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Updated Canadian Guideline Reflects Latest Advances and Adds Palliative Care Section

Canadian Guideline Parkinson's

Updated recommendations on Parkinson’s disease have been published in the Canadian Guideline for Parkinson Disease, which includes a new section about palliative care.

Focused on issues relevant to the Canadian healthcare system, the update reflects the latest evidence and advances — particularly regarding diagnostic criteria and treatment options — and draws on recommendations from the United States, Scotland, the United Kingdom, and the European Union.

The Parkinson Canada-funded publication, which was published in the Canadian Medical Association Journal, offers fundamental guidance to healthcare professionals, patients, and families, and was developed with help from experts in Canada from various disciplines.

“This guideline provides evidence-based recommendations to improve the overall standard of care of individuals with Parkinson disease in Canada, not only for healthcare professionals, but also for policy makers, patients themselves, and their caregivers,” Veronica Bruno, MD, a neurologist with a subspecialty in movement disorders at the University of Calgary, said in a news release. “Managing the complexity of Parkinson disease requires clear, standardized procedures that can be used by all actors involved.”

The new guideline has five sections: communication, diagnosis and progression, treatment, non-motor features, and palliative care, which was added in this update. Palliative care, including an option of medically assisted death, should be considered throughout the course of the disease, the publication states.

“End-of-life choices, including advanced care planning with an open and frank discussion with the patient and the person designated as decision-maker, should be initiated early in the disease process,” the guideline says. “Conversations occurring in the ambulatory setting are likely to be more productive and less crises-driven than leaving such conversations until an acute stay in hospital.”

Other highlights include:

“A limitation to implementing the guideline is the lack of access to health care providers experienced in caring for people with Parkinson disease,” David Grimes, a neurologist at The Ottawa Hospital, said.

“In addition to specialist physicians, we need more nurses, and speech, occupational and physical therapists with training in this area, as well as adequate palliative care for Parkinson patients,” he added.

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Deep Brain Stimulation Eases Parkinson’s Symptoms by Directly Raising Dopamine Levels, Study Suggests

deep brain stimulation study

Deep brain stimulation (DBS) eases tremors and muscle rigidity, and improves cognition and mood in Parkinson’s patients by raising dopamine levels in the brain, a small study from Johns Hopkins Medicine suggests.

The research, “Effect of STN DBS on vesicular monoamine transporter 2 and glucose metabolism in Parkinson’s disease,” was published in the journal Parkinsonism and Related Disorders.

DBS is given to Parkinson’s patients whose motor symptoms do not respond well to medication. In this procedure, fine wires are inserted into the brain and connected to an electrical current source to stimulate areas responsible for movement control, such as the subthalamic nucleus (STN).

But the processes through which DBS changes brain activity are not completely understood.

Studies using positron emission tomography (PET) imaging indicate that brain metabolism is altered but dopamine levels unchanged after DBS. Still, the vast network linking dopamine-producing neurons to various brain regions suggested to the Hopkins team that this chemical messenger could still be a key part in the efficacy of DBS.

“Even if dopamine-producing cells are not activated directly, electrically stimulating other parts of the brain, particularly those that receive information from dopamine-producing cells, can indirectly increase dopamine production,” Kelly Mills, MD, a study co-author, said in a news release written by Vandana Suresh.

Specifically, the investigators focused on a protein called vesicular monoamine transporter (VMAT2), which regulates dopamine packaging into tiny vesicles and its subsequent release into the synapse, the site where two nerve cells communicate. Using PET scans, prior research confirmed that increases in brain dopamine levels with levodopa — a mainstay of Parkinson’s treatment — are associated with decreases in the amount of VMAT2, and vice versa.

The team used a tracer for VMAT2 and another for glucose, intended to track changes in brain activity. Among the seven patients (mean age of 67, range 60–74; all white), four were men and three were women.

Besides PET scans taken before and four-to-six months after DBS targeting of the subthalamic nucleus, these patients also underwent motor function evaluations with the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale, psychological assessments — such as the Hamilton Depression Rating Scale and the Neuropsychiatric Inventory — and cognitive tests.

Results revealed that DBS led to significantly fewer tremors and, to a lesser extent, lesser muscle rigidity. Other benefits included improvements in cognitive function and mood, with depression scores lowering as much as 40%.

Suggesting higher amounts of dopamine, all seven patients showed lower levels of VMAT2 after DBS in the caudate and the putamen — two brain areas important to motor control — and in the brain’s cortical and limbic regions, which are implicated in movement, mood, and cognition.

Glucose metabolism was also lower in the striatum — which includes the caudate and the putamen — and higher in cortical areas and the cerebellum, which has a major role in motor coordination, balance, and speech. Of note, the striatum is a key component of the motor and reward systems of the brain.

The data further demonstrated that lower VMAT2 levels were associated with eased tremors and lesser depressive symptoms. They also correlated with decreased striatal, and increased cortical and limbic, metabolism.

Overall, the correlation between VMAT2 and glucose PET scans suggest that having more dopamine may be central to the restored brain activity achieved with DBS, Mills said.

Shifting the approach taken to track dopamine was key for these findings, the scientist added. “Rather than looking at the amount of dopamine bound on receptors of dopamine-receiving cells, we looked at VMAT2 concentrations within dopamine-producing cells, which may be more sensitive to detecting changes in dopamine with deep brain stimulation,” she said.

Gwenn Smith, PhD, the study’s lead author, added: “Our study is the first to show in human subjects with Parkinson’s disease that deep brain stimulation may increase dopamine levels in the brain, which could be part of the reason why these people experience an improvement in their symptoms.”

Although cautioning that larger studies are needed to more effectively gain from DBS use, likely by determining better targets for stimulation, the scientists added that a deeper understanding of how this procedure works in Parkinson’s “will inform [the] development of more effective treatments, treatment response predictors and ultimately, will have implications for improving the clinical care” of people with Parkinson’s, depression and Alzheimer’s.

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Coupling of Brain Electrical Signals May Be Parkinson’s Biomarker, Way to Improve Deep Brain Stimulation, Study Suggests

cross-frequency coupling electrical signals

The coupling of electrical signals in the brain — as it responds to levodopa and is associated with motor improvements — may provide ways to better assess the clinical state of people with Parkinson’s disease, and improve the efficacy of deep brain stimulation (DBS), according to new research.

The researchers say coupling patterns may enable broader insight into Parkinson’s, and have potential use as a biomarker.

The study, “Distinct subthalamic coupling in the ON state describes motor performance in Parkinson’s disease,” appeared in the journal Movement Disorders.

The human brain displays repetitive patterns of neural activity, or electrical pulses, due to the communication between brain nerve cells (neurons). These are called brainwaves.

Measuring a type of electrical pulses called local field potentials (LFPs) from the subthalamic nucleus (STN) — a brain region hyperactive in Parkinson’s patients — has shown the existence of frequency bands, or wave oscillations, that correlate with motor impairment and respond to medication.

The interactions between high- and low-frequency brain waves — cross-frequency coupling — also has been increasingly studied. This is particularly evident in unmedicated patients. Yet, what these interactions mean is still scarcely understood.

A team at the University of Houston addressed how these bands are changed by medication, as well as their coupling, via a 24-hour monitoring period that included three trials. Those trials involved nine people (seven men, ages 39-70 years) with idiopathic Parkinson’s, meaning the disease with no known cause. The participants underwent local field potential recording three weeks after deep brain stimulation of the subthalamic nucleus. The recordings were then correlated with motor improvements over three treatment cycles.

Clinical and behavioral assessments were made within 30 minutes prior to taking levodopa, which controls Parkinson’s symptoms. Similar evaluations were then done within 30 minutes after the participants said they felt the medication kicking in, in terms of motor function (verbal on state).

Specifically, the clinicians used the Unified Parkinson’s Disease Rating Scale to assess numerous symptoms: hand and foot tremors (item 20); upper and lower extremity rigidity (item 22); and finger tapping, hand open and close, hand pronation and supination — which means flipping the palm face up or face down — and leg agility (items 23–26).

A computer-based task also was used, with a keyboard. Participants had to press the left and right arrow keys sequentially and as fast as possible, for 30 seconds, using the index and middle fingers. The total number of keypresses was then analyzed.

The results showed that bradykinesia — slowness of movement — and keyboard scores differed between “off” and “on” states, meaning the periods before and after taking levodopa and regaining motor control. However, these responses did not correlate in all patients. Two patients showed eased bradykinesia yet minimal-to-no improvement in the performance of the keyboard task.

The data also showed distinct peaks across different bands. In the off state, the activity of low-beta (13-22Hz) and high-frequency oscillations (200-300Hz) was higher than normal. It was either suppressed, or shifted to a different frequency, after taking levodopa. Among other findings, six patients also showed a peak in the gamma range (50–200 Hz).

The investigators also found that, in the off state, the amplitude or signal strength of high-frequency oscillations was coupled with a specific parameter — called phase — of low-beta bands in all participants.

After the transition to the on state, this coupling shifted to a different subset of beta bands (22-30Hz) and high-frequency oscillations (300-400Hz). It also was linked with more pronounced improvements in the keyboard task scores. Only two patients failed to show this coupling after taking levodopa. That could be due to suboptimal dose, the team said.

Overall, the findings show that cross frequency coupling also exists in treated patients. “So in effect we have ‘cleared coupling’s name’ and showed the frequencies involved in coupling impacts whether its effects are negative or positive,” Musa Ozturk, the study’s lead author, said in a press release.

“Together with the differences in the ON-state coupling according to the degree of motor improvement, our observations suggest that [cross-frequency coupling] patterns provide a broader insight into [Parkinson’s], and have potential utility as a biomarker for the clinical state of patients,” the researchers said.

One potential application is deep brain stimulation.

“We can now make the closed-loop stimulator adaptive to sense a patient’s symptoms, so it can make the adjustments to the fluctuations in real time, and the patient no longer has to wait for weeks or months until the doctor can adjust the device,” said Nuri Ince, PhD, the study’s senior author.

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Ignorance vs. Grace: How Do We Deal with People Who Disappoint?

Journeying Through Parkinson's

I have Parkinson’s disease, but unless you have a good eye and a good listening ear, most days you won’t notice. On most days, my symptoms are internal. Occasionally, such as when I have forgotten to take my medications, I will have breakthrough tremors. And when my deep brain stimulation needs adjusting, I may present other external symptoms. Unless you know I have Parkinson’s, you may not understand the significance of these symptoms.

To some people, it doesn’t matter what I have.

Two nights ago, I broke my little toe. It always amazes me how much pain can be associated with something so small, such as a tiny splinter in your finger or a grain of sand in your eye. Careless words spoken in ignorance are painful, too. We’ve all said them (at least in our head) and heard them spoken to us at some point in our lives.

Yesterday, I went to Costco to pick up my prescription from the pharmacy.

I wasn’t quite “on,” having run out of one of my prescriptions the previous day. I walked to the back of the store, paid for my medication, then headed to the exit. As I was walking toward the door (not very fast, given the pain in my foot), I heard a woman’s voice behind me comment rather loudly, “If this woman would ever get out of the way, we might actually get out the door.” 

I wasn’t trying to go slow. I wasn’t trying to be an annoyance in her day. However, between dealing with my “on time” turning into an “off time” and my foot throbbing, I wasn’t capable of hurrying. 

It wasn’t until I had gone through the door — not at a snail’s pace, but not feeling as though I was in a race — that the guy who was with the snooty woman decided to be snooty, as well.

“People like that shouldn’t be in places like this,” he said. “They just take up space and make it miserable for the rest of us who have things to do.”

Ouch.

After gaining his coveted lead to get to his car, he glanced back at me and shook his head. He also continued his rant so that I could hear him. 

Shaking the head expresses shame. It represents disappointment and failure. At that moment, I felt it all.

I’ve made ignorant remarks. I’ve even shaken my head at someone for not measuring up to my standards.

Shame on me. 

We all need a refresher course in grace, a reminder that things are not always what they seem. Sometimes, we can’t see the underlying condition that causes the person in front of us in the checkout line to go so slower than we would like. Sometimes, we can’t see what is keeping them back from being able to run through the exit at Costco: a broken toe, Parkinson’s disease, a splinter.

Grace has been extended to us at times so that we can, in turn, extend it to others, and I would rather hand out grace than ignorance anytime.

***

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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Delays in Parkinson’s Treatment Due to Fear of Side Effects a Serious Problem, Neurologist Says

delays in treatments

A fear of the potential side effects of Parkinson’s disease treatments, dubbed “levodopa phobia,” can cause patients and their doctors to delay the use of these therapies, a neurologist says.

However, evidence suggests that starting adequate levodopa therapy early is safe, particularly for patients with increased functional disability, according to a lecture by Joseph Jankovic, MD, a professor of neurology at Baylor College of Medicine, which was presented by the Parkinson Voice Project (PVP.)

Jankovic’s lecture, “New and Emerging Treatments for Parkinson’s Disease,” was presented to patients and caregivers via Skype as part of the PVP’s Parkinson’s Lecture Series, from the Clark and Brigid Lund Parkinson’s Education Center. A video of the presentation is available online.

Disease-modifying therapies

There are no therapies currently available that slow or prevent the progression of Parkinson’s, though several are in clinical trials. A Phase 3 trial (NCT00256204), called ADAGIO, completed in 2011, suggested that early Azilect (rasagiline) treatment might be able to delay the progression of the disease. However, the study included two dosages, 1 mg and 2 mg, and while the benefits were true for the the lowest dose, they didn’t hold up for the larger dose. Because the two doses were associated with different outcomes, the results needed careful interpretation, and the U.S. Food and Drug Administration (FDA) did not approve Azilect as a disease-modifying therapy. 

Researchers are exploring several treatments with the potential to modify the disease, including inosine (which elevates urate levels), and isradipine (a calcium channel inhibitor). Both are in Phase 3 trials (NCT02642393 and NCT02168842).

However, Jankovic said, the “most important strategy in development” is reducing alpha-synuclein, the protein that doesn’t work properly and accumulates in the brains of Parkinson’s patients, leading to neuronal death.

Jankovic and his colleagues last year published a study based on a Phase 2 trial  (NCT03100149) of an antibody — prasinezumab (PRX002/RG7935) — that’s designed to clear alpha-synuclein proteins. The 80-patient, ascending-dose study showed that the treatment was safe, and reduced alpha-synuclein concentrations in the blood over the course of 52 weeks, with no serious adverse events reported. The study supported the continuation of the Phase 2 trial.

Similar antibodies currently being tested in trials include Biogen’s BIIB054 (NCT03318523), AstraZeneca’s MEDI1341 (NCT03272165) — both currently recruiting — and AbbVie’s ABBV-951 (NCT03781167), which is not yet enrolling participants.

Early symptomatic therapies

When patients first start to experience symptoms severe enough to require treatment, they and their doctors may be reluctant to start levodopa or levodopa-carbidopa — the most commonly used treatment for Parkinson’s symptoms — for fear they will develop motor complications such as dyskinesias.

Some patients may turn to natural supplements, such as bacopa extract or mucuna pruriens. Jankovic “strongly discouraged” the use of these products for “many, many reasons,” chief among them that some supplements contain levodopa at inconsistent doses.

An alternative for patients and neurologists concerned about starting levodopa too early are dopamine agonists such as Mirapex (pramipexole), Requip (ropinirole), Dostinex (cabergoline), and Permax (pergolide). Instead of helping the brain produce more of the dopamine it lacks, these treatments directly stimulate the receptors that dopamine would normally act on.

A 2009 study, which compared pramipexole with levodopa in patients who had not yet been treated with levodopa, found that 50% of those on pramipexole experienced dyskinesia, compared with 68.4% of the levodopa patients.

“There is no doubt that delaying levodopa therapy by using dopamine agonists early may delay the onset of levodopa-related motor complications,” Jankovic said.

Although levodopa has some potential for side effects in vitro (or in the laboratory), Jankovic said there is no evidence that this translates to patients. Therefore, delaying the use of the therapy, particularly for patients with increased functional disability, is not backed by currently available scientific data, he said.

However, he believes that because every patient is different, the timing, choice, and dosage of therapy must be individualized according to the needs of each particular patient.

Emerging and experimental therapeutics

Almost all patients with severe Parkinson’s who take levodopa or levodopa-carbidopa will, over time, experience motor fluctuations and dyskinesias. Thus, many emerging therapies are designed to make the treatment more effective and reduce the side effects.

There are three therapies work to extend the effectiveness of levodopa by maintaining increased dopamine concentrations in the brain. Xadago (safinamide) inhibits monoamine oxidase, an enzyme that normally breaks down dopamine. Opicapone works by preventing a different enzyme, catechol-O-methyltransferase (COMT), from breaking down dopamine. Gocovri (amandine) prevents cells from recycling dopamine.

Several new formulations of levodopa are intended to stretch the effects of a single dose, or act almost immediately to help patients recover from “off” episodes between doses.  

Rytary, a capsule that can be taken orally, contains beads of carbidopa-levodopa that dissolve and release the medicine at different times. Since the treatment needs to be taken more than once a day, patients end up ingesting a higher dose of levodopa than they would otherwise. But the effects start sooner and last longer than the common formulation of carbidopa-levodopa.

Researchers have experimented with administering the treatment continuously for 24 hours using an intestinal gel, which is surgically implanted into the small intestine and programmed to consistently administer the treatment at the appropriate dose.

But choosing this surgery “cannot be taken lightly,” Jankovic said. While patients did increase their “on” time without dyskinesia (by 4.11 hours for those who used the intestinal gel compared with 2.24 hours for those who used oral levodopa), almost all of the 66 patients in a 2014 study experienced gastrointestinal side effects as a result of the device insertion.

Jankovic also described the “accordion” pill currently being tested in a Phase 3 trial (NCT02605434). The pill, developed by Intec Pharma, is a multilayer film that unfolds in the stomach and stays there for 12 hours, releasing a combination of levodopa and carbidopa.

Rather than extending the life of a dose of levodopa, some companies develop “rescue therapies” that can be taken during “off” periods, or when treatment wears off. These therapies take effect almost immediately, and help the patient make it until their next scheduled dose of levodopa. Several forms — both approved and in trials — are dopamine agonists injected under the skin.

Other companies are developing dopamine agonists they hope will be delivered through less invasive methods, such as under the tongue, in the case of APL-130277, or through inhalation, like Inbrija.

Surgical therapies are gaining more attention, with scientists testing focused ultrasound, which was approved by the FDA at the end of 2018. However, it is available in very few centers, and costs more than $4 million.

Also during 2018, researchers conducted a pilot study of five patients suggesting that spinal cord stimulation may be able to help patients improve gait.

Jankovic says it is too early to meaningfully discuss several other experimental therapies, such as gene therapies or stem cell treatments. “Ask me in 10 years,” he said.

Different agents are being investigated to treat non-motor symptoms, including Exelon (rivastigmine) and memantine (sold under the brand name Namenda, among others) for cognitive impairment, paroxetine and venlafaxine for depression, and SEP-363856 for psychosis. Nuplazid (pimavanserin) is the only therapy currently approved by the FDA for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis.

In addition to all the therapies on the market, Jankovic said, he “couldn’t emphasize enough the importance of physiotherapy,” and high-intensity exercise — “something that really makes you huff and puff.”

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Parkinson’s Patients with Poorer Quality of Life May Benefit the Most from Deep Brain Stimulation, Study Finds

dbs oucome quality of life

Individuals with Parkinon’s disease who have worse quality of life due to their disease-related impairments may benefit most from treatment with deep-brain stimulation.

The study with that finding, “Quality of life predicts outcome of deep brain stimulation in early Parkinson disease,” was published by the journal Neurology.

Deep-brain stimulation (DBS) is an invasive surgical technique in which thin wires are implanted in the brain to deliver electric pulses to specific areas, such as the subthalamic nucleus (STN), to ease motor symptoms in patients for whom standard medications are not effective.

Studies have shown that DBS can effectively help manage motor symptoms and reduce the necessary daily dose of medication, improving quality of life in those with advanced or early-stage Parkinson’s.

In a previous Phase 4 clinical trial (NCT00354133) called the EARLYSTIM study, researchers evaluated the long-term impact of STN-DBS as an add-on to best medical treatment regarding quality of life in patients with Parkinson’s disease for a period of more than two years.

The study enrolled patients younger than 61 who had a good response to levodopa therapy, but who still had developed motor complications. Among the participants, 124 were treated with DBS-STN and best medical treatment, while 127 patients received the best medical treatment only.

In the most recent study researchers reviewed the trial data to understand which factors contributed to the detectable changes in disease-specific quality of life, as measured using the 39-item Parkinson’s Disease Questionnaire summary index (PDQ-39-SI). The self-reported questionnaire assesses Parkinson’s-specific health across eight quality-of-life dimensions.

The analysis revealed that quality of life over the two years of follow-up correlated with the initial value of the PDQ-39-SI in both treatment groups. Still, this association was more pronounced among patients who were treated with STN-DBS.

Patients with very mild impairment due to Parkinson’s, corresponding to PDQ-39-SI values lower than 15, were found not to benefit from STN-DBS as compared to patients treated with standard care alone. In contrast, patients treated with STN-DBS who had PDQ-39-SI sores higher than 15 (worse quality of life) at the beginning of the study experienced better quality of life changes.

“In patients with very low baseline ratings on the PDQ-39-SI, the natural progression of impairment of [quality of life] may outweigh the improvement achieved by STN-DBS,” researchers wrote. “On the other hand, some patients with very modest impairment of their [quality of life] seem to have less to gain from STN-DBS,” they added.

Patients’ cognitive status before the treatment, as determined by the Mattis Dementia Rating Scale (MDRS), was not predictive of change in quality of life in either treatment group. However, higher scores for depression and poorer mood correlated with larger improvements in quality of life among patients in the STN-DBS group.

These findings “may indicate that these patients have a potential for nonmotor improvement to gain from surgery,” researchers suggested.

Changes in quality of life during the two years of follow-up were independent of patient age, disease duration, duration of motor complications, severity of parkinsonian motor manifestation under levopoda therapy, or treatment complications.

Supported by these findings, the team believes that “baseline impairment of quality of life is (…) a reasonable aspect to consider for the decision to treat with STN-DBS.”

“The subjective individual suffering as measured with the PDQ-39-SI should be taken into account as a predictive factor for outcome when selecting patients with early motor complications for STN-DBS,” researchers concluded.

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Deep-brain Stimulation Can Reverse Mitochondria Defects Linked to PD, Study Finds

DBS mitochondria

 

Deep brain stimulation therapy can help lessen Parkinson’s symptoms, partly by increasing the number of mitochondria — cells’ powerhouses — in brain nerve cells, a study shows.

The study, “Post mortem examination of Parkinson’s disease brains suggests decline in mitochondrial biomass, reversed by deep brain stimulation of subthalamic nucleus,” was published in The FASEB Journal.

DBS is an invasive technique in which thin wires are surgically implanted into the brain to deliver electric pulses to specific brain areas and ease motor symptoms, such as tremors, in patients for whom standard medications are not effective.

Studies have shown that DBS can effectively reduce motor symptoms and the necessary daily dose of medication, improving quality of life both in patients with advanced Parkinson’s and those  with early-stage disease.

However, despite being the most commonly used surgical treatment for Parkinson’s disease, the exact mechanisms through which DBS may work to help prevent nerve cells’ degeneration remain elusive.

Now, researchers at the Imperial College London analyzed brain cells collected from individuals with Parkinson’s disease who had either received DBS (three patients) or not (four patients), as well as from three healthy individuals. All the tissue samples were collected post mortem and had been stored at the Parkinson’s UK Brain Bank, at the Imperial College London.

The team found that Parkinson’s-affected brain cells had fewer mitochondria compared to healthy ones. Also, the mitochondria were not located inside the cells where they normally are, such as the synaptic terminals.  Synapses are junctions between two nerve cells that allow them to communicate.

“These results suggest a change in the availability of mitochondria in synaptic terminals as a precursor or a result of Parkinson’s disease,” researchers said.

Samples from patients who had undergone DBS had fewer mitochondria than control samples, but slightly more than Parkinson’s patients not treated with DBS. In addition, the volume of these energy-producing organelles in DBS-treated samples was closer to that observed in healthy brain cells.

“DBS treatment seemed to have inhibited or reversed the reduction in mitochondrial volume and numbers caused by Parkinson’s disease,” researchers wrote. These results suggest “enhanced metabolic plasticity leading to neuroprotection” in the brain areas most affected by the disease as a result of DBS.

Additional studies are still warranted to better understand the effects of DBS therapy on mitochondria and overall nerve cell survival.

“This potentially opens avenues for exploring how to replicate this cell power-up with non-surgical treatments, without the need for implanting electrodes in the brain,” Kambiz Alavian, PhD, lecturer in the department of medicine at the Imperial College London and senior author of the study, said in a news release written by Kate Wighton.

Brain tissue samples are one of the most reliable sources of information on neurological disorders. However, studies using this type of sample can be challenging, as they can only be performed after an individual has died.

“We now hope to carry out larger studies to explore new treatments that may preserve brain cell mitochondria. The ultimate goal would be to keep cells powered up for longer, and Parkinson’s symptoms at bay,” he said.

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Parkinson’s Patients on DBS Aren’t More Impulsive, Study Finds

deep brain stimulation, impulsivity

Parkinson’s patients treated with deep brain stimulation (DBS) are not more impulsive than other patients or healthy people toward food or monetary rewards, according to new research.

The study, “Deep brain stimulation of the subthalamic nucleus and the temporal discounting of primary and secondary rewards,” was published in the Journal of Neurology.

Although DBS of the subthalamic nucleus (STN) — a brain region hyperactive in Parkinson’s and implicated in motor control — is an effective way to ease the disease’s hallmark motor symptoms, it may induce confusion and changes in behavior and in decision-making processes, such as those regarding food. This may lead to a tendency toward risky decision-making in gambling tasks and increased impulsivity.

Aiming to better understand impulsivity in this patient population, a research team from Italy used a task called delay discounting, in which the patients had to decide whether they preferred an immediate, smaller reward over a larger one later. A preference for the immediate reward would be expected from impulsive participants. However, studies using monetary rewards in people with Parkinson’s who underwent DBS have led to contradictory results.

While money is a secondary reward, food is a primary reward as it is necessary for one’s survival. In rats, stimulation of the STN increased the motivation to obtain food, but reduced motivation toward cocaine, a secondary reward.

In accordance, Parkinson’s patients undergoing DBS attributed increased value to food rewards, which was associated with weight gain, a common non-motor side effect of the surgery.

The 45 participants were divided into three groups: 15 Parkinson’s patients who underwent bilateral DBS into the STN (mean age 62.8 years, 4.4 years since the surgery), 15 patients without DBS on dopaminergic replacement therapy (mean age 69.1 years) and 15 healthy controls (mean age 67.7 years).

All patients were tested under their best medical treatment condition, which means on stimulation in DBS and on medication for dopaminergic treatment.

All participants performed three computer tasks where they had to choose a smaller reward immediately or a reward that was larger but delayed — by two days, two weeks, one month, three months, six months, or one year.

“In these tasks, the choice usually depends on the time that passes between one option and the other: if it is very short, delayed gratification is chosen and vice versa,” Marilena Aiello, the study’s lead author, said in a press release.

In the food task, the participants were asked to choose from six foods, three sweet and three salty. When using discount vouchers as rewards, they had to choose from six hobbies or activities presented through pictures — a theater trip, a restaurant visit, book purchases, gardening equipment, sewing tools, or tools to paint — for which they would like to get a discount voucher.

The results revealed no differences in food or discount voucher choice comparing the three groups, even in patients who experienced weight gain and/or eating alterations after DBS.

The data further showed greater preference for immediate rewards — greater impulsivity — in patients with fewer years since DBS, on higher doses of levodopa, and with better memory.

“Our study confirms that patients with DBS are no more impulsive in this kind of situation and they do not try to find gratifications more hastily than the others,” Aiello said.

The investigators said, “In addition, our results also extend the current literature by showing, for the first time, that this result is independent of the type of reward.”

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Having More Comorbidities Linked with Confusion After DBS in Parkinson’s Patients

deep brain stimulation, confusion

Having a higher number of comorbidities is associated with postoperative confusion in Parkinson’s patients undergoing deep brain stimulation (DBS), according to a new study in Brazilian patients.

The study, “Postoperative Confusion in Patients with Parkinson’s Disease Undergoing Deep Brain Stimulation of the Subthalamic Nucleus,” appeared in the journal World Neurosurgery.

DBS targeting the subthalamic nucleus (STN) — a brain region hyperactive in Parkinson’s patients and implicated in motor control — has been shown to ease motor symptoms, but it may be associated with side effects such as postoperative confusion. This complication may damage the surgical hardware due to agitation and require treatment with antipsychotics, many of which are contraindicated in Parkinson’s.

Postoperative confusion has been correlated with imaging and clinical factors, such as older age and longer disease duration. However, no studies explored its incidence and associated factors in Brazilian patients with Parkinson’s undergoing DBS of the STN.

Aiming to address this, researchers conducted a retrospective chart review of 49 patients (33 men, mean age 57.5 years) undergoing this procedure from January 2013 to October 2017 at Hospital de Clínicas de Porto Alegre, in Brazil. Patients with dementia, severe/untreated neuropsychiatric disorders, or spontaneous or antiparkinsonian medication-induced psychosis were excluded. All surgeries were performed under local anesthesia.

Among the analyzed imaging factors were brain atrophy, or shrinkage; lesions in the white matter — made of nerve fibers — intracranial hemorrhage after surgery, and ventricular wall transgression (breaching the walls of the brain’s ventricles, a network of interconnected cavities). Clinical factors evaluated included gender, history of depression and hallucinations, age, disease duration, comorbidities — the presence of one or more additional diseases or disorders co-occurring with Parkinson’s — length of hospital stay, and duration of surgery.

Confusion was defined as any degree of disorientation and attention and/or perception impairment, associated with cognitive dysfunction and with a sudden beginning and short duration, from the first postoperative hours until hospital discharge.

The results showed that the incidence of postoperative confusion was 26.5% (13 patients), which was higher than in prior studies, researchers noted. This may have been due to the small number of patients in their study and to technical differences in DBS, they suggested.

In comparison to patients not developing confusion, those with confusion were older (mean age 63.2 vs. 55.4 years), had longer disease duration (16.5 vs. 13.2 years), higher comorbidities, longer hospital stays after surgery and a greater width of the third ventricle, one of the four brain ventricles.

There was a trend toward more intracranial hemorrhage in patients who developed confusion, as assessed with computed tomography, although not statistically significant. No patient needed re-intervention or prolonged sedation.

A subsequent statistical analysis accounting for potential confounding factors revealed that only the association with comorbidities remained significant. The team commented that “it is well-recognized that the presence of various comorbidities is a risk factor for postoperative delirium.”

The investigators said that studies with larger groups of patients are needed to identify which variables are more relevant in the development of confusion in Parkinson’s patients undergoing this surgery.

 

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Study Highlights Importance of Personalized Parkinson’s Treatment

DBS IJLI Apokyn comparative study

Invasive treatment approaches for advanced Parkinson’s disease have differential effects on disease-associated motor and non-motor symptoms, a real-life observational study shows.

These findings suggest that selection of a treatment should be based on each patient’s particular clinical profile, researchers say.

The study, “EuroInf 2: Subthalamic stimulation, apomorphine, and levodopa infusion in Parkinson’s disease,” was published in Movement Disorders.

Parkinson’s is a progressive neurological disease mostly recognized for its motor symptoms, such as tremor, bradykinesia (impaired body movement control), and muscular rigidity. In advanced cases, oral therapies may not be sufficient to control these motor symptoms and patients often require device-aided therapies.

There are three well-established, safe, and effective treatments to improve quality of life and alleviate motor and non-motor symptoms of Parkinson’s disease: deep brain stimulation, intrajejunal levodopa infusion (IJLI), and Apokyn (apomorphine) infusion (APO).

In deep brain stimulation, electrodes are surgically implanted in certain areas of a patient’s brain. Through electrical signals received from a small device, the electrodes will stimulate these brain areas to produce dopamine — the chemical compound (neurotransmitter) lacking in Parkinson’s disease.

IJLI is one of the most influential therapies used in patients with moderate to late-stage Parkinson’s disease, shown to have positive effects on both motor and non-motor symptoms and quality of life. This approach uses a portable infusion pump that continuously dispenses levodopa gel through a tube inserted into the intestine.

Apokyn is an engineered therapy that mimics dopamine’s ability to stimulate nerve cells. Unlike other dopamine agonist agents, Apokyn is administrated by injection or continuous infusion using a pump.

Despite the demonstrated efficacy of these therapies, there is little information comparing their impact.

An international group of researchers, on behalf of the EUROPAR and the Non-motor Parkinson’s Disease Study Group of the International Parkinson’s Disease and Movement Disorders Society, compared the differential effects of DBS applied to the subthalamic nucleus (STN), IJLI, and APO in patients with advanced Parkinson’s disease.

The study included 101 Parkinson’s patients who underwent bilateral STN-DBS, 33 who received IJLI, and 39 patients who received APO treatment. Patients had a mean age of 62.3 years and had been diagnosed with the disease for a mean of 12.1 years.

Six months after receiving the treatment, patients were evaluated to determine changes in Parkinson’s symptoms.

Significant improvements concerning non-motor symptoms and motor-related complications were noted in the three groups of patients six months after receiving the treatment, as determined by the Nonmotor Symptom Scale (NMSS) and Unified Parkinson’s Disease Rating Scale-motor complications (UPDRS-IV), respectively.

Significant changes in quality of life, as assessed by the Parkinson’s Disease Questionnaire-8 Summary Index (PDQ-8 SI), were also reported by all treatment groups during follow-up.

IJLI and APO treatments were found to effectively prevent disease worsening during the follow-up period, according to Hoehn and Yahr scores, which rate severity of symptoms in Parkinson’s disease.

STN-DBS treatment reduced the amount of daily levodopa use by approximately 52%. As expected, levodopa equivalent daily dose remained stable in infusion therapies.

The three treatment approaches were found to have similar effects on dyskinesia (involuntary movements)/motor fluctuation ratios. In contrast, they had different effects on patients’ non-motor symptoms.

A more detailed analysis showed that STN-DBS had a significant positive effect on sleep and fatigue, mood and cognition, perceptual problems and hallucinations, urinary symptoms, and sexual function.

IJLI had a positive effect on sleep, mood, and cognition, and gastrointestinal symptoms, while APO therapy significantly improved patients’ mood and cognition, lessened occurrence of perceptual problems and hallucinations, as well as improved attention and memory.

In general, STN-DBS and IJLI seemed to improve non-motor symptom burden, and APO therapy was favorable for neuropsychological and neuropsychiatric symptoms and improved quality of life.

Patients who underwent IJLI treatment had more frequent non-serious adverse events (abdominal pain and gastrointestinal symptoms) immediately after the procedure, compared to those in the other two groups.

“Distinct effect profiles were identified for each treatment option,” researchers said. “This study highlights the importance of holistic assessments of motor as well as non-motor aspects of Parkinson’s that could provide a means to personalize treatment options to patients’ individual disease profiles.”

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