAs. To confirm results, they next assessed three independent replication cohorts: 1) a cohort of adult subjects undergoing their first treatment with a single SGA (clozapine), 2) a cohort of adult subjects treated with the same SGAs as in our discovery sample, and 3) a cohort of adult subjects in the first episode of schizophrenia and enrolled in a randomized clinical trial of antipsychotic drugs. The discovery cohort consisted of 139 pediatric patients undergoing first exposure to SGAs. The 3 additional cohorts consisted of 73, 40, and 92 subjects. Patients in the discovery cohort were treated with SGAs for 12 weeks. Additional cohorts were treated for 6 and 12 weeks.

This GWAS yielded 20 single-nucleotide polymorphisms at a single locus exceeding a statistical threshold of P10-5. This locus, near the melanocortin 4 receptor (MC4R) gene, overlaps a region previously identified by large-scale GWAS of obesity in the general population. Effects were recessive, with minor allele homozygotes gaining extreme amounts of weight during the 12-week trial. These results were replicated in 3 additional cohorts, with rs489693 demonstrating consistent recessive effects; meta-analysis revealed a genome-wide significant effect. Moreover, consistent effects on related metabolic indices, including triglyceride, leptin, and insulin levels were observed.

Source: Science Daily

ScienceDaily (May 7, 2012) — Depressive symptoms that are present in midlife or in late life are associated with an increased risk of developing dementia, according to a report in the May issue of Archives of General Psychiatry, a JAMA Network publication.

Nearly 5.3 million individuals in the United States have Alzheimer disease (AD) and the resulting health care costs in 2010 were roughly $172 billion, the authors write as background information in the study. “Prevalence and costs of AD and other dementias are projected to rise dramatically during the next 40 years unless a prevention or a cure can be found. Therefore, it is critical to gain a greater understanding of the key risk factors and etiologic underpinnings of dementia from a population-based perspective,” the authors write.

Deborah E. Barnes, Ph.D., M.P.H., of the University of California, San Francisco and the San Francisco Veterans Affairs Medical Center, and colleagues evaluated data from 13,535 long-term Kaiser Permanente members and examined depressive symptoms assessed in midlife (1964-1973) and in late life (1994-2000) and risks of developing dementia, Alzheimer disease (AD) and vascular dementia (VaD; dementia resulting from brain damage from impaired blood flow to the brain).

Depressive symptoms were present in 14.1 percent of study participants in midlife only, 9.2 percent in late life only and 4.2 percent in both. During six years of follow-up, 22.5 percent of patients were diagnosed with dementia; 5.5 percent with Alzheimer disease and 2.3 percent with VaD.

When examining AD and VaD separately, patients with late-life depressive symptoms had a two-fold increase in AD risk, and patients with midlife and late-life symptoms had more than a three-fold increase in VaD risk.

"Our findings suggest that chronic depression during the life course may be etiologically associated with an increased risk of dementia, particularly VaD, whereas depression that occurs for the first time in late life is likely to reflect a prodromal stage of dementia, in particular AD," the authors conclude.

Source: Science Daily

ScienceDaily (May 7, 2012) — The deletion of part of a gene that plays a role in the synthesis of carnitine — an amino acid derivative that helps the body use fat for energy — may play a role in milder forms of autism, said a group of researchers led by those at Baylor College of Medicine and Texas Children’s Hospital.

"This is a novel inborn error of metabolism," said Dr. Arthur Beaudet, chair of molecular and human genetics at BCM and a physician at Texas Children’s Hospital, and the senior author of the report that appears online in the Proceedings of the National Academy of Sciences. "How it is associated with the causes of autism is as yet unclear. However, it could point to a means of treatment or even prevention in some patients."

Deletion leads to imbalance

Beaudet and his international group of collaborators believe the gene deletion leads to an imbalance in carnitine in the body. Meat eaters receive about 75 percent of their carnitine from their diet. However, dietary carnitine levels are low in vegetarians and particularly in vegans. In most people, levels of carnitine are balanced by the body’s ability to manufacture its own carnitine in the liver, kidney and brain, starting with a modified form of the amino acid lysine.

Carnitine deficiency has been identified when not enough is absorbed through the diet or because of medical treatments such as kidney dialysis. Genetic forms of carnitine deficiency also exist, which are caused when too much carnitine is excreted through the kidneys.

In this new inborn error, there is a deletion in the second exon — the protein-coding portion of a gene — of the TMLHE gene, which includes the genetic code for the first enzyme in the synthesis of carnitine (TMLHE stands for trimethyllysine epsilon which encodes the enzyme trimethyllysine dioxygenase).

Studies in the laboratory that identified the deletion were led by Dr. Patricia B.S. Celestino-Soper, as a graduate student in Beaudet’s laboratory at BCM, and by Dr. Sara Violante, a graduate student in the laboratory of Dr. Frédéric M. Vaz of the Academic Medical Center in Amsterdam.

Frequency of deletion

To determine the frequency of the gene deletion, Beaudet and his colleagues tested male autism patients who were the only people with the disorder in their families (simplex families) from the Simons Simplex Collection, the South Carolina Early Autism Project and Houston families. In collaboration with laboratories and researchers in Nashville, Los Angeles, Paris, New York, Toronto and Cambridge (United Kingdom), they tested affected male siblings in families with more than one male case of autism (multiplex families).

When they looked at the TMLHE genes in males affected by autism and compared them to normal controls, they found that the gene alteration is a fairly common one, occurring in as many as one in 366 males unaffected by autism. It was not significantly more common in males within families in which there is only one person with autism. However, it is nearly three times more common in families with two or more boys with autism.

No syndromic form

Beaudet said most of the affected males with the deletion did not have syndromic autism that is frequently associated with other serious diseases. In many instances, syndromic autism affects physical development as well as cognitive, which is reflected in their facial features as well as other parts of their bodies. None of the six boys affected with autism (where information was available) had the syndromic form of disease. Their intelligence quotients and cognitive scores varied, with some being far below normal and others normal.

"Most of the males we identified with the TMLHE deficiency were apparently normal as adults," said Beaudet, although detailed information on learning and behavior was not available on these "control" males. "The gene deletion is neither necessary nor sufficient in itself to cause autism."

"TMLHE deficiency itself is likely to be a weak risk factor for autism, but we need to do more studies to replicate our results," Beaudet said. He estimated that at the rates found in his study, the deficiency might be a factor in about 170 males born with autism per year in the United States. This would equate to about one-half of one percent of autism cases.

The authors from Amsterdam found major increases in some carnitine-related chemicals and absence of others in both urine and plasma. These metabolic alterations were found to be predictive of the dysfunction of the TMLHE gene and therefore can be used to identify males with this disorder.

It remains uncertain whether TMLHE deficiency is benign or causes autism by affecting the function of neurons through toxic accumulation or deficiency of a variety of chemical metabolites.

"We believe that the most attractive hypothesis at this time is that the increased risk of autism is modified by dietary intake of carnitine from birth through the first few years of life," said Beaudet.

He and his colleagues are undertaking three studies to further their understanding of the TMLHE deficiency. In one, they will attempt to replicate the findings in multiplex families. In a second, they will study carnitine levels in the cerebrospinal fluid of infants with autism — both those who have the gene deficiency and those who do not. In a third study, they plan to begin giving boys under age 5 with autism carnitine or a related supplement and determine whether this improves the behavior of those with the TMLHE deficiency and those without.

Source: Science Daily

ScienceDaily (May 7, 2012) — One of the world’s most important fossils has a story to tell about the brain evolution of modern humans and their ancestors, according to Florida State University evolutionary anthropologist Dean Falk.

Taung surrounded by a juvenile chimp skull and human skull, the latter having a fontanelle and metopic suture. The metopic suture is visible on the frontal lobe of Taung’s endocast. (Credit: CT-based images by M. Ponce de León and Ch. Zollikofer, University of Zurich)

The Taung fossil — the first australopithecine ever discovered — has two significant features that were analyzed by Falk and a group of anthropological researchers. Their findings, which suggest brain evolution was a result of a complex set of interrelated dynamics in childbirth among new bipeds, were published May 7 in the Proceedings of the National Academy of Sciences.

"These findings are significant because they provide a highly plausible explanation as to why the hominin brain might grow larger and more complex," Falk said.

The first feature is a “persistent metopic suture,” or unfused seam, in the frontal bone, which allows a baby’s skull to be pliable during childbirth as it squeezes through the birth canal. In great apes — gorillas, orangutans and chimpanzees — the metopic suture closes shortly after birth. In humans, it does not fuse until around 2 years of age to accommodate rapid brain growth.

The second feature is the fossil’s endocast, or imprint of the outside surface of the brain transferred to the inside of the skull. The endocast allows researchers to examine the brain’s form and structure.

After examining the Taung fossil, as well as huge numbers of skulls belonging to apes and humans, as well as corresponding 3-D CT (three-dimensional computed tomographic) scans, and taking into account the fossil record for the past 3 million years, Falk and her colleagues noted three important findings: The persistent metopic suture is an adaptation for giving birth to babies with larger brains; is related to the shift to a rapidly growing brain after birth; and may be related to expansion in the frontal lobes.

"The persistent metopic suture, an advanced trait, probably occurred in conjunction with refining the ability to walk on two legs," Falk said. "The ability to walk upright caused an obstretric dilemma. Childbirth became more difficult because the shape of the birth canal became constricted while the size of the brain increased. The persistent metopic suture contributes to an evolutionary solution to this dilemma."

The later fusion of the metopic suture is most likely an adaptation of hominins who walked upright to be able to more easily give birth to babies with relatively large brains. The unfused seam is also related to the shift to rapidly growing brains after birth, an advanced human-like feature as compared to apes.

"The later fusion was also associated with evolutionary expansion of the frontal lobes, which is evident from the endocasts of australopithecines such as Taung," Falk said.

The Taung fossil, which is estimated to be around 2½ million years old, was discovered in 1924 in Taung, South Africa. It became the “type specimen,” or main model, of the genus Australopithecus africanus when it was announced in 1925.

An australopithecine is any species of the extinct generaAustralopithecus or Paranthropus that lived in Africa, walked on two legs and had relatively small brains.

Source: Science Daily

May 7, 2012

A study on a handful of people with suspected mild Alzheimer’s disease (AD) suggests that a device that sends continuous electrical impulses to specific “memory” regions of the brain appears to increase neuronal activity. Results of the study using deep brain stimulation, a therapy already used in some patients with Parkinson’s disease and depression, may offer hope for at least some with AD, an intractable disease with no cure.

"While our study was designed mainly to establish safety, involved only six people and needs to be replicated on a larger scale, we don’t have another treatment for AD at present that shows such promising effects on brain function," said the study’s first author, Gwenn Smith, Ph.D., a professor in the Department of Psychiatry and Behavioral Sciences at the Johns Hopkins University School of Medicine. The research, published in the Archives of Neurology, was conducted while Smith was on the faculty at the University of Toronto, and will be continuing at Toronto, Hopkins and other U.S. sites in the future. The study was led by Andres M. Lozano, chairman of the Department of Neurosurgery at the University of Toronto.

One month and one year after implanting a device that allows for continuous electrical impulses to the brain, Smith and her colleagues performed PET scans that detect changes in brain cells’ metabolism of glucose, and found that patients with mild forms of AD showed sustained increases in glucose metabolism, an indicator of neuronal activity. The increases, the researchers say, were larger than those found in patients who have taken the drugs currently marketed to fight AD progression. Other imaging studies have shown that a decrease in glucose metabolism over the course of a year is typical in AD. Alzheimer’s disease cannot be precisely diagnosed by brain biopsies until after death.

The team observed roughly 15 percent to 20 percent increases in glucose metabolism after one year of continuous stimulation. The increases were observed, to a greater extent, in patients with better outcomes in cognition, memory and quality of life. In addition, the stimulation increased connectivity in brain circuits associated with memory.

Deep brain stimulation (DBS) requires surgical implantation of a brain pacemaker, which sends electrical impulses to specific parts of the brain. For the study, surgeons implanted a tiny electrode able to deliver a low-grade electrical pulse close to the fornix, a key nerve tract in brain memory circuits. The researchers — most with the University of Toronto — reported few side effects in the six subjects they tested. Just as importantly, says Smith, was seeing that DBS appeared to reverse the downturn in brain metabolism that typically comes with AD.

AD is a progressive and lethal dementia that mostly strikes the elderly. It affects memory, thinking and behavior. Estimates vary, but experts suggest that as many as 5.1 million Americans may have AD and that, as baby boomers age, prevalence will skyrocket. Smith says decades of research have yet to lead to clear understanding of its causes or to successful treatments that stop progression.

The trial of DBS came about, Smith reports, when Lozano used DBS of the fornix to treat an obese man. The procedure, designed to target the regions of the brain involved in appetite suppression, unexpectedly had significant increases in his memory. Inspired, the scientists persisted through rigorous ethical and scientific approvals before their AD phase I safety study could begin.

Smith, who also is director of the Division of Geriatric Psychiatry and Neuropsychiatry at Johns Hopkins Bayview Medical Center, is an authority on mapping the brain’s glucose metabolism in aging and psychiatric disease. It was Smith’s earlier analysis of AD patients’ PET scans that revealed their distinct pattern of lowered brain metabolism. She determined that specific parts of the temporal and parietal cerebral cortex — memory network areas of the brain where AD’s earliest pathology surfaces— became increasingly sluggish with time.

Provided by Johns Hopkins Medical Institutions

Source: medicalxpress.com

ScienceDaily (May 7, 2012) — Badly controlled diabetes are known to affect the brain causing memory and learning problems and even increased incidence of dementia, although how this occurs is not clear. But now a study in mice with type 2 diabetes has discovered how diabetes affects a brain area called hippocampus causing memory loss, and also how caffeine can prevent this. 

Curiously, the neurodegeneration that Rodrigo Cunha  from the Centre for Neuroscience and Cell Biology of the University of Coimbra in Portugal see caused by diabetes is the same that occurs at the first stages of several neurodegenerative diseases, including Alzheimer’s and Parkinson’s, suggesting that caffeine (or drugs with similar mechanism) could help them too.

 Type 2 diabetes (which accounts for about 90%of all diabetic cases) is a full blown public health disaster – 285 million people affected worldwide (6.4% of the world population) with numbers expected to almost double by 2030. And this without counting pre-diabetic individuals. The problem is that the disease is triggered by obesity, sedentary lifestyle and bad eating habits (although there is also a genetic predisposition), all of which are increasingly widespread. 

Diabetes is caused by high levels of sugar in the blood, and in type 2 this occurs because the body becomes increasingly resistant to insulin –the hormone that allows the cells to take the sugar from the blood to use it as “fuel” – resulting in toxic high levels of sugar  in the blood that damage nerves and blood vessels and, with time, cause severe complications

 In the study out now in the journal PLoS , João Duarte, Rodrigo Cunha and colleagues take advantage of a new mouse model of diabetes type 2, which, like humans, develops the disease in adults as result of a high-fat diet, to look at one of the least understood complications of diabetes – the disease effect on the brain, more specifically, on memory. They also investigate a possible protective effect by caffeine as this psychostimulant has been suggested to prevent memory loss in a series of neurodegenerative diseases, maybe even in diabetes, although how this happens is not known. And when we consider that coffee is the world leading beverage right after water, with about 500 billion cups consumed annually, this, if true, needs to be better understood.

With that aim  the Portuguese researchers compared four groups of mice - diabetic or normal animals without or with caffeine (equivalent to 8 cups of coffee a day) in their water – to find that long-term consumption of caffeine not only diminished the weight gain and the high levels of blood sugar typical of diabetes, but also prevented the mice’s memory loss (diabetic animals had significantly poorer memory than normal ones). This confirmed that caffeine could, in fact, protect against diabetes as well as prevent memory impairment, probably by interfering with the neurodegeneration caused by toxic sugar levels.

To investigate this, next, the researchers looked at a brain region linked to memory and learning, which is often atrophied in diabetics, called hippocampus. And in fact, diabetic mice had abnormalities in this area showing synaptic degeneration (synapses are the structures at the end of each neuron used to communicate between neurons) and astrogliosis (an abnormal increase of the cells that surround neurons normally as result of the deathof nearby neurons). Both phenomena are known to affect memory and caffeine consumption  prevented the abnormalities.

But to be able to develop drugs based on caffeine’s protective effect, it was necessary to understand its molecular mechanisms. So next the researchers looked at the only brain molecules known to respond to caffeine – the adenosine receptors A1R and A2AR - in the hippocampus. And here, A2AR seemed to be the key for caffeine’s memory rescue since its density - which increases with noxious insults - was high in diabetic animals but normal in those treated with caffeine. This agrees with the previous studies that showed that A2AR inhibition protected against synaptic degeneration and memory dysfunction.

In conclusion, Duarte and Cunha’s work – using an animal model of diabetes type 2 that closely mimics the human form of the disease – suggests that diabetes affects memory by causing synaptic degeneration, astrogliosis and increased levels of A2AR. The study indicates as well that chronic consumption of caffeine can prevent the neurodegeneration and the memory impairment. And this not only in diabetes, since synaptic degeneration and astrogliosis are both part of a cascade of events common to several neurodegenerative diseases, suggesting that caffeine (or similar drugs) could help them too through the same mechanisms.

So does this means that we should drink eight cups of coffee a day to prevent memory loss in old age or diabetes? 

Not really as Rodrigo Cunha, the team leader explains: “Indeed, the dose of caffeine shown to be effective is just too excessive. All we can take from here is that a moderate consumption of caffeine should afford a moderate benefit, but still a benefit. Such experimental design is common in pre-clinical studies: in order to highlight a clear benefit, one dramatises the tested doses. But it’s an important first step. Our ultimate goal is the design of a drug more potent and selective (i.e. with less potential side effects) than caffeine itself; animal studies enable us to pinpoint the likely target of caffeine with protective benefits in type 2 diabetes. So now we will be testing chemical derivates of caffeine, which act as selective adenosine A2A receptor antagonists,to try to prevent diabetic encephalopathy. It might turn out to be a therapeutic breakthrough for this devastating disease”. 

And a breakthrough in a disease that is already affecting 6.4% of the population and growing can never come too soon.

Source: Science Daily