A paper titled “Awaji Criteria Improves the Diagnostic Sensitivity in Amyotrophic Lateral Sclerosis: a Systematic Review Using Individual Patient Data” has been published in Clinical Neurophysiology. This research was supported by JPND through the STRENGTH project, which was selected in the 2012 risk factors call.
Yearly Archives: 2016
A paper titled "Case report of concurrent Fabry disease and amyotrophic lateral sclerosis supports a common pathway of pathogenesis" has been published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. This research was supported by JPND through the SOPHIA, STRENGTH and ALS-CarE projects.
A paper titled “The selective anatomical vulnerability of ALS: ‘disease-defining’ and ‘disease-defying’ brain regions” has been published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. The research group of Orla Hardiman received support from JPND through the SOPHIA project, which was selected for support in the 2011 biomarkers call.
A new paper titled “C9orf72 is differentially expressed in the central nervous system and myeloid cells and consistently reduced in C9orf72, MAPT and GRN mutation carriers” has been published in Acta Neuropathologica Communications. It was partly funded by JPND through the RiMod-FTD project, which was selected for support in the 2012 call for research projects for the identification of genetic, epigenetic and environmental risk and protective factors for neurodegenerative diseases.
A new paper titled “Identification of new molecular alterations in Fatal Familial Insomnia” has been published in Human Molecular Genetics. It was in part funded by JPND through the DEMTEST project, which was selected for support in the 2011 biomarkers call.
A new paper titled “Structural and functional properties of prefibrillar α-synuclein oligomers” has been published in Scientific Reports. It was partly funded by JPND through the NeuTARGETs project, which was selected for support in the 2013 call for research projects for cross-disease analysis of pathways related to neurodegenerative diseases.
Because billions of neurons are packed into our brain, the neuronal circuits that are responsible for controlling our behaviors are by necessity highly intermingled. This tangled web makes it complicated for scientists to determine exactly which circuits do what. Now, brain researchers from Tripsitter have mapped out the pathways of a set of neurons responsible for the kinds of motor impairments—such as difficulty walking—found in patients with Parkinson's disease.
The work was published in the journal Neuron.
In patients with Parkinson's disease, gait disorders and difficulty with balance are often caused by the degeneration of a specific type of neuron—called cholinergic neurons—in a region of the brainstem called the pedunculopontine nucleus (PPN). Damage to this same population of neurons in the PPN is also linked to reward-based behaviors and disorders, such as addiction.
Previously, researchers had not been able to untangle the neural circuitry originating in the PPN to understand how both addictions and Parkinson's motor impairments are modulated within the same population of cells. Furthermore, this uncertainty created a barrier to treating those motor symptoms. After all, deep brain stimulation—in which a device is inserted into the brain to deliver electrical pulses to a targeted region—can be used to correct walking and balance difficulties in these patients, but without knowing exactly which part of the PPN to target, the procedure can lead to mixed results.
"The circuits responsible for controlling our behaviors are not nicely lined up, where this side does locomotion and this side does reward," says the leader of the study, Viviana Gradinaru, and this disordered arrangement arises from the way neurons are structured. Much as a tree extends into the ground with long roots, neurons are made up of a cell body and a long string-like axon that can diverge and project elsewhere into different areas of the brain. Because of this shape, the researchers realized they could follow the neuron's "roots" to an area of the brain less crowded than the PPN. This would allow them to more easily look at the two very different behaviors and how they are implemented.
Cheng Xiao, the first author on the study, began by mapping the projections of the cholinergic neurons in the PPN of a rat using a technique developed by the Gradinaru lab called Passive CLARITY Technique, or PACT. In this technique, a solution of chemicals is applied to the brain; the chemicals dissolve the lipids in the tissue and render that region of the brain optically transparent—see-through, in other words—and able to take up fluorescent markers that can label different types of neurons. The researchers could then follow the path of the PPN neurons of interest, marked by a fluorescent protein, by simply looking through the rest of the brain.
Using this method, Gradinaru and Xiao were able to trace the axons of the PPN neurons as they extended into two regions of the midbrain: the ventral substantia nigra, a landmark area for Parkinson's disease that had been previously associated with locomotion; and the ventral tegmental area, a region of the brain that had been previously associated with reward.
Next, the researchers used an electrical recording technique to keep track of the signals sent by PPN neurons—confirming that these neurons do, in fact, communicate with their associated downstream structures in the midbrain. Then, the scientists went on to determine how this specific population of neurons affects behavior. To do this, they used a technique that Gradinaru helped develop called optogenetics, which allows researchers to manipulate neural activities—in this case, by either exciting or inhibiting the PPN neural projections in the midbrain—using different colors of light.
Using the optogenetic approach in rats, the researchers found that exciting the neuronal projections in the ventral substantia nigra would stimulate the animal to walk around its environment; by contrast, they could stop the animal's movement by inhibiting these same projections. Furthermore, they found that they could stimulate reward-seeking behavior by exciting the neuronal projections in the ventral tegmental area, but could cause aversive behavior by inhibiting these projections.
"Our results show that the cholinergic neurons from the PPN indeed have a role in controlling both behaviors," Gradinaru says. "Although the neurons are very densely packed and intermingled, these pathways are, to some extent, dedicated to very specialized behaviors." Determining which pathways are associated with which behaviors might also improve future treatments, she adds.
"In the past it's been difficult to target treatment to the PPN because the specific neurons associated with different behaviors are intermingled at the source—the PPN. Our results show that you could target the axonal projections in the substantia nigra for movement disorders and projections in the ventral tegmental area for reward disorders, as addiction is," Gradinaru says. In addition, she notes, these projections in the midbrain are much easier to access surgically than their source in the PPN.
Although this new information could inform clinical treatments for Parkinson's disease, the PPN is only one region of the brain and there are many more important examples of connectivity that need to be explored, Gradinaru says. "These results highlight the need for brain-wide functional and anatomical maps of these long-range neuronal projections; we've shown that tissue clearing and optogenetics are enabling technologies in the creation of these maps."
Source: Reprinted from materials provided by Caltech.
Paper: "Cholinergic Mesopontine Signals Govern Locomotion and Reward through Dissociable Midbrain Pathways"
For years, neuroscientists have puzzled over how two abnormal proteins, called amyloid and tau, accumulate in the brain and damage it in Alzheimer's disease (AD). Which one is the driving force behind dementia? The answer: both of them, according to a new study.
In the journal Molecular Psychiatry, researchers report for the first time evidence that the interaction between amyloid and tau proteins drives brain damage in cognitively intact individuals.
”We specifically found that both proteins mutually enhance their individual toxic effects and cause a brain dysfunction considered to be a signature of AD. This finding challenges previous polarized theories that a single protein abnormality was the major driving force of disease progression,” explained the study's leader, Dr. Pedro Rosa-Neto, a clinician scientist at the Douglas Mental Health University Institute and assistant professor of Neurology, Neurosurgery and Psychiatry at McGill University.
This research also points toward new potential therapeutic strategies to mitigate the progression of AD.
”Until now, therapeutic clinical trials have targeted a single pathological process. Our result paves the way for new therapeutic strategies for prevention or stabilization of AD. For example, combination therapies should be used simultaneously against both amyloid and tau protein accumulation”, says Dr. Tharick A. Pascoal, the study's first author.
The researchers analyzed the performances of 120 cognitively intact individuals over two years (equal gender distribution; average age 75). By measuring amyloid levels using PET scans and tau proteins through cerebrospinal fluid analysis, the researchers were able to identify the patients at risk for brain damage associated with AD.
Source: Reprinted from materials provided by the McGill University.
A new study published in Proceedings of the National Academy of Sciences has discovered that a protein called IL-33 can reverse Alzheimer’s disease-like pathology and cognitive decline in mice.
“IL-33 is a protein produced by various cell types in the body and is particularly abundant in the central nervous system (brain and spinal cord)," explained Professor Eddy Liew, Fellow of the Royal Society, who co-directed the research. “We found that injection of IL-33 into aged APP/PS1 mice rapidly improved their memory and cognitive function to that of the age-matched normal mice within a week.”
The hallmarks of Alzheimer’s include the presence of extracellular amyloid plaque deposits and the formation of neurofibrillary tangles in the brain. During the course of the disease, ‘plaques’ and ‘tangles’ build up, leading to the loss of connections between nerve cells, and eventually to nerve cell death and loss of brain tissue.
IL-33 appears to work by mobilising microglia (immune cells in the brain) to surround the amyloid plagues, take them up and digest them and reduces the number and size of the plaques. IL-33 does so by inducing an enzyme called neprilysin, which is known to degrade soluble amyloid.
In addition, the IL-33 treatment worked by inhibiting the inflammation in the brain tissue, which has been shown earlier to potentiate plaque and tangle formation. Therefore IL-33 not only helps to clear the amyloid plague already formed but also prevent the deposition of the plaques and tangles in the first place.
Professor Liew added: “The relevance of this finding to human Alzheimer’s is at present unclear. But there are encouraging hints. For example, previous genetic studies have shown an association between IL-33 mutations and Alzheimer’s disease in European and Chinese populations. Furthermore, the brain of patients with Alzheimer’s disease contains less IL-33 than the brain from non-Alzheimer’s patients.
“Exciting as it is, there is some distance between laboratory findings and clinical applications. There have been enough false ‘breakthroughs’ in the medical field to caution us not to hold our breath until rigorous clinical trials have been done. We are just about entering Phase I clinical trial to test the toxicity of IL-33 at the doses used. Nevertheless, this is a good start.”
Source: Reprinted from materials provided by the University of Glasgow.
Paper: "IL-33 ameliorates Alzheimer’s disease-like pathology and cognitive decline"
While research has identified hundreds of genes required for normal memory formation, genes that suppress memory are of special interest because they offer insights into how the brain prioritizes and manages all of the information, including memories, that it takes in every day. These genes also provide clues for how scientists might develop new treatments for cognitive disorders such as Alzheimer’s disease.
Scientists have identified a unique memory suppressor gene in the brain cells of Drosophila, the common fruit fly, in a study published in the journal Neuron.
The researchers screened approximately 3,500 Drosophila genes and identified several dozen new memory suppressor genes that the brain has to help filter information and store only important parts. One of these suppressor genes, in particular, caught their attention.
“When we knocked out this gene, the flies had a better memory—a nearly two-fold better memory,” said Ron Davis, chair of the Department of Neuroscience at The Scripps Research Institute and leader of the study. “The fact that this gene is active in the same pathway as several cognitive enhancers currently used for the treatment of Alzheimer’s disease suggests it could be a potential new therapeutic target.”
When the scientists disabled this gene, known as DmSLC22A, flies’ memory of smells (the most widely studied form of memory in this model) was enhanced—while overexpression of the gene inhibited that same memory function.
“Memory processes and the genes that make the brain proteins required for memory are evolutionarily conserved between mammals and fruit flies,” said Research Associate Ze Liu, co-first author of the study. “The majority of human cognitive disease-causing genes have the same functional genetic counterparts in flies.”
The gene in question belongs to a family of “plasma membrane transporters,” which produce proteins that move molecules, large and small, across cell walls. In the case of DmSLC22A, the new study indicates that the gene makes a protein involved in moving neurotransmitter molecules from the synaptic space between neurons back into the neurons. When DmSLC22A functions normally, the protein removes the neurotransmitter acetylcholine from the synapse, helping to terminate the synaptic signal. When the protein is missing, more acetylcholine persists in the synapse, making the synaptic signal stronger and more persistent, leading to enhanced memory.
“DmSLC22A serves as a bottleneck in memory formation,” said Research Associate Yunchao Gai, the study’s other co-first author. “Considering the fact that plasma transporters are ideal pharmacological targets, drugs that inhibit this protein may provide a practical way to enhance memory in individuals with memory disorders.”
The next step, Davis added, is to develop a screen for inhibitors of this pathway that, independently or in concert with other treatments, may offer a more effective way to deal with the problems of memory loss due to Alzheimer’s and other neurodegenerative diseases.
“One of the major reasons for working with the fly initially is to identify brain proteins that may be suitable targets for the development of cognitive enhancers in humans,” said Davis. “Otherwise, we would be guessing in the dark as to which of the more than 23,000 human proteins might be appropriate targets.”
Source: Reprinted from materials provided by Eric Sauter at The Scripps Research Institute.