Patients’ Self-reported Symptoms Reflect Clinical Assessments of Parkinson’s Severity, Study Finds

Parkinson's, patient-reported symptoms

A patient’s perception of how Parkinson’s disease affects their motor and non-motor skills reflects clinical assessments of disease severity, a study has found.

The findings of the study were presented in the poster, “Modeling the Effect of Patient’s Perception of Non-Motor and Motor Function on Parkinson’s Disease Severity,” during the recent International Congress of Parkinson’s Disease and Movement Disorders, in Nice, France.

In recent years, worldwide regulatory and clinical health authorities have been increasingly interested in evaluating the link between patient-reported outcomes and clinicians’ assessments of Parkinson’s severity.

“Understanding the specific self-reported non-motor and motor functional impairments that contribute to PD [Parkinson’s disease] severity is important to treatment efforts,” the researchers wrote.

These researchers from Rush University set out to determine whether a patient’s perception of how Parkinson’s affected their motor and non-motor skills would match the conclusions of healthcare professionals who assessed disease severity using clinically objective criteria.

To that end, investigators analyzed data from 6,684 patients with Parkinson’s disease that were pooled from the international Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Translation database.

These data contained information from patient-reported impairments in non-motor (Part I) and motor (Part II) categories. These outcomes (assessed in Part I and II) were used to create models of overall disease severity, as objectively measured by healthcare professionals (MDS-UPDRS Part III).

The team created two different models: one focused on patient-reported non-motor outcomes and the other focused on patient-reported motor outcomes. Statistical analyses demonstrated that both models conveyed important information to assess disease severity, as independently measured by examiners in Part III.

In the non-motor model, 10 different categories were found to be important measures of disease severity, including urinary function, cognitive impairment, constipation, hallucinations and psychosis, fatigue, apathy, depressiondaytime sleepiness, pain, and light-headedness.

In the motor model, 13 different categories were considered relevant measures of disease severity, including tremor, walking and balance, getting out of bed, hygiene, handwriting, turning in bed, speech, eating, saliva and drooling, “freezing” of gait, dressing, chewing and swallowing, and hobbies.

The researchers noted that, based on these two models, a patient’s perception of motor function seemed superior to their perception of non-motor function.

“This is an important piece of research coming from a world-renowned group and objectively defines what is now considered the benchmark concept of Parkinson’s disease (PD), that it is effectively as much a non-motor disorder as it is motor, the latter being the traditionally defined concept of this fastest growing neurodegenerative disorder in the world,” K. Ray Chaudhuri, professor of movement disorders and clinical director of the National Parkinson Foundation Centre of Excellence at Kings College in London, said in a news release.

“The researchers were able to show that self-reporting of motor and importantly, non-motor symptoms can successfully be used to construct a severity model of PD,” Chaudhuri added. “This research supports the importance and validity of combining motor and non-motor measurements of PD in terms of grading disease severity as can be done using the MDS-UPDRS.”

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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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Low Vitamin D Levels Linked to Added Falls, More Sleep Problems, Depression, Study Shows

low Vitamin D

Low vitamin D levels are associated with a greater tendency for falls, sleep problems, anxiety, and depression in people with Parkinson’s disease, according to a recent study.

The findings, “Relationship between 25‐Hydroxyvitamin D, bone density, and Parkinson’s disease symptoms,” were published in the journal Acta Neurologica Scandinavia.

Vitamin D deficiency and low bone mass are frequently observed in people with Parkinson’s disease (PD). In fact, one particular study found that lack of this vitamin is more common in people with Parkinson’s (55% of patients) than other populations, such as people with Alzheimer’s disease (41% of patients).

But the relationship between vitamin D levels and Parkinson’s has remained controversial. Some studies suggest that taking vitamin D3 — a form of vitamin D used in supplements — can stabilize the disease, while others see no relation with the risk of Parkinson’s.

However, most studies have focused on limited aspects of the disease and did not include important outcomes — notably, non‐motor symptoms.

Vitamin D has a vital role in bone health, since it promotes calcium absorption and bone mineralization, which keeps bones strong and healthy. It also blocks the release of parathyroid hormone (PTH), an hormone that promotes bone tissue reabsorption and bone thinning.

Some studies support that lack of vitamin D results in a greater risk of falls and fractures in Parkinson’s patients, which can increase hospitalization and even fatal disability. Its levels also have been associated with cognition and mood, as well as stomach malfunction, in people with the disease.

While it is possible that deficits in this vitamin impact several symptoms of PD, the connection remains unclear.

To shed light on this relationship, researchers at the Second Affiliated Hospital of Soochow University and Soochow University, in China, set out to determine if vitamin D levels correlated with bone mineral density (BMD) and non‐motor symptoms in Parkinson’s patients.

The team measured blood levels of 25-hydroxyvitamin D, or 25(OH)D — a precursor of the active form of vitamin D and the most accurate indicator of vitamin D levels in the body — and performed extensive clinical evaluations in 182 Parkinson’s patients as well as 185 healthy people (controls).

Participants were recruited from the Second Affiliated Hospital of Soochow University from March 2014 to December 2017.

Bone mineral density — a measure of bone mass and health — was measured at the lumbar spine and the top of the femur (thigh bone) by bone densiometry, which measures bone loss.

The data showed that people with Parkinson’s had significantly lower vitamin D levels in the blood compared with healthy controls — an average of 49.75 versus 43.40 nanomol per liter of 25(OH)D.

In agreement, low levels of vitamin D (below 50 nmol/l) also were more common in Parkinson’s patients (68.68%) than controls (54.05%).

People with lower vitamin D levels were more likely to fall and experience sleep problems, including difficulty in falling asleep (insomnia). They also had significantly more depression and anxiety.

Mean bone densities in both the spine and femur were lower in PD patients, however no correlation was seen between the levels of BMD and vitamin D.

“Together, these results indicate that vitamin D deficiency may play a role in PD pathogenesis [disease manifestations], while vitamin D supplementation may be used to treat the non‐motor symptoms of PD,” the researchers  said.

“As various non-motor symptoms place a burden on individuals with Parkinson’s disease and their caregivers, vitamin D might be a potential add-on therapy for improving these neglected symptoms,” study’s senior author Chun Feng Liu, MD, PhD, said in a press release.

However, the researchers stressed that future studies with a larger sample size are necessary to clarify the role of vitamin D in Parkinson’s disease.

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Parkinson’s Non-Motor Symptoms More Keenly Felt by Care Partners Than Patients, PMD Alliance Survey Finds

non-motor symptoms

An online survey by the nonprofit group PMD Alliance found that care partners are more likely to report Parkinson’s disease-related non-motor symptoms than are patients themselves, and to feel more affected by them.

These responses underscore the need for better recognition and education about Parkinson’s non-motor symptoms, many of which significantly affect quality of life.

A study based on the survey, “Impact of non-motor symptoms in Parkinson’s disease: a PMDAlliance survey,” was published in Neuropsychiatric Disease and Treatment.

Besides its typical motor symptoms, people with Parkinson’s often experience such disease-related issues as cognitive impairment, sleep difficulties, depression, anxiety, and psychosis.

These symptoms affect patients’ quality of life and increase the burden felt by care partners, who play an important role in keeping patients engaged in daily activities.

Care partner, according to the study, refers to a partnership between a care receiver (patient) and giver that’s characterized by mutual cooperation and joint responsibility. It’s distinct from caregiver, which usually implies care provided to people unable to take care for themselves.

To evaluate and better understand the perceptions, experiences, and educational needs of Parkinson’s patients and their care partners in terms of non-motor symptoms, researchers designed a 17-question, patient-oriented survey. The online questionnaire was sent to all members of the PMD Alliance — also known as the Parkinson & Movement Disorder Alliance — most of whom are patients and their care partners. A majority, about 75%, of members are older than 65.

Investigators registered 700 completed surveys. Of these, 378 (54%) came from care partners and 287 (41%) from Parkinson’s patients; the remaining 5% were from “others,” a term that includes health professionals as well as other family members or friends.

“About 90% of the respondents reported having experience with [non-motor symptoms] in [people with Parkinson’s], including sleep problems (84%), cognitive symptoms (76%), anxiety (65%), depression (56%), hallucinations (40%), and delusions (23%),” the researchers wrote.

Compared to patients, care partners were most likely to report these non-motor manifestations, except for sleep problems or excessive tiredness (84% of care partners and 85% of patients).

Overall, non-motor symptoms were reported by more care partners (97%) than by people with the neurodegenerative disorder (80%). Differences in the reported prevalence between care partners (357 respondents) and patients (216) of these symptoms were statistically significant for cognitive challenges (84% vs. 62%), anxiety (69% vs. 57%), depression (59% vs. 50%), hallucinations (51% vs. 23%), and delusions (32% vs. 8%), the researchers state.

Among the 579 respondents with non-motor symptom experience, symptom onset was evident within three years of diagnosis for more than half (53%), and within five years after diagnosis for 72%.

Almost half of all respondents — more care partners than patients — said non-motor manifestations were harder to deal with than motor symptoms.

More care partners than patients also “indicated that [non-motor symptoms] had either ‘very much’ of an impact (28% vs. 7%) or ‘quite a bit’ of an impact (38% vs. 26%) on quality of life,” while patients were more likely (42% vs. 24%) to define these symptoms as having only “‘some’ impact on quality of life,” the researchers wrote.

Daily activities most affected ranged from completing self-care (72%) and making plans or socializing with family and friends (57% and 58%, respectively), to running errands and finishing household chores (both 53%).

Most respondents, especially care partners with or without non-motor symptom experience, expressed an interest in more information and better education regarding cognitive symptoms, sleep problems, anxiety, depression, hallucinations or delusions.

“This survey underscores the significant impact of [non-motor symptoms] on the quality of life of [people with Parkinson’s] and highlights the need for improved recognition and education about its effects,” the researchers concluded.

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TNM Device for Thermal Brain Stimulation Eases Motor and Other Symptoms of Parkinson’s, Small Trial Reports

TNM device study

Twice daily treatment with ThermoNeuroModulation (TNM), a non-invasive device for at-home use, provided sustained motor and non-motor benefits and was associated with high satisfaction in a small group of Parkinson’s patients on standard medications, a clinical trial reports.

The study based on its findings,“Caloric vestibular stimulation for the management of motor and non-motor symptoms in Parkinson’s disease,” was published in the journal Parkinsonism and Related Disorders.

Results of a previous study in a 70-year-old man with Parkinson’s found that daily use of caloric vestibular stimulation (CVS) eased both disease motor and non-motor symptoms by nearly 50%.

CVS, which stimulates the vestibular system, is self-administered via the portable TNM device, delivering thermal waveforms through ear pieces in a headset (37° C–42°C to one ear and 37 °C–17 °C to the other, over about 19 minutes). Ears given the slow warming and cooling waveforms are switched every two days.

The vestibular system is a sensory network with diffuse pathways throughout the brain, and responsible for providing the brain with information about motion, head position, and spatial orientation.

Researchers in the U.K. and U.S. conducted a double-blind and randomized trial (NCT02703844) with 33 Parkinson’s patients to determine whether the TNM device, developed by Scion, could provide sustained and clinically relevant motor and non-motor benefits.

All were on standard anti-parkinsonian therapies, most frequently oral levodopa-based treatments. The median age of the 16 patients undergoing TNM stimulation (10 men, median 10 years since diagnosis) was 68. The remaining 17 patients received a sham (placebo) treatment.

Use of the TNM device for two months followed a four-week baseline period. Participants were further evaluated at five and 24 weeks after treatment. At each visit, the patients were assessed during “on” states – which refer to periods when anti-parkinsonian medications are effective — to judge changes in motor and non-motor symptoms, activities of daily living, and quality of life.

Compared to those on placebo, the 16 patients undergoing TNM showed significantly improved scores in the MDS-UPDRS Part I scale, which refers to non-Motor Aspects of Experiences of Daily Living. “Therapeutic gains for this assessment were greatest 5 weeks after the cessation of treatment although change scores at both time-points surpassed a previously established minimal clinically important difference,” the researchers wrote.

Similar benefits were observed in the Montreal Cognitive Assessment of cognitive impairment, MDS-UPDRS Part II — motor aspects of daily life activities — and Part III (motor exam), the Modified Schwab & England Activities of Daily Living scale, the 10-meter test of walking speed, the Timed Up and Go test of mobility and balance, and the MDS-UPDRS Part IV (motor complications).

Most of these benefits were attributed to lesser dyskinesia, or involuntary and jerky movements, and most levels returned to baseline (those at the study’s start) after six months.

Patients given TNM treatment were unable to correctly guess their study group, which the team partly attributed to difficulty perceiving the gradual improvements.

A total of 34 adverse events (AEs) were reported, 24 in the group undergoing TNM stimulation. The three serious AEs were deemed unrelated to the device. Four AEs — ear discomfort, dizziness/motion sickness and migraine — were considered possibly related to the device, and all resolved after the end of treatment. All other AEs were minor and thought most likely due to the disease.

Most, 25 people, found the device easy to use at home, while six had the opposite opinion but continued its use anyway. All but three found the time spent in treatment as “enjoyable” or “acceptable.” Twelve patients on TNM and 16 on placebo rated their overall experience with the device as “very positive” or “somewhat positive.”

“The results provide evidence that repeated CVS can provide safe and enduring adjuvant relief for motor and non-motor symptoms associated with [Parkinson’s],” the scientists wrote.

“One typically doesn’t see such consistency in study results when evaluating a new therapy,” Hubert Fernandez, director of the Cleveland Clinic’s Neurological Institute, who reviewed the data, said in a press release. “The fact that the gains observed were on top of the standard therapies is quite promising.”

Kallol Ray Chaudhuri, the medical director of the Centre of Excellence in Parkinson’s and Movement Disorders at King’s College, also considered the results “very encouraging.” Chaudhuri added that achieving benefits in non-motor symptoms “would be especially notable.”  Such symptoms, he said, “are often untreated or poorly treated and have a particularly detrimental impact on quality of life, and their treatment is a key unmet need.”

“I am intrigued and want to see where this device technology might go,” Chaudhuri added.

The TNM Device 3.2 was cleared for marketing in the U.S. (ages 12 and older) and the E.U. (adults) for the prevention of episodic migraine. Parkinson’s patients may currently only use the device (TNM Device 4.0) in clinical trials.

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Sleep Deprivation May Amplify Cognitive and Emotional Issues in Parkinson’s, Study Finds

sleep deprivation studied

Not getting enough sleep may cause memory defects and emotional changes in Parkinson’s disease due to changes in dopamine metabolism, according to a study of zebrafish.

The study, “Sleep Deprivation caused a Memory Defects and Emotional Changes in a Rotenone-based Zebrafish Model of Parkinson’s Disease,” was published in Behavioural Brain Research.

Most Parkinson’s patients experience disease-related non-motor symptoms often preceding the onset of hallmark motor signs. Some of Parkinson’s non-motor symptoms include anxiety, apathy, mood changes, cognitive impairment and emotional disorders, which individually or taken together eventually affect patients’ quality of life.

“In addition to cognitive and emotional disorders, sleep abnormalities are also prevalent in [Parkinson’s disease],” the researchers wrote. “The problem of sleep is not only the characteristics of the disease itself, but also related to medication and dyskinesia such as tremor and rigidity.”

Sleep is an essential physiological process, and lack or shortage of sleep time causes fatigue, increase of mood swings, and can affect learning and memory. Some studies have shown that sleep deprivation can result in emotional and cognitive impairments.

Now, a team of Chinese researchers investigated the effects of sleep deprivation on locomotor activity, memory and emotional behavior in a zebrafish model of Parkinson’s disease.

To mimic the neurodegenerative disorder, animals were given rotenone — a pesticide that inhibits function of mitochondria (cells’ powerhouses) — which leads to cellular death and onset of parkinsonian features. People who come in contact with rotenone are at an increased risk of developing Parkinson’s disease.

Zebrafish were deprived of sleep for four weeks by being in an aquarium with around-the-clock lighting. Of note, fish usually are exposed to 10 hours of “lights off” a day. Rotenone-treated and sleep-deprived animals’ results were compared to control animals who were not given rotenone.

Rotenone-treated zebrafish exhibited parkinsonian-like symptoms, particularly slowness of movement. Motor symptoms’ progression was not aggravated by sleep deprivation.

Rotenone treatment alone impaired the zebrafishs’ memories. Compared to control animals, animals treated with rotenone that were sleep deprived had trouble memorizing and discerning similar objects that were presented to them, suggesting sleep deprivation further damages short-term cognitive deficits.

Not getting enough sleep also was found to worsen anxiety and depression-like behavior in the rotenone treated animals.

Scientists then sought to understand if the observed behavioral changes could  be related to the metabolism of dopamine – the chemical messenger that’s in short supply in Parkinson’s disease.

When compared to control animals, those treated with rotenone had lower levels of dopamine in the brain. However, sleep deprivation did not decrease dopamine concentrations any further. DOPAC, the principal metabolite (i.e., product of metabolism) of dopamine, which was reduced after rotenone treatment alone, had its levels restored upon sleep deprivation.

High levels of two types of dopamine receptors (to which dopamine binds), specifically D2 and D3, were observed in rotenone-treated zebrafish, in comparison to the control group. Interestingly, the levels of those same receptors significantly decreased after sleep deprivation.

Dopamine metabolism appears to be altered in rotenone-treated animals and sleep deprivation seems to play a part in such alteration, however there is not a clear understanding as to how this happens yet.

“[Z]ebrafish displayed an anxiety-depressed mood and a decline in memory after [exposure] to Rotenone, and sleep deprivation caused more severe phenotype [disease characteristics] in this model via altering the [dopamine] metabolism and D2 and D3 receptors,” the researchers wrote. “Our studies not only provided the understanding the roles of [sleep deprivation] in PD non-motor dysfunctions, but also provided a useful model for future pathogenesis and therapeutic studies,” they concluded.

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Study Highlights Disparities in Patient and Physician Perceptions Of Parkinson’s

Parkinson's perspectives

A new study highlights some of the differences in perspective on disease management between people living with Parkinson’s disease and doctors treating them.

The study looks at non-motor symptoms, method of medication delivery, and awareness of support services as places where doctors’ and patients’ perceptions don’t line up, and suggests that getting these perceptions in better alignment could help improve treatment outcomes.

Patient and physician perceptions of disease management in Parkinson’s disease: results from a US-based multicenter survey” was published in the journal Neuropsychiatric Disease and Treatment.

The process of treating Parkinson’s disease is complicated and works best when both patients and doctors are on the same page. When there is disconnect, treatment is more likely to be less than optimal, particularly in terms of patients’ quality of life.

To identify such areas of divergence in perspective, researchers developed a questionnaire, which they gave to physicians treating Parkinson’s patients. The physicians’ patients were given a separate questionnaire to complete.

In addition to gathering demographic and health data, the questionnaires included more subjective questions about treatment regimes. For example, both physicians and patients were asked about the effect of Parkinson’s on patients’ quality of life, and both groups were asked about patient satisfaction with medications. There were also questions about what a conversation between a physician and a patient might look like.

The questionnaire was sent to 107 physicians, 70 of whom responded and provided answers regarding 350 different patients. Additionally, 71 patient questionnaires were completed and collected. Of all these, there were 66 patients for whom both physician and patient questionnaires were completed, allowing for the most direct comparison.

There were many areas in which physicians and patients were in agreement. For example, both groups rated the efficacy and safety of a potential treatment as very important in selecting treatments, as would be expected.

Generally, patients and physicians also had similar perceptions on how Parkinson’s was affecting patients’ quality of life, even though physicians reported that this isn’t often formally assessed. The researchers noted that doing such assessments more often might further improve Parkinson’s treatment.

There were also some areas where patients and physicians reported significantly different views.

Patients rated the form of medication delivery (e.g. a pill versus an injection) as more important than physicians in deciding what the best treatment is.

Physicians reported spending more time during patient visits discussing motor symptoms (e.g. tremors, which they felt were most bothersome for most patients) than non-motor symptoms (e.g. depression and anxiety).

In contrast, patients reported a perception of a fairly even split.

“From a physician perspective, there was alignment between the motor symptoms that were most bothersome for patients and those that were most discussed … but disconnect between the most bothersome and most discussed non-motor symptoms (physicians felt fatigue was most bothersome for most patients … [and] cognitive impairment was the most discussed non-motor symptom…),” researchers said.

Finally, physicians tended to view their patients as more knowledgeable about Parkinson’s disease than did the patients themselves. This extended to physicians being much more aware of available support services than the patients.

Nonetheless, this study has numerous limitations, including its sample which, in addition to being small, probably isn’t representative of Parkinson’s patients in terms of age, education, disease status, etc. The study also focused only on patients in the United States, potentially limiting its ability to be generalized.

However, the investigators propose that getting patients and physicians on the same page about these issues could be clinically helpful.

“Non-motor symptoms, form of medication delivery, and awareness of support services are areas where physician and patient alignment could be increased to potentially improve patient outcomes,” they concluded.

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Endurance Exercise May Help Manage Cortisol Levels in Parkinson’s Patients, Study Suggests

cortisol exercise PD

Doing high-intensity endurance exercise reduces morning cortisol levels in patients with Parkinson’s disease, which may have an impact on the progression of non-motor signs and symptoms, a pilot study suggests.

While other studies are needed to confirm if lowering cortisol with physical exercise works for delaying disease worsening, this data supports the further exploration of the role played by the hormone in non-motor symptoms of Parkinson’s.

The study, “Endurance Exercise Reduces Cortisol in Parkinson’s Disease With Mild Cognitive Impairment,” was published in the journal Movement Disorders.

Parkinson’s disease is a complex disorder associated with both motor and non-motor symptoms including sleep problems, depression, and cognitive impairment.

There is evidence that a malfunction of the hypothalamic-pituitary-adrenal axis (HPA) is involved in the progression of non-motor symptoms of Parkinson’s due to an overproduction of the hormone cortisol.

HPA is a system in the body crucial for stress management. It involves a set of complex interactions between two parts of the brain — the hypothalamus and the pituitary glands — and the adrenal glands located at the top of each kidney, which are regulated by different hormones.

After a stressful or threatening event, the HPA axis is activated and several “stress hormones,” primarily cortisol and adrenaline, are released by the adrenal glands into the bloodstream. As the blood levels of cortisol rise, they start to block the release of other hormones from the hypothalamus and the pituitary that, in turn, will induce a drop in cortisol levels.

This type of negative feedback loop is one mechanism by which HPA regulates itself to avoid excessive and sustained production of cortisol.

Beside this natural stress management process, cortisol is also important for a wide range of vital processes, including metabolism and the immune response. There has been a long-standing association between raised or impaired regulation of cortisol levels and a number of psychiatric conditions such as anxiety and depression, even though this is not yet fully understood.

Elevated morning cortisol levels have been reported in Parkinson’s patients. Accordingly, there is evidence that elevated cortisol in Parkinson’s patients is linked to symptoms such as depression and risk behavior.

Physical exercise is associated with a lower production of cortisol in healthy individuals, and there is evidence that it may also reduce the risk and rate of Parkinson’s progression.

Based on this data, the researchers reasoned that doing exercise could lower daytime production of cortisol in Parkinson’s patients, with possible implications for delaying the progression of their non-motor symptoms.

To test this theory, they conducted a small study in which they measured the levels of cortisol in saliva samples collected from eight Parkinson’s patients with mild cognitive impairment (ages 53 to 79). Over six months, participants were asked to perform high-intensity treadmill endurance exercise.

The exercise program included five to 10 minutes of warm-up, 30 minutes of exercise at 80-85% maximum heart rate, followed by five to 10 minutes of cool-down. Participants exercised an average of 2.5 days per week, and over the first eight weeks of training, exercise duration and intensity were gradually increased to target levels.

Saliva samples were collected before and after completing the program, and at specific times immediately after waking up (0, 0.25, 0.50, and 0.75 hours after awakening) and at periods throughout the day (three, six, nine, and 12 hours after awakening).

Overall, cortisol secretion of Parkinson’s patients more closely resembled that of healthy people after they had completed the training program.

Results showed there was an average 19% reduction in cortisol secretion, compared with the pre-training period. In addition, while cortisol reduction was significant during the times immediately after waking up, it was not in the periods later in the day.

“These data support the need for further exploration of HPA axis dysregulation in Parkinson’s disease,” the researchers wrote. “To understand not only its potential role in the mechanisms underlying non-motor symptoms of Parkinson’s, but also its responsiveness to intervention studies such as physical exercise that can improve non-motor symptoms.”

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Parkinson’s Medications Relieve Central Pain Better than Other Types of Pain, Study Finds

central pain, Parkinson's therapies

Treatment with standard Parkinson’s therapies, such as levodopa or dopamine agonists, can provide effective relief of central parkinsonian pain, but they may fail to manage motor symptoms in these patients, a study has found.

As many patients with Parkinson’s disease experience some type of pain, these findings suggest that clinicians should take an integrated approach to ensure adequate care for motor and non-motor symptoms in this population.

The study, “Unveiling the Relationship Between Central Parkinsonian Pain and Motor Symptoms in Parkinson’s Disease,” was published in the European Journal of Pain.

Pain is a common non-motor symptom in Parkinson’s patients, but little is known about its clinical characteristics and possible predictors.

Parkinson’s can affect the way patients experience pain, and it can lead to pain even in the absence of any evident cause for it. This is the case of central parkinsonian pain, which is characterized by a constant, aching type of pain affecting most of the body and is caused by Parkinson’s disease itself. This type of pain is poorly understood and can be difficult to treat.

Nuno Vila-Chã, MD, neurologist and researcher at Centro Hospitalar do Porto and the University of Porto, in Portugal, and his collaborators were interested in studying the prevalence and types of pain experienced by people with Parkinson’s. They examined the relationship between central pain and patient characteristics, as well as the impact of Parkinson’s targeted treatments on this type of pain.

They analyzed the clinical records, and performed interviews and neurological examinations of 292 patients with Parkinson’s, aged 63 to 79. The patients’ motor symptoms and degree of independence were assessed using different rating scales, while the patients were on medications (in the morning) or off medications. Anxiety, depression, and impulse control disorders (such as dopamine dysregulation syndrome) were also evaluated through patient-reported questionnaires.

Pain was categorized as central parkinsonian or non-central parkinsonian by a neurologist, based on the patients’ description of their pain. Central parkinsonian pain was defined as “burning, tingling, formication, or ‘neuropathic’ sensations, often relentless and bizarre in quality, not confined to root or nerve territory, and not explained by rigidity, dystonia, musculoskeletal, or internal lesion.”

Except for four patients, all (99%) were taking levodopa alone or combined with a dopamine agonist (taken by 39% of the patients), which included ropinirole (108 patients; brand name Requip, among others), pramipexole (two patients; sold as Mirapex and other names), and piribedil (three patients; sold as Trivastal, among other names).

Most patients (73%) reported feeling some sort of pain, which had lasted for a median time of five years. These patients classified it as either musculoskeletal (in 63% of the patients), dystonia-related (27%), central parkinsonian (22%), and/or radicular or neuropathic (9%).

About one-third (68 or 32%) of the patients reported that the pain developed before their Parkinson’s motor symptoms, and half (105 or 50%) said that they could achieve pain relief with antiparkinsonian therapy.

Many of them (78%) reported to have one type of pain, while some patients (22%) claim to experience two or more forms of pain. Many also complained of feeling pain everyday (63%) and rated it as moderate or severe (83%).

The team found that patients who experienced pain also were the ones with more comorbidities (particularly diseases affecting the bones and joints) and more severe motor symptoms.

These findings “confirmed that pain is a common non-motor symptom in Parkinson’s disease and that the presence of pain is associated with more severe motor manifestations of Parkinson’s,” the researchers wrote.

The researchers found that patients with central pain specifically had certain demographic and clinical characteristics. These patients were significantly younger, and their disease often started earlier, but had fewer comorbidities, compared with patients with non-central pain.

They also showed more disability related to pain and worse non-axial motor symptoms while on medications. Non-axial symptoms include all motor symptoms not related to speech, rigidity of the neck, posture and postural stability, and gait (which are considered axial symptoms).

The patients with central pain reported having greater relief in their pain with the medications they were taking for Parkinson’s, compared with those with non-central pain. Also, there was a tendency for more motor fluctuations in the subgroup of patients who took antiparkinsonian medication to relieve their pain.

“This set of demographic and clinical associations suggests the need for an integrated approach to motor and non-motor symptoms in the clinical care of Parkinson’s patients with central parkinsonian pain,” the researchers stated. Also, the association between pain and mood “appears to be weaker and even more complex in Parkinson’s” than in other diseases, they added.

Future studies should continue to search for a deeper understanding of central pain in Parkinson’s, the team noted, as “the improvement of central parkinsonian pain should be considered as a treatment outcome in Parkinson’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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