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MDS International Congress

Access daily, concise peer-reviewed reports from the MDS International Congress selected by the Neurology Today editors.

Tuesday, October 1, 2019

NICE, France—Genetic testing on samples from two elderly community population studies shows that gray zone expansion of the fragile X mental retardation 1 (FMR1) gene is associated with parkinsonism in men, researchers said here at the International Congress of Parkinson's Disease and Movement Disorders.

The findings are the first time the link has been found in a community population. The data came from two longitudinal studies of elderly subjects at the Rush Alzheimer's Disease Center and adds strong data to the growing evidence of a link between the fragile X gray zone and a heightened risk of parkinsonism in men.

"This is the third study to show similar results, albeit in a different population, making a real association of parkinsonism with the gene more likely," said Deborah A. Hall, MD, PhD, FAAN, professor of neurological sciences at Rush Medical College.

Those with an expansion of more than 200 in the CGG repeat region of the FMR1 gene are considered to have the full mutation of the gene and are at risk of fragile X syndrome. Expansion of 55–199 CGG repeats causes fragile X-associated tremor/ataxia syndrome (FXTAS). Researchers are trying to bring into better focus the significance of the expansion of 41 to 54 repeats—the "gray zone."

At Rush University, researchers conducted genetic testing on 2,380 participants, finding that 4.5 percent were fragile X gray zone carriers, which is higher than the two percent seen in the general population. Most screening studies are done in newborn populations, which may account for the discrepancy in frequencies, Dr. Hall said.  

In addition to the link with parkinsonism (p< 0.01)—determined by a modified Unified Parkinson Disease Rating Scale score—researchers found that men who carried the fragile X gray zone had a shorter lifespan, by about three years. Dr. Hall said these associations could be relevant in conversations with patients, although this information needs to be delivered carefully.

"Currently genetic counseling guidelines suggest that a gray zone carrier should be told they will be neurologically normal. The conversation may need to be modified to inform a man who is a gray zone carrier that if he lives long enough, he will have a higher risk of developing parkinsonism."

Researchers found no differences between gray zone carriers and normal subjects in cognitive diagnosis, global motor function, or pathological findings, such as neuronal and glial intranuclear inclusions seen in FXTAS  and other pathologies, even after controlling for age, sex, education, race, and ethnicity.

Melissa Nirenberg, MD, PhD, FAAN, clinical professor of neurology at the Icahn School of Medicine at Mount Sinai, said an important aspect of the findings was that the subjects had consented to brain donation, allowing researchers to determine whether gray-zone carriers had pathology similar to what is seen in premutation carriers, and finding they did not.

"These findings provide further evidence to suggest that fragile X gray zone alleles—which are relatively common in the general population—may be a genetic risk factor for parkinsonism in men," she said.

Many questions remain to be explored, she said. For instance, do gray-zone carriers have pathological changes similar to those in fragile X tremor ataxia syndrome or idiopathic PD, or are their changes unique?

It is also unknown what it is about fragile X gray zone carrier status that predisposes someone to PD, and the factors—whether environmental or epigenetic—that makes someone with a gray-zone mutation more likely to develop parkinsonism.

"Are the clinical features of parkinsonism associated with gray zone mutation carriers different from those with idiopathic PD?" she asked.

Drs. Hall and Nirenberg had no disclosures.

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International Congress Abstract 514: Hall D, Nag S, Berry-Kravis E, et al. Fragile X gray zone alleles in men are associated with parkinsonism.

Tuesday, October 1, 2019

NICE, France—Parkinson's patients face a heavy burden of neuropsychiatric symptoms that only grow over time, according to a presentation here at the International Congress of Parkinson's Disease and Movement Disorders.

The analysis was based on data collected prospectively from a study of markers of Parkinson's disease (PD) progression.

About 78 percent of patients had at least one neuropsychiatric symptom at the first yearly visit in the Parkinson's Progression Markers Initiative, and 29 percent had three or more, said Daniel Weintraub, MD, professor of psychiatry at the University of Pennsylvania. By the fifth year, that burden had mushroomed to 88 percent with at least one symptom and 56 percent with three or more.

Researchers evaluated the prevalence and treatment of 10 symptoms, as well as correlates with those symptoms: depression, anxiety, REM sleep behavior disorder (RBD), impulse control disorders (ICDs) and related behaviors, psychosis, apathy, insomnia, excessive daytime sleepiness, fatigue and cognitive impairment. There were 423 PD participants and 196 healthy controls enrolled at the start of the study; 315 of the PD participants remained in the study at the fifth year.

When prevalence was defined as meeting a threshold using an instrument, such as the General Depression Scale, the most common symptoms at baseline were RBD at 26 percent, anxiety at 25 percent, and insomnia at 24 percent.

In this analysis, researchers took an unusual step and factored in treatment for a disorder in a separate prevalence calculation, so that treatment counted as having the symptom. In some cases this made for just a small difference, but in the case of depression, prevalence jumped from 14 percent at baseline to 27 percent.

"You also have to consider the people who are starting treatment of these disorders," Dr. Weintraub said. "If they're treated, that means the symptom may no longer be present or the clinician, even if it didn't cross the threshold of the instrument, felt they had the symptom and wanted to treat."

Researchers found that at some point over the five years, 70 percent of patients either had instrument-measured insomnia or had been treated for it. That was true for 51 percent of patients in the case of depression, for 54 percent for anxiety, 52 percent for excessive sleepiness, 61 percent for RBD, 52 percent for impulse control disorders (which did not take into account treatment), and 57 percent for cognition.

"By year five, it's just really high for a lot of these [patients]," Dr. Weintraub said.

By year five, seven of the 10 disorders had either been present in a patient or treated for at some point over the course of the study in at least half of the patients.

Use of antidepressants and anti-anxiety medications was common at baseline—18 percent and 13 percent of patients were already on these medications at year one—and their use increased over time, to 27 percent for antidepressants and 24 percent for anti-anxiety drugs. Use of anti-psychotic and cognitive-enhancing drugs was uncommon throughout the study.

Commenting on the study, Suketu Khandhar, MD, medical director of the Kaiser Permanente Northern California Movement Disorders Program, said it's important to understand that baseline is not a pure baseline, and that the early prevalence of these non-motor symptoms underscores this.

"Baseline implies that you have no disease at a certain time—the reality is that the vast majority of Parkinson's patients are diagnosed well into the pathology of this disease," said Dr. Khandhar, who was not involved with the study. "There's a prodrome to this condition that we are not capturing, and that prodrome is all these non-motor neurologic symptoms like REM sleep behavior disorder, constipation, anxiety, and depression."

"There are studies that show that, if you were to see an individual who had an understanding that these prodromal symptoms actually have an increased likelihood of developing Parkinson's, we could capture the disease early, capture a better baseline, and better understand the trajectory of this condition. So I think this [study] is really unfortunately falsely representing what's truly happening."

Drs. Weintraub and Khandar had no disclosures.

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International Congress Abstract 1644: Weintraub D, Caspell-Garcia C, Cho H, et al. Cognitive and psychiatric course in the initial lustrum of Parkinson disease: The glass is half full.

Tuesday, October 1, 2019

NICE, France—The economic burden of Parkinson's disease (PD) in the US was at least $52 billion in 2017, according to a comprehensive assessment presented here at the International Congress of Parkinson's Disease and Movement Disorders.

The analysis is certainly an underestimate, the researchers who led the study at the University of California, San Francisco (UCSF) and independent experts said.

Lead author Caroline Tanner, MD, PhD, FAAN, professor of neurology at UCSF, said she hopes the data form the groundwork for improvements and resources made available to fight the disease.

"In addition to the debilitating symptoms of Parkinson's disease itself, people with Parkinson's disease also experience injuries from falls and other comorbidities," Dr. Tanner and her colleagues wrote in the abstract. "As a result, people with Parkinson's have higher medical needs, often miss work, retire early, and require caregiver assistance. Parkinson's disease prevalence is predicted to increase in the coming decades. Comprehensive information on the economic burden of PD is needed."

The study, which intended to account for factors that are less understood or overlooked, drew data from a de-identified database of the privately insured population, Medicare claims and Census population projections, a survey designed to capture the indirect costs of PD, and other sources.

Direct medical costs—calculated as the amount paid by people with PD above the amount paid by matched controls—were estimated at $25.4 billion. This came out to a per-capita total of $24,439 for Medicare patients, $22,671 for the privately insured, and $19,489 for those with other coverage or the uninsured.

Indirect and non-medical costs—such as reduced employment, disability income payments, and modification to the home—amounted to $26.5 billion. Nearly $20 billion of that was for those with PD and another $6.6 billion was for unpaid caregiver burden. Per capita indirect and non-medical costs totaled $19,242 but went up to $25,558 when caregiver burden was added in.

"The indirect costs are equal to the direct costs, and they're also probably underestimated because we probably don't fully represent that population who we know have huge indirect costs because of the need for additional care in the home and things like that," Dr. Tanner said. "I think these are really important numbers for policy purposes and for health care planning. Hopefully this will allow people to have better justification for the need to have preventive strategies for Parkinson's, better treatment for Parkinson's, and more support."

The study was funded in part by the Michael J. Fox Foundation and the Parkinson's Foundation.

Commenting on the study, Suketu Khandhar, MD, medical director of the Kaiser Permanente Northern California Movement Disorders Program, said the study is impressive.

"I think this is a huge economic burden to anyone everywhere," he said, adding that the figures should spur the government to offer incentives to improve Parkinson's care. The burden, he said, "ultimately falls on government finances and government resources."

Just putting numbers to the cost of PD is a breakthrough, he said. "I'm not sure I've seen those numbers in the past."

But he said the real cost must be even higher than the cost presented in the study, particularly because indirect costs are so hard to quantify. "I'm not sure you can truly capture all that."

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International Congress Abstract 1841: Tanner C, Albin R, Dahodwala N, et al. The economic burden of Parkinson's disease (PD) in the United States.

Tuesday, October 1, 2019

NICE, France—Tourette syndrome and tic disorders exact a heavy toll on patients' ability to form relationships and succeed at school and in careers, according to findings from a web-based survey of people with the disorders presented here at the International Congress of Parkinson's Disease and Movement Disorders.

More than half of the respondents of the survey—which included 281 adults and 623 children—said they experienced some form of discrimination and financial strain.

The findings point to the need for improved diagnostic tools for earlier diagnosis and interventions targeting the educational and vocational needs of people with Tourette syndrome and tic disorders, said the lead author of the report and an independent expert.

Fifty-three percent of the adult respondents with Tourette syndrome and tic disorder had a delay of at least six years until diagnosis, said the lead author of the report, Irene Malaty, MD, FAAN, associate professor of neurology at the University of Florida. And despite the fact that approximately 30 percent of patients had tried five or more medications, nearly half of patients felt their symptoms were not adequately treated.

Sixty-three percent of children and 68 percent of adult patients said they had experienced discrimination due to the disorders, and 44 percent of the adults who responded—children weren't asked this—said they'd been hindered in developing meaningful friendships or romantic relationships. Twenty-five percent of the adult respondents reported substance abuse.

Among other findings, 83 percent of children and 76.7 percent of adults said they felt their educational success was hindered by the disorder. Forty percent of children said they had to miss school due to the disorders, 43 percent said they'd been discriminated against by teachers, and 35 percent said they weren't provided with an education that matched their abilities. Sixty-nine percent reported receiving educational accommodations.

Forty-three percent of patients reported financial strain due to the disorders, attributing it mostly to the high cost of needed services.

In the survey, patients said that neurologists diagnosed the disorder in 60 percent of the cases, much more often than other physician groups. Psychiatrists made the diagnosis 15 percent of the time and primary care physicians and pediatricians in less than 10 percent of cases.

"We would anticipate pediatricians or psychiatrists would be doing most diagnosing," Dr. Malaty said. "I found it completely fascinating that among both kids and adults, the majority were diagnosed first by a neurologist."

The survey was conducted by the Tourette Association of America.

Tamara Pringsheim, MD, FAAN, associate professor in the department of clinical neurosciences, psychiatry, pediatrics and community health sciences at the Cumming School of Medicine of the University of Calgary, Canada, said the findings dovetail with work done by her center. Dr. Pringsheim is the director of the Calgary Tourette and Pediatric Movement Disorder Clinic at the Alberta Children's Hospital.

"These results are consistent with a Canadian population-based study we performed a few years ago, which also found that individuals diagnosed with Tourette syndrome were less likely to obtain a post-secondary education, had lower household incomes, and were less likely to be employed," she said. "Interventions targeting the educational and vocational needs of people with Tourette syndrome are needed to maximize their potential at school and in the workplace."

She said the tools to help neurologists with Tourette syndrome diagnosis have recently been improved.

"As neurologists are the physicians most often making the diagnosis of Tourette syndrome, we hope that our recently published AAN guideline on the assessment and management of tics in people with Tourette syndrome and chronic tic disorders will help improve the overall standard of care for people living with Tourette syndrome."

Harvey S. Singer, MD, FAAN, professor of neurology at Johns Hopkins, said: "There is much more to Tourette syndrome than just tics. Clearly, establishing an effective therapeutic plan requires the careful assessment of tics, determining the presence of co-occurring issues, and clarifying the resulting impairment of each issue. In terms of treatment, it is essential to determine whether tics or associated problems—for example, attention deficit-hyperactivity disorder, obsessive-compulsive disorder, anxiety, mood, disruptive behaviors, or other (issues)—are causing the greatest impairment."

Drs. Malaty and Pringsheim had no disclosures.

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International Congress Abstract 1384: Malaty I, Shineman D, Deeb W. The impact of Tourette syndrome and tic disorders on education, occupational and personal life.

Tuesday, October 1, 2019

NICE, France—Pesticide use has been associated with an increased risk of Parkinson's disease (PD). Now new research presented here at the International Congress of Parkinson's Disease and Movement Disorders offers insight into the role that genetic variants may play in modulating that risk.

The findings suggest that the risk for PD associated with exposure to pesticides may be mediated by the presence of certain genetic variants.

Using an "exposed-only" approach involving only people who were known to use or apply pesticides, researchers found several single nucleotide polymorphisms (SNPs) present at a significantly greater frequency among those with pesticide exposure and PD than among those who were also exposed but did not have PD, said Samuel Goldman, MD, MPH, associate professor of medicine at the University of California, San Francisco (UCSF).

"The interaction between pesticides and genetics is very difficult to test because you need these huge subsets," Dr. Goldman said. "So most large genetic studies don't collect environmental data and so there's been a real deficiency in the ability to look at gene-environment interactions…This is another approach that maximizes the power in an exposed-only analysis."

The approach allows interactions to be seen even with smaller samples of those with exposure to a particular agent and who have the disease.

The case-control study was part of the Agricultural Health Study, which included 52,000 pesticide users and their spouses in Iowa and North Carolina. Researchers performed genotyping on 100 subjects who had been diagnosed with PD and 371 matched controls, analyzing for 123 genes and a total of 3,309 SNPs with the potential for PD involvement—metabolic enzymes, xenobiotic membrane transporters, and antioxidant or glutathione-related genes. They looked at subcohorts for the insecticide rotenone, the herbicide paraquat, the insecticide permethrin, cycloidiene insecticides, and the herbicide 2,4-D.

Researchers reported on four SNPs that were significantly associated with PD. One, among those with rotenone exposure, was for the nucleoredoxin gene (p = 0.04; OR = 6.8), which is important for protection against oxidative stress. Another, among those exposed to 2,4-D—a major component of Agent Orange—was a SNP in the gene coding for cytochrome P450 2E1 (p = 0.03; OR = 14.9), which metabolizes a wide variety of chemicals.

In gene-wide burden tests, they found that SNPs for particular genes were more likely for those with PD than those without. Among those with rotenone exposure, for instance, variants were higher in those with PD for the gene ABCB1, which encodes P glycoprotein, a membrane transporter that prior studies have shown binds rotenone and transports it across the cell membrane, Dr. Goldman said.

This new approach may not have been used to study movement disorders or any neurodegenerative conditions before, Dr. Goldman said, and it provides added evidence that genetics and pesticides seem to play an interwoven role in the development of PD.

"It reinforces the evidence that pesticide exposure and genes are involved in pesticide metabolism," he said. "Hopefully others will take this same approach with an exposed-only analysis."

Caroline Tanner, MD, PhD, FAAN, another author on the study and professor of neurology at UCSF, said the findings point to the heterogeneity of mechanisms that seem to be involved in pesticide-genetic interactions.

Alexis Elbaz, MD, PhD, research professor at the Center for Research in Epidemiology and Population Health (INSERM) in Paris who has also studied pesticides' role in PD, said he thought the findings were impressive and show that "not everyone who is exposed to these pesticides has an increased risk, so the risk associated with pesticides depends on your genetic background."

But he wondered about the usefulness of the findings since there was no genetic testing performed in those who were not exposed to the pesticides.

"We have done these sorts of studies, too, and it's interesting to explore these gene-environment interactions, to understand how it works and to see people who are more susceptible than others," he said. "But the implications of it are not very clear because you're not going to test persons before they use pesticides…How can you apply this information?"

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International Congress Abstract 1515: Kaye J, Lima L, Tanner C, et al. Exposed-only analysis of gene-pesticide interaction in Parkinson's disease (PD).