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APOE Gene Variants Alter Alpha-synuclein Dynamics, Could Affect Dementia Occurrence in Parkinson’s, Study Suggests

APOE Gene Variants

Genetic variations in the gene apolipoprotein E (APOE) alter the dynamics of alpha-synuclein protein buildup in the brains of mice with Parkinson’s disease (PD), according to a new study. This suggests suggests that alterations in APOE could affect the occurrence of dementia in humans with the neurodegenerative disease, the researchers said.

Titled “APOE genotype regulates pathology and disease progression in synucleinopathy,” the study was published in Science Translational Medicine.

As many as 80% of people with PD will develop dementia — a group of symptoms affecting memory, thinking and social abilities — within two decades of being diagnosed. Nonetheless, the occurrence of dementia in Parkinson’s varies greatly person-to-person: “Many patients take years to develop dementia, whereas others have a more rapid course, and in some cases, dementia precedes motor symptoms,” the researchers said.

Parkinson’s is associated with the formation of toxic protein aggregates, or clumps, in the brain — particularly involving the protein alpha-synuclein. Alzheimer’s disease also is characterized by the accumulation of toxic protein aggregates in the brain, though the exact proteins involved are somewhat different.

The gene APOE encodes a protein of the same name, which helps form molecules called lipoproteins, which are responsible for packaging cholesterol and other fats and carrying them through the bloodstream.

A variant in this gene, called E4, is associated with a significantly increased risk of Alzheimer’s. APOE variants are known to affect how certain Alzheimer’s-associated proteins clump together in the brain. However, whether these variants also affect alpha-synuclein aggregation hasn’t been clear, nor has been the effect of variants in APOE on dementia in Parkinson’s.

Now, researchers at Washington University School of Medicine in St. Louis are trying to bridge this knowledge gap. Using mice with a form of alpha-synuclein prone to aggregation, the scientists engineered mice with one of three genetic variants in APOE — E2, E3, or E4 — or no APOE gene at all, called a knockout. They then compared alpha-synuclein in the brains of these mice.

Using multiple molecular assays, the researchers demonstrated that alpha-synuclein levels were significantly lower in mice with the E2 variant than in mice with the E4 variant or knockout mice. Animals with the E3 variant had alpha-synuclein levels in between these two extremes, though differences were generally not statistically significant in either direction.

Motor function and survival patterns followed trends consistent with this finding: E2 mice had higher motor scores, followed by E3, then E4, and knockout. Similarly, E2 mice survived significantly longer (median 18.4 months) than E4 (11.7 months) or knockout mice (11.6 months), with E3 mice in between the extremes (median 12.7 months).

These data suggest that APOE genetic variants affect the dynamics of alpha-synuclein in the brain.

“What really stood out is how much less affected the APOE2 mice were than the others,” Albert (Gus) Davis, MD, PhD, a professor at Washington University School of Medicine and the study’s lead author, said in a press release.

“It actually may have a protective effect, and we are investigating this now,” Davis said. “If we do find that APOE2 is protective, we might be able to use that information to design therapies to reduce the risk of dementia.”

The team then looked for connections between APOE variants and dementia in people with Parkinson’s.

First, the researchers assessed two groups of PD patients who had been followed for several years: one from the Parkinson’s Progression Markers Initiative, involving 251 people, and the other, which includes 170 people, from the Washington University Movement Disorders Center. In both groups, individuals with the E4 variant had significantly faster rates of decline in cognitive scores as compared with those with other variants. Importantly, this effect remained significant after adjustment for other factors known to affect cognitive decline, including the presence of neurotoxic proteins in the fluid around the brain, and educational attainment.

Additionally, in a separate group — the NeuroGenetics Research Consortium, numbering 1,030 people, in which cognitive scores were measured at only one time point — the E4 variant was associated with significantly lower cognitive scores at the time of assessment, and with the onset of cognitive difficulties at a younger age.

“Together, these data corroborate the finding that APOE ε4 is associated with cognitive impairment and a faster rate of cognitive decline in PD,” the researchers said.

Because this effect was independent of other toxic brain proteins, the team concluded this most likely was a consequence of increased alpha-synuclein in the brain, as evidenced by the data in mice.

All in all, these findings implicate APOE in the molecular progression of Parkinson’s and, specifically, the onset of dementia. Thus, APOE or related proteins in the brain might be a viable therapeutic target for treating dementia in Parkinson’s, the researchers said. Further studies will be needed to test this idea.

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IRL752 May Help Manage Symptoms Unresponsive to L-Dopa, Phase 2 Data Suggests

IRLAB IRL752 dementia

The small molecule IRL752 may be a safe and effective treatment, which could potentially help manage symptoms known to be unresponsive to levodopa, for people with Parkinson’s disease dementia, results from a Phase 2a clinical study suggest.

Preliminary data suggests treatment with IRL752 could reduce apathy, as well as improve executive function and body postural control.

The results were discussed at the 2019 International Congress of Parkinson’s Disease and Movement Disorders, in a poster titled, “A phase IIa trial studying the safety and tolerability of IRL752 in patients with Parkinson’s disease dementia.” The conference is being held Sept. 22-26 in Nice, France.

IRL752 is a small molecule designed by IRLAB Therapeutics that has the ability to enhance communications between nerve cells in the frontal cortex — a major brain area that controls cognitive functions.

In preclinical studies, this new therapeutic candidate was found to increase the availability of two important neurotransmitters — norepinephrine and dopamine — and to modulate nerve cells’ responses and activity. Neurotransmitters are chemical messengers that allow nerve cells to communicate.

Both norepinephrine and dopamine levels are reduced in the frontal cortical brain areas of people with Parkinson’s who also have dementia, previous studies have shown. Scientists hope treatment with IRL752 may counteract these features and help manage cognitive and psychiatric symptoms in this patient population.

The safety and tolerability of IRL752 were first evaluated in 40 healthy volunteers in a placebo-controlled, double-blind Phase 1 trial. Participants were randomly selected to receive single or multiple ascending doses of IRL752 or a placebo, which covered the clinically anticipated dose.

IRL752 was well-tolerated and had a very good safety profile. No serious adverse events were reported during the study.

Supported by these positive results, IRL752’s potential was further explored in a Phase 2a trial (2017-001673-17) conducted in Sweden and Finland.

The study enrolled 32 patients with Parkinson’s disease dementia. Participants were randomly selected to receive either IRL752 or placebo for four weeks in addition to their standard antiparkinsonian medication. The IRL752 dose was adjusted for each patient during the first 14 days, after which dosing was kept stable for an additional 14 days of treatment.

A total 29 of the 32 participants completed the four-week treatment.

Similar to the previous clinical trial, no serious adverse events were reported. In general, all adverse effects were mild in severity and more frequent during the initial titration phase of the trial, when the dose is adjusted until it achieves the desired effect with as few side effects as possible.

Preliminary data on efficacy outcomes suggested that treatment with IRL752 could reduce apathy, as well as improve executive function and body postural control — symptoms known to be unresponsive to levodopa, the gold standard treatment used to manage Parkinson’s.

“These [preliminary] results will be of guidance for the design of further efficacy studies,” the researchers said.

IRLAB Therapeutics also is exploring the potential of another candidate, named IRL790, for the treatment of Parkinson’s-related dyskinesia — involuntary movements that can interfere with normal daily activities. Supported by positive results from a Phase 2 clinical study, the company is now planning a Phase 2b/3 study to be launched in the first half of 2020.

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Fox Foundation Offers Guide to Help with Parkinson’s Cognitive Symptoms

cognition and Parkinson's

The Michael J. Fox Foundation (MJFF) is offering a new guide to help people better understand Parkinson’s cognitive symptoms and ways of dealing with them.

The 33-page guide, “Navigating Cognitive Changes in Parkinson’s Disease,” was developed by the MJFF’s Patient Council — which includes caregivers, social workers, and physicians specialized in movement disorders and cognitive function — working together with Parkinson’s patients, their families, and their clinicians.

An hourlong webinar discussing topics addressed in the guide and including a question period is set for Sept. 19 at noon ET. Those interested can register here.

“The goal of this guide is to encourage people with Parkinson’s and their loved ones to learn more about cognitive changes and to take action — whether that’s opening a discussion to lessen fear and improve care or practicing healthy habits to boost brain health,” Rachel Dolhun, the guide’s author, and MJFF’s vice president of medical communications and a movement disorder specialist, said in a press release.

While a diagnosis of Parkinson’s disease is based on characteristic motor symptoms like tremor, slowness of movement, and rigidity, cognitive impairment is a significant non-motor manifestation of the disease.

Among the 6 million people estimated to be living with Parkinson’s worldwide, 40% are likely to develop dementia and 25% may develop milder cognitive changes. “These symptoms are, unfortunately, also some of the least talked about,” Dolhun wrote.

The guide explores different aspects of cognitive function and their roles in daily life, such as executive function, memory, language, attention, and visual-spatial skills. It provides several strategies to help patients and their families keep track of possible cognitive changes, which can be expressed differently in each patient.

It also encourages patients to practice activities known to be good for the body, and thought to also boost brain health. These include exercising regularly, eating a healthy and balanced diet, training the brain with “mind games” or crosswords, getting enough sleep, reducing stress, being socially active, and getting involved with the Parkinson’s or local community.

A large part of the guide is dedicated to dementia, one of the most concerning potential symptoms of Parkinson’s for many patients and their families.

It starts by clarifying what defines dementia, the differences between three causes of dementia — Alzheimer’s disease, Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB) — and current treatment options for this condition.

PDD and DLB share the presence of abnormal protein clumps in the brain known as Lewy bodies, as well as several symptoms. Currently, DLB diagnosis is distinguished from PDD if dementia occurs before or during the first year of motor symptoms related to Parkinson’s.

The guide also provides strategies to work through Parkinson’s cognitive changes and dementia, including: finding a physician with expertise on cognitive changes, being patient and flexible with oneself and one’s difficulties, communicating in an open and honest way, learning as much as one can about the disease, asking for and accepting help from others, joining supportive groups, and participating in clinical research.

Another section offers tips to help caregivers and relatives manage a patient’s hallucinations and delusions, which can be the most difficult manifestation of dementia.

Finally, the guide shares some of the latest information in ongoing research into disease-related dementia.

“The Patient Council welcomed the opportunity to provide input on this new guide in order to offer families the knowledge and resources to talk about a sensitive topic that’s sometimes inadequately addressed at home or even in the doctor’s office,” said Dave Iverson, a founding member of MJFF’s Patient Council and a broadcast journalist.

“More resources, research, and collaboration can help us address the complex issue of cognitive decline and support people who experience it,” said Todd Sherer, MJFF’s CEO.

The free guide, and a complementary video, are available for download here. The Sept. 19 webinar features Dolhun and other disease experts, and members of the Parkinson’s community.

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Participants Sought for Clinical Trial Testing ENT-01 for Parkinson’s Dementia

ENT-01

Enterin Inc has enrolled the first patient in its Phase 1b DEMET clinical trial investigating the effectiveness, safety and tolerability of small molecule ENT-01 to treat Parkinson’s disease dementia.

Contacts and locations of participating sites can be found here.

Many neurodegenerative disorders involve aggregation of misfolded (harmful) proteins in the brain. Parkinson’s is characterized by a buildup of the protein alpha-synuclein in the brain, which forms clumps known as Lewy bodies that damage and kill nerve cells.

In order to form aggregates, these clumps need to stick to the membranes that line the inside of neurons. It is the sticky form of alpha-synuclein protein that causes most of the damage seen in Parkinson’s, more so than if this protein was freely floating within a neuron.

ENT-01 (kenterin) enters neurons from the enteric nervous system (ENS), attaches itself to the nerve cells’ membrane and dislodges Parkinson’s-related alpha-synuclein clumps. By unsticking harmful alpha-synuclein, the investigational treatment reduces the amount of alpha-synuclein aggregates within neurons and, in theory, cellular death.

The enteric nervous system is a network of neurons that independently governs the function of the gastrointestinal tract. Previous studies claim that alpha-synuclein begins accumulating in the ENS and then travels from the gut to the brain, where it is linked to the development and progression of Parkinson’s.

The multicenter, randomized, double-blind DEMET study (NCT03938922) will assess ENT-01’s effectiveness, safety and tolerability in patients diagnosed with Parkinson’s disease dementia. It expects to enroll 40 participants (aged 30 to 90 years), who will be assigned randomly to receive ENT-01 or a placebo tablet. Both will be taken once a day.

By being taken orally, and because ENT-01 is not absorbed into the bloodstream, the molecule will solely act on the gut’s neurons, changing the communication between the gut and brain.

The trial will be conducted on an outpatient basis and each patient will have to visit the clinic five times. The study’s primary goal is to evaluate if the experimental therapy improves cognition in people with Parkinson’s  dementia. Investigators also will assess ENT-01’s effects on attention, social function and frequency and/or severity of hallucinations/delusions.

In two separate Phase 2 clinical trials, NCT03047629 and NCT03781791, ENT-01 has been shown to ease both motor and non-motor symptoms of Parkinson’s, indicating its potential to change disease progression.

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Zonisamide with Levodopa May Reduce Risk of Dementia, Other Parkinson’s-related Symptoms, Japanese Study Suggests

Zonisamide, Parkinson's

Japanese researchers have reported that zonisamide — an antiparkinsonian medicine approved in Japan as a combination therapy with levodopa — may be associated with a lower risk of dementia, insomnia, and gastric ulcers in Parkinson’s disease, compared with other non-levodopa medicines.

Their research was published in the study “Comparison of zonisamide with non-levodopa, anti-Parkinson’s disease drugs in the incidence of Parkinson’s disease-relevant symptoms,” in the Journal of the Neurological Sciences.

Marketed under the name Zonegran in the U.S. for adjunctive therapy in the treatment of partial seizures in adults with epilepsy since 2000, zonisamide has been approved in Japan (where it’s called Trerief) as an antiparkinsonian agent to be used in combination with levodopa therapy.

Parkinson’s patients have low levels of the chemical messenger dopamine in their brains due to disease-specific death of dopaminergic (meaning “dopamine-producing”) neurons. Among other brain functions, sleep, memory, and movement are all affected by the lack of dopamine and, as such, patients often develop insomnia and dementia, along with the hallmark motor symptoms of Parkinson’s disease.

Levodopa (L-DOPA) is the first choice when it comes to effective Parkinson’s motor symptom control, and as the disease progresses, patients typically need to gradually increase their treatment dose for maximum benefit. After that, they might sometimes experience reappearance or worsening of symptoms due to diminishing effects of dopaminergic therapy. Because of this, most patients will require combination therapy at some point.

Although zonisamide’s mechanism of action is not yet fully understood, studies indicate the compound acts by preventing the breakdown of dopamine, increasing its levels in the brain, and relieving Parkinson’s symptoms. Evidence also suggests that the medicine may have neuroprotective effects.

Clinical trials have shown zonisamide significantly alleviates Parkinson’s motor and non-motor symptoms. “However, partly because zonisamide is off-label for PD [Parkinson’s disease] except for in Japan, situations in which it is more suitable than other drugs have not been sufficiently elucidated,” the researchers noted.

For the study, investigators from Ehime University Graduate School of Medicine in Japan sought to evaluate if zonisamide use in Parkinson’s patients, 40 years or older, was associated with the time of onset of Parkinson’s disease-relevant symptoms, mainly mental, autonomic nervous system, movement, and gastric symptoms.

The results were compared to seven other non-levodopa drug classes that are often used when primary therapy is not fully effective (also referred to as second-line therapy).

For this analysis, levodopa was not considered as a comparison drug to zonisamide, as the majority of study participants were taking levodopa together with zonisamide or another second-line medicine.

Patients had to be on levodopa or other antiparkinsonian medicine without having switched to or recently combined use with other drug classes.

Using a set of statistical approaches, the researchers investigated the time it took for a given symptom of interest to occur while participants were on zonisamide, compared with other non-levodopa medications indicated for Parkinson’s disease.

Of the 9,157 studied subjects, those who were on COMT inhibitors, anticholinergics, or amantadine were two to nearly five times more likely to develop dementia. In addition, zonisamide use was found to be associated with a lower risk of developing insomnia and gastric ulcers, compared with three other non-levodopa medicines.

An increased prevalence of gastric ulcers has long been associated with Parkinson’s disease, and they are generally accepted as a symptom experienced by patients.

“Zonisamide also showed significant lower risk in the incidence of orthostatic hypotension, constipation, and limb fracture,” the researchers wrote, adding that the treatment was, however, also associated with a higher risk “in the incidence of depression and aspiration pneumonia than at least one of the other drug classes.”

Compared with three other classes of medications, zonisamide appears to be associated with a lower risk of developing dementia, insomnia, and gastric ulcers in Parkinson’s disease. However, it was not always the same three-treatment set that was found to be somehow associated with the lowest risk for a given symptom.

Nonetheless, “[t]here may be a potential clinical impact of zonisamide on some of the [Parkinson’s disease]-relevant symptoms,” the authors concluded.

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Music and Laughter Are Strong Medicine Against Dementia

music and laughter

When my 67-year-old mother was diagnosed with stage 4 uterine cancer I was devastated. My mother already was disabled from depression and fibromyalgia, so being diagnosed a few months later with Alzheimer’s disease along with terminal cancer seemed like a cruel joke.

Soon after I learned of the diagnosis, Mom and I were trying to forget our troubles by watching TV when a commercial for a chemo medication came on, creating an awkward moment. The commercial couldn’t end soon enough, and lo and behold, the next commercial was for Cancer Treatment Centers of America.

When the next commercial was for an Alzheimer’s medication, I couldn’t help thinking to myself, “Please make it stop.” After the next commercial was for Parkinson’s disease, all I could say to Mom was, “At least you don’t have that disease, too.” We both started laughing at the absurdity of the situation. After all, there are just some things in life that you can’t control. The old adage that laughter is the best medicine is true and sometimes the only thing that works. The other remedy I have found for cheering up a dismal day is music.

Studies have shown that music stimulates the memory as well as emotional areas of the brain in dementia patients, and as a caregiver for an Alzheimer’s patient, I have found that music is quite therapeutic.

According to neurologist Oliver Sacks, our memories are embedded in familiar music, and dementia patients can temporarily retrieve lost experiences by listening to it. “With Alzheimer’s, you lose your past, your story, your identity to a considerable extent. … [W]ith familiar music, you can at least regain that for a little while.”

Finding her words is often difficult, but if music is playing or a commercial comes on the TV with a catchy tune, Mom is suddenly singing and dancing in her chair. Playing music in the morning or before she will be socializing has been helpful because she is in a better mood and more engaged in the conversation. I’ve also noticed that she is more coordinated, or at least able to laugh about it when she is not.

Music also releases dopamine in the brain, which produces stimulation. Sometimes I will sing (badly) as I am doing tasks, changing the lyrics to make them silly or rhyme, which prompts her to laugh or create her own humorous comment. Music makes her more engaged in the conversation and her natural sense of humor more abundant. It is during moments like these when I am the most at peace because for a few moments, original Mom is back and all the lights are on.

***

Note: Alzheimer’s News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The opinions expressed in this column are not those of Alzheimer’s News Today or its parent company, BioNews Services, and are intended to spark discussion about issues pertaining to Alzheimer’s Disease.

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Review Study Provides Update on Treatments for Parkinson’s Non-motor Symptoms

non-motor symptoms, Parkinson's

Although there are now more treatment options available for non-motor symptoms in Parkinson’s disease, a lack of evidence on their effectiveness and safety means that more studies and new therapeutic strategies are needed, according to a review study.

The study, “Update on Treatments for Nonmotor Symptoms of Parkinson’s Disease — An Evidence‐Based Medicine Review,” appeared in the journal Movement Disorders.

The International Parkinson and Movement Disorders Society Evidence-Based Committee reviewed research published from 2011 through 2016 on Parkinson’s non-motor symptoms to help physicians select the most effective treatments and provide an update to a 2011 study.

Two online databases were searched, resulting in the inclusion of 37 studies with 20 patients or more. In all of the included studies, treatment lasted a maximum of six months, except for one low-quality safety study, meaning the recommendations do not cover long-term symptom management, the team noted. The studies included pharmacological, surgical, and nonpharmacological interventions, which had to be available in at least one country.

According to their level of evidence, the different approaches were classified as efficacious, likely efficacious, unlikely efficacious, non-efficacious, or with insufficient evidence. To address practice implications, the team also rated the interventions as clinically useful, possibly useful, and unlikely useful, not useful, or investigational.

Christopher G. Goetz, MD, president of the International Parkinson and Movement Disorders Society, noted the differences between this approach and practice guidelines issued by medical associations such as the American Academy of Neurology. In a Neurology Today article written by Susan Fitzgerald, titled “Which are the Most Efficacious Therapies for Nonmotor Parkinson Disease Symptoms?” he said that “guidelines are really culturally based,” and take into account “regulatory issues, access issues, and insurance issues.”

“With evidence-based methodology, we are strictly looking at the published evidence. We don’t tell you whether we recommend it (a specific therapy),” he added.

No clinical trials met the inclusion criteria for the treatment of anxiety disorders, excessive sweating, rapid eye movement behavior disorder, and olfactory or ophthalmologic dysfunction.

Six new studies were reviewed for depression. One addressed venlafaxine, characterized as efficacious, with an acceptable safety risk and no need for specialized monitoring, and clinically useful. This contrasted to amitriptyline, which has insufficient efficacy evidence to treat depression in Parkinson’s patients and was rated as possibly useful. Paroxetine, citalopram, fluoxetine and sertraline, all selective serotonin reuptake inhibitors (SSRIs), were categorized in a similar way.

Rotigotine, marketed as Neupro, was found unlikely efficacious based on the results of one study, and rated as investigational regarding practice implications. Rasagiline, marketed as Azilect, also showed insufficient evidence of efficacy and was classified as investigational as well.

As for nonpharmacological interventions, two studies on repetitive transcranial stimulation showed inconsistent effects on depression. However, its benefits in the general population and in specific measures in people with depression make this approach possibly useful for short-term treatment of Parkinson’s.

Cognitive-behavioral therapy (CBT) could only be rated as likely efficacious and has insufficient safety evidence in the treatment of depression in Parkinson’s due to the lack of replication of its benefits, the investigators cautioned.

Treatments for apathy were also evaluated. Rivastigmine, marketed as Exelon, was found efficacious in one study, but its small group of patients mean that this medication is only possibly useful in the clinic. A similar conclusion was reached for piribedil following deep brain stimulation. In contrast, Neupro was classified as unlikely efficacious based on one trial.

As for the treatment of impulse control disorders, naltrexone, marketed as ReVia, showed insufficient efficacy and safety evidence, while CBT was rated as likely efficacious and possibly useful clinically based on one new study.

Regarding dementia, Aricept (donepezil) and Razadyne (galantamine) still have insufficient efficacy evidence, but were rated possibly useful in clinical practice due to their established benefits outside Parkinson’s.

Both rasagiline and rivastigmine have insufficient efficacy evidence to treat cognitive impairment. A similar conclusion was reached for transcranial direct current stimulation and for cognitive rehabilitation in patients on computer-based cognitive training.

Three new studies were evaluated for psychosis. While olanzapine, marketed as Zyprexa, is not efficacious and therefore not useful from a clinical perspective, Nuplazid (pimavanserin) was characterized as efficacious over six weeks and clinically useful. Seroquel (quetiapine) has insufficient evidence though it is possibly useful in the clinic.

Studies of sleep disorders indicated that Lunesta (eszopiclone) and melatonin have insufficient evidence for the treatment of insomnia, but are possibly useful. Modafinil, marketed as Provigil, is also possibly useful for excessive daytime somnolence and sudden onset of sleep in people with Parkinson’s. Continuous positive airway pressure was considered likely efficacious and possibly useful in lessening daytime sleepiness in patients with obstructive sleep apnea, and Neupro was rated the same for improving sleep quality in Parkinson’s patients.

Assessed treatments of orthostatic hypotension — defined as a drop in blood pressure when standing up — included midodrine and fludrocortisone, marketed as Florinef. Although both have insufficient efficacy evidence, they are classified as possibly useful in the clinic due to benefits seen in clinical trials.

The only trial concerning urinary dysfunction addressed solifenacin, marketed as VESIcare, as a treatment for overactive bladder. It showed that this medication has insufficient evidence on efficacy, but is possibly useful in clinical practice due to benefits observed outside Parkinson’s, while having an acceptable safety risk without specialized monitoring.

One other study addressed erectile dysfunction. Viagra (sildenafil) was considered efficacious and clinically useful, with data in the general population indicating an acceptable safety risk.

Similar efficacy and clinically utility conclusions were presented for botulinum toxin B as a therapy for drooling. Both botulinum toxin type A and B should be administered by well-trained physicians with access to specialized monitoring tools, the researchers emphasized.

Three studies evaluated approaches for gastrointestinal dysfunction. Results of one trial led to lubiprostone, marketed as Amitiza, being considered likely efficacious and possibly useful to treat constipation in people with Parkinson’s. Its safety data in the general and elderly populations indicate that lubiprostone has an acceptable risk in Parkinson’s patients.

Probiotics were categorized as efficacious and clinically useful, which support their over-the-counter use and lack of safety concerns. In contrast, abdominal massages with lifestyle advice have insufficient evidence on safety and efficacy to ease constipation.

Rasagiline was also evaluated as an approach for fatigue, considered efficacious and possible useful based on one small study. One trial analyzed acupuncture in Parkinson’s, but although benefits were found, this approach still has insufficient efficacy evidence.

For pain, prolonged-release oxycodone-naloxone has insufficient evidence, but is possibly useful for Parkinson’s patients with chronic pain, with an acceptable safety risk without specialized monitoring. Rotigotine also has insufficient evidence as a way to lessen pain in Parkinson’s patients, despite benefits seen in one trial.

Overall, despite the substantial growth in the evidence base of approaches for non-motor symptoms in Parkinson’s, this update shows that treatment options remain limited, making the development and testing of new therapies “a top priority,” the team said.

According to Daniel Weintraub, MD, research on Parkinson’s psychiatric and cognitive symptoms is key due to the specificity of the disease compared with the same manifestations found in the general population. He also said this update may help investigators spot areas in need of clinical trials, such as anxiety.

Laura Marsh, MD, a professor of psychiatry and neurology at Baylor College of Medicine, cautioned that although the new review provides “a useful analysis for clinicians to consider,” they still have to practice “the art of medicine.” This involves challenges such as evaluating if dopaminergic therapies for motor function are causing non-motor side effects and what symptom to address first in people with more than one of these complications, she said.

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Motor Dysfunction Among Predictive Markers of Parkinson’s in People with Sleep Disorder, Study Reports

sleep disorder, Parkinson's risk

Mild cognitive impairment, motor and olfactory deficits, and erectile dysfunction are among the markers able to predict the development of Parkinson’s and associated disorders in people with rapid eye movement sleep behavior disorder, according to a large study.

The research was published in the article, “Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study,” in the journal Brain.

Disorders characterized by the aggregation of alpha-synuclein — such as Parkinson’s, dementia with Lewy bodies, and multiple system atrophy  — may all have an early period of more than 10 years that’s characterized by signs of neurodegeneration, but without full clinical disease.

Unlike most markers of this early — or prodromal — period, rapid eye movement sleep behavior disorder (RBD) has been specifically linked to the development of synuclein-related diseases. RBD of no known cause, or idiopathic RBD (iRBD), occurs in approximately 1% of people older than 60, and usually converts to Parkinson’s or related disorders over a decade or more. This means that 1% of the elderly population have an identifiable but often undetected early-stage neurodegenerative syndrome.

As most studies on predictors of these parkinsonism diseases had been single-center, a team at The Neuro — Montreal Neurological Institute and Hospital — and the Montreal General Hospital of the McGill University Health Centre combined the research experience of 24 centers in North America, Europe, Seoul, and Sydney, which participated in the International RBD Study Group, to measure the risk of developing such disorders and test 21 potential predictors.

At the beginning of the study, a total of 1,280 participants (average age of 66.3 years, and 82.5% men) with iRBD but without parkinsonism or dementia underwent a variety of tests to assess sleep disturbances, motor function, cognition, depression, anxiety, olfaction, and autonomic function. The patients were then followed for up to 19 years. According to the team, this was “the largest study ever performed in iRBD.”

Over a mean period of 4.6 years, 352 patients (28%, with a mean age of 67.6 years) acquired an overt neurodegenerative syndrome, which corresponded to an annual rate of 6.25%. The risk of developing such diseases progressively increased from 10.6% after two years to 73.5% after 12 years. Among these 352 patients, 199 first showed signs of parkinsonism, while 153 developed dementia first.

Then the analysis revealed that motor dysfunction — as assessed through different measures — olfactory deficit, mild cognitive impairment, erectile dysfunction, an abnormal dopamine transporter (DAT) scan, color vision impairment, constipation, REM sleep without muscle atonia (reduced strength), and older age significantly predicted neurodegenerative disease development.

DAT is responsible for the uptake of dopamine — the neurotransmitter found in lower levels in people with Parkinson’s — into nerve cells.

In contrast, sex, insomnia, daytime sleepiness, restless legs syndrome, sleep apnea, urinary dysfunction, and depression or anxiety were not significant predictors.

Only those predictive markers that tested cognition and quantitative motor function differentiated the people who first developed dementia from those first showing signs of parkinsonism. These assessments of quantitative motor function were simple office-based tests that took less than five minutes.

“Clearly these are strong candidates for selecting patients for future neuroprotective trials, and could even obviate the need for sophisticated imaging techniques,” the investigators wrote.

“We confirmed a very high risk of (Parkinson’s) in people with REM sleep disorder and found several strong predictors of this progression,” Ron Postuma, the study’s lead author, said in a press release. “As new disease-modifying treatments are being developed for (Parkinson’s) and related diseases, these patients are ideal candidates for neuroprotective trials.”

A separate analysis estimated that 366 patients per experimental group would need to be recruited into a two-year trial for a therapy to reduce in half the incidence of RBD converting to parkinsonism or dementia. Increasing the trial duration or assuming a greater reduction in disease development led to lower estimates for the number of patients required. Also, this analysis showed that using different predictive markers to classify patients would significantly alter the number of patients required for clinical trials.

“Of course, exact sample size calculations will depend on the specifics of a clinical trial; nevertheless, the fact that 24 centers combined to produce these estimates can provide some confidence for trial planners that sample sizes will be representative of the global experience,” the study stated. “Notably, the total sample size for a future neuroprotective trial is less than the number of participants who were recruited to this study.”

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Anavex 2-73 Trial Recruitment Reaches Halfway Mark

Anavex 2-73

A Phase 2 trial evaluating the efficacy and safety of investigational Anavex 2-73 as a treatment for Parkinson’s disease dementia has recruited half of its targeted patients, the therapy’s developer, Anavex Life Sciences, has announced.

The study is still recruiting Parkinson’s disease patients age 50 or older who have been diagnosed with dementia. The Phase 2 trial is being conducted across several clinical sites in Spain, and has received the support of the Michael J. Fox Foundation for Parkinson’s Research and León Research.

“We are encouraged by the rate of patient enrollment in this Phase 2 study and the potential for Anavex 2-73 to become a therapy for this unmet need given that up to 80% of Parkinson’s patients develop dementia,” Christopher U. Missling, PhD, president and chief executive officer of Anavex, said in a press release.

The Phase 2 trial (2017-004335-36expects to enroll 120 patients who will be randomized to receive orally 10 or 20 mg of Anavex 2-73 or a placebo for 14 weeks. Researchers will evaluate the impact of the treatment on cognition, as determined by the cognitive drug research computerized assessment system, as well as patients’ motor function and sleep quality.

The study will also assess genomic precision medicine biomarkers, previously identified to respond to Anavex 2-73 in a Phase 2 trial (NCT02244541) in Alzheimer’s disease.

Anavex 2-73, originally developed as a potential disease-modifying therapy for Alzheimer’s, is given orally to activate a cellular receptor called Sigma-1 (SIGMAR1), known to have neuroprotective effects. Specifically, activation of SIGMAR1 can help reduce neuroinflammation, as well as the accumulation of beta-amyloid and tau proteins and oxidative stress, all known to contribute to the progression of neurodegenerative disorders.

According to a recent study published in the journal Cells, the therapy exerts its neuroprotective effects by re-establishing the normal functioning of cells’ “recycling system,” preventing the accumulation of toxic protein clumps.

Preclinical studies with mouse models of Parkinson’s disease have shown that Anavex 2-73 was able to restore the function of damaged nerve cells and significantly improve motor function.

Currently, only one medicine, Nuplazid (pimavanserin) is approved by the the U.S. Food and Drug Administration (FDA) as a therapy for hallucinations and delusions associated with Parkinson’s disease.

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Deep Brain Stimulation May Increase Dementia Risk in Some Parkinson’s Patients, Study Suggests

deep brain stimulation

Parkinson’s disease patients with mild cognitive impairment who undergo deep brain stimulation are at a higher risk of cognitive decline and dementia, a long term “real-life”study suggests.

The study, “Longterm outcome of cognition, affective state, and quality of life following subthalamic deep brain stimulation in Parkinson’s disease,” was published in the Journal of Neural Transmission.

Subthalamic nucleus-deep brain stimulation (STN-DBS) is a surgical treatment for Parkinson’s motor symptoms where a device that generates electrical impulses is implanted into specific regions of the patient’s brain.

Increasing evidence suggests that STN-DBS significantly improves motor symptoms as well as some non-motor symptoms, such as sensory issues and sleep disturbances. However, some reports point to a potential decline in cognition in Parkinson’s patients following STN-DBS.

Researchers here investigated the cognitive status of 104 Parkinson’s patients who received STN-DBS for nine years, from 1997 and 2006, at a single center in Germany.

Neuropsychological data from before the surgery were available for 79 of the patients, of whom 37, diagnosed with Parkinson’s for more than 11 years, were followed long term for a median of 6.3 years after surgery. During this time, they underwent several neuropsychological and motor tests.

In the remaining 42 patients, no follow-up was possible due to patients’ death (21 of the cases), loss of contact (nine patients) and patients’ refusal to undergo follow-up (12 patients).

Researchers measured patients’ dementia rate (using the Mattis dementia rating scale) and cognitive status, focusing on five domains — memory, executive function, language, attention, and working memory — mood (depression and anxiety), and quality of life using the Parkinson’s Disease Questionnaire and the 36-item Short-Form Health Survey.

Motor function was assessed using several motor tests, including the Unified Parkinson Disease Rating Scale motor subscore (UPDRSm) and Hoehn and Yahr Stage, a widely used clinical rating scale, with broad categories of motor function in Parkinson’s.

Prior to the surgery, 28 patients (75.7%) had mild cognitive impairment, while nine patients (24.3%) had normal cognitive function. Moreover, no patients showed signs of Parkinson’s-related dementia.

Patients in the two groups — with and without mild cognitive impairment — showed no differences in age, disease duration, response to treatment, and dosage with levopoda, motor function, and education. Mood and quality of life were also similar.

Patients’ verbal intelligence, measured by a multiple choice word test, and memory were lower in the mild cognitive impairment group.

After undergoing STN-DBS, 18.9%, or seven, of the patients had no cognitive impairment, while the remaining patients (41%) were diagnosed with either mild cognitive impairment (15 patients) or dementia (15 patients).

Mild cognitive impairment has been previously identified as a risk factor for dementia in Parkinson’s patients. Twenty-eight patients categorized as having mild cognitive impairment before STN-DBS developed dementia within 6.3 years after surgery.

Researchers observed a trend, although not statistically significant, between mild cognitive impairment before STN-DBS and progression to dementia according to the patients’ age, sex, and education at the beginning of the study.

Compared with non-demented Parkinson’s patients, those with dementia had longer disease duration (15 years versus 20.2 years, respectively) and more severe motor impairments (UPDRSm score of 23.7 versus 36.1), with demented patients showing a faster progression of several typical Parkinson’s symptoms — bradykinesia (slowness of movement), rigidity, impaired speech, posture, gait, and postural stability.

In general, researchers observed a decline in cognition, including memory and language, in all STN-DBS-treated patients in the 6.3 years after surgery. However, partial working memory (also referred to as short-term memory) was preserved and slightly improved in some cases.

Disease duration, but not age, at the time of DBS surgery had a significant relation to the risk of developing dementia.

“This observational, ‘real-life’ study provides long-term results of cognitive decline in STN-DBS-treated patients with presurgical [mild cognitive impairment] possibly predicting the conversion to dementia,” the researchers wrote.

“Although, the present data is lacking a control group of medically treated PD [Parkinson’s disease] patients, comparison with other studies on cognition and PD do not support a disease-modifying effect of STN-DBS on cognitive domains,” they concluded.

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