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MDS International Congress

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

Friday, September 18, 2020

Microglial activation in the brains of patients with isolated REM sleep behavior disorder (iRBD), a prodromal phenotype of Parkinson's disease (PD), is associated with a more rapid progression of nigrostriatal dysfunction, according to a report presented during the MDS Virtual Congress 2020, the annual meeting of the International Congress of Parkinson Disease and Movement Disorders.                

The current findings suggest that microglial activation may play a role in earlier stages of PD, the study authors suggested in their abstract.

A collaborative effort between scientists from Aarhus University Hospital in Denmark and the Hospital Clinic de Barcelona, the study aimed to determine if the immune system's microglial activation is protective or if it worsens iRBD.

Previous research by Nicola Pavese, MD, PhD, a professor at Aarhus University, and his colleagues had shown activated microglia in the substantia nigra—evidence of neuroinflammation—on PET scans of patients with iRBD who had no clinical signs of parkinsonism.

For the current study, the team scanned 15 patients with iRBD with 11C-PK11195 to measure microglial activation and 18F-DOPA PET for a baseline measure. Three years later, they returned for another 18F-DOPA PET scan to monitor changes that may have occurred over time.

At baseline, six of the 15 patients had abnormal 11C-PK11195 binding in the substantia nigra and striatum. The 18F-DOPA uptake from baseline to follow-up across the iRBD patients showed a decrease of dopamine uptake in the caudate nuclei and the anterior portion of the putamen bilaterally.

The researchers assessed binding in patient cohorts with and without abnormal 11C-PK11195 separately and observed more widespread and severe changes across the striatal areas in the patients who showed microglial activation at baseline; those who did not have evidence of microglial activation had minimal changes in the left caudate. 

"This (finding) would suggest a detrimental rather than a neuroprotective effect of neuroinflammation even in the early stages of parkinsonism," the scientists said. Neuroinflammation may be a  potential treatment target in the early phases of PD, they suggested.

"The study addresses an exciting and important topic in the field of neurodegenerative diseases, including PD," said Katharina A. Schindlbeck, MD, a scientist and movement disorders expert at the Feinstein Institute for Medical Research, who was not involved with the research.

Several studies support a pathological mechanism of microglial activation in advanced disease stages of PD, but its role in the early stages was less clear. Only recently, the presence of neuroinflammation has been shown in the prodromal phase of the alpha-synucleinopathy-related disease. However, how immune and inflammatory pathways interact with disease progression is still poorly understood, that is, whether increases in microglial activation are associated with more rapid disease progression.

 "These findings encourage the development of drugs targeting neuroinflammation in PD," Dr. Schindlbeck said. "Since neuroinflammatory changes are present early in the disease course, the research supports a potential disease-modifying effect of such therapies."

She added that further studies should investigate whether these imaging modalities are useful to monitor such therapeutic effects. "Multimodal imaging biomarkers could prove useful as secondary outcome measures in clinical trials targeting microglial activation. Given the relatively small sample size of early phase clinical trials, imaging biomarkers may enhance the likelihood of detecting therapeutic effects."

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MDS Abstract 638: Staer K, Iranzo A, Stokholm M, et al. Microglial activation associated with a faster progression of nigrostriatal dysfunction in patients with isolated REM sleep behavior disorder.

Stokholm MG, Iranzo A, Ostergaard K, et al. Assessment of neuroinflammation in patients with idiopathic rapid-eye-movement sleep behaviour disorder: A case-control study. Lancet Neurol 2017;16(10):789-796.

Friday, September 18, 2020

People with different risk genes associated with Parkinson's disease (PD) show unique compensatory brain mechanisms and faulty wiring patterns on functional imaging, according to research described at MDS Virtual Congress 2020, the annual meeting of the International Parkinson and Movement Disorder Society.

The distinct network patterns could be used to assess the degenerative disease process and a person's response to treatment, the senior study author, David Eidelberg, MD, FAAN, director of the Center for Neurosciences at the Feinstein Institute for Medical Research, told Neurology Today At the Meetings.

Functional imaging studies have previously identified distinct brain network patterns in PD, but it was not clear whether these were maladaptive or compensatory responses to the underlying disease pathology.

In the current study, Dr. Eidelberg and his colleagues used functional scanning technology to look at the metabolic brain networks underlying PD patients with LRRK2 mutations or GBA variants. People with a GBA mutation in one copy of the gene who develop PD often have a more rapid and severe course and experience motor symptoms years earlier than people with sporadic forms of PD and cognitive deficits. They also tend to have more problems with gait and balance. People with a LRRK2 mutation have milder motor deficits and do not experience the same cognitive problems as people with GBA variants who develop PD.

The research team measured the wiring pattern or assortativity—the tendency of connections to link together nodes of a similar degree in a disease network—in people with a GBA mutation and others with a LRKR2 mutation.  

The patients with the LRRK2 mutant had reduced assortativity compared with GBA patients and healthy controls in the core zone of the PD network. Core assortativity was increased in patients with GBA variants, said Dr. Eideberg.

"The gain of connections can make someone better or worse depending on where the connections are formed," Dr. Eidelberg added. The core is not a good place for too many connections, he said, adding that this can cause instability to the network.

"Neurons have a propensity to take to each other in different environmental conditions. In LRRK2-PD patients, we see a specific connection between the two disease networks, and it is stable," Dr. Eisenberg explained.

"If we can create a therapy that lowers assortativity, we could improve the disease," he speculated, adding that other studies have shown that gene therapy can modulate maladaptive expression patterns.

"The ability to image the communication between brain regions, has revolutionized the study of human brain disorders," said Douglas Rothman, PhD, professor of radiology and biomedical engineering at the Yale School of Medicine, who was not involved with the study. "However, it has not been possible to distinguish whether changes in networks are responsible for disease symptoms or alternatively reflect compensation."

The abstract from Dr. Eidelberg and his colleagues "describes a novel approach to brain network analysis that reveals a property called assortativity, a measure of how strong specific components of the brain network are communicating."

The observation that assortativity is increased in cohorts who go on to develop more severe symptoms strongly suggests that this property is intrinsic to the pathogenesis of the disease, Dr. Rothman said.  "The work is highly significant for the diagnosis and prognosis of PD and for the development of future treatments."

Dr. Eidelberg serves on the scientific advisory board and receives honoraria from the Michael J. Fox Foundation. He serves on the scientific advisory board and receives personal fees from Ovid Therapeutics, and receives consultant fees from MeiraGTx.

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MDS Abstract 628: Schindlbeck K, Vo A, Nguyen N, et al. Distinct compensatory and maladaptive wiring patterns in genotypic Parkinson's disease.

Friday, September 18, 2020

Patients with Parkinson's disease (PD) who report feeling lonely also say they have a more severe disease course, according to results from a cross-sectional analysis presented at the MDS Virtual Congress 2020, the annual meeting of the International Parkinson and Movement Disorder Society.

The study aimed to assess the relationship between self-reported quality of life, loneliness, and patient-reported symptoms of PD severity.

The existing literature doesn't offer much information on PD patients and loneliness or social isolation, noted study author Indu Subramanian, MD, a neurologist at the David Geffen School of Medicine at the University of California in Los Angeles and Director of the Southwest Veteran Affairs Parkinson’s Disease Research, Education and Clinical Centers.

Dr. Subramanian said when she and her colleagues reviewed the medical literature, they found some studies on longevity and aging, which touched on depression, but very little related to PD patients and loneliness.

Being socially connected is a basic human need, Dr. Subramanian said, noting that some studies have shown that the lack of social connections can make people hypervigilant, anxious, and have disrupted sleep.

Neurologists need to be proactive in identifying loneliness and social isolation as risk factors in PD patients, said Dr. Subramanian. "Just as we would ask them about falls and hallucinations, we need to ask them [about loneliness] and ask in a way that is out of the box. They are not going to come to us. There's a big stigma with loneliness. Patients are embarrassed and ashamed to be lonely."

To better understand the problem, the researchers asked 1,746 idiopathic PD patients from the CAM Care PD study to participate in two self-reported surveys: the Patient-Reported Outcomes Measurement Information System (PROMIS) to evaluate quality of life and Patient-Reported Outcomes in Parkinson's Disease (PRO-PD) to determine PD severity.  

PROMIS looks at social, mental, and physical health in children and adults with various demographic characteristics and chronic conditions. Higher scores on the scale equate to a more severe course of PD, while lower scores were associated with a less severe disease course.

The researchers factored in gender, age, income, and years since diagnosis in their analysis. Lower scores on the PROMIS social health questionnaire were associated with worse scores on PRO-PD.

Participants who indicated they felt lonely had, on average, a score of 354 on the PRO-PD score, which was higher than the average score of 195 found among individuals who reported feeling under a lot of stress or a score of 259 reported by those who were smokers.

Having several friends seemed to be associated with a low PRO-PD score of -177, indicating a less severe course of the disease.

Dr. Subramanian acknowledged that the study did not establish a causal link between loneliness and disease severity. The fact that the surveys were computer-based could have impacted the study's accessibility, she said, which could have been a study limitation.

 "By recognizing loneliness as a risk factor for worsened PD severity, health care providers can become more proactive in preventing social isolation," Dr. Subramanian and colleagues wrote in the study abstract. "Counseling about the need to stay socially connected from the time of diagnosis is essential. Group exercises and support groups that allow inter-patient connection would be beneficial. Referral to a religious or spiritual group, internet support group, or even virtual connection may be helpful as patients become more isolated or in remote areas," they wrote.

This is a very important study that focuses on a topic that few medical professionals and researchers have attended to until recently, noted Timothy B. Smith, PhD, professor of counseling psychology at Brigham Young University in Provo, UT,  whose research focuses on the impact of social isolation on health.

"The data showed that social isolation and loneliness is associated with worse PRO-PD scores. Similar findings have been found with other populations."

"Clinicians clearly need to take into account the social aspects of disease management. Those are less at the forefront of a physician or neurologist's consideration. But what this study shows is that those factors must be at the forefront," said Dr. Smith.

Clinicians should present patients with screening questions about social support for their patients with Parkinson's disease, Dr. Smith noted. "The findings clearly indicate that social support is a major factor" in quality of life when living with chronic diseases such as PD.

Disclosures:

Drs. Subramanian and Smith did not report any disclosures.

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MDS Abstract 1244: Subramanian I, Mischley L, Farahnik J. Loneliness/social isolation as a risk factor for worsened Parkinson disease severity. 

Friday, September 18, 2020

Three years after receiving brain infusions of an experimental gene therapy drug, patients with moderately advanced Parkinson's disease (PD) showed improvements in motor function and quality of life with no serious adverse events, researchers reported at the MDS Virtual Congress 2020, the annual meeting of the International Parkinson and Movement Disorder Society.

The experimental therapy,VY-AADC01, provides the genetic code for the enzyme aromatic L-amino acid decarboxylase (AADC), which coverts levodopa to dopamine. The genetic material is encased in a capsid created from AAV2, a non-pathogenic virus.

"The loss of AADC over time in PD likely explains part of the need to increase levodopa treatment as PD progresses," said lead author Chadwick W. Christine, MD, FAAN, professor of neurology at the University of California, San Francisco Weill Institute for Neurosciences.

"This gene therapy expresses this enzyme in the putamen where the conversion of levodopa to dopamine will improve PD motor function. Surgical infusion of the gene therapy allows us to target the area of the brain where we want the enzyme to be expressed."

Researchers divided 15 patients into three cohorts—receiving low (cohort one), medium (cohort two), and high doses (cohort three). The patients had advanced PD with disabling motor fluctuation, despite optimal medical therapy. They underwent general anesthesia for a procedure that involved drilling a hole about the size of a dime through the top of the skull to allow for two or three penetrations into the brain, Dr. Christine explained. The treatment was mixed with a contrast agent, and surgeons conducted the infusions in an MRI suite, which allowed them to adjust the catheter position to direct the anatomic coverage of the putamen. Each patient received two or three infusions simultaneously to each side of the putamen. The average overall infusion time was just over five hours, he added.

The phase 1b open-label study, presented at the MDS 2020 Virtual Congress, reported three-year results for cohorts two and three. A paper published last year in Annals of Neurology had reported three-year results from cohort one, the lowest dosed group, as well as 18-month results from cohort two, and 12-month results from cohort three.

At the end of the three-year study period, Parkinson's patients in cohorts two and three reported that their motor function and quality of life improved or was stable: "On" time (without dyskinesia) increased by up to 2.2 hours (in cohort two) and up to 0.3 hours (in cohort three), "off" time decreased by up to 1.9 hours (in cohort two) and by 0.15 hours (in cohort three), and scores on the United Parkinson's Disease Rating Scale III improved for cohorts two and three both on and off medication.

One patient experienced atrial fibrillation and pulmonary embolism, which the researchers attributed to immobility from the surgery. Another had two small intestinal obstructions that the researchers said were not related to the drug. Four patients experienced dyskinesias that resolved with reductions of PD medications or with use of amantadine, the researchers reported.

The study was funded by Voyager Therapeutics and Neurocrine Biosciences.

Melissa J. Nirenberg, MD, PhD, FAAN, a professor of neurology at the Icahn School of Medicine at Mount Sinai who was not involved with the study, said any positive results need to be tempered because of the small sample size and possibility of a placebo effect—a common problem in open-label trials of PD, particularly those involving novel or invasive treatments. Dr. Nirenberg also questioned the drug's risk-benefit profile given the use of a viral vector and experimental delivery technique as well as the existence of established therapies to treat symptoms related to dopamine deficiency.

"It's exciting that there's a potential new approach for the treatment of the dopaminergic manifestations of Parkinson's disease, but it is much too soon to tell if it is efficacious on a short- or long-term basis, and how it might compare with deep brain stimulation, focused ultrasound, or other investigational treatments," she said. "What we really need are disease-modifying therapies or treatments that address PD manifestations that are unrelated to dopamine deficiency."

Dr. Christine disclosed that research grants from Voyager Therapeutics have supported his salary.  Dr. Nirenberg had no relevant disclosures. She is a member of the Neurology Today editorial advisory board.

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MDS Abstract 879: Christine C, Richardson R, Van Laar A, et al. Three-year safety and clinical outcomes from the PD-1101 trial of AADC gene therapy for advanced Parkinson's disease.

Christine CW, Bankiewicz KS, Van Laar AD, et al. Magnetic resonance imaging-guided phase 1 trial of putaminal gene therapy for Parkinson's disease. Ann Neurol 2019; Epub 2019 Feb 25.

 

 

 


Friday, September 18, 2020

Patients in a movement disorders clinic who underwent brain imaging were more accurately diagnosed with Parkinson's disease (PD) using 6-18F-fluoro-L-dopa (F-DOPA PET) than with 3T susceptibility weighted imaging (SWI) MRI, researchers reported at the MDS Virtual Congress 2020, the annual meeting of the International Parkinson and Movement Disorder Society.

The researchers wanted to compare visual analyses of nigrosome 1 (N1) imaging using 3T SWI MRI in the substantia nigra or with striatal F-DOPA PET. Nigrosome abnormalities have been demonstrated in PD patients, and nigrosome imaging has shown high sensitivity and specificity for distinguishing PD from healthy patients.

Lead author Antonio Martin-Bastida, MD, PhD, clinical associate professor of neurology and neuroscience and consultant neurologist at the Clínica Universidad de Navarra in Madrid, Spain, told Neurology Today At the Meetings that up to 30 percent of PD cases are misdiagnosed at early stages of the disease.

"I wanted to determine the accuracy in diagnosis of PD by using these two imaging techniques," he said. "I found that F-DOPA PET is potentially far more accurate than nigrosomal imaging."

Researchers recruited a total of 59 patients from the Movement Disorders Clinics of Clínica Universidad de Navarra (Madrid-Pamplona, Spain). Nearly half (28) had previously been diagnosed with PD, according to UK Brain Bank Criteria, and 31 patients had been diagnosed with other non-PD conditions: essential tremor (15), vascular parkinsonism (four), dystonia (four), drug-induced parkinsonism (three), hydrocephalus (two), Alzheimer's disease (two), and ataxia (one). MRIs were used to visualize nigrosome 1 signals in the substantia nigra and F-DOPA PET was used to measure aromatic L-amino acid decarboxylase distribution of the tracer within the striatum.

Two neuroradiologists and two nuclear medicine specialists visually evaluated the imaging results. MRI correctly diagnosed 18 out of 31 of patients without PD and 13 of 28 patients with PD. In contrast, F-DOPA PET correctly diagnosed 29 out of 31 patients without PD and 26 out of 28 patients with PD. The diagnostic sensitivity was 92.9 percent and the specificity was 93.5 percent for 18F-DOPA PET, compared with a diagnostic sensitivity of 53.6 percent and 58.1 percent specificity for 3T SWI MRI.

Dr. Martin-Bastida said further morphometric analysis by using quantitative susceptibility mapping of the substantia nigra, as well as inclusion of multiplatform and longitudinal cohorts are needed to elucidate the potential clinical accuracy and validity of nigrosomal iron imaging in PD.

"You have to keep in mind that PET is not widely available in hospitals. In addition, it is an expensive technique," he said. "There is an urgent need to develop MRI biomarkers that can be implemented in clinical practice."

One of the current challenges with Parkinson's disease imaging is that "each imaging modality provides measures of one aspect of the disease," said Arthur W. Toga, PhD, director of the University of Southern California Mark and Mary Stevens Neuroimaging and Informatics Institute, who was not involved with the study. Identifying better biomarkers is important, as is "understanding genetic associations and furthering our understanding of the cellular injuries that are part of PD," he said.

Nicola Pavese, MD, PhD, FRCP, FEAN, director of the Clinical Ageing Research Unit at Newcastle University in Newcastle upon Tyne in the UK, said the reported sensitivity and specificity for F-DOPA PET in differentiating PD from non-PD diagnoses are in line with what have been reported in other studies. The reported sensitivity/specificity for SWI-MRI, however, seems lower as compared with what has been reported in other published papers, he noted.

"The findings are very interesting and show that although SWI-MRI for the visualization of nigrosome 1 is a promising imaging tool in the differential diagnosis of PD, there are still several issues that need to be addressed," he said.

Drs. Martin-Bastida and Pavese had no relevant disclosures. Dr. Toga has received a speaking honorarium from Biogen.

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MDS Abstract 596: Martin-Bastida A, Suarez-Vega V, Dominguez-Echavarri P, et al. Visualization of nigrosome 1 at 3T MRI and 18F-DOPA PET for the diagnosis of Parkinson's disease.