Veterans with PTSD or Brain Injury at Risk of Sleep Disorder That Might Signal Parkinson’s, Study Finds

sleep disorders and vets

Military veterans with post-traumatic stress disorder (PTSD) or who experienced a traumatic brain injury have more than double the risk of a rare sleep disorder — called rapid eye movement (REM) sleep behavior disorder — previously reported as a risk factor for Parkinson’s disease, a study finds.

Researchers at the VA Portland Health Care System and Oregon Health and Science University, who were responsible for this study, are now planning to explore this association and the incidence of Parkinson’s among veterans with REM sleep behavior disorder (or RBD).

“This is important because, in the general population, RBD has been linked to Parkinson’s disease, and RBD often precedes classic symptoms of Parkinson’s by years,” Miranda Lim, MD, PhD, a staff physician at the VA and the study’s senior author, said in a news release.

The study, “Post-traumatic stress disorder increases odds of REM sleep behavior disorder and other parasomnias in Veterans with and without comorbid traumatic brain injury” was published in the journal SLEEP.

RBD is characterized by uncontrolled and violent arm and leg movements, and acting out dreams during sleep. This sleep disorder has been specifically linked to the development of synuclein-related diseases. RBD of no known cause, called idiopathic RBD, occurs in approximately 1% of the general population.

Previous studies suggest that people with RBD are at a greater risk of neurodegenerative disorders — such as Parkinson’s and dementia — with 6.25% of them acquiring an overt neurodegenerative disease within a mean period of 4.6 years. The risk of developing such diseases was also found to progressively increase, from 10.6% after two years to 73.5% after 12 years.

Veterans are at a particularly high risk of traumatic brain injury (TBI) and PTSD, and as such represent a “population enriched for a history of trauma.” Concussions and other mild brain injuries, which many experience during their military service, are also linked to an increased Parkinson’s risk. One study reported that veterans with any kind of traumatic brain injury had a 71% higher likelihood of Parkinson’s than other vets.

Researchers now evaluated veterans’ sleeping patterns according to their pre-existing history of brain injury or other neuropsychiatric trauma, investigating the prevalence of RBD in 394 veterans —mainly male (94%) and middle-aged (54.4 years) — and its association with TBI and PTSD.

Analysis of veterans’ sleep patterns, based on the electrical activity in muscles, found that 9% of them experienced RBD, 7% had higher muscle tone during REM or deep sleep — a condition known as REM sleep without atonia — and 31% had other sleeping problems (parasomnias). This suggested that RBD is considerably more common in veterans than the general population.

They found that veterans with a brain injury or PTSD had a higher incidence of parasomnias. In particular, among those with PTSD or PTSD plus brain injury only 32% and 20% had normal sleeping behaviors, while 56% of these people experienced REM sleep behavior disorder.

Overall, veterans with PTSD had 2.81 and 3.13 times higher odds of RBD and other parasomnias, while those with PTSD plus TBI had 3.43 and 3.22 times higher odds of RBD or other parasomnias.

Given the strong association between RBD and progressive neurodegenerative disorders, it remains to be determined whether RBD and neuropsychiatric symptoms “increases the risk of similar long-term neurologic sequelae [consequences],” the researchers wrote.

“We don’t know whether veterans who have PTSD and higher rates of RBD will go on to develop Parkinson’s, but it is an important question we need to answer,” Lim said. “If you could intervene when people first start to show RBD, maybe you could prevent later symptoms of Parkinson’s.”

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Nuplazid Eases Depression in Parkinson’s Patients, Phase 2 Trial Shows


Treatment with Nuplazid (pimavanserin), approved in the U.S. for treating hallucinations and delusions associated with Parkinson’s psychosis, eased depression and sleep problems in patients with Parkinson’s, according to results from a Phase 2 clinical trial.

The research, “Open-Label Study of Pimavanserin Patients With Comorbid Parkinson’s Disease and Depression,” was presented at the 2019 International Congress of Parkinson’s Disease and Movement Disorders in Nice, France.

Depression is one of the most frequent non-motor symptoms of Parkinson’s. While its severity and duration typically increase with disease progression, easing depression has been linked with greater quality of life and less disability.

An eight-week, open-label, study (NCT03482882) assessed Acadia Pharmaceuticals’ Nuplazid either as a stand-alone therapy, or as an add-on to a selective serotonin reuptake inhibitor (SSRI, a type of antidepressant) or a selective norepinephrine reuptake inhibitor (SNRI) for Parkinson’s patients with depressive symptoms. The 47 participants, all 50 or older, received two 17 mg oral tablets per day of Nuplazid.

Nuplazid is a selective serotonin inverse agonist that targets serotonin receptors called 5HT2A receptors. Inverse agonists bind to the same receptors as agonists, but induce the opposite pharmacological response. Serotonin receptors are found throughout the nervous system. Specifically, 5HT2A has been associated with mental disorders such as depression and epilepsy.

The results found significant benefits as early as week 2 assessed with the 17-item Hamilton Depression Rating Scale (HAMD-17) — the study’s primary goal. At week 8, 60% of the participants showed an improvement of at least 50% on the HAMD-17 score, with 44.4% of patients reaching remission (HAMD-17 score up to 7).

The study also showed improvements on the Clinical Global Impression-Severity scale (a measure of disease severity) and the Clinical Global Impression-Improvement — a 0.5 lower score from week 2 to week 8, as rated by clinicians.

Sleep measures, namely the SCOPA-nighttime sleep and SCOPA-daytime sleepiness scales, also revealed benefits from week 4 to week 8. Likewise, the SCOPA-Global Sleep Quality scale showed significant improvements comparing week 8 to baseline.

“Results of this open-label study suggest that pimavanserin may be a potential treatment to be further investigated for depression associated with Parkinson’s,” Gus Alva, MD, a co-author of the study, and founder and medical director of ATP Clinical Research, said in a press release.

Treatment with Nuplazid was well-tolerated, with treatment emergent adverse events (TEAE) being in line with other studies of this therapy. Reported TEAEs included falls (8.5%), nausea (6.4%), diarrhea (4.3%), edema, or swelling (4.3%), skin abrasion (4.3%), and urinary tract infection (4%).

“Pimavanserin [Nuplazid] as adjunctive or monotherapy is associated with early sustained improvement of depressive symptoms in patients with [Parkinson’s] and is well tolerated,” the scientists wrote.

“We are pleased with the exploratory study results which show a positive treatment effect with pimavanserin [Nuplazid] for depression in patients with Parkinson’s,” said Serge Stankovic, MD, Acadia’s president.

Stankovic commented that the results are consistent with those of the 10-week CLARITY Phase 2 study (NCT03018340). Using Nuplazid as an add-on led to improved HAMD-17 scores, while also easing disability and sleepiness,  and improving sexual function in patients with major depressive disorder with inadequate response to standard SSRI/SNRI treatments.

Nuplazid is currently being tested in two six-week Phase 3 studies named CLARITY-2 (NCT03968159) and CLARITY-3 (NCT03999918), each with approximately 280 patients. Patients who complete these trials will be able to participate in a 52-week open-label extension study (NCT04000009) to assess long-term safety and tolerability. These three studies are currently enrolling. (For more information, follow the links on the NCT identifiers.)

“We are committed to continued research for pimavanserin [Nuplazis] to address unmet medical needs in central nervous system disorders, including our ongoing Phase 3 clinical program in major depressive disorder,” Stankovic said.

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Early Involvement of Caudate Brain Region Linked to Worse Prognosis in Parkinson’s Patients, Study Finds

caudate involvement

Almost half of people in the early stages of Parkinson’s disease already have signs of neurodegeneration in a brain region called the caudate, which was previously thought to affect mostly those at advanced disease stages, a study reports.

Early caudate involvement on both sides of the brain, as seen by DaTscan imaging of the brain, appeared to predict the risk for worse outcomes, including cognitive impairment, depression, and gait problems, over a four-year follow-up period.

These findings suggest that caudate involvement detected through DaTscan neuroimaging may serve as an early biomarker to identify patients at a greater risk of faster disease progression in the near future.

The study, “Clinical implications of early caudate dysfunction in Parkinson’s disease,” was published in the Journal of Neurology, Neurosurgery & Psychiatry.

Parkinson’s disease is believed to be caused by the impairment or death of dopamine-producing nerve cells (neurons) in a region of the brain called the substantia nigra, which controls the body’s balance and movement.

When the disease is established, or advanced, the degeneration of dopaminergic neurons and nerve fibers frequently extends to a brain region called the caudate nucleus. This region plays important roles in motor control as well as in various other non-motor tasks, such as learning and sleep.

In fact, the loss of dopaminergic function in this region is known to contribute to the hallmark symptoms of Parkinson’s including cognitive impairment, depression, sleep disorders, and gait problems.

Although less common, caudate dopaminergic dysfunction may also emerge in the early stages of the disease, in which case it could also contribute to the onset of non-motor symptoms. However, the frequency of this specific brain impairment in early Parkinson’s is unknown as are its clinical implications for patients.

To address this lack of knowledge, a team, led by researchers at the University of Milan in Italy and Newcastle University in England, investigated the prevalence of caudate dopaminergic dysfunction in people who were still in the very early stages of Parkinson’s.

By comparing the participants’ state at the beginning of the study and four years later, they also looked for associations between caudate involvement and an increased risk of disease progression.

They analyzed clinical data from 397 patients who had had a Parkinson’s diagnosis for two years or less, and were participating in the Parkinson’s Progression Markers Initiative (PPMI), an ongoing study attempting to identify biomarkers of disease progression. The team compared the collected clinical data from Parkinson’s patients with that of 177 healthy volunteers.

Caudate dysfunction was detected using 123I-FP-CIT single-photon emission computed tomography, commonly known as DaTscan. This is an imaging technique that depicts the levels of dopamine transporters in the brain that is often used to confirm a Parkinson’s diagnosis.

Based on DaTscan imaging data, the participants were divided into three groups: those who had no reduction of dopamine transporters, those who showed reduction in just one side of the brain, and those who had involvement of both sides of the brain.

Initial data showed that 51.6% of the patients had signs of normal caudate dopamine function, while 26% had caudate dopaminergic dysfunction on one side of the brain (unilateral), and 22.4% on both sides (bilateral).

Four years later, the patients who initially had bilateral caudate involvement were found to experience more frequent and worse cognitive impairment and depression, and more severe gait disability.

In general, after four years of follow-up, more patients showed a loss of dopaminergic nerve fibers in the caudate, compared with the study start, affecting 83.9% of patients (unilateral 22.5%, bilateral 61.4%).

“In this study, we have demonstrated a high frequency of early caudate dopaminergic dysfunction in patients with recently diagnosed [Parkinson’s disease],” the researchers wrote.

“Our study suggests that early bilateral caudate dopaminergic dysfunction is associated with an increased frequency of clinically significant depression and to worse depressive symptoms, regardless of age,” they added.

DaTscan parameters used to define the presence of early caudate dysfunction may be a “valid indicator of more rapid onset of such symptoms,” they said, which may help in “identifying patients at risk of clinical progression to cognitive impairment, depression, and gait problems in the near future.”

Assessment of caudate dopaminergic denervation may also assist clinicians in better predicting disease course at an early stage and identifying patients who may benefit the most from early, targeted disease-modifying therapies.

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Parkinson’s Patients with Diabetes at Higher Risk of Impulse Control Disorders, Other Issues, Study Suggests

diabetes, Parkinson's

Untreated Parkinson’s patients who also have type 2 diabetes mellitus may be at a higher risk of developing impulse control disorders, severe depression, apathy, and sleep problems, research suggests.

The study, “Preexisting Diabetes Mellitus is Associated with More Frequent Depression and Impulse Control Disorders in Drug Naïve Parkinson’s Disease” will be presented during the 14th​ International Conference on Alzheimer’s and Parkinson’s Diseases and related neurological disorders March 26-31 in Lisbon, Portugal.

Higher doses of dopamine agonists — which act as a substitute for (or mimic) dopamine in the brain — and longer treatment periods have been seen to make Parkinson’s patients more prone to developing impulse control disorders, including gambling, compulsive shopping, over-eating, and compulsive sexual behaviors.

Evidence indicates that type 2 diabetes increases the risk of developing Parkinson’s disease. Interestingly, an association among type 2 diabetes, depression, and impulse control behaviors has also been suggested.

Researchers from the University of Pécs in Hungary sought to study the impact of pre-existing type 2 diabetes mellitus on Parkinson’s-related non-motor symptoms and on impulse control behaviors in people with Parkinson’s not yet taking prescribed antiparkinsonian medications.

The team performed detailed neurological and neuropsychological examinations on 299 newly diagnosed Parkinson’s patients who were not on any medication.

Of these Parkinson’s patients, 77 (25.8%) had pre-existing type 2 diabetes. Diabetic Parkinson’s patients were older, heavier (with a higher body mass index) and included more men. Importantly, and in comparison to non-diabetic Parkinson’s patients, diabetic patients had more severe depression, apathy, sleep problems and more severe non-motor symptoms, measured by the Non-Motor-Experiences of Daily Living part of the Movement Disorders Society-sponsored Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) and the Non-motor Symptoms Scale.

Scientists also reported that 40.3% of Parkinson’s patients with diabetes had impulse control behaviors, which was significantly different from the 22.3% observed in the non-diabetic sample.

Untreated Parkinson’s patients with diabetes were 3.58 times more likely to have impulse control disorders. Due to this, type 2 diabetes mellitus was considered to be an independent predicting factor for the development of these behavior disorders.

Preexisting diabetes may be a risk factor for more frequent impulse control disorders and more frequent and more severe depression, apathy and sleep problems in drug naïve PD patients. However, further prospective longitudinal studies are warranted to study its effects on the disease course,” the researchers concluded.

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Human Clock-swapping: The Good, the Bad, and the Ugly

Graphics by Dr. C
I hate the bad days, and what I have to say about the ugly ones is not fit for print. But the good days — well, they are delightful. I write these columns during those times.
It’s not about “Jekyll and Hyde” mood swings, but about days where the PD symptoms present themselves as only a minor problem (the good), days when it’s a struggle to function well (the bad), and then days when the symptoms are the most disabling (the ugly). There may be a cyclicity to the good, the bad, and the ugly (see diagram, below). John D. Palmer, author of “The Living Clock,” writes about this cyclicity, saying that we are all governed by a human clock.
(Graphic by Dr. C)
Sleep is governed by the human clock, and sleep disturbances are common with PD. Having the strong desire to go to bed when the sun is shining, and to stay awake when it is not, is the human clock swapping day for night. Think of a serious case of jet lag. But it is not just the sleep cycle function of the human clock that is swapped. With PD, there are many human biological cycles in which the normal is swapped for the abnormal.
I used to get up in the morning, jump right into projects, and go all day (16 hours). This energy helped me get four college diplomas. This is no longer the case. Those days have been swapped out for a daily cycle of times when the body and mind are available, and times when they are not (off-periods). Each day has at least three off-periods, with the one in the evening being the worst. Then, there are bad days when the off-periods are longer and more intense. In the middle of these bad days, there will be some time when it’s just plain ugly and I am bedridden. The normal human cycle of daily life has been swapped out for this PD cycle of the good, the bad, and the ugly.
Charting aspects of how PD is experienced, using a numerical scale from 1 to 10, and putting that on a calendar each day can be quite useful in getting to know your personal cycles. You can chart pain, fatigue, tremors, or any other symptom that is significantly interfering with your quality of life.
Charting can also help you to become more aware, and maybe even get to the point in which you can say to your partner “it feels like a bad day is right around the corner,” or “today is a level 5 day.” The other piece of information that comes from charting is an idea of how long it will be until the good days return. They do return, and it helps to have an idea of when that will be when you’re in the middle of the torture that accompanies the bad and the ugly days.
Communication about the good, bad, and ugly days is important for healthy relationships with family and

Source: Parkinson's News Today