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Non-motor Symptoms Affect Sleep Quality in Early Parkinson’s, Study Finds

sleep quality in early Parkinson's

People with early-stage Parkinson’s disease and non-motor symptoms such as depression, anxiety, urinary tract issues, and hallucinations or delusions are more likely to experience sleep disorders, a recent study has found.

Better cognitive function appears to predict better sleep quality in these patients, according to the researchers who conducted the study, titled “Nonmotor Symptoms Affect Sleep Quality in Early-Stage Parkinson’s Disease Patients With or Without Cognitive Dysfunction” and published in Frontiers in Neurology.

Parkinson’s is characterized by motor symptoms such as tremor, slowness of movement (bradykinesia), and uncontrolled involuntary movement (dyskinesia), as well as by non-motor symptoms including sleep problems and cognitive decline.

In Parkinson’s, sleep issues include not only difficulties in falling asleep but also sleep fragmentation, temporary paralysis during the night, obstructive sleep apnea, and daytime sleepiness.

Several non-motor symptoms of the disease, such as depression, anxiety, and excessive urination at night (nocturia), are known to affect sleep quality in Parkinson’s patients. But not a lot of research has been done on the potential link between non-motor symptoms and sleep quality among those with early-stage disease, either with or without cognitive impairment.

To address this, a team of researchers in China assessed a group of 389 patients with early-stage Parkinson’s disease who had been diagnosed in the previous five years. Patients were an average of 63.9 years old, and 63.5% were men.

After answering a questionnaire about their demographics and clinical information, participants were assessed for sleep problems using the Parkinson’s disease sleep scale (PDSS) and for cognitive function with the Montreal Cognitive Assessment (MoCA).

Motor symptoms were examined with the Unified PD Rating Scale (UPDRS) part III and global non-motor symptoms with the Non-Motor Symptoms Questionnaire (NMS-Quest). Depression was also assessed with the Hamilton Depression Scale (HAMD), while the Hamilton Anxiety Rating Scale (HAMA) was administered to examine anxiety.

Results showed that 23.7% of participants reported significant sleep problems, and 39.8% had cognitive impairment. More patients with cognitive impairment experienced sleep disorders than those without (34.8% vs. 16.2%).

Patients with and without sleep disorders were fairly similar in terms of sex, age, disease duration, levodopa-equivalent dose, and motor symptoms. But those with sleep disorders had higher (worse) scores in seven of the nine subdomains of the NMS-Quest, including gastrointestinal symptoms, urinary tract symptoms, apathy/attention/memory, depression/anxiety/anhedonia, cardiovascular symptoms, and miscellaneous.

This same population also had higher scores in all domains of the HAMD scale, which is indicative of depression, and the HAMA scale, indicating anxiety.

Those with sleep disorders also had worse overall scores on MoCA and in the specific domains of naming, attention, delayed memory, and orientation, compared with those without sleep problems.

The researchers then divided the patients into groups according to whether or not they had cognitive impairment to study the differences among those with and without sleep problems in each group.

Of those without cognitive problems, patients with sleep disorders had worse motor symptoms, a more advanced disease, and used a higher dose of levodopa than those without sleep disorders.

After controlling for these differences, the team found that people with sleep problems also had worse scores on the same seven domains of the NMS-Quest as those in the overall population, had worse scores in depression, and more frequently experienced anxiety. These patients without cognitive impairment but with sleep problems also had worse cognitive function.

Findings were largely similar when people with and without sleep problems were compared in the group with cognitive impairment. But cognitive function was not significantly different between the two groups.

Statistical analysis to determine which symptoms were associated with poor sleep quality demonstrated that urinary tract symptoms, hallucinations and delusions, a feeling of hopelessness, and anxiety all significantly increased the odds of having sleep disorders. But a better cognitive performance, particularly in the orientation domain, lowered these odds by about 88%.

In the group of patients with cognitive impairment, hallucinations and delusions increased the odds of sleep disorders by nearly four times, greater scores in the HAMD scale weight loss domain increased them by twofold, and anxiety by 15%.

Among those without cognitive impairment, factors increasing the odds of sleep disorders included greater anxiety scores and higher levodopa doses, while better cognitive performance on the naming and orientation domains were predictive of better sleep quality.

These findings suggest that approximately one-quarter of Parkinson’s patients experience sleep problems, and that there is an association between the presence and severity of non-motor symptoms and sleep quality.

“Patients with cognitive dysfunction suffered a higher percentage of sleep disorders,” the researchers wrote, suggesting that “better cognition may predict better sleep quality.”

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Invertigo’s ‘Dancing Through Parkinson’s’ Moves Online During COVID-19 Pandemic

dancing

Throughout the global COVID-19 pandemic, the Invertigo Dance Theatre will conduct its weekly Dancing Through Parkinson’s (DTP) classes online.

Starting May 7, the Los Angeles, California-based company will offer free streaming classes live on Zoom each Thursday at 1:30 p.m. PT. The sessions will be recorded and available for later viewing. There also are online video classes available at invertigodance.org/dtp.

The DTP dance curriculum is designed to meet the needs of those with Parkinson’s or other neurological conditions, regardless of disease stage. The classes are taught by professional dancers trained in methods to specifically benefit Parkinson’s patients, and designed to promote physical stability, mental clarity, and creativity.

Participants may move at their own pace, and no dance experience is required. Movement may be done while seated, standing, or with the help of a walker.

“Our dance classes invite people with Parkinson’s and those with limited mobility into movement as a source of joy, strength, and discovery,” K. Bradford, Invertigo’s community engagement manager, said in a press release.

“Our participants tell us they find healing and a sense of belonging in the DTP community, and that the classes foster a greater wellbeing in what can be an isolating time. Our teachers’ hearts are fully engaged in the classes, and we’re so glad that our online studio can transmit care, art, and community while people shelter — and dance — at home,” she said.

The DTP online classes are modeled after its in-person studio classes, and are taught by Kelsey Ang, Linda Berghoff, Heidi Buehler, Jess Evans, Haylee Nichele, and Rachel Whiting.

Longtime DTP participant Jeanie McNamara said this about her first online class: “This is phenomenal. What a wonderful collaborative class, and what a gift to all of us who are working hard to continue moving without going anywhere. Thank you for all that you are doing so that we can continue to battle [Parkinson’s] while trapped at home.”

Each session starts with a seated warm-up exercise that incorporates breath work, upper body stretches, and joint mobility. While remaining seated, participants perform choreography, tap work and other routines. Then, while seated or standing, dancers engage in a modified ballet barre exercise. At the end, instead of the traditional in-person “circle of gratitude,” each participant is asked to place a hand over his or her heart.

“We believe everyone is a dancer. We just ask you to give us a chance to prove that to you,” said  Berghoff, a DTP instructor and Invertigo board member. “…We still need to dance. Parkinson’s doesn’t stop just because the world does.”

A lifetime dancer, Berghoff was diagnosed with Parkinson’s in 2006 and thought she’d never dance again. A “Dance for PD” class in New York changed that perspective, and she began collaborating with Invertigo to create a dance class for Parkinson’s patients on the West Coast.

Established in 2011, DTP is an ongoing Invertigo Dance Theatre community program. It traditionally offers Parkinson’s patients free weekly dance classes in studios throughout southern California.

Because Parkinson’s patients usually experience motor and cognitive impairment, as well as mood changes and social isolation, dance may positively affect their quality of life, according to the International Parkinson and Movement Disorder Society.

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Blood Test May Help Predict Cognitive Decline in Parkinson’s, Study Shows

blood biomarkers of Parkinson's

A blood test may be able to predict early cognitive decline in people with Parkinson’s disease by measuring the length of chromosomal telomeres (the “tips” of chromosomes) in immune cells and the presence of inflammatory markers, a study shows.

The study, “Senescence and Inflammatory Markers for Predicting Clinical Progression in Parkinson’s Disease: The ICICLE-PD Study,” was published in the IOS Press Journal of Parkinson’s Disease.

Cognitive impairment is a well-known non-motor symptom of Parkinson’s disease. Biological markers identifying those at highest risk of early cognitive decline may help better predict disease progression of newly diagnosed Parkinson’s patients. 

Telomeres are a protective region of DNA at the end of each chromosome that facilitates proper genome replication. As people age, the ends of telomeres shorten with each cell division. Telomere shortening and dysfunction can also be indicators of disease processes in the brain.

However, studies that have used telomere length as a marker for Parkinson’s incidence and progression have reported conflicting results. 

Telomere shortening in humans can also trigger cellular senescence, a process characterized by the irreversible shutdown of cell division, and the release of pro-inflammatory signaling proteins and tumor-suppressor proteins such as p21 and p16

The senescence of different types of brain cells is associated with neurodegeneration and inflammation, and while the potential of both p21 and p16 as biomarkers for age-related diseases has been investigated, their use as markers for Parkinson’s disease progression and early cognitive decline has not been explored. 

Thus, researchers based at Newcastle University, in the United Kingdom, designed a three-year study to compare the length of immune cell telomeres isolated from newly diagnosed Parkinson’s patients and healthy controls over time. The team also examined whether blood-derived markers of cell senescence and inflammation are associated with cognitive and motor function. 

The authors previously published work in 2016 about the Incidence of Cognitive Impairments in Cohorts with Longitudinal Evaluation-Parkinson’s Disease (ICICLE-PD) study, which found that inflammatory markers in the blood measured at diagnosis were linked to more rapid cognitive and motor decline.

Continuing this line of investigation, the team studied 154 newly diagnosed Parkinson’s patients who had been part of the ICICLE-PD study, along with 99 age- and gender-matched control subjects. The average age of both groups was around 67 years. 

The participants were assessed at 18-month intervals in which demographic information, blood samples, and cognitive and clinical data were collected. The average telomere length in immune cells and senescence markers p21 and p16 were measured at two time points, baseline and 18 months. An additional five inflammatory markers were also included from the first ICICLE-PD study.

The results revealed that Parkinson’s patients had significantly shorter telomere length at baseline compared to controls, and their telomere length shortened faster over the 18-month period. 

Over 36 months of follow-up, 11 Parkinson’s patients (15.5%) developed dementia. They had significantly shorter telomeres at baseline and at 18 months, compared to those without dementia.  

Significantly lower levels of p21 were found in Parkinson’s patients compared to controls at baseline, and there was no difference in change with time. The differences between the levels of p16 at baseline or the rate of change over time was not statistically significant. However, unexpectedly, higher p16 levels at baseline predicted slower motor and cognitive decline over 36 months. 

The examination of the five inflammatory markers found significantly higher levels of pro-inflammatory signaling proteins TNF-alpha and interleukin-10 in the Parkinson’s group than in the controls. 

A baseline composite inflammatory score based on all five markers found a significant difference between the groups as well. This score was able to predict cognitive decline at 36 months, consistent with the first ICICLE-PD study.

“In summary, our study demonstrates that telomere lengths at baseline and 18 months were lower in [Parkinson’s disease] patients compared to age-matched healthy controls with shorter telomere length at baseline and at 18 months also associated with development of dementia within 36 months,” the researchers wrote. 

“A baseline inflammatory score consisting of five different cytokines gave the best prediction for cognitive scores of [Parkinson’s disease] cases 3 years later, while lower p16 gene expression predicted a more rapid disease progression over the same period in relation to both cognitive and motor scores,” they added.

Of note, gene expression is the process by which information in a gene is synthesized to create a working product, such as a protein.

“The markers that we have identified need to be validated in further studies but could ultimately help with planning more targeted management for patients earlier in their disease course,” said lead investigator Gabriele Saretzki, PhD, in a press release.

“Furthermore, a better understanding of the biological changes that predict disease course has implications for possible future therapies for the disease,” she added.

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Oral Treatment in Phase 2 Trial, NYX-458, Seen to Aid Cognition in Primate Model Study

NYX-458 and cognition

Aptinyx‘s investigational oral compound NYX-458 was able to ease cognitive difficulties in a non-human primate model of Parkinson’s disease, including attention, working memory and executive thinking, a study reports.

Its findings also suggest that NYX-458 — now in a Phase 2 clinical trial (NCT04148391) enrolling patients across the U.S. — does not interfere with levodopa treatment.

The study, “NYX‐458 improves cognitive performance in a primate Parkinson’s disease model,” was published in Movement Disorders.

Although Parkinson’s is often classified as a movement disorder, non-motor symptoms of the disease can have a major impact. For instance, as many as a quarter of people with Parkinson’s meet the criteria for at least mild cognitive impairment when they are diagnosed, and this frequency increases to around 80% after years with the disease.

Parkinson’s is characterized by a loss of dopamine-producing neurons in the brain. One of dopamine’s many functions is to regulate a protein called N-methyl-D-aspartate receptor (NMDAR). It is believed that dysregulation of NMDAR, as a result of dopamine’s lack, contributes to cognitive impairment in Parkinson’s disease.

NYX-458 was designed to modulate NMDAR activity to correct this problem.

Researchers evaluated NYX-458 in a non-human primate (macaque) model of Parkinson’s disease. In this model, cognitive defects are induced with low doses of the neurotoxin MPTP, which selectively damages the same kind of dopamine-producing neurons that are lost in Parkinson’s.

Notably, this model has “a minimal impact on motor function,” the researchers wrote. This is important because of how cognitive impairment was measured in the study: the animals were trained to complete learning/memory tasks to get a food reward, and the researchers measured things like how quickly the animals learned and how often they completed the tasks correctly. These tasks invariably involve movement (like having a monkey point at a particular image). So, the MPTP model allowed assessment of cognitive impairment with minimal motor interference.

The researchers first confirmed that MPTP was inducing cognitive impairment as expected. Then, the animals were given a single oral dose (0.03 mg/kg) of NYX-458.

Significant improvements in scores on the cognitive tasks (“across the domains of attention, working memory, and executive function”) were seen, and “occurred as early as 24 hours postdosing and continued for at least 3 weeks after a single dose,” the researchers wrote.

Subsequent doses of NYX-458 (0.03 mg/kg for 26 days following the first dose, and 0.1 mg/kg for 39 days following the first dose) resulted in further improvement over time.

The monkeys were then re-administered the neurotoxin, which again worsened their cognitive abilities. Subsequent NYX-458 treatment at a higher dose (0.1 mg/kg after MPTP reuse, and 1.0 mg/kg two weeks later), again eased evident impairment.

Animals that showed consistent improvements in the previous experiments next underwent a ‘washout’ period, allowing their cognitive scores to drop back to near pre-NYX-458 levels. They were then given NYX-458 daily (1.0 mg/kg) for 10 consecutive days. Cognitive improvements were seen as long as three months following this treatment round.

Such long-term effects “cannot be explained by continued drug action, as the half-life of NYX-458 in primate plasma is short,” the researchers wrote. Instead, these data suggest that NYX-458 treatment leads to changes in the biochemistry of the affected brain cells, with long-lasting consequences. Further studies, however, are needed to directly confirm this idea.

In a separate experiment, animals were given MPTP at much higher doses, such that motor impairments were induced. NYX-458 treatment did not significantly lessen these motor symptoms.

Levodopa (L-dopa), a mainstay of Parkinson’s treatment, did significantly improve motor symptoms in this model. This effect was also seen when L-dopa and NYX-458 were given simultaneously. These result suggest that NYX-458 does not interfere with the action of L-dopa, supporting the use of the two therapies in combination.

“[T]he cognitive improvement seen in this small primate study and the lack of drug-induced motor impairment or dyskinesia seen in the primate motor study support the continued development of NYX-458 as a potential therapeutic for [cognitive impairment] in early PD,” the researchers wrote.

“Cognitive impairment is increasingly recognized as a burdensome component of Parkinson’s and the few available therapies are inadequate,” Norbert Riedel, PhD, president and chief executive officer at Aptinyx, said in a press release. “In a highly translatable model, these data indicate that the novel mechanism of NYX-458 can address aberrant glutamatergic signaling underlying cognitive impairment in Parkinson’s disease.”

NYX-458 was recently assessed in a Phase 1 clinical trial done in healthy volunteers. Results reported by Aptinyx showed a good safety profile, with no treatment-related adverse events reported.

The ongoing Phase 2 clinical trial (NCT04148391) is evaluating NYX-458 in up to 135 people with Parkinson’s disease who have mild cognitive impairment. Recruitment is underway at multiple locations in the United States; additional information can be found here.

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Brain MRIs Can Be Used to Detect Early Signs of Parkinson’s Cognitive Impairment, Study Suggests

brain MRI

Brain magnetic resonance imaging (MRI) scans could be used to detect early and subtle markers of cognitive impairment in people with Parkinson’s, which may help predict patients’ prognoses and disease progression, a recent study suggests.

Such early detection also allows people with the neurodegenerative disease to start appropriate care strategies earlier, the researchers say.

The results of the study, “Texture features of magnetic resonance images: A marker of slight cognitive deficits in Parkinson’s disease,” were published in the journal Movement Disorders.

Cognitive impairment is a common non-motor symptom of Parkinson’s disease and a cause of significant disability for patients and a burden for caregivers. The extent and progression of cognitive deficits vary, with about 20.3% to 60.5% of individuals experiencing mild cognitive impairments (MCI). In more severe cases, such impairment can result in dementia.
Those at-risk can benefit from early detection of cognitive alterations, which allows them to initiate appropriate care strategies such as cognitive stimulation therapy. Such therapy can result in a marked improvement in cognition and quality of life, according to researchers. However, standard neuropsychological assessments are time-consuming and not easy to do in routine clinical practice. Moreover, such evaluations can be influenced by medication, pain, anxiety, and other factors.
Therefore, additional markers of cognitive deficits are needed for Parkinson’s patients, the researchers say. One potential option is the use of magnetic resonance imaging (MRI), an imaging exam that uses a powerful magnetic field, radio waves, and a computer to produce detailed pictures of the body’s internal structures.
“Texture features” — a well-known method of MRI image processing used for medical purposes — could offer insights on subtle brain changes.  These features could be used to detect the damage to brain cells, long before any symptoms of cognitive impairment develop.
Recognizing the potential of this method, a team of French researchers now tested whether such signals could be used as early markers of Parkinson’s cognitive impairments — “potentially even before the atrophy [loss of brain volume, a usual sign of cognitive decline] becomes manifest,” they said.

The team investigated if MRI texture analysis is sensitive enough to be an early marker of cognitive alterations, specifically of cognitive slowing, in Parkinson’s patients.

They analyzed brain MRI scans of 102 people with Parkinson’s from centers in Lille, France, and Maastricht, the Netherlands, who were involved in a previous study.

Based on tests of attention, memory, executive function, language, and visuospatial functions, three groups of patients were considered for the study. These groups were cognitively intact patients (PDCN); cognitively intact patients with slight cognitive slowing (PDCN-S); and patients with mild cognitive deficits, particularly in executive functioning (PD-EXE).

A group of 17 age‐matched healthy people (controls) was included for comparison. All participants were examined on a 3T whole-body scanner and T1‐weighted images were acquired.

Six regions of the brain previously reported to suffer from atrophy (volume loss) in Parkinson’s patients with cognitive impairments were specifically chosen by the researchers for analysis. These regions were the thalamus, the hippocampus, the puramen, the pallidum, the caudate nucleus, and the amygdala.

The researchers found that values for two texture features — skewness and entropy — could distinguish individuals who had normal cognition from those with slight cognitive slowing, and from those with mild impairments. Skewness is a parameter that quantifies the asymmetry of the intensity of MRI signals. Entropy represents the degree of uncertainty of the texture intensity.

These texture features were at three specific regions in the brain: the hippocampus, the thalamus, and the amygdala.

The values for these features gradually decreased in those patients with worse cognitive function, suggesting it is possible to detect early cognition deficits in people with Parkinson’s using MRIs. The researchers noted that the best performances regarding sensitivity and specificity were obtained by measuring skewness in the hippocampus. In fact, skewness in the hippocampus was a significant marker of slight cognitive slowing.
“Our results suggest that hippocampal neurons could be affected very early in PD patients, even before atrophy can be detected with commonly used methods, and this could cause a general slowing of information processing,” the researchers said.
“These results support the assumption that signal alterations associated with Parkinson’s disease–related cognitive decline can be captured very early by texture analysis,” they added.
The researchers believe that brain MRI imaging could be combined with other methods, such as cognitive assessments and electroencephalograms. That would allow scientists to build a combined model “not only for the profiling but also for the prognosis and the prediction of evolution” of cognitive impairment, they said.

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Polypharmacy Linked to Cognitive Decline in Newly Diagnosed Parkinson’s Patients, Study Finds

Polypharmacy

Taking several different medications at the same time to treat concurrent health conditions — known as polypharmacy — may be associated with cognitive decline in people newly diagnosed with Parkinson’s disease, according to a recent study.

Reducing the number of medications prescribed would be one option to minimize the potentially harmful effects of polypharmacy on patients’ cognitive abilities, the researchers said.

The study, “Polypharmacy Associated with Cognitive Decline in Newly Diagnosed Parkinson’s Disease: A Cross-Sectional Study,” was published in the journal Dementia and Geriatric Cognitive Disorders.

Polypharmacy — most commonly defined as taking five or more medications concurrently for different conditions — is an emerging concern, particularly for the elderly. It has been associated with falls, adverse medication events, and hospitalization, researchers say.

A previous study found that polypharmacy also is associated with cognitive impairment in older adults who live independently.

However, its effects on the cognitive function of newly diagnosed patients with Parkinson’s disease — a neurodegenerative disorder associated with cognitive impairments and, at later stages, dementia — are still unclear.

In this study, investigators from the University of Miyazaki in Japan set out to explore the possible association between polypharmacy and cognitive decline in people who were recently diagnosed with Parkinson’s.

The cross-sectional study enrolled 131 patients who had been consecutively hospitalized at the University of Miyazaki Hospital and were newly diagnosed with Parkinson’s. Participants were divided into two groups, depending on whether they met the criteria for polypharmacy — which was defined for this study as taking six or more medications to treat different health conditions.

Cognitive function was assessed in all study participants using the Mini-Mental State Examination (MMSE) and compared between the two groups. All comparisons were normalized for potential confounders, including age, sex, education and medical history.

Among the 131 patients (mean age 69.8 years, 46.6% male) enrolled in the study, 43 (32.8%) met the criteria for polypharmacy.

After performing data adjustments for possible confounders, researchers found that the individuals who met the polypharmacy criteria had significantly lower MMSE scores compared with those who did not (26.2 versus 27.7). These results were indicative of cognitive decline.

“This is the first study to demonstrate an association between polypharmacy and cognitive decline in patients with newly diagnosed PD [Parkinson’s disease], as well as in community-dwelling older adults,” or people living independently, the researchers said.

“Medication reduction might be a promising intervention to prevent the development of dementia in patients with early PD,” the investigators said.

“Further prospective studies are needed to confirm whether medication reduction in patients with newly diagnosed PD can improve cognitive function and prevent the development of dementia,” they added.

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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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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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Specific BDNF Mutation May Be Linked to Higher Risk of Cognitive Impairment in Parkinson’s, Study Suggests

BDNF gene mutation

One amino acid change in the brain-derived neurotrophic factor (BDNF) gene, which provides instructions for a protein important to neuronal survival, may be associated with cognitive impairment in Parkinson’s disease patients, a study has found.

The study, “BDNF Val66Met polymorphism and cognitive impairment in Parkinson’s disease—a meta-analysis,” was published in the journal Neurological Sciences.

BDNF protein is produced inside brain cells and is crucial for their function as well as supporting their growth and protecting them against premature cell death. When its coding sequence is changed, this can have a major impact on brain cell outcomes.

Previous studies have suggested that one specific BDNF gene mutation called Val66Met that results in the change of a valine (Val) by a methionine (Met) at position 66 — both amino acids, also known as the protein’s building blocks — could be linked to cognitive impairment in Parkinson’s disease. However, there is no consensus on the relevance of this genetic mutation on outcomes of Parkinson’s patients.

Chinese researchers searched for available literature on this matter, and analyzed pooled data from six studies involving a total of 1,467 patients with Parkinson’s disease. These studies had been carried out in Italy, Spain, Poland, Brazil, Belgrade (Serbia), and the Netherlands.

Results revealed a significant association between the Val66Met BDNF mutation and risk of Parkinson’s disease-related cognitive impairment. Patients who had two copies of the BDNF gene with methionine (mutated version) were found to have a 3.82 times higher risk of developing cognitive impairment than those who had two BDNF copies with valine (non-mutated version).

However, it’s worth mentioning that the studies in this analysis only included Caucasian study samples, so these results should not be generalized to other ethnicities.

Parkinson’s disease affects people of all races and ethnicity worldwide. Some studies indicate that neurodegenerative disorders affect more white people than any other ethnicity, but a solid conclusion cannot be drawn from available research as they tend to vary widely regarding diagnostic criteria, sample sizes, and methodology.

“Future studies should verify our findings in larger populations, particularly in other ethnicities,” the researchers wrote.

Still, the team believes that this study provides evidence that mutated BDNF “may be associated with increased risk of cognitive impairment of Parkinson’s disease, at least among Caucasians.”

In addition, this Val66Met change in the BDNF sequence should be studied in different Parkinson’s patients presenting tremor dominant or postural instability gait disorders. Further understanding of the impact of genetics on the long-term outcomes of these patients “may better guide clinical treatments and judge the prognosis,” they said.

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Aptinyx to Launch Phase 2 Study of NYX-458 to Treat Cognitive Impairment

NYX-458

Positive preclinical and Phase 1 clinical data support further assessmentof Aptinyx‘s investigational compound NYX-458 for the treatment of cognitive impairment associated with Parkinson’s disease in new Phase 2 studies.

Aptinyx expects to launch a new Phase 2 clinical study in Parkinson’s patients this year, the company announced in a press release.

“So far, 2019 has been marked by the achievement of key milestones and important clinical study results that form the basis for several of our upcoming Phase 2 studies,” said Norbert Riedel, PhD, president and CEO of Aptinyx.

“[W]e reported highly encouraging data from a non-human primate study of NYX-458 … showing its ability to reverse cognitive deficits. We also observed a favorable safety, tolerability, and pharmacokinetic profile with NYX-458 in our healthy volunteer Phase 1 study,” he said.

NYX-458 is a small molecule compound that controls the activity of N-methyl-D-aspartate (NMDA) receptors in the brain. These receptors are involved in the communication between nerve cells, which occur at a structure located at the junction between two nerve cells, called a synapse.

It is thought that loss of dopamine-producing neurons — a hallmark feature of Parkinson’s disease — also impairs the function of NMDA receptors in the brain, leading to cognitive impairment. By controlling their activity, NYX-458 has the potential to restore the function of NMDA receptors and reverse cognitive impairment associated with Parkinson’s.

Preclinical studies have shown that treatment with NYX-458 could lead to fast, strong, and long-lasting improvements in the cognition of animals that had been treated with low doses of a neurotoxin that destroys dopaminergic neurons and induces Parkinson’s symptoms.

Also, treatment with NYX-458 did not interfere with levodopa, a standard therapy for the treatment of motor symptoms associated with Parkinson’s, and did not contribute to worsening of motor symptoms.

These preclinical findings were recently discussed at the 14th International Conference on Alzheimer’s & Parkinson’s Diseases in Lisbon, Portugal.

To explore further explore the potential of the investigational therapy, Aptinyx launched a Phase 1 clinical trial in healthy volunteers. This study was designed to assess the safety, tolerability, and overall stability and metabolism (pharmacokinetics) of NYX-458 in the body.

The randomized, double-blind, placebo-controlled, Phase 1 trial involved 62 healthy volunteers who were treated with NYX-458 administered orally at doses ranging from 10 to 200 mg.

Results showed that NYX-458 was in general safe and well-tolerated by study participants. No serious adverse events associated with the treatment were reported.

Additional analysis also showed that the compound could successfully cross the blood-brain barrier (a semipermeable membrane that isolates the brain from the blood that circulates in the body), behaving as expected in a dose-proportional manner.

Supported by these positive preclinical data and favorable Phase 1 safety and tolerability profiles, the company plans to launch a Phase 2 trial to assess NYX-458 in patients with Parkinson’s disease in the second half of 2019.

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