Category Archives: Research News (General)

A scientific team led by the Gladstone Institutes and UC San Francisco has discovered that a common form of a gene already associated with long life also improves learning and memory, a finding that could have implications for treating age-related diseases like Alzheimer’s.

The researchers found that people who carry a single copy of the KL-VS variant of the KLOTHO gene perform better on a wide variety of cognitive tests. When the researchers modeled the effects in mice, they found it strengthened the connections between neurons that make learning possible – what is known as synaptic plasticity – by increasing the action of a cell receptor critical to forming memories.

The discovery is a major step toward understanding how genes improve cognitive ability and could open a new route to treating diseases like Alzheimer’s. Researchers have long suspected that some people may be protected from the disease because of their greater cognitive capacity, or reserve. Since elevated levels of the klotho protein appear to improve cognition throughout the lifespan, raising klotho levels could build cognitive reserve as a bulwark against the disease.

"As the world’s population ages, cognitive frailty is our biggest biomedical challenge," said Dena Dubal, MD, PhD, assistant professor of neurology, the David A. Coulter Endowed Chair in Aging and Neurodegeneration at UCSF and lead author of the study,published May 8 in Cell Reports. "If we can understand how to enhance brain function, it would have a huge impact on people’s lives."

Klotho was discovered in 1997 and named after the Fate from Greek mythology who spins the thread of life. The investigators found that people who carry a single copy of the KL-VS variant of the KLOTHO gene, roughly 20 percent of the population, have more klotho protein in their blood than non-carriers. Besides increasing the secretion of klotho, the KL-VS variant may also change the action of the protein and is known to lessen age-related cardiovascular disease and promote longevity.

The team’s report is the first to link the KL-VS variant, or allele, to better cognition in humans, and buttresses these findings with genetic, electrophysiological, biochemical and behavioral experiments in mice. The researchers tested the associations between the allele and age-related human cognition in three separate studies involving more than 700 people without dementia between the ages of 52 and 85. Altogether, it took about three years to conduct the work.

"These surprising results pave a promising new avenue of research," said Roderick Corriveau, Ph.D., program director at NIH’s National Institute of Neurological Disorders and Stroke (NINDS). "Although preliminary, they suggest klotho could be used to bump up cognition for people suffering from dementia."

Having the KL-VS allele did not seem to protect people from age-related cognitive decline. But overall the effect was to boost cognition, so that the middle-aged study participants began their decline from a higher point.

Source:  NIH, USA

Conditions which may accelerate the spread of Parkinson’s disease, and a potential means of enhancing naturally-occurring defences against neurodegenerative disorders, have been identified in two new studies.

Both sets of results have emerged from collaborations between the research groups led by Chris Dobson, Tuomas Knowles and Michele Vendruscolo at the University of Cambridge, who focus on understanding protein "misfolding" diseases. These include Alzheimer’s and Parkinson’s diseases, as well as numerous others.

The first study provides evidence that the early spread of the protein aggregates associated with Parkinson’s appears to happen at an accelerated rate in mildly acidic conditions. This suggests that particular compartments within brain cells, which are slightly more acidic than others, may turn out to be appropriate targets for future treatments fighting the disease.

Meanwhile, researchers behind the second study appear to have identified a way in which the effectiveness of so-called molecular "chaperones", responsible for limiting the damage caused by misfolded proteins, can be significantly enhanced.

The papers appear in the latest issue of Proceedings of the National Academy of Sciences.                                   

Source: University of Cambridge                                                                                                                                                                                                                                                                                                                                                             

French research into the impact of a premature menopause (less than 40 years old) on cognitive function in later life indicates that premature surgical menopause and premature ovarian failure are associated with long-term negative effects on cognitive function.

These effects are not offset by menopausal hormone therapy (HT) completely.

The potential long-term effects on cognitive function should be included in the risk / benefit considerations for surgical menopause (ovariectomy) in younger women.

No significant link was discovered between premature menopause and the risk of dementia in later life.

The three Dementia Challenge Champion Groups have written brief reports detailing their progress during the past year.

These reports feature in aletter to the UK Prime Minister which also reiterates achievements since the Prime Minister’s Dementia Challenge was launched 2 years ago and describes the Champion Groups’ ambitions for the third year of the dementia challenge.

To recap, the challenge’s three champion groups comprise:

1. The Dementia Health and Care Champion Group: co-chaired by: Sir Ian Carruthers (NHS South West) and Sarah Pickup (ADASS).
2. The Dementia Friendly Communities Champion Group: co-chaired by: Jeremy Hughes (Alzheimer’s Society) and Angela Rippon.
3. The Research Champion Group: led by the Ministerial Advisory Group on Dementia Research (MAGDR) and co-chaired by Dame Sally C. Davies and Professor Patrick Maxwell.

A glucagon-like peptide-1 agonist (GLP-1 agonist) medication, Exenatide, marketed as Byetta® and Bydureon® is used in the treatment of insulin resistance in patients with Type 2 diabetes.

Several recent discoveries have highlighted common cellular pathways that potentially relate neurodegenerative processes with abnormal mitochondrial function and abnormal glucose metabolism.

A follow-up study of patients with Parkinson’s disease (PD) who participated in an earlier "proof of concept" clinical trial using exenatide showed that improvements persisted twelve months after discontinuing exenatide therapy. These data provide strong encouragement for the further study of this drug in patients with PD, report researchers in theJournal of Parkinson’s Disease.

Earlier studies had shown that exenatide is neuroprotective and promotes functionally beneficial neuroplasticity in animal models of neurodegeneration. Furthermore, exenatide has a favorable safety profile, with only relatively mild gastrointestinal side effects (including nausea and weight loss) as frequent adverse events.

In an earlier "proof of concept" randomized controlled trial published in May 2013, participants were randomized to either self-administer exenatide in addition to their regular PD medications or to act as controls, i.e., receive their conventional PD treatment only. All of the participants had moderate severity PD. In total, 44 patients (20 in the exenatide group and 24 controls) completed the trial. After 12 months the results showed significant and clinically meaningful differences in both motor and cognitive symptoms between those patients receiving exenatide and the controls. At 14 months, when the patients had discontinued exenatide for two months, the exenatide-treated and control groups still differed from each other. The authors concluded that the study supported potential disease-modifying benefits of exenatide in PD, while acknowledging the lack of a placebo arm.

Source: Science Codex

Are patients with Parkinson’s disease “blind to blindsight?” That’s not a trick question, but the focus of an inquiry by neuroscientists from Rush University Medical Center as well as the Centre Hospitalier and University of Luxembourg.

Scientists have developed the concept of "blind to blindsight" to integrate data on visual impairments that contribute to the disability and diminished quality of life in patients with Parkinson’s disease.

Blindsight is observed in people who are blind as a result of a lesion in the visual cortex of their brain. Although these individuals are blind, they maintain the ability to sense accurately a light source or a rapid movement without being aware of it. Strangely, blindsighted patients even can respond appropriately to emotional facial expressions, especially those expressing fear or danger. It is believed that these visual stimuli can be turned directly into actions (e.g., movement of the eyes) by passing through lower areas of the brain. Thus, these retained visual functions operate as unconscious responses to visual stimulation even when there is extensive damage to the visual cortex.

Conversely, patients with Parkinson’s disease, who do not have a problem with their general vision, are unable to do these tasks: they display slowness and reduced accuracy of pursuit eye movements. They often have difficulties grasping a moving object, and show decreased sensitivity to low contrast and impaired ability to read "right away" other people’s facial expressions.

Taken together, these Parkinson’s disease symptoms represent major impairments in blindsight – hence, "blind to blindsight."

The "blind to blindness" concept is described in theJune issue of the journal Brain by Dr. Nico J. Diederich, from Centre Hospitalier and University of Luxembourg, who is a visiting scholar at Rush University. He was joined by the Rush researchers Glenn Stebbins, PhD, and Dr. Christopher G. Goetz, and neuropsychologist Christine Schiltz, PhD, from the University of Luxembourg.

Based on this new concept, the researchers could now propose a new concept how to comprehensively understand within one visual system—blindsight—numerous visual signs and symptoms of patients with Parkinson’s disease. Impairment of the evolutionary old networks in the brain operating within the blindsight visual system form the basis of the visual problems in Parkinson’s disease.

Source: Rush University USA

A recent study conducted by researchers from the Mayo Clinic in Florida examines the discovery of an atypical type of Alzhiemer’s–one that neuroscientists claim is not well recognized nor appropriately treated.

The variant, called hippocampal sparing AD, made up 11 percent of the 1,821 AD-confirmed brains examined by Mayo Clinic researchers — suggesting this subtype is relatively widespread in the general population. The Alzheimer’s Association estimates that 5.2 million Americans are living with AD. And with nearly half of hippocampal sparing AD patients being misdiagnosed, this could mean that well over 600,000 Americans make up this AD variant, researchers say.

In an oral presentation at the annual meeting of the American Academy of Neurology in Philadelphia, scientists say hippocampal sparing AD often produces symptoms that are substantially different from the most commonly known form of AD, which affects the hippocampus, the center of memory.

The patients, mostly male, are afflicted at a much younger age, and their symptoms can be bizarre — behavioral problems such as frequent and sometimes profane angry outbursts, feelings that their limbs do not belong to them and are controlled by an “alien” unidentifiable force, or visual disturbances in the absence of eye problems, researchers say. They also decline at a much faster rate than do patients with the most common form of AD.

“Many of these patients, however, have memories that are near normal, so clinicians often misdiagnose them with a variety of conditions that do not match the underlying neuropathology,” says the study’s lead author, Melissa Murray, Ph.D., an assistant professor of neuroscience at Mayo Clinic in Florida.

Many of these patients are diagnosed with frontotemporal dementia, a disorder characterized by changes in personality and social behavior, or corticobasal syndrome, characterized by movement disorders and cognitive dysfunction. Language dysfunction is also more common in hippocampal sparing AD, although patients do not have vocal or hearing deficits.

“What is tragic is that these patients are commonly misdiagnosed and we have new evidence that suggests drugs now on the market for AD could work best in these hippocampal sparing patients — possibly better than they work in the common form of the disease,” Dr. Murray says.

Source: Canada Journal.net

According to the results of the EU FP7-funded REPLACES project (completed 2013), the pattern of brain alterations may be similar in several different neurodegenerative diseases, which may lead to alternative therapeutic strategies to treat these diseases.

The project sheds light on the abnormal working of a particular brain circuitry related to Parkinson’s disease. The project focused on the study of a highly plastic brain circuitry, which connects regions of the cerebral cortex with the basal ganglia. Researchers studied the function and plasticity of this circuit in different animal models of Parkinson disease.

The researchers found the exact same alterations were present and conserved, which makes it an alternative target for trying to re-establish the appropriate functioning and reverse the symptoms of the disease.

In addition, the research has also shed some light into unrelated diseases. The same alterations in the working of the communication systems among neurons are shared among different diseases. The results of the project suggest these same circuits are implicated in different forms of pathologies, which may provide vital insight into the possible common links between neurodegenerative diseases.

Claudia Bagni, PhD, explains, “This is why we speak about ‘synaptopathies’: there are common players among Parkinson’s disease, autism, and other forms of intellectual disabilities and even schizophrenia. Several of the mutated genes are the same, and affect the signalling systems through common molecules.” Progress is in sight thanks to a much better understanding of the working of the abnormal synapses in Parkinson disease.

Project researchers hope the door is now open for the first clinical trials in humans, as the prior experiments performed in monkeys showed encouraging results. Monica Di Luca, PhD, project coordinator, says, “We have identified a potential new target for treatment, and tested a couple of molecules in animals, [and the] next step would be to find a partnership with pharmaceutical industries interested in pursuing this research.”

Source:  Science Daily

Researchers from the Institute of Neuroscience at the Universitat Autònoma de Barcelona claim to have reversed memory loss in Alzheimer’s disease mouse models, using gene therapy.

The team of researchers discovered the cellular mechanism involved in memory consolidation and were able to inject the hippocampus with a gene which causes the production of a protein blocked in patients with Alzheimer’s, Crtc1 (CREB regulated transcription coactivator-1). Once restored, the protein allows free passage to signals needed to activate the genes involved in long-term memory functioning.

“When the Crtc1 protein is altered, the genes responsible for the synapsis or connections between neurons in the hippocampus cannot be activated and the individual cannot perform memory tasks correctly”, explained Carlos Saura, head of the research team.

The study authors suggest that a cure for AD lies in developing pharmacological therapies, which can activate the Crtc1 protein thus preventing, slowing down or reverting cognitive changes.

Their research appears on the cover of the 23 April edition of The Journal of Neuroscience.

Source: Journal of Neuroscience

A new line of mice promises to circumvent many of the problems of existing models by recapitulating much of the pathology seen in presymptomatic Alzheimer’s, without overexpressing APP or interrupting other mouse genes.

Over the last two decades, researchers have generated dozens of different mouse models of Alzheimer’s disease. The most commonly used lines carry mutant forms of human Abeta precursor protein (APP), either alone or in combination with human presenilin, tau, or other genes.

Used for both basic research and drug discovery, these animals have provided a wealth of information. However, there have been niggling doubts from the beginning that some of their phenotypes may have little to do with the human disease, and negative clinical trials later reinforced critical debate about the validity of overexpression models.

For example, some models can only be maintained on specific genetic backgrounds, some die young or have surprising phenotypes when crossed with other mouse lines, and in others amyloidosis drifts later in successive generations, suggesting gene expression changes from parents to offspring.

Enter a new line of mice that promises to circumvent many of these problems. Researchers led by Takaomi Saido have engineered APP knock-ins. These animals recapitulate much of the pathology seen in presymptomatic AD, without overexpressing APP or interrupting other mouse genes. How do these knock-ins compare? Click on the link below:

Source: AlzForum