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Music and Laughter Are Strong Medicine Against Dementia

music and laughter

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

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

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

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

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

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

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

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

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

non-motor symptoms, Parkinson's

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

sleep disorder, Parkinson's risk

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Anavex 2-73 Trial Recruitment Reaches Halfway Mark

Anavex 2-73

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

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

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

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

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

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

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

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

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

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

deep brain stimulation

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Subjective Cognitive Decline Could Help Predict Parkinson’s Dementia, Study Contends

cognitive decline

Subjective cognitive decline in Parkinson’s disease could predict the development of dementia. As such, a suitable cognitive screening test could help provide an accurate diagnosis and prognosis.

The study with those findings, “Subjective cognitive decline and progression to dementia in Parkinson’s disease: a long-term follow-up study,” was published in Journal of Neurology.

Even during the early stages of disease, mild cognitive impairment can affect non-demented Parkinson’s patients, and is considered a risk factor for the development of dementia (PDD).

In fact, the prevalence of PDD increases as the disease progresses: from 28% after five years of evolution to 80% after 20 years of the disease.

Subjective cognitive decline — self-reported acquired difficulties with cognitive functioning — is common in the elderly and can be used as a predictor of dementia. In Alzheimer’s disease, subjective cognitive decline has been linked to disease-related tissue/molecular changes and a higher risk for dementia development. However, the predictive value of this type of cognitive status impairment has not been demonstrated yet in Parkinson’s disease.

Scientists from the University of La Laguna, Spain, investigated the neuropsychological profile of subjective cognitive decline in Parkinson’s disease and explored which components could better predict the development of PDD. The team also compared different screening tests to assess subjective cognitive complaints.

A total of 43 Parkinson’s patients and 20 healthy subjects were subjected to neuropsychological examination using a battery of cognitive tests. All patients were being medicated for Parkinson’s and were evaluated during their “on” state — when they are responding to medication and have reduced symptoms.

Subjective cognitive decline was diagnosed using two distinct approaches. A semi-structured interview in which the patient provided his/her subjective opinion on his/her attention, memory, spoken language, naming, written language, visuospatial skills and executive functions; diagnosis was considered when the patient had at least one cognitive complaint. Additionally, a subjective cognitive decline diagnosis also was established on the basis of the interview question concerning memory complaint.

For a mild cognitive impairment diagnosis, investigators followed the criteria proposed by the Movement Disorder Society (MDS)

Based on the results of the interview and on the MDS Task Force criteria, patients were diagnosed as having either subjective cognitive decline or mild cognitive impairment. Of the 43 patients, 13 (30.2%) were diagnosed with subjective cognitive decline, 22 (51.2%) with mild cognitive impairment and 8 (18.6%) had no subjective cognitive complaints. Difficulties in naming and memory were the most frequent cognitive complaints.

Based on memory complaints alone 10 patients (23.25%) were diagnosed with subjective cognitive decline. Interestingly, 10 of the 22 (45.45%) who had been diagnosed with mild cognitive impairment reported no memory complaints.

Mild cognitive impairment subjects performed poorer in the processing speed (the time it takes a person to do a mental task), executive functions (a set of mental skills that helps with organization and regulation), visuospatial skills, memory, and language domains, compared to the other groups.

There were no significant differences between healthy participants (controls)  and Parkinson’s disease patients with subjective cognitive decline in any of the neuropsychological measures.

The team also assessed how many patients diagnosed with subjective cognitive decline progressed to dementia after a mean follow-up of 7.5 years. Fifty percent of mild cognitive impairment patients, 33.3% of individuals diagnosed with subjective cognitive decline, and 14.3% of patients without subjective cognitive complaints developed dementia, which was found to be associated with a poor performance in verbal and visuospatial memory and naming at the beginning of the study.

Additionally, both the language and memory domains were good predictors of dementia development.

“These results are highly relevant for future investigations and also for clinicians: the [subjective cognitive decline] assessment is frequently the first step of cognitive examination and can influence future decisions (e.g., to administer a screening test or a comprehensive neuropsychological assessment),” researchers wrote.

“Assessments that do not include procedures to adequately explore cognitive complaints may underestimate the proportion of [Parkinson’s-related subjective cognitive decline] and, therefore, [mild cognitive impairment] and thus misclassify patients as [Parkinson’s disease] with normal cognition, especially when brief cognitive examinations are chosen,” they concluded.

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Cognitive Performance in Parkinson’s Linked to Sleep Efficiency, Study Shows

sleep study

University of São Paulo researchers have found that Parkinson’s patients with dementia sleep less and less efficiently, which affects their overall cognitive performance.

The study with that finding, “Global cognitive performance is associated with sleep efficiency measured by polysomnography in patients with Parkinson’s disease,” was published in Psychiatry and Clinical Neurosciences.

Non-motor complications associated with Parkinson’s disease, including cognitive impairment and sleep disturbances, can drastically affect patients’ quality of life.

Evidence suggests an interaction between sleep disorders and cognition. For instance, sleep after learning helps memory consolidation.

In addition, people with obstructive sleep apnea syndrome or chronic insomnia have cognitive abnormalities, which could be reversed after proper treatment of the underlying sleep disturbance.

Although there is still no consensus about whether sleep disorders are associated with cognitive dysfunction, studies suggest an association and add that rapid eye movement (REM) sleep behavioral disorder may be associated with increased risk for cognitive decline. REM is a sleep stage in which the eyes move rapidly in various directions.  During sleep, the body cycles between intervals of basic states: REM sleep and non-REM sleep.

Researchers in Brazil now examined a possible association between clinical variables, cognitive status and the presence of sleep abnormalities and symptoms in Parkinson’s patients.

Investigators performed detailed clinical and cognitive assessment in 79 patients. Participants were mostly men (61%), 51-72 years old, and a disease duration varying between 3.9 and 13.9 years.

Based on cognitive diagnosis, researchers categorized patients as those with normal cognition (29 patients), mild cognitive impairment (39 patients) or dementia (11 patients).

Within two weeks after initial medical evaluation, participants were submitted to an overnight polysomnography, meaning they had their brain waves, blood oxygen level, heart rate, breathing patterns, and eye and leg movements monitored while they were asleep.

Compared to Parkinson’s patients with normal cognition, the dementia group was older, had more severe disease, and more difficulty performing daily activities. Dementia patients also took higher daily levodopa-equivalent dose than participants without abnormalities.

Patients with dementia had lower sleep efficiency, less total sleep time and lower number of sleep state changes, in comparison to the normal cognition group.

Researchers also found an association between sleepiness, measures of obstructive sleep apnea and sleep symptoms, which were assessed by the Parkinson’s Disease Sleep Scale and the Pittsburgh Sleep Quality Index.

“Concerning sleep disorders and sleep symptoms, [there was] no significant differences between groups in the proportion of cases with obstructive sleep apnea, chronic insomnia, [REM sleep behavioral disorder] and [restless legs syndrome]. We also did not observe significant differences between scores of patients in the three groups about excessive daytime sleepiness, quality of sleep and general sleep-related symptoms. There was also no significant differences in the number of sleep disorders between the groups,” authors wrote.

There was a significant association between overall (aka “global”) cognitive performance and wakefulness and the number of sleep state changes during sleep.

“However, we did not find any other association between sleep disorders or symptoms and cognitive status or cognitive performance of patients with Parkinson’s,” researchers wrote.

The team believes the association with the number of state changes during sleep may be because Parkinson’s disease patients with dementia slept less than the other subsets and as such, had less time to change between sleep states.

“We hope that, in the near future, new prospective controlled studies, with more significant numbers of patients, could evaluate, in detail, the relationship of different variables related to sleep with cognitive functions in this specific population,” researchers concluded.

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Nuedexta Often Used to Treat Symptoms of Parkinson’s and Dementia Off-label, Study Finds

medications

An oral medicine approved to treat pseudobulbar affect — involuntary outbursts of laughing or crying — in people with amyotrophic lateral sclerosis  or multiple sclerosis  is most often prescribed to treat those with Parkinson’s disease or dementia, a study based on U.S. health databases reports.

The study “Assessment of Use of Combined Dextromethorphan and Quinidine in Patients With Dementia or Parkinson Disease After US Food and Drug Administration Approval for Pseudobulbar Affect,” published in JAMA Internal Medicine, also noted a higher risk of falls and possible cardiac issues in these older patient groups.

Nuedexta (dextromethorphan-quinidine), by Avanir Pharmaceuticals, was approved to treat pseudobulbar affect (PBA) in ALS and MS patients by the U.S. Food and Drug Administration (FDA) in 2010. PBA refers to sudden, uncontrollable, and often inappropriate episodes of crying or laughing.

Approval was based on results of a Phase 3 clinical trial (NCT00573443) conducted in people with ALS and MS that showed these outbursts were reduced by nearly half among treated patients over 12 weeks compared to those given placebo.

Its initial label noted that Nuedexta was not known to be “safe or effective in other types of emotional lability that can commonly occur, for example, in Alzheimer’s disease and other dementias.” But a 10-week Phase 2 trial (NCT01584440) found its use lowered agitation scores by one or two points in patients with probable Alzheimer’s disease over 10 weeks compared to those on placebo.

Alzheimer’s patients given the dextromethorphan-quinidine medication also had higher rates of falls and urinary tract infection, but it was “generally well tolerated,” according to a study published in 2015 reporting on that trial. Prescribing information for Nuedexta was updated that same year to remove that initial warning statement.

Extrapolating a therapy’s efficacy and safety to patients who have not been the focus of rigorous research is common but can be clinically challenging, particularly when there is little evidence supporting likely clinical benefit and safety. Because Parkinson’s and dementia patients can experience rapid and exaggerated mood changes, researchers decided to look at prescribing patterns for Nuedexta and changes in prescription and cost trends over time.

Because there has been evidence that Nuedexta is commonly prescribed to patients with dementia and/or Parkinson’s disease, as they can also experience rapid and exaggerated mood changes, researchers examined the medicine’s prescribing patterns and how the prescription and cost trends have changed over time.

They used data from two commercial insurance databases, Optum Clinformatics Data Mart and Truven Health MarketScan, to evaluate the numbers of prescriptions and total reported spending by the Centers for Medicare & Medicaid Services. Data were collected on 12,858 patients given prescriptions from Oct. 29, 2010 (Nuedexta approval date), until Dec. 31, 2015 (most recent data for the Truven database), and March 1, 2017.

Combining results from both databases, the researchers found that only 8.4% of patients prescribed Nuedexta had an MS diagnosis and only 6.8% had one for ALS.

Rather, the majority of patients prescribed Nuedexta — 57.0% — were Parkinson’s or dementia patients. “Our findings suggest that dextromethorphan-quinidine was primarily prescribed for patients with dementia and/or PD,” the study noted.

Additionally, 13.3% of prescribed patients had a history of heart failure, which is a contraindication for the therapy.

A more than 15-fold increase in the number of patients prescribed Nuedexta from 2011 to 2016 — 3,296 to 50,402, respectively – was also found. Likewise, the reported spending by Centers for Medicare & Medicaid Services on Nuedexta increased from $3.9 million in 2011 to $200.4 million in 2016, the study found.

These results show that despite the fact that approval of Nuedexta by the FDA for pseudobulbar affect was based on studies conducted in patients with ALS or MS, the medicine appears to be primarily prescribed for elderly patients with dementia and/or Parkinson’s disease.

“Current therapies to treat behavioral symptoms of dementia are largely ineffective, and thus clinicians may want to prescribe dextromethorphan-quinidine to see if it helps their patients, despite the dearth of trial evidence on its efficacy in this context,” the researchers wrote. “Yet the absence of data showing efficacy, coupled with the demonstrated risks of falls and possible cardiac effects, calls this strategy into question.”

Similar to antipsychotics, Nuedexta is also being prescribed to a broader and older patient population than its preapproval study group, the researchers said. “[W]e found that it is being used in a population that is approximately 15 years older than those included in the main preapproval clinical trial (mean ages, 66.0 years compared with 52.0 years). Age is one of the strongest risk factors across all drugs for adverse drug events.”

In light of these findings, the researchers emphasized that further attention needs to be paid to educating physicians about the potential benefits and risks of this medication. They added that the FDA should be more closely monitoring the patient populations using a medication after its approval, and recommended further study of Nuedexta in people with Parkinson’s and dementia.

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Genetic Variant Predetermines Risk of Cognitive Decline in Parkinson’s, Research Suggests

genetic variant

Researchers have found that Parkinson’s patients whose cognitive ability is intact, but who have a specific genetic variant, have significantly less gray matter in the regions of their brain that are related to dementia.

The study with that finding, “Reduced gray matter volume in cognitively preserved COMT 158Val/Val Parkinson’s disease patients and its association with cognitive decline,” was published in Brain Imaging and Behavior.

Several mutations in the COMT gene have been associated with the risk of developing Parkinson’s disease. This gene provides instructions for making catechol-O-methyltransferase (COMT), an enzyme that helps break down certain chemical messengers like dopamine.

The most common alteration in the DNA sequence that makes up the COMT gene is the Val158Met mutation in which a valine (Val) is replaced by a methionine (Met) at position 158. Val and Met are both amino acids, also known as the protein’s building blocks.

Every individual has two copies of each gene, one inherited from each parent. Therefore, a person can have two Val’s in the same position at both COMT gene copies (also known as the Val/Val genotype), a Val in one gene and a Met in the other (Val/Met genotype), or two Met’s (Met/Met genotype). Scientists use the word “genotype” to describe a person’s genetic constitution.

Changes in COMT’s molecular structure, lead to high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzymatic activity.

The Val158Met mutation in the COMT gene has been associated with an increased risk of cognitive decline in Parkinson’s disease, particularly in people with greater COMT activity. When this happens, there is too much neurotransmitter degradation, thus leading to reduced levels of dopamine and affecting basic brain functions such as motor coordination and memory.

Evidence suggests a correlation between cognitive impairment, one of Parkinson’s non-motor features, and reduced gray matter volume.

The brain is composed of gray and white matter. The first consists of cell bodies — the control center of neurons — while the latter is made up of nerve cell projections, known as axons or fibers, connecting distinct parts of gray matter.

A Spanish team of researchers used magnetic resonance imaging (MRI), a non-invasive imaging technology, to investigate a possible structural brain compromise in Parkinson’s patients with highly active COMT activity that could explain their increased risk for subsequent cognitive impairment.

The study included 120 newly diagnosed Parkinson’s patients with normal cognition (who were not previously treated for the disease) and 48 healthy controls from the Parkinson’s Progression Markers Initiative database.

Results showed that there was a widespread, significant reduction in cerebral gray matter volume in patients with the Val/Val genotype. They observed alterations in the fronto-subcortical and posterior-cortical brain regions, where motor and cognitive functions originate.

Gray matter volume at some of the identified regions was associated with cognitive decline in a four-year follow-up period, suggesting that gray matter volume reduction during the early stages of disease predisposes Val/Val patients to cognitive impairment.

Nonetheless, gray matter volume analysis at one-year follow-up was not increased in Val/Val subjects, in comparison to Val/Met and Met/Met participants, indicating a somewhat stable atrophy in the Val/Val subset and that those brain changes might already be present prior to diagnosis.

The team believes their research “sparks the need to further characterize the association between a modified COMT enzymatic effect and a structural brain compromise in the early stages of [Parkinson’s disease].”

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Tangled Up with Dementia in Parkinson’s Disease

dementia

Sherri Journeying Through

A reader recently posed the following question: “Why are there never any comments on dementia in regards to Parkinson’s disease? It is very real, and 40 percent of Parkinson’s patients deal with it.”

So, I began looking into it. My answer could have been, “Because I don’t want to think about that stuff.”

The idea that this disease could dominate my mind (as opposed to taking over my “brain”), among the other things it’s already taken from me, is frightening. And it’s a real possibility.

It is estimated that 50 to 80 percent of people with Parkinson’s disease (PD) will develop dementia. It takes about 10 years from the onset of PD to develop dementia, according to the Alzheimer’s Association.

In those with PD dementia, “plaques” and “tangles” are present. Plaques (not the kind dentist removes from your teeth) are deposits of a type of protein that form around nerve cells. These little monsters begin to cling to one another and form clumps, plaques, which prevent nerve cells from sending messages to each other properly.

Tangles, not the kind you comb out of your hair, are formed of tau protein, found in nerve cells. They are either on their way or have made it to death row. They bunch together, twisting around each other and forming tangles of nerve cell fibers. While tangling up the parallel strands of tau protein nerve cells, they fall apart, disintegrate, and cripple the cells’ communication system.

While this is going on, unawares to the patient, the plaques and the tangles continue to gather inside of the brain, causing other nice and healthy nerve cells to eventually wither away and die a silent death, leading to shrinkage in the area of the brain in which these little monsters had their fun fest.

Plaques and tangles present further complications in people with Parkinson’s, as these are the hallmark brain changes linked to Alzheimer’s disease.

I warned you. I told you we didn’t want to think about this stuff. But, unfortunately, it’s a part of the reality of Parkinson’s disease we must be aware of, not so we can worry and fret, but so that we can receive treatment sooner rather than later.

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

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