Fragile X: preclinical portfolio for PI3k drug strategy

Research in mice shows that a pharmacological strategy can alleviate multiple behavioral and cellular deficiencies in a mouse model of fragile X syndrome (FXS), the most common inherited form of intellectual disability and a major single-gene cause of autism spectrum disorders.

The results were published online last week by Neuropsychopharmacology, and were presented at the NFXF International Fragile X Conference in Cincinnati.

When the compound GSK6A was given to mice lacking the Fmr1 gene, an established animal model of fragile X syndrome, it relieved symptomatic behaviors, such as impaired social interactions and inflexible decision making, which can be displayed by humans with fragile X syndrome.

The findings indicate that treatment with GSK6A or a similar compound could be a viable strategy for addressing cognitive and behavioral problems in fragile X syndrome; this would need to be tested directly in clinical trials. GSK6A inhibits one particular form of a cellular signaling enzyme: the p110β form of PI3 (phosphoinositide-3) kinase. A closely related p110β inhibitor is already in clinical trials for cancer.

Video from the iBook “Basic Science Breakthroughs: Fragile X Syndrome”. Narration by Emory genetics chair Stephen Warren, whose team identified the gene responsible for fragile X.

“Our results suggest that p110β inhibitors can be repurposed for fragile X syndrome, and they have implications for other subtypes of autism spectrum disorders that are characterized by similar alterations of this pathway,” says Gary Bassell, PhD, professor and chair of cell biology at Emory University School of Medicine.

“Right now, no proven efficient treatments are available for fragile X syndrome that are targeted to the disease mechanism,” says Christina Gross, PhD, from Cincinnati Children’s. “We think that p110β is an appropriate target because it is directly regulated by FMRP, and it is overactivated in both mouse models and patient cell lines.”

The paper represents a collaboration between three laboratories: two at Emory led by Bassell and Shannon Gourley, PhD, and one at Cincinnati Children’s, led by Gross. Gourley is based at Yerkes National Primate Research Center; see this earlier item on her collaboration with Bassell here.

While the researchers are discussing clinical trials of p110β inhibitors in fragile X syndrome, they say that long-term studies in animals are needed to ensure that undesirable side effects do not appear. More here.

With respect to clinical trials, the fragile X community has been disappointed before. Based on encouraging studies in mouse models, drugs targeting mGluR5 glutamate receptors were tested in adolescents and adults. mGluR5 drugs did not show clear benefits; recent re-evaluation suggests the choice of outcome measures, the ages of study participants and drug tolerance may have played a role.

Warren played a major role in developing the mGluR5 approach and Emory investigators were part of those studies. More recently, clinical trials for one of the mGluR5 medications were revived in younger children and Emory is a participating site. Also, see this 2016 discussion in Spectrum with Elizabeth Berry-Kravis on the fragile X mouse model; Bassell, Gross and Gourley have made some inroads on the limitations Berry-Kravis describes.

Posted on July 19, 2018 by Quinn Eastman in Neuro Leave a comment

The blue spot: where seeds of destruction begin

Neuroscientist and geneticist David Weinshenker makes a case that the locus coeruleus (LC), a small region of the brainstem and part of the pons, is among the earliest regions to show signs of degeneration in both Alzheimer’s and Parkinson’s disease. You can check it out in Trends in Neurosciences.

The LC is the main source of the neurotransmitter norepinephrine in the brain, and gets its name (Latin for “blue spot”) from the pigment neuromelanin, which is formed as a byproduct of the synthesis of norepinephrine and its related neurotransmitter dopamine. The LC has connections all over the brain, and is thought to be involved in arousal and attention, stress responses, learning and memory, and the sleep-wake cycle.

Cells in the locus coeruleus are lost in mild cognitive impairment and Alzheimer’s. From Kelly et al Acta Neuropath. Comm. (2017) via Creative Commons

The protein tau is one of the toxic proteins tied to Alzheimer’s, and it forms intracellular tangles. Pathologists have observed that precursors to tau tangles can be found in the LC in apparently healthy people before anywhere else in the brain, sometimes during the first few decades of life, Weinshenker writes. A similar bad actor in Parkinson’s, alpha-synuclein, can also be detected in the LC before other parts of the brain that are well known for damage in Parkinson’s, such as the dopamine neurons in the substantia nigra.

“The LC is the earliest site to show tau pathology in AD and one of the earliest (but not the earliest) site to show alpha-synuclein pathology in PD,” Weinshenker tells Lab Land. “The degeneration of the cells in both these diseases is more gradual. It probably starts in the terminals/fibers and eventually the cell bodies die.” Read more

Posted on July 3, 2018 by Quinn Eastman in Neuro Leave a comment

Complexity of NMDA receptor drug discovery target revealed

Know your target. Especially if your target is coming into focus for treating diseases such as schizophrenia and treatment-resistant depression.

NMDA receptors, critical for learning and memory, are sensors in the brain. Studying them in molecular detail is challenging, because they usually come in four parts, and the parts aren’t all the same.

Researchers at Emory have been probing one variety of NMDA receptor assembly found in the cerebellum, and also in the thalamus, a central gateway for sensory inputs, important for cognition, movement and sleep. This variety includes a subunit called GluN2C – together with two partners, GluN1 and GluN2A.

The results were published Thursday, June 28 in Neuron.

Outside of a living brain, NMDA receptor assemblies are typically studied with either two copies of GluN2C or two of GluN2A, but not with one of each, says senior author Stephen Traynelis, PhD, professor of pharmacology at Emory University School of Medicine

“Our data suggest that GluN2C is rarely by itself,” Traynelis says. “It’s typically paired up with another GluN2 subunit. This means we really don’t know what the properties of the main NMDA receptor in the cerebellum or the thalamus are.”

Psychiatrists have become interested in GluN2C because it appears to decline in the brains of schizophrenia patients. Mice without adequate levels of GluN2C display abnormalities in learning, memory and sensory processing, which together resemble schizophrenia in humans. In addition, GluN2C appears to be important for the mechanism of ketamine, a drug being studied for its rapid anti-depressant effects.

Using drugs that are selective for particular combinations of NMDA receptor subunits, Traynelis’ laboratory showed that an assembly of GluN2A and GluN2C is the dominant form in the mouse cerebellum. When GluN2C is introduced into cortical neurons, it prefers to pair up with GluN2A, the researchers found. This raises the question, in regions such as the thalamus, of whether GluN2C also appears with a partner GluN2 subunit. They also observed that the GluN2A-GluN2C assembly has distinct electrochemical properties. Read more

Posted on July 2, 2018 by Quinn Eastman in Neuro Leave a comment

Measuring sleepiness: alternatives to five naps

In a 2015 episode of The Simpsons, Homer is diagnosed with narcolepsy. Overwhelming sleepiness at the nuclear power plant lands him in the hospital. Sampling his spinal fluid (ouch!), Homer’s chuckling, deep-voiced doctor quickly performs a test for hypocretin, a brain chemical important for staying awake and regulating REM sleep.

Reality check: testing for hypocretin takes time, and is not currently available in the United States. Let’s talk about how sleep disorders such as narcolepsy and idiopathic hypersomnia are actually diagnosed: operationally, rather than biologically. The less flashy, but standard, way to assess patients is to ask them to take a series of five naps and see how fast they doze off, and how fast they go into REM sleep (the rapid eye movement dreaming phase).

This process, known as the Multiple Sleep Latency Test or MSLT, works pretty well for narcolepsy type 1, the more distinctive form of narcolepsy that includes cataplexy. And it’s hard to fake being sleepy enough to zonk out within a few minutes. But it has a bunch of problems, and dissatisfaction with the MSLT has been developing among sleep specialists for the last several years.

Lynn Marie Trotti, MD

At Emory, neurologists Lynn Marie Trotti and David Rye published an analysis of what I will call the “flip flop problem” in 2013, with others in the field following up more recently. The flip flop problem is: someone who takes the MSLT one day will frequently get another result if they take it again on a different day. Read more

Posted on June 29, 2018 by Quinn Eastman in Neuro 1 Comment

‘Unbiased’ approaches to Alzheimer’s

In recent news stories about Alzheimer’s disease research, we noticed a word popping up: unbiased. Allan Levey, chair of Emory’s neurology department and head of Emory’s Alzheimer’s Disease Research Center, likes to use that word too. It’s key to a “back to the drawing board” shift taking place in the Alzheimer’s field.

Last week’s announcement of a link between herpes viruses and Alzheimer’s, which Emory researchers contributed to, was part of this shift. Keep in mind: the idea that viral infection contributes to Alzheimer’s has been around a long time, and the Neuron paper doesn’t nail down causality.

Still, here’s an example quote from National Institute on Aging director Richard Hodes: “This is the first study to provide strong evidence based on unbiased approaches and large data sets that lends support to this line of inquiry.”

What is the bias that needs to be wrung out of the science? The “amyloid hypothesis” has dominated drug development for the last several years. Amyloid is a main constituent of the plaques that appear in the brains of people with Alzheimer’s, so treatments that counteract amyloid’s accumulation should help, right? Unfortunately, antibodies against amyloid or inhibitors of enzymes that process it generally haven’t worked out in big clinical trials, although the possibility remains that they weren’t introduced early enough to have a decent effect. Read more

Posted on June 28, 2018 by Quinn Eastman in Neuro Leave a comment

Inflammation in PD hits the gut

Several groups studying Parkinson’s have had a hunch – a gut feeling, even – that intestinal inflammation is involved in driving the disease. Now Emory researchers led by Malu Tansey, PhD have some evidence from patient samples to back it up, published in the journal Movement Disorders.

IMP graduate student Madelyn Houser

German pathologist Heiko Braak has been honored by the Michael J. Fox Foundation for Parkinson’s Research for his theory, originally published in 2003, proposing that disease pathology – marked by aggregation of the toxic protein alpha-synuclein — may begin in the gastrointestinal tract and migrate from there to the central nervous system. This proposal was both provocative and influential in the Parkinson’s disease (PD) field. And Tansey herself has long been interested in the role of microglia, the immune cells resident in the brain, in PD.

The first author of the new paper, Immunology and Molecular Pathogenesis graduate student Madelyn Houser, notes that digestive problems such as constipation are frequently reported in PD patients. But what is the cause and what is effect? As neurologist Stewart Factor observed for a Emory Medicine article on PD’s non-motor symptoms: “A patient might tell me he’s had recurring constipation for 10 years, but he wouldn’t say anything to a neurologist about it until he starts having other symptoms.” Read more

Posted on May 2, 2018 by Quinn Eastman in Immunology, Neuro Leave a comment

Fermentation byproduct suppresses seizures in nerve agent poisoning

A compound found in trace amounts in alcoholic beverages is more effective at combating seizures in rats exposed to an organophosphate nerve agent than the current recommended treatment, according to new research published in eNeuro.

This work comes from Asheebo Rojas, Ray Dingledine and colleagues in Emory’s Department of Pharmacology. Just as an aside, we don’t know the nature of the recent alleged chemical attack in Syria, and the chemical used in the Emory experiments is not a “weaponized” nerve agent such as Sarin. Organophosphates were also widely used as insecticides, but their use has been declining.

Left untreated, organophosphate poisoning can lead to severe breathing and heart complications, because of the inhibition of acetylcholinesterase. It also causes seizures. Some patients are resistant to treatment with the anti-anxiety drug diazepam (Valium), a standard first-line treatment for such poisoning, and its effectiveness decreases the longer the seizure lasts.

The researchers compared the ability of two treatments — diazepam and the anesthetic urethane (ethyl carbamate), commonly formed in trace amounts during fermentation of beer and wine from the reaction of urea and ethanol — to interrupt seizures in rats exposed to the organophosphate diisopropyl fluorophosphate. The researchers found urethane to be more effective than diazepam, suppressing seizures for multiple days and accelerating recovery of weight lost while protecting the rats from cell loss in the hippocampus.

Urethane/ethyl carbamate is a carcinogen in animals, which led to concerns over its presence in alcoholic beverages in the 1980s. It was also used as a sedative for many years in Japan. The researchers did not observe any evidence of lung tumors in the urethane-treated animals seven months later, suggesting that the dose used in this study is not carcinogenic. The findings point to urethane or a derivative as a potential therapeutic for preventing organophosphate-triggered seizures from developing into epilepsy. Read more

Posted on April 20, 2018 by Quinn Eastman in Neuro Leave a comment

Post-anesthetic inertia in IH

A recent paper from neurologists Lynn Marie Trotti and Donald Bliwise, with anesthesiologist Paul Garcia, substantiates a phenomenon discussed anecdotally in the idiopathic hypersomnia (IH) community. Let’s call it “post-anesthetic inertia.” People with IH say that undergoing general anesthesia made their sleepiness or disrupted sleep-wake cycles worse, sometimes for days or weeks. This finding is intriguing because it points toward a trigger mechanism for IH. And it pushes anesthesiologists to take IH diagnoses into account when planning patient care, just as is already done for myotonic dystrophy.

Lab Land obtained some confirmation from a couple IHers. One woman had surgery a couple of months ago and felt like the anesthetic was still in her system for weeks and she still didn’t feel right. Another reported “severe insomnia for months and it felt like every body system was completely scrambled.”

Where does this all come from? People with IH getting together and telling their stories. Journalist Virginia Hughes described a moment at the 2014 patient-organized IH meeting in Atlanta in her article “Wake No More”:

Andy Jenkins, the neuroscientist who developed the spinal fluid test, gave an impressively entertaining lecture on GABA receptors. “Why do we have more GABA activity?” somebody asked. Nobody knows, said Jenkins. One idea is that it’s triggered by anesthesia. Lloyd [Johnson, a meeting organizer from Australia] asked the audience how many of them believed their hypersomnia was the result of anesthesia. About one-quarter of the hands went up. “Whoa, whoa, whoa, whoa, whoa,” Jenkins said as he watched the sleepyheads* come alive.

The new paper, in Frontiers in Human Neuroscience, is more quantitative than that informal show of hands. In a way, it begins to question the basis for the term idiopathic hypersomnia, since idiopathic means “arising spontaneously or having no cause”. For some people surveyed in the paper, anesthesia was an exacerbating factor, if not the only factor.

Confusion or agitation post-anesthesia can happen in people who don’t have sleep disorders. What’s peculiar to the hypersomnolent group is how long sleepiness or disrupted sleep-wake cycles last — long after the anesthetic has left the body. The hypersomnolent group was mostly people with IH or narcolepsy type 2 (30 plus 15 out of 57). In the paper, people with restless legs syndrome were used as controls:

While patients in both groups were equally likely to report surgical complications and difficulty awakening from anesthesia, hypersomnolent patients were more likely to report worsened sleepiness (40% of the hypersomnolent group vs. 11% of the RLS group, p = 0.001) and worsening of their sleep disorder symptoms (40% of the hypersomnolent group vs. 9% of the RLS group, p = 0.0001).

Hypersomnolent patients who perceived their symptoms to worsen reported that symptoms had never returned to baseline in 66.7%, took months or years to return to baseline in 9.5%, and resolved in days to weeks in 23.8%.

Note: first author Vincent LaBarbera is now a neurology resident at Brown.

Mechanistic speculation

Several years ago, Emory researchers found that some IH patients appear to have a substance in their cerebrospinal fluid that acts similarly (but not quite the same) as a benzodiazepine drug. This still-mysterious substance enhances signaling by GABA, the major inhibitory neurotransmitter.

Inhaled anesthetics such as sevoflurane, as well as the injected anesthetic propofol, act by enhancing GABA too. So when someone undergoes general anesthesia, their GABA receptors are being pushed hard for an extended period of time. GABA signaling has a kind of global “dimmer switch” function as well as working through specific circuits in the brain to bring on anesthesia.

GABA receptors are complex, but they usually adjust to pressure. It explains development of tolerance to benzodiazepine drugs. GABA receptors also modulate in response to alcohol or women’s menstrual cycles (certain derivatives of progesterone, so-called “neurosteroids,” act on them). What may be happening after anesthesia is that GABA receptors of people with IH have trouble adjusting back, or may overshoot, perhaps because their internal clocks are less resilient.

The Emory authors conclude:

Because the half-life of anesthetic agents is generally short, any prolonged worsening of sleepiness post-procedure cannot easily be attributed to immediate GABA-mediated effects. Whether the putative long-term changes in hypersomnolence that we are detecting in our patients’ reports may be related to changes in GABA-related neural circuitry caused by anesthetic neurotoxicity or other mechanisms remains to be determined.

A similar interaction, with reversed polarity, may be occurring in post-partum depression.

*Lab Land has been told that sleepyhead is not a fully accepted term in the IH community.

Posted on April 20, 2018 by Quinn Eastman in Neuro Leave a comment

How much does idiopathic hypersomnia overlap with ME/CFS?

In everyday linguistic usage among non-specialists, sleepiness can blend together with tiredness and fatigue. Someone might feel “tired” after climbing a mountain or chopping down a tree, while “sleepiness” is different. Emory sleep scientists explore the pathological distinctions in a paper published in Journal of Sleep Research.

A team led by neurologists Lynn Marie Trotti and David Rye has been studying idiopathic hypersomnia (IH) for several years: people who experience excessive daytime sleepiness and “sleep drunkenness,” not explained by other medical conditions.

IH’s symptoms don’t usually include persistent muscle pain or a severe response to exertion. This separates the disorder from myalgic encephalomyelitis, also known as chronic fatigue syndrome (ME/CFS). But there is some overlap, which is what neurology resident Caroline Maness, Trotti and colleagues report in the new paper. The authors use the official term SEID (systemic exertion intolerance disease), which was recommended by an Institute of Medicine panel in 2015, but hasn’t really stuck among those in the ME/CFS field.

Some people with IH have disclosed that they were previously diagnosed with ME/CFS. Outside of the sleepy vs tired issue, some people with IH report symptoms shared with ME/CFS, such as impaired circulation in their extremities in response to cold, or dizziness upon standing. Speculatively, this may point to a possible problem with the autonomic nervous system. Trotti and a collaborator at Stanford, Mitchell Miglis, are now examining this issue further.

ME/CFS has had a history of controversy. Despite its devastating impacts, some have viewed it as psychological or somehow unreal, and sufferers have felt neglected or maligned by mainstream medicine. The National Institutes of Health has made efforts to turn that situation around by investing in ME/CFS research, and there has been a surge of attention recently covering ME/CFS (Amy Maxmen items in Nature, Stanford magazine feature, Unrest documentary).

Trotti, Maness and colleagues didn’t set out to dive into ME/CFS – they explicitly label this paper a pilot study, and the results say more about the “hypersomnolent” group of patients they have been seeing for the last several years, rather than the broader ME/CFS population. Read more

Posted on April 16, 2018 by Quinn Eastman in Neuro Leave a comment

An exceptional electrical thrill ride #CNS2018

A recent paper in Neuropsychologia got a lot of attention on Twitter and at the Cognitive Neuroscience Society meeting in Boston over the weekend. It discusses what can happen when the amygdala, a region of the brain known for regulating emotional responses, receives direct electrical stimulation. A thrill ride – but for only one study participant. Two of nine people noticed the electrical stimulation. One individual reported (a video is included in the paper):

“It was, um, it was terrifying, it was just…it was like I was about to get attacked by a dog. Like the moment, like someone unleashes a dog on you, and it’s just like it’s so close…

He also spontaneously reported “this is fun.” He further explained that he could distinguish feelings in his body that would normally be associated with fear recognized and the absence of an actual threat, making the experience “fun”.

But wait, why were Emory neuroscientists Cory Inman, Jon Willie and Stephan Hamann and colleagues doing this? Read more

Posted on March 29, 2018 by Quinn Eastman in Neuro Leave a comment

« Previous 1 2 3 4 5 6 7 8 9 10 ... 20 21 Next »