It is known that the formation of α-synuclein (α-syn) clumps causes dopaminergic cell death and, as a result, the development of Parkinson’s disease (PD). However, the mechanism behind the formation of these clumps has remained unknown, until now.
In both in vitro and in vivo experiments, scientists from the Saint Louis University Health Sciences Center (MO, USA) and Washington University School of Medicine (MO, USA) have found that the culprit is in fact a toxic byproduct of dopamine (DA) itself, 3,4-dihydroxyphenylacetaldehyde (DOPAL).
“This is exciting,” William Burke, coauthor of the study commented. “This is the first time anyone has ever established that it is a naturally occurring byproduct of DA that causes α-syn to aggregate, or clump together. It’s actually DOPAL that kicks this whole process off and results in PD.”
Published in an early online edition of Acta Neuropathologica, the group reported that DOPAL induced α-syn aggregation in cell culture and that injection of DOPAL into the substantia nigra of Sprague-Dawley rats lead to loss of DA neurons and the accumulation of high-molecular-weight oligomers of α-syn.
The study authors are extremely positive about the potential implications this finding could have on the future of PD therapy. “We’ve solved a basic puzzle in PD,” explained Burke, “I think it’s tremendously significant. Once you know how a disease process works, you can attack the disease. Now that we have scientific evidence of how this works, it provides a rational basis for therapy,” he added. “We believe these findings can be used to develop therapies that can actually stop or slow this process.”
Current therapies for PD work by replacing lost DA. However, this discovery may enable neuroprotective therapies to be developed, which could prevent dopaminergic cell death rather than simply replacing lost DA. Novel neuroprotective strategies to treat PD could vastly improve the prognosis and quality of life of the estimated four million people worldwide that currently suffer from PD.
Source: Burke WJ, Kumar VB, Pandey N et al. Aggregation of α-synuclein by DOPAL, the monoamine oxidase metabolite of dopamine. Acta Neuropathol (Berl). (2007) (Epub ahead of print).
Noninvasive neurogenesis biomarker identified
In a landmark study, researchers have discovered a marker that may be used to detect neural progenitor cells (NPCs) using magnetic resonance spectroscopy (MRS). Disruption of neurogenesis has been associated with a variety of neurological disorders, including brain tumors, schizophrenia, depression and Parkinson’s disease. Therefore, this novel biomarker has the potential to revolutionize the diagnosis and treatment of a wide range of debilitating neurological disorders.
Published in the 8th November issue of Science, researchers demonstrated that the currently unnamed biomarker was capable of identifying NPCs in both mice and humans. “This study identifies a novel biomarker and shows that we can use it to see progenitor cells in the live brain,” commented coauthor Grigori Enikolopov, from the Cold Spring Harbor Laboratory (NY, USA). “This protocol can now be used to study a variety of problems.”
When MRS was carried out on embryonic mice the researchers identified a specific signal that was present only in NPCs and not in the non-neuronal cells: astrocytes and oligodendrocyes. The group then went on to study the levels of this biomarker at various time points and found that, as with neurogenesis, the signal decreased over time and less signal was produced from cells from adult mice compared with embryonic cells. The NPC signal was also found to be significantly higher in hippocampal cells than in those from the cortex, correlating with the fact that neurogenesis continues throughout adulthood in the hippocampus. Finally, electrical stimulation was applied to mice in order to increase the level of neurogenesis. Following this, a significant increase in the levels of the marker was found.
The levels of the biomarker on MRS were then examined in healthy humans. Matching the results found in mice, levels of the biomarker were found to be higher in the hippocampus compared with the cortex, in pre-adolescents compared with adults and the level of biomarker decreased with age.
The study authors are extremely positive about the potential this new biomarker may have, with coauthor Walter J Koroshetz commenting, “The recent finding that NPCs exist in adult human brain has opened a whole new field in neuroscience. The ability to track these cells in living people would be a major breakthrough in understanding brain development in children and continued maturation of the adult brain. It could also be a very useful tool for research aimed at influencing NPCs to restore or maintain brain health.”
“The technique the team has developed is based on MRI technology that is currently in widespread use to perform noninvasive scans of the living brain and can tell us where stem-like cells are dividing,” explained Enikolopov. “Although we are only just beginning to test applications, it is clear that this biomarker may have promise in identifying cell proliferation in the brain, which can be a sign of cancer. In other patients, it could show us how neurogenesis is related to the course of diseases such as depression, bipolar disorder, Alzheimer’s, PD, multiple sclerosis (MS) and post-traumatic stress disorder.”
Indeed, the group are already investigating the potential use of the biomarker in MS as Mirjana Maleti-Savati explained, “We are now doing a study that already started a year ago on patients with MS, and we plan to prospectively follow them and see whether we can use this biomarker as a prognostic tool.”
Source: Manganas LN, Zhang X, Li Y et al. Magnetic resonance spectroscopy identifies neural progenitor cells in the live human brain. Science 318(5852), 980–985 (2007).
BMA urges an ethical debate into cognitive enhancers
It is anticipated that there will be a significant increase in the ability of drugs and surgical procedures to improve intellectual performance in the next 20–30 years. In light of these increasing advances, the British Medical Association (BMA) have released a paper “to facilitate informed debate amongst doctors, scientists, policy-makers and members of the public about the future development and use of cognitive enhancements.”
Currently, supplements such as cod liver oil are taken as they have been associated with improved attention. Coffee and other caffeine-containing drinks are used to improve concentration on a daily basis by many people. However, the BMA are concerned that, in a similar way to having plastic surgery to improve your looks, people will be eager to use drugs such as Ritalin (which improves concentration in children with attention-deficit/hyperactivity disorder but can also improve brain function in children without the disorder) or surgical methods such as transcranial magnetic stimulation in order to improve their own, or their children’s intellectual performance.
“We know that there is likely to be a demand by healthy individuals for this treatment,” Tony Calland, chairman of the BMA’s Medical Ethics Committee commented. “However, given that no drug or invasive medical procedure is risk free, is it ethical to make them available to people who are not ill?”
The BMA stress that this paper does not provide guidelines, rather they hope that it will spark further debate into the ethics of cognitive enhancement. “We need to balance the benefits against the risks,” explained Vivienne Nathanson, head of ethics at the BMA.
“We’re not making any recommendations – but we do want people to look up and engage with this issue before it becomes the norm and it’s too late to do anything about it.”
The paper finishes with five key questions “for debate and consideration”, which ask whether individuals should be free to make decisions about the use of cognitive enhancers for themselves or for existing or future children, whether or not the same principles should apply for all methods of cognitive enhancement, whether doctors should be involved in providing and monitoring cognitive enhancers, and finally what regulation is needed.
Source: Boosting your brainpower: ethical aspects of cognitive enhancements. A discussion paper from the BMA, November 2007
http://www.bma.org.uk/ap.nsf/content/CognitiveEnhancement2007
Epilepsy “masked” by combination of genes
In the first study of its kind, researchers from the Baylor College of Medicine (TX, USA) have found that defects in two genes associated with different forms of epilepsy actually reduces seizure occurrence, rather than exacerbating epilepsy symptoms.
Published in the November 4 online issue of Nature Neuroscience, the researchers bred mice with mutations in both Kcna1, a gene associated with temporal lobe epilepsy and also sudden death in young mice, and Cacna1a, which can cause absence epilepsy. The genes are known to regulate potassium and calcium levels, respectively.
Surprisingly, mice with both mutations showed attenuated seizures and reduced risk of sudden death. “In the genetics of the brain, two wrongs can make a right,” commented lead researcher Jeffrey Noebels. “If you have a potassium channel defect, then a drug blocking certain calcium channels might also benefit you.”
The researchers went on to suggest that their findings could lead to novel methods of treatment for epilepsy using gene-directed therapy, as Noebels explained, “We believe these findings have great significance to clinicians as we move toward relying upon genes to predict neurological disease … Rather than screening for ‘bad’ genes one at a time, it may be essential to create a complete profile of many or even all genes in order to accurately assess the true genetic risk of any single defect in many common disorders such as epilepsy … Fortunately, this amount of background information will soon become routinely obtainable in individual patients thanks to rapid technological progress in the field of neurogenomics.”
Source: Glasscock E, Qian J, Yoo JW, Noebels JL. Masking epilepsy by combining two epilepsy genes. Nat. Neurosci. (2007) (Epub ahead of print).
Imaging advances show how common brain abnormalities really are
Dutch researchers have recently reported that brain abnormalities are more common than previously realized, with some form of brain lesion or another being identified in an alarming 13% of healthy patients. However, the majority of the abnormalities were said to be “incidental” and only a small proportion required further treatment.
“Our study shows that incidental findings are much more frequent than was thought previously,” commented study coauthor Aad van der Lugt, Associate Professor of Radiology at Erasmus MC University Medical Center (Rotterdam, The Netherlands).
A total of 2000 healthy adults with an average age of 63.3 years (range 45.7–96.7 years) participated in the study, published in the November 1 issue of the New England Journal of Medicine. Each participant’s brain was scanned using MRI in order to determine whether any abnormalities were present.
Of the 2000 participants, 145 (7.2%) were found to have asymptomatic brain infarcts, 35 (1.8%) had aneurysms and 32 (1.6%) had brain tumors. However, only five of the aneurysms were considered dangerous and one of the brain tumors was found to be cancerous. All of the patients who required additional treatment were referred to specialists.
Although the high level of abnormalities found was surprising, the authors stressed that this should not be a cause for concern; rather, the findings should highlight the regularity of these incidental abnormalities in the general population in order to prevent unnecessary treatment/surgery when such incidental abnormalities are identified from increasingly utilized imaging techniques.
Arno Fried, Chairman of the Department of Neurosurgery at Hackensack University Medical Center mirrored these concerns commenting, “The problem is what to do about incidental findings. What’s most important is to correlate clinical status with what we see on the scan. Most of the time, we won’t do anything about those incidental findings. Some people will be asymptomatic forever … technology and imaging don’t take the place of good clinical judgment. If the technology is taken out of context, it may lead to surgeries that don’t need to be done.”
Source: Vernooij MW, Ikram MA, Tanghe HL et al. Incidental findings on brain MRI in the general population. N. Engl. J. Med. 357(18), 1821–1828 (2007).
NYU scientists discover maternal Alzheimer’s link
Researchers from New York University School of Medicine (NY, USA) have reported that there appears to be a maternal but not paternal link to Alzheimer’s disease (AD), suggesting that perhaps maternally inherited genes alter brain metabolism, resulting in an increased risk of developing AD.
In the first study of its kind, the scientists studied the levels of energy metabolism in the brains of participants who had a mother or a father with AD, or who had no family history of the disease. Reduced energy metabolism in the brain has previously been associated with AD.
Neuropsychological and clinical tests were carried out on 49 cognitively normal participants, aged between 50 and 80 years. A tracer was used to label neuronal glucose during PET scans in order to determine the levels of energy metabolism in the brain. Of the 49 participants, 16 had a maternal history of AD, eight had a paternal history and the remaining 25 had no family history of the disease.
Published in the November 14 online edition of Proceedings of the National Academy of Sciences USA, the researchers reported reduced glucose metabolism in the medial temporal lobes and posterior cingulate cortex (regions that are involved in memory storage and retrieval) of participants who had a maternal history of AD. Participants with paternal or no family history of the disease showed normal glucose metabolism.
“This is a preliminary study and the results have to be replicated,” commented Lisa Mosconi, coauthor of the study. “What we need even more is to follow subjects over time until they develop clinical symptoms, and we really need to assess whether the metabolic reductions predict and correlate with disease progression … Energy metabolism hasn’t been a major focus of research in AD, so we hope that this study will stimulate further discussion on brain activity and disease risk, which could also be important for planning targeted therapeutic interventions.”
Sources: NYU Medical Center News Release. A maternal link to Alzheimer’s disease http://www.med.nyu.edu/communications/news/pr_249.html
Moscroni R, Brys M, Switalski et al. Maternal family history of Alzheimer’s disease predisposes to reduced blood glucose. Proc. Natl Acad. Sci. USA (2007) (Epub ahead of print).