Neurology News

Follow our Neurology News blog for the latest news on neurologic diseases and research.

Tuesday, April 17, 2018



A new study done in New York City found that people who live near a highway are significantly more likely to have an ischemic stroke than those living farther from a major roadway. The findings add to a growing body of research pointing to traffic-generated air pollution as an important risk factor for cerebrovascular disease.

One of the reasons we thought about doing this study is that the question of adverse health associated with living in cities is becoming a really important public health issue," said the study's lead author, Erin Kulick, a PhD student in epidemiology at Columbia University Mailman School of Public Health. "We found that living within 100 meters, or about two city blocks, of a major roadway in Manhattan was associated with significant increased risk of ischemic stroke over time."

Kulick noted that it is important to identify novel risk factors for stroke because traditionally known risk factors, such as hypertension and diabetes, don't explain the full burden of disease. Her team published its findings in the April edition of Stroke.

Stroke remains the leading cause of serious long-term disability in the U.S., even though there has been a decline in stroke mortality. The estimated direct cost of stroke is $17.5 billion annually in the US, the study noted.

With urbanization growing around the globe, stroke researchers have become increasingly interested in the effects of air pollution from traffic and other sources.


The new study utilized data collected for the Northern Manhattan Study (NOMAS), an ongoing, prospective, population-based cohort study begun in 1993 to examine risk factors for cerebrovascular disease. NOMAS is a joint project of Columbia and University of Miami. The multi-ethnic cohort includes 3,287 people living in one of five zip codes in Northern Manhattan who were at least 40 years old and stroke-free at baseline. Participants are followed up annually by telephone and researchers confirm reports of cardiovascular events by checking medical records. Residential addresses provided researchers with a means to look at the potential effects of exposure to traffic-generated air pollution.

During a median follow-up of 15 years, 361 participants (11 percent) were diagnosed with ischemic stroke. Participants living less than 100 meters from a major roadway had a 42 percent higher rate of ischemic stroke compared to those living more than 400 meters from a highway, the study found. Elevated risk of stroke also occurred for those living 100 to 400 meters from a major roadway, although the numbers were not statistically significant.


When individual smoking status was factored in the analysis, the association between living close to a highway and higher risk for ischemic stroke held true for current smokers but not for former smokers. The study also found no clear pattern of association between proximity to a highway and other events, including myocardial infarction, all-cause death or vascular death, but why that was the case is not clear.

"The evidence supporting the deleterious health effects of living near a major roadway is growing," the researchers concluded, noting that other research has shown that people who reside close to a highway have increased risk for stroke, cardiovascular disease, hypertension and post-stroke mortality.

A key component of this exposure is air pollution, though other factors such as noise pollution and stress are also involved, Kulick said.

The NOMAS researchers noted their study had limitations. It could only establish an association between ischemic stroke and living near a highway, not prove a cause and effect. The study was based on a person's residential address and did not take into consideration exposure to pollution at the workplace or time spent at locations away from home.

The Manhattan neighborhoods included in the study are in the vicinity of the George Washington Bridge, an especially congested, high-traffic area. Whether the findings apply to areas outside of New York City is unknown.

The researchers noted that there are several hypotheses on how air pollution may affect the brain and cerebral vasculature. They said animal studies suggest that ambient particles may enter the central nervous system either through the circulatory system or intranasally.

"Once inside, pollutant particles activate a series of systemic inflammatory pathways leading to vascular inflammation, impaired microvascular reactivity, and changes in cerebral hemodynamics," they wrote.

The researchers also noted that it's been suggested that the association between traffic-generated pollution and cerebrovascular disease may be mediated through cardiovascular mechanisms, noting that prior studies have shown an association between long-term exposure to air pollution and several cardiovascular risk factors, including diabetes, cholesterol and triglycerides, and blood pressure.

When NOMAS researchers, however, adjusted for other cardiovascular risk factors, including age, sex, smoking, diabetes and hypertension, it strengthened the association between distance to roadway and stroke, indicating that in this population cardiovascular risk factors were not acting as mediators, Kulick said.

Mitchell S. Elkind, MD, FAAN, professor of neurology and epidemiology at Columbia, who was a study coauthor, told Neurology Today that "our data fit within the growing recognition that environmental and population-level factors, as well as individual-level risk factors, contribute to stroke risk."

"Reducing pollution may be as important to health as prescribing drugs," Dr. Elkind said in an email. He said environmental remedies need to be part of the strategy to reduce the prevalence of stroke.

At the clinical level, "Neurologists need to keep in mind the world in which their patients live," in evaluating stroke risk, Dr. Elkind said.

Dr. Elkind said the NOMAS study is continuing to examine the connection between exposure to air pollution and stroke risk in their cohort as well as the relationship between air pollution and risk for cognitive decline and dementia. Understanding the mechanisms at work is also a focus.


Joel Kaufman, MD, MPH, professor of environmental & occupational health sciences, medicine and epidemiology, and interim dean of the University of Washington School of Public Health, said the new findings provide added evidence of the role that air pollution plays in cardiovascular disease risk including ischemic stroke.

"The literature has become increasingly consistent over the past 15 years that risk is increased with air pollution exposure, including near-road traffic-related air pollution," said Dr. Kaufman.

Dr. Kaufman was part of a team that published a 2016 study in the Lancet that found that people living in areas with high levels of outdoor pollution accumulate calcified atherosclerotic plaques in their coronary arteries at a greater rate than those living in areas with less air pollution. The study involved more than 6,000 people in six states. The team is continuing to look at the occurrence of clinical cardiovascular disease events and at how much cleaner our air needs to be to prevent these effects.

"We need to have less exposure to traffic and traffic-related air pollution," said Dr. Kaufman, who has served on the EPA's Clean Air Science Advisory Committee panels on particulate matter, carbon monoxide, and nitrogen oxides. While people often can't control where they live, he said communities can lessen the potentially harmful impacts of traffic through better urban design, such as locating new homes and schools away from highways and consider retrofitting old roadways with "lids."

At a societal level, policies that tighten auto emission standards, increase fuel economy, and speed the transition from vehicles that burn fossil fuels will improve the overall picture of cardiovascular health, he said. "There is a steady drumbeat of evidence that pollution does matter, and we haven't yet gotten to the point that we are clean enough," said Dr. Kaufman. "We have to continue to be vigilant."

Vladimir Hachinski, MD, FAAN, professor of neurology and epidemiology at Western Ontario University, said there is mounting evidence that air pollution is a significant risk factor for both stroke and dementia. Pollution generated by auto emissions has been going down, he said, but emissions involving volatile organic compounds found in items such as pesticides, cleaning agents, coatings, ink and personal products, are on the rise.

"We tend to focus on individual risk factors, but our view of prevention can't simply be, 'Eat better.' We have to provide a healthy environment," said Dr. Hachinski, who studies variation in stroke patterns across Canada's provinces, some of which have province-wide stroke strategies.  He said an emerging concern is increasing use of marijuana because the smoke contributes to air pollution, both indoors and out. Separate from the issue of whether marijuana should be legalized, is the question of its impact air pollution, Dr. Hachinski said.


Kulick ER, Wellenius GA, Boehe AK, et al. Residential proximity to major roadways and risk of incident ischemic stroke in NOMAS (The Northern Manhattan Study​). Stroke 2018; 49(4):835-841. Epub 2018 Mar 14.​​

Wednesday, April 11, 2018


People with epilepsy have a three-fold higher risk of unnatural mortality and a five-fold higher risk of unintentional medication poisoning, according to results from a study published first online on April 9 in JAMA Neurology.

"This is the first study to comprehensively examine cause-specific unnatural mortality risks, including both unintentional and intentional medication poisoning separately, in people with epilepsy," the study authors, led by Hayley C. Gorton, PhD, of the Centre for Pharmacoepidemiology and Drug Safety at the University of Manchester in the United Kingdom, wrote.

The study used two electronic primary care data sets with hospitalization and mortality information from England and Wales. For comparison, 58,729 people with epilepsy were matched by age and sex to over one million people without epilepsy.

The researchers found that people with epilepsy were two times more likely to die from suicide and almost four times more likely to die from intentional self-poisoning with medication than the general population. The medications most commonly involved in drug poisoning were opioids and psychotropic medications, not antiepileptic drugs. Furthermore, psychiatric diagnoses including alcohol or other substance abuse, schizophrenia, bipolar disorder, and depression were significantly more prevalent among those with epilepsy.

The study authors concluded that doctors should consider the potential for toxicity of the medications they prescribe their patients and provide advice on unintentional injury, poisoning, and suicide prevention for their patients with epilepsy.

While it is well-known in the medical community that epilepsy is associated with an increased risk of premature death, previous research largely focused on direct causes of death such as sudden unexpected death in epilepsy, status epilepticus, drowning, and unintentional injury.

But "indirect causes of death due to the psychiatric and other consequences of epilepsy may exceed direct causes," wrote Orrin Devinsky, MD, FAAN, and colleagues from NYU Langone Medical Center, in an editorial accompanying the study.

They noted that depression and anxiety are easily recognized, for example, but often go undiagnosed and are not treated. Researching indirect causes of death are important, they wrote, because "many of these paradoxically present a more tractable opportunity to reduce overall epilepsy mortality," because "there are proven public health, medical, or rehabilitative techniques available for prevention."

In addition, they urged clinicians to combat societal biases that may cause them to blame victims for their lifestyle choices and addictions, and to view psychiatric consequences as part of patients' disease biology.


Gorton HC, Webb RT, Carr MJ, et al. Risk of unnatural mortality in people with epilepsy​. JAMA Neurol 2018: Epub 2018 Apr 9.

Devinsky O, Singh A, Friedman D. Editorial: Deaths in Epilepsy: What we are missing​. JAMA Neurol 2018; Epub 2018 Apr 9.

Wednesday, April 11, 2018


A new study designed to detect Alzheimer's disease (AD) at its earliest stages found that some people began to experience subtle memory decline even when brain amyloid-beta (Abeta) levels measured on positron emission tomography (PET) scans were in the "negative" range.

The study, which was published in the March 23 online edition of Neurology, lends support to the widely-held belief that AD is a long process that begins years, and perhaps decades, before it becomes clinically evident. But it adds further insight into the development of AD by suggesting that even slight elevations in brain amyloid within the so-called negative range may be linked to cognitive changes.

The researchers arrived at their findings after giving study participants, all older individuals who were deemed cognitively healthy at the start, periodic PET scans and cognitive tests over a span of about four years.

"These results indicate that even individuals categorized as 'A-beta negative' may be in preclinical stages of AD, and that subtle memory decline is an early consequence of cortical amyloid-beta deposition that can be detected within the negative range," the researchers reported.

The study's lead researcher, Susan M. Landau, PhD, associate research scientist at the Helen Wills Neuroscience Institute at the University of California, Berkeley, said "people in the negative range are thought to be free of Alzheimer's disease pathology and, in general, this is true." In the cognitively normal people they studied, however, amyloid that was negative on PET scan but gradually increasing coincided with memory decline, she said.

"There is variability within the normal range," Dr. Landau told Neurology Today. "Even small increases in amyloid are linked to small subtle declines in memory performance." The changes may not even be noticeable to the individual, she added.

The study findings have no clinical relevance currently since PET scanning to measure Abeta is not typically done in cognitively normal people, but they could help inform researchers designing clinical trials, particularly those involving AD prevention therapies.

The study authors noted that the "appearance of widespread cortical amyloid-beta occurs in about 25-30 percent of the cognitively normal older population over age 70, and it is hypothesized to be the initial event in the pathological cascade that leads to AD." Recent research has shown that amyloid-beta positive status is associated with cognitive decline even in cognitively normal people, the study authors said.

"However, the earliest stages of amyloid-beta deposition, before amyloid is widespread throughout the cortex remains poorly understood," they wrote. "While some studies have reported no relationship between cognitive change and beta amyloid deposition in the negative range these observations could be due to relatively limited follow-up and small sample size."


To further examine the question, the researchers focused on a group of 142 cognitively normal individuals enrolled in the Alzheimer's Disease Neuroimaging Initiative, a multicenter longitudinal biomarker study. The participants were on average 74.7 years old at baseline (55 to 90 years old was the range) and 45 percent of them were women. They were all considered amyloid negative at baseline and had at least two (18F)-florbetapir PET scans over an average of 3.9 years of follow-up. The goal of the study, which was funded, in part, by the National Institutes of Health and the US Department of Defense, was to determine whether amyloid accumulation was associated with longitudinal changes in memory or executive function.

The cutoff between "negative" and "positive" brain amyloid is based on amyloid pathology detected at autopsy, the gold standard for defining the cutoff, according to Dr. Landau. Commonly used standardized tests were administered to assess cognitive changes.

Over the four to six years of follow up, 13 of the 142 participants (9.2 percent) converted to an amyloid positive status as measured by florbetapir accumulation on PET scan. Fourteen of the 142 (9.9 percent) converted from being cognitively normal to a different diagnosis; 12 of them were diagnosed with mild cognitive impairment (MCI) and two with AD. (One of those who converted to MCI had also converted to an amyloid positive status.)

"Across all baseline negatives, florbetapir accumulation was associated with poorer memory trajectories, but there was no association with executive function," the researchers reported.

Factors such as apolipoprotein E4 status, age, sex, education, and baseline memory did not seem to influence whether a person would have changes in amyloid. However, the researchers did find that greater accumulation was associated with higher baseline Abeta, indicating that accumulation was ongoing prior to the start of the scanning.

 "A key feature of our finding is that slight elevations in amyloid-beta within the negative range have not been previously linked to cognitive changes," the researchers wrote. But they acknowledged that the study left many questions unanswered.

Dr. Landau said it is important to emphasize that "not all older people are accumulating amyloid. Most of the people we studied — 82 percent — were still amyloid negative and still cognitively normal by the end of the study," so the big picture is not totally discouraging. "Many people never cross that threshold."

Dr. Landau said her group is now interested in investigating the involvement of tau, another biomarker for AD, in people whose PET scans are in the negative range.

She said understanding the very earliest stage of AD is important for both drug development and prevention efforts because "once enough pathological change and cognitive change is underway it may not be reversible."


David S. Knopman, MD, FAAN, professor of neurology at the Mayo Clinic in Rochester, MN, told Neurology Today that the study findings made sense from a biological perspective. "I wasn't surprised by the idea that brain amyloid-beta levels couldn't be neatly divided into positive or negative," with values below a dividing line suggesting no worries.
"It creates a false expectation that if an amyloid level is negative, there is no risk. Cutoff points are useful, but they are inherently over-simplifying," he said.

Dr. Knopman cautioned, however, that the study only showed an association between accumulating brain amyloid in the so-called negative range and subtle memory decline, not that the amyloid was causing the memory changes.

 "I think the most plausible explanation is that brain amyloid elevations are a marker for neurodegeneration. The elevation of amyloid is a proxy for some other neurodegenerative process that, in the end, is causing neuronal dysfunction and death," said Dr. Knopman.

Dr. Knopman said PET scan studies such as this latest one in Neurology are invaluable to Alzheimer's researchers because being able "to image the pathophysiology in real time in real people over the course of the disease, not to mention longitudinally, is fundamentally changing how we view the disease."

Roberta Brinton, PhD, an Alzheimer's researcher who is professor in the departments of pharmacology and neurology at the University of Arizona, said the findings from the new study align with those of a study she conducted using PET scan and MRI that found that "amyloid-beta can accumulate very early in life," perhaps well before any clinical signs. She is particularly interested in what happens during the hormonal transition that occurs as women approach menopause.

"We have evidence in the perimenopausal and menopausal female that amyloid-beta is already accumulating" when women are in their forties and fifties, said Dr. Brinton, whose findings were published last year in Neurology

"At some point in this amyloid-beta negative phase, something is happening that leads to the development of the hallmark pathology of Alzheimer's," Dr. Brinton said. "Our data indicate that decline in glucose metabolism in the brain is an early key driver activating hallmark pathologies of AD."

While it would be impractical outside of a clinical trial for people to have a PET scan of their brain to check for amyloid buildup, Dr. Brinton said there are already "clinically deployable metrics," that are routinely gathered during a doctor appointment that could be useful for predicting AD risk.

 Dr. Brinton said she and colleagues published findings in 2016 suggesting that "it is possible, using standard clinical and laboratory analyses, to detect women who are showing signs of impending metabolic dysfunction. The earliest indicators of metabolic dysfunction were associated with cognitive decline, which is a risk for later life development of AD."

Paul B. Rosenberg, MD, associate professor of psychiatry and behavioral science at Johns Hopkins School of Medicine, said the new study provides useful information for researchers and drug developers who are looking at the very earliest signs and risk factors for AD to help develop targets for intervention. Dr. Landau's team "turned the clock backwards and found that below the (amyloid positive) cutoff you can still be at some risk, you can still be accumulating risk," he said.

"The changes may be small and [may] not be enough to make a clinical difference," said Dr. Rosenberg, but he said that the subset of seemingly vulnerable people in the negative range may be of interest to developers of anti-amyloid therapies because they may be the people most likely to benefit from such therapies.

Dr. Rosenberg is a site investigator for a large multicenter trial known as A4 (Anti-Amyloid in Asymptomatic Alzheimer's) that is testing an anti-amyloid antibody developed by Eli Lilly. The study involves 1,500 persons between the ages of 65 and 85 who have evidence on PET scan evidence of amyloid buildup but no clinical signs of cognitive decline. They are given monthly infusions of the drug for five years and being tracked with follow-up brain scans and cognitive tests.


Landau SM, Horng A, Jagust WJ, for the Alzheimer's Disease Neuroimaging Initiative. Memory decline accompanies subthreshold amyloid accumulation. Neurology 2018; Epub 2018 Mar 23.

Mosconi L, Berti V, Quinn C, et al. Sex differences in Alzheimer risk: Brain imaging of endocrine vs chronologic aging​. Neurology 2017: 89(13): 1382-1390.

Tuesday, April 10, 2018



Synesthesia — a neurological phenomenon that causes unusual connections between senses or cognitive pathways, like "tasting" colors or "hearing" letters —has been described in literature dating back to the ancient Greeks, with the first medical description appearing in a German physician's thesis from 1812.  In 1880, Charles Darwin's cousin Francis Galton, published a paper in Nature on the phenomenon 

Imaging studies have demonstrated increased structural and functional connectivity in a number of regions of the brain among people with synesthesia, but any molecular basis for the condition has eluded scientists, with previous linkage studies searching for shared genetic loci across multiple families yielding limited success.  

But now a new study from researchers at the Max Planck Institute and Raboud University in the Netherlands and the UK's Cambridge University has, for the first time, identified specific genes that are linked to synesthesia.

Because of a lack of candidate genes, lead author Simon Fisher, DPhil, director of the Max Planck Institute for Psycholinguistics and professor of language and genetics at the Donders Institute for Brain, Cognition and Behaviour, and his colleagues applied whole-exome sequencing to three families who all have sound-color synesthesia affecting multiple relatives across at least three generations. 

Published in Proceedings of the National Academy of Sciences on March 20, the analysis identified rare genetic variants that align with synesthesia in each family — a total of 37 genes of interest — on six genes: COL4A1, ITGA2, MYO10, ROBO3, SLC9A6, and SLIT2. These genes are all associated with axonogenesis and expressed during early childhood when synesthetic associations are formed.  

"These results are consistent with neuroimaging-based hypotheses about the role of hyperconnectivity in the etiology of synesthesia and offer a potential entry point into the neurobiology that organizes our sensory experiences," the authors wrote. 


The families in the study were selected from an existing cohort of 43 sound-color synesthesia families, who had been originally recruited by Simon Baron-Cohen, and colleagues at the University of Cambridge.

"The bigger cohort was used for an earlier genetic mapping study using older methods, before next-generation DNA sequencing was available," said Dr. Fisher. "This larger cohort included families of a range of sizes; quite a number of them only had two synesthestic members, for example. Since the main message from the prior work was that there is a lot of genetic heterogeneity, in our new study we wanted to focus on the largest of the families with sufficient DNA left to allow high-quality exome sequencing. The larger the individual family, the more power we have to reliably identify if there is a rare risk variant that segregates with the trait. We were able to zero in on three families with five synesthetic relatives, across three or four successive generations of the pedigree, as the most promising from the available cohort." 

"Although the causative variants identified in this paper appear to be rare —none are shared across families — they may yield unique insights into the biological processes involved in synesthesia. There were just a few biological themes that were significantly enriched across the candidate genes identified, and one of those was axonogenesis, a crucial process helping neurons get wired up to each other in the developing brain," Dr. Fisher explained.

"This is fascinating, because it is consistent with well-established prior findings of altered connectivity in neuroimaging of synesthesia, and so the pattern fits with a prominent hypothesis about how synesthesia develops," he continued.  "This means that, although we confirm the genetic heterogeneity of synesthesia, we at the same time show that the candidate genes cluster in shared pathways that are well aligned with neurobiological accounts, offering us potential entry points into the relevant mechanisms." 

Synesthesia comes in many varieties: in grapheme-color synesthesia, numbers and letters trigger a color experience, although the color associations differ from person to person. With ordinal-linguistic personification, numbers or words have personalities.  Individuals with conceptual synesthesia may see abstract concepts, such as units of time or mathematical operations, as shapes. Many people with synesthesia experience more than one form of the condition.  ​


For a long time, however, people with synesthesia were thought to have some form of mental illness, the after effects of drug use, or just to be making the whole thing up or speaking metaphorically.

Vilyanur Ramachandran, MBBS, FRCP (London), PhD, director of the Center for Brain and Cognition at the University of California, San Diego, was one of the first scientists to theorize that synesthesia arises from a cross-activation between brain regions. 

"In experiments that we published about 15 years ago, we proposed the neural basis for synesthesia," Dr. Ramachandran said. "We discovered that the condition occurs early in perceptual processing and is tractable scientifically."

For example, he said, on a "pop-out" test in which a triangular pattern of twos is embedded in a large field of fives — all in black and white — non-synesthetes must look carefully to find the twos, while for those with synesthesia, it pops out faster, like a bright red triangle in a forest of greens. 

This amenability to "test genuineness" is why Dr. Fisher's research focuses primarily on forms of synesthesia that induce perceptions of color. "An inherent feature of studying synesthesia is that it needs us to somehow get insights into people's internal experiences of the outside world, quite a challenge," he said. "In particular, for genetic analyses, we want to have as objective an assessment of the phenotype as possible, so we can't depend solely on asking for a self-report. For sound-color and grapheme-color forms there are robust well-accepted methods for validating whether someone is indeed synesthetic, by presenting them with many different primary stimuli and assessing the consistency of their color responses over repeated presentations." 

Neuroimaging studies such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) scans have also documented differences in brain region activation among synesthetes compared to non-synesthetes, but those studies have yielded somewhat inconsistent results —perhaps because of the differing forms that synesthesia takes. Overall, however, there is some consistent evidence suggesting that color-selective region V4 of the posterior-inferior temporal cortex and parieto-occipital junction is involved with word-color synesthesia. 

"It is possible that genetic mutations, such as the ones identified in this paper cause connections to emerge between brain areas that are usually segregated," said Dr. Ramachandran. "Or a mutation may lead to defective pruning of early connections between areas that are normally connected only sparsely."  


Synesthesia appears to be much more common than had previously been thought; some studies have suggested that as many as one in 50 people have this quirk. "Why would a gene that makes excess connections survive in the population such that it is so common?" Dr. Ramachandran asked.

"Perhaps a clue comes from the fact that it's about eight times more common in artists and poets. Synesthesia may not just be a quirky color-number thing, but a broader sign of connections linking far-flung brain regions," he said. "If it's expressed diffusely, then perhaps you are more metaphorical and tend to think of unrelated, creative ideas in general. Synesthesia may be a manifestation of abstract and metaphorical thinking in general." 

Think of Shakespeare, and Romeo's famous line: "It is the East, and Juliet is the sun," Dr. Ramachandran suggested. "Isaac Newton associated wavelengths with colors for his famous discovery of the spectrum of light, at a time when the wavelengths of sound had long been known but that hadn't been thought about yet with color. It makes me wonder if he had it, especially since he made a toy musical instrument which would flash colors corresponding to tones."

Rates of synesthesia are also elevated in both autism spectrum disorder and savantism. "While it's important to realize that synesthesia (and associated hyperconnectivity) often occurs in people without any kind of neurological diagnosis, there are reports suggesting that atypical sensory sensitivity may be a shared feature seen in synesthesia and in autism," said Dr. Fisher. "Our data don't point to any simple link, because the candidate genes we identified are not enriched for genes known to be involved in autistic traits. On the other hand, there is overlap in terms of biological pathways, and that is something that we would want to investigate more systematically in our future work." 

He noted that the literature is unclear on connectivity differences in autism. "While some studies find that autism involves reduced connectivity, others have actually claimed hyperconnectivity ." 

Dr. Fisher cautioned that there are limitations to the study's conclusions, given that the numbers and sizes of families studied with these next-generation techniques are relatively small. "We are now running whole genome sequencing of other large families with different forms of synesthesia, including grapheme-color and sequence-color," he said. "The approach there is similar to the current study, trying to find rare variants with potential large effects on the trait. We hope to test whether the same pathways from the current study emerge in additional multigenerational families, as well as if the patterns are convergent for different types of synesthesia." 

There may be other inheritance pathways for synesthesia beyond these rare gene variants as well, such as the combined action of many common polymorphisms, each with a small effect. To search for those, Dr. Fisher and his group are using web- and app-based testing to recruit hundreds of independent unrelated cases of grapheme-color synesthesia and using DNA chips to characterize common polymorphisms across the genome.

"The community of synesthesia researchers is a nicely interactive one, so we have colleagues helping us spread the word and identify participants, and we already have nearly 1,000 cases enrolled in our study, and we are happy for more to join!" he said.

"With more of the genetic data in hand in the coming years, including both rare and common variation, we hope to be able to robustly address the issues of overlaps with other cognitive traits and disorders, and bring a new molecular perspective on the biological pathways, as well as connecting to brain imaging and neuropsychological findings." 


Tilot AK, Kucera K, Vino, et al. Rare variants in axogenesis genes connect three families with sound-color synesthesia​. Proc Natl Acad Sci USA 2018;115(12):3168-3173.

Wednesday, April 4, 2018


Siponimod reduced the risk of three-month disability progression in patients with secondary progressive multiple sclerosis (SPMS) by 21 percent compared to placebo, according to a clinical trial published first online on March 22 in The Lancet.

The EXPAND trial (EXploring the efficacy and safety of siponimod in PAtients with secoNDary progressive multiple sclerosis) analyzed data from 1,645 SPMS patients at 292 hospital clinics and MS centers in 31 countries. Results of the phase 3, randomized, double-blind trial showed that 32 percent of patients receiving placebo showed worsening of disability at three months compared to 26 percent patients receiving siponimod.

"The siponimod EXPAND study is, to our knowledge, the first large trial of any disease-modifying therapy to show superiority over placebo in terms of disability progression in a representative population of patients with SPMS," wrote lead author Ludwig Kappos, MD, chair of the department of neurology at University Hospital Basel in Switzerland and colleagues.

Researchers randomly assigned 1,099 patients to once daily oral siponimod 2 mg and 546 patients to the placebo group for up to three years. The primary endpoint was time to three-month confirmed disability progression (CDP), defined as a 1-point increase in the Expanded Disability Status Scale (EDSS), which quantifies disability based on symptoms like limb weakness, ataxia, speech and swallowing difficulty, sensory deficit, bowel and bladder dysfunction, and others. Impairment is graded on a scale from 0 to 10 in 0.5-unit increments representing higher levels of disability. Other key secondary outcomes were time to six-month CDP, walking impairment measured by a timed 25-foot walk test (T25FW), and change in brain volume. Researchers also kept track of adverse events.

In addition to benefits in their primary outcome for disease progression, researchers found a 26 percent relative risk reduction in six-month CDP by siponimod. Brain volume also decreased at a lower rate with siponimod than with placebo. However, there was no significant difference in the worsening of T25FW walking test at three months.

Siponimod binds selectively to sphingosine-1-phosphate (S1P) receptors on lymphocytes, inhibiting their migration to areas of inflammation in the central nervous system (CNS). Preclinical studies suggest it might prevent synaptic degeneration and promote remyelination in the CNS.

Researchers found that the safety profile of siponimod was similar to that of other S1P modulators. Compared to patients taking placebo, those taking siponimod were more likely to experience liver transaminase elevations, bradycardia, macular edema, hypertension, varicella zoster virus reactivation, and convulsions. Frequencies of death and malignancies between the two groups were not increased.

"Siponimod reduced the risk of disability progression with a safety profile similar to that of other S1P modulators and is likely to be a useful treatment for SPMS," the researchers concluded.

An accompanying editorial by Luanne M. Metz, MD, and Wei-Qiao Liu, MD, from the department of clinical neurosciences and Hotchkiss Brain Institute at the University of Calgary suggested, however, that the degree of disability reduction was not significant enough to make siponimod an effective treatment for SPMS.

"Although siponimod seems to reduce the time to confirmed disability in SPMS, the treatment effect was small," they wrote. "In our opinion, the reduction in the proportion of participants reaching the primary endpoint of only 6% and the absence of a significant difference for the key secondary clinical outcome are disappointing results and do not suggest that siponimod is an effective treatment for SPMS." They concluded: "Confidence in the treatment benefit of siponimod in progressive MS will, in our opinion, require confirmation in a second trial."


Kappos L, Bar-OR A, Cree BAC, et al, for the EXPAND Clinical Investigators. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND), a double-blind, randomized phase 3 study. Lancet 2018; 391(10127): 1263-1273; Epub 2018 Mar 22.

Metz LM, Liu W-Q. Comment: Effective treatment of progressive MS remains elusive. Lancet 2018: 391(10127): 1239-1240; Epub 2018 Mar 22.​