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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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Specific Dopamine-producing Neurons Crucial to Adaptive Movement, Early Study Finds

motor skills and Parkinson's

Dopaminergic neurons — nerve cells gradually lost to Parkinson’s progression — that contain an enzyme called aldehyde dehydrogenase 1A1 are essential for acquiring the motor skills needed for proper movement in given situations, a mouse study reports.

The research, “Distinct connectivity and functionality of aldehyde dehydrogenase 1A1-positive nigrostriatal dopaminergic neurons in motor learning,” was published in Cell Reports. The work was developed by the Intramural Research Program of the National Institute on Aging (IRP-NIA).

Parkinson’s disease severely affects dopaminergic neurons, those that produce dopamine, a neurotransmitter (cell-signaling molecule) that relays information between nerve cells and between the brain and the rest of the body.  These neurons are found in two specific brain regions involved in motor control: the striatum and the substantia nigra.

Nerve cells may or not contain aldehyde dehydrogenase 1A1 (ALDH1A1), an enzyme that is involved in cellular detoxification. Parkinson’s seems to mostly damage ALDH1A1-positive dopaminergic neurons, suggesting the enzyme may be a key player in this neurodegenerative disorder.

Both ALDH1A1-positive and ALDH1A1-negative dopaminergic nerve cells contribute to voluntary motor behavior. But the degree to which ALDH1A1-positive neurons are crucial to acquiring motor skills remains to be understood.

Using a mouse model of Parkinson’s, scientists targeted  dopaminergic neurons positive for ALDH1A1, and produced a detailed connectivity map of these specific neuronal networks in the mouse brain.

ALDH1A1-positive neurons were found to be in constant communication with other brain structures there. Importantly, researchers found that those dopamine-producing neurons of the striatum and substantia nigra that received the greatest percentage of molecular information (input) were located in the caudate-putamen nuclei, a brain region involved in movement control.

Researchers then selectively removed ALDH1A1-positive neurons to mimic the degeneration pattern observed in late-stage Parkinson’s disease. The animals’ ability to show new motor skills — new ways of voluntary movement, like foot position for maintaining balance while walking on a moving surface — was assessed using the rotarod test. In this test, mice must learn to balance while walking on a constantly rotating rod much like a treadmill.

Mice without ALDH1A1-positive neurons displayed a distinctly poorer ability to learn new motor skills, and slower walking speeds compared to control animals.

“Compared with a modest reduction in high-speed walking, the ALDH1A1+ nDAN-ablated mice showed a more severe impairment in rotarod motor skill leaning,” the researchers wrote. “Unlike control animals … [these] mice essentially failed to improve their performance during the course of rotarod tests.” (nDANs are nigrostriatal dopaminergic neurons.)

These animals were then treated with dopamine replacement therapy, either levodopa or a dopamine receptor agonist, one hour before a new motor skills assessment. Dopamine replacement therapy is standard treatment for the motor symptoms associated with Parkinson’s.

Levodopa (L-DOPA) treatment allowed the animals without ALDH1A1-positive neurons to travel longer distances, and to walk more frequently at higher speeds during a session. But it failed to improve their ability to acquire new motor skills during repeated tests. Treatment with a dopamine receptor agonist was also ineffective.

“When the ALDH1A1+ nDANs were ablated after the mice had reached maximal performance, the ablation no longer affected the test results, supporting an essential function of ALDH1A1+ nDANs in the acquisition of skilled movements. These findings are in line with the theory that nigrostriatal dopamine serves as the key feedback cue for reinforcement learning,” the researchers wrote.

These results provide “a comprehensive whole-brain connectivity map,” they concluded, and reveal a key role of ALDH1A1-positive neurons in newly learned motor skills, suggesting that motor learning processes require these neurons to receive a multitude of information from other nerve cells and to supply dopamine with “dynamic precision.”

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Imbalance in Dopamine and Acetylcholine Levels May Drive Disease Progression, Study Finds

neurotransmitters

Therapies against motor loss and progression in Parkinson’s’ disease (PD) may need to tackle the imbalance between two neurotransmitters, dopamine and acetylcholine, instead of focusing on dopamine alone, an early study suggests.

The study, “Dopamine Deficiency Reduces Striatal Cholinergic Interneuron Function in Models of Parkinson’s Disease,” was published in the journal Neuron.

Motor and cognitive functions depends on the coordinated interaction in the brain of two neurotransmitters — substances produced in response to nerve signals that act as chemical messengers — called dopamine and acetylcholine.

In Parkinson’s, the degeneration of motor neurons that produce dopamine in a brain region called the striatum results in difficulties with voluntary movement control.

Therapies that increase dopamine or activate dopamine receptors, such as levodopa, are currently used to restore motor skills. However, these treatments are not fully effective and their benefits wear off over time.

Researchers have thought that a decline in dopamine levels would increase acetylcholine production. Higher levels of acetylcholine are suggested to cause the dyskinesia — uncontrolled, involuntary movements — observed in Parkinson’s patients under long-term dopamine therapy.

Researchers at Yale University questioned points in these assumptions. They investigated how dopamine affects acetylcholine by looking at a specific type of nerve cell, called striatal interneurons, that is the main source of acetylcholine in the striatum.

To test the effects of dopamine loss, the team used a mouse model genetically modified to mimic Parkinson’s that has a progressive decline in dopamine levels. When motor symptoms appear in these mice, it is estimated that about 30% of dopamine is already lost, increasing to 60–80% at their death.

This progressive dopamine loss, the researchers saw, was matched in the animals by an initial and smaller decrease in the production of acetylcholine by striatal interneurons, creating an imbalance.

“While the concentrations of both dopamine and acetylcholine decline, the balance between these two neurotransmitters shifts to favor acetylcholine,” the researchers wrote.

Subsequent release of dopamine from remaining axon terminals push an increase of acetylcholine, worsening the imbalance between both neurotransmitters.

Under dopamine depleted conditions, proper motor function is dependent on adequate levels of both acetylcholine and dopamine, the study concluded.

Its findings suggest that progressive dopamine deficiency reduces the activity of striatal cholinergic interneurons, resulting in progressive motor difficulties.

Future treatments aiming to slow Parkinson’s progression should include those targeting the balance between acetylcholine and dopamine.

“Our findings suggest that targeted cholinergic therapy [those that mimic the action of acetylcholine] has a place in the management PD and highlight the need for additional experiments that will offer therapeutic options distinct from disease prevention,” the researchers wrote.

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Gene Therapy Used to Produce and Sustain Dopamine in Brains of Primate Model of Parkinson’s

gene therapy study

Direct delivery of two dopamine-synthesizing enzymes to the midbrain, using a safe and inactive form of an adenovirus, was able to reverse signs of motor difficulties in a primate model of Parkinson’s disease, a study reports.

Continuous dopamine production via a gene therapy approach may be a promising one-time treatment strategy for Parkinson’s patients, providing long-lasting improvement and lowering the chances of motor fluctuations and other side effects associated with oral dopaminergic medication, its researchers suggest.

The study, “Vector-mediated L-3,4-dihydroxyphenylalanine delivery reverses motor impairments in a primate model of Parkinson’s disease,” was published in the journal Brain.

Treatment with levodopa — a precursor molecule of dopamine — remains the leading standard treatment of Parkinson’s, easing effects caused by damaged or dead dopamine-producing brain cells, the main cause of this disease.

Such treatment effectively helps to manage Parkinson’s motor symptoms, but dopamine agonists often becomes less effective over time. This is believed to be due, at least in part, to lesser production of the enzymes involved in dopamine production.

Recently researchers have focused on developing types of gene therapy that might overcome the long-term ineffectiveness of available treatments.

An international team of researchers designed a gene therapy approach to re-establish the amount of available enzymes known as TH and GCH1 — both necessary for dopamine production — in the midbrain.

Using an engineered adeno-associated viral (AAV) vector to simultaneously deliver the DNA coding sequences of the two enzymes, researchers injected different doses of the gene therapy directly into the putamen — one of the brain areas mostly affected by the disease — of 29 rhesus monkeys. Four animals were left untreated as a control group.

The putamen is also the brain region where most dopamine-producing cells are located.

One group of animals, initially given the lowest dose, was given a second and higher dose six months after a first injection to simulate “a clinical scenario where patients entering early in the safety trial could be offered a therapeutic dose at the end of the trial.” All animals were analyzed 10 months after the initial dosing.

“The re-dosed animals showed a significant recovery over the following 2 months, reaching the same level of recovery as the initial high-dose treatment group,” the study notes.

Importantly, the primates had been treated with increasing L-DOPA doses before the injection of the gene therapy, “given twice daily for 2 weeks to induce L-DOPA-induced dyskinesia,” the scientists wrote.

Findings showed that the therapy induced a significant and dose-dependent improvement in motor control up to a level similar to that obtained with the optimal dose of injectable levodopa.

Reported improvements in motor function also came without any signs of dyskinesia — the uncontrolled, involuntary movements that are often associated with long-term levodopa use.

Analysis of brain tissue samples collected from the monkeys showed that this AAV-mediated gene therapy could induce an increase of 760- to 5600-fold of TH and 1.2- to 1.5-fold of GCH1 enzymes compared to untreated animals.

“These results provide proof-of-principle for continuous vector-mediated L-DOPA [dopamine] synthesis as a novel therapeutic strategy for Parkinson’s disease,” the researchers wrote.

“This gene therapy approach may thus offer the possibility to prolong and sustain the ‘good years’ many patients with Parkinson’s disease experience during the initial stages of L-DOPA therapy,” they added.

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Dietary Supplement Eases Parkinson’s Symptoms, Improves Dopamine Function, Study Shows

antioxidant supplement

N-acetyl-cysteine (NAC), a compound that is used by the body to produce an antioxidant called glutathione, may improve dopamine function and ease Parkinson’s disease symptoms, researchers report.

Their study, “N-Acetyl Cysteine Is Associated With Dopaminergic Improvement in Parkinson’s Disease” was published in Clinical Pharmacology & Therapeutics.

Low brain levels of the antioxidant glutathione (GSH) is one of the earliest biochemical changes in Parkinson’s, leading to oxidative stress — an imbalance between the production of free radicals and the cells’ ability to detoxify them — and eventually, cellular death.

N-acetyl-cysteine (NAC) is an antioxidant supplement that provides a source of an amino acid called cysteine, which then is used by the body to produce glutathione. As such, supplementation with a glutathione precursor could increase overall glutathione levels in the brain, reducing oxidative stress levels and lessening the symptoms of this neurodegenerative disorder.

Investigators at Thomas Jefferson University in Philadelphia, Pennsylvania,  previously demonstrated that NAC treatment improved dopamine metabolism in dopamine-producing neurons of the midbrain, a region that’s significantly damaged in Parkinson’s disease. Importantly, NAC also was found to improve patients’ motor symptoms. However, their results were from a small patient population (23 participants).

The same team now explored whether nutritional supplementation with NAC improves dopamine-related brain function and alleviates Parkinson’s symptoms in a larger study sample. Dopamine acts as a neurotransmitter, which passes signals between neurons and is essential in sending messages from the brain to direct muscle movement and coordination. Throughout disease progression, dopamine-producing neurons die and the levels of dopamine in the brain gradually decrease.

Forty-two Parkinson’s patients (21 men and 21 women) were included in this trial (NCT02445651). Of those, 28 participants were randomized to receive a combination of daily and intravenous (50mg/kg) NAC for three months, while the remaining 14 were assigned to the control group.

“On the days that subjects did not receive the intravenous NAC, they took 600mg NAC tablets orally 2 times per day,” the researchers wrote. NAC injections were given once a week. “For the duration of the study, both groups continued to receive their current standard of care treatment for PD [Parkinson’s disease],” investigators added.

Subjects had their dopamine brain function and disease motor features evaluated before and after NAC treatment.

In comparison to the control group, NAC supplementation significantly increased dopamine transporter binding (mean increase from 3.4% to 8.3%) in the caudate and putamen, key structures that regulate body movement. Dopamine transporter is a protein that works to recycle dopamine after its release in the brain. In Parkinson’s, dopamine transporter levels may be reduced to up to 70%.

Researchers reported that dopamine transporter binding measures were higher in subjects who were not taking levodopa compared to those who were.

Patients who received NAC had a significant lessening of motor and non-motor symptoms. Changes in patients’ symptoms were significantly correlated with dopamine transporter binding in the putamen, but not in the caudate region of the brain.

“The results suggest that a combination of intravenous and oral administration of NAC in PD [Parkinson’s disease] patients results in increased DAT [dopamine transporter] binding as well as improved symptoms,” the researchers wrote.

However, the team noted that larger placebo-controlled studies are necessary to assess NAC’s potential to manage Parkinson’s disease.

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

sleep deprivation studied

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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New Strategy Targets Parkinson’s by Improving Dopamine Metabolism, Study Reports

Nurr1 dopamine Parkinson's

In contrast to what was previously believed, a key protein implicated in Parkinson’s disease — called Nurr1 — can be modulated using naturally existing molecules or engineered small molecules to restore dopamine production in brain cells, according to a study.

Conducted by researchers from the University of California San Francisco (UCSF), the new study provides evidence that the activation of Nurr1 may represent a viable strategy to slow or halt the progression of Parkinson’s disease.

The study, “Covalent Modification and Regulation of the Nuclear Receptor Nurr1 by a Dopamine Metabolite,” was published in the journal Cell Chemical Biology.

The nuclear receptor-related 1 protein, or Nurr1, plays an important role in the development and survival of dopamine-producing nerve cells in the brain. This protein can control the production of other critical proteins in these particular brain cells, while it also regulates cell death mechanisms.

Previous studies have suggested that Nurr1 could be implicated in the loss of dopaminergic neurons in Parkinson’s patients. Preclinical data has shown that elevating the levels of Nurr1 can reduce inflammation and improve the survival of neurons, while reduction of the protein leads to motor symptoms in mice similar to those seen in Parkinson’s disease.

Researchers have tried to modulate the levels of this protein in cells using gene therapy strategies. However, many of these attempts have failed due to Nurr1’s inability to enter cells or reach the cell’s nucleus (where Nurr1 normally works).

Small molecules that could bind to Nurr1 and modulate its activity have also been considered as a potential therapeutic approach. But, until now, researchers have failed to design molecules that can effectively change this protein’s activity. This is mostly due to a lack of knowledge on the structure and activity of Nurr1.

To overcome this limitation, UCSF researchers used different experimental approaches to figure out how Nurr1 binds to its targets and how it is activated.

Contrary to what happens in other similar proteins, Nurr1 binds directly to its targets without requiring additional binding elements to be activated. In particular, the team found that the naturally occurring molecule 5,6-dihydroxyindole (DHI), a dopamine metabolite, binds directly to and modulates the activity of Nurr1.

Using experimental cell and fish models, the researchers tested the potential of DHI to enhance Nurr1’s activity.

They found that cells exposed to DHI had up to 1.6 times more active protein than before exposure. In addition, DHI-triggered activation of Nurr1 led to increased production of dopamine transporters in fish, including VMAT2 — a protein that regulates the packaging and release of dopamine into the synapse, the junction between two nerve cells that allow them to communicate.

“Improving the packaging of dopamine into vesicles by upregulating transcription of VMAT2 may slow the progression of Parkinson’s disease and extend the treatment window for L-DOPA [the standard of care for Parkinson’s] by reducing side effects,” the researchers wrote.

These findings demonstrate that “Nurr1 may be regulated by an endogenous metabolite, contradicting previous suggestions that it has no small-molecule regulation,” they added.

“This molecule is widely regarded as one of the top therapeutic targets for Parkinson’s disease, but this is the first convincing evidence that it can be directly drugged,” Pamela England, PhD, associate professor at UCSF and senior author of the study, said in a news story written by Nicholas Weiler.

“We hope these insights will lead to drugs that for the first time can target the underlying causes of Parkinson’s disease,” she said.

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GDNF Shows Potential as Neurorestorative Treatment for Parkinson’s

GDNF studied

Infusion of a naturally occurring protein, GDNF, into a motor control area of the brain may restore cells damaged by Parkinson’s disease and ease patients’ symptoms, results from a European clinical trial suggest.

The study, “Extended Treatment with Glial Cell Line-Derived Neurotrophic Factor in Parkinson’s Disease” was published in the Journal of Parkinson’s Disease.

Evidence shows that glial cell line-derived neurotrophic factor (GDNF) supports the growth, survival, and differentiation of dopaminergic neurons — those that produce dopamine and progressively degenerate in Parkinson’s disease. In animal models of Parkinson’s, GDNF has consistently demonstrated both neuroprotective and neurodegenerative effects when provided continuously.

Researchers developed a three-part clinical trial (EudraCT Number: 2013-001881-40) to study the safety and effectiveness of GDNF infusions in Parkinson’s patients. The trial first recruited six patients to assess the safety of the treatment. Then, 35 more participants entered the nine-month, double blind trial in which half were given monthly infusions of GDNF. The other half received placebo infusions through an implant that delivered the treatment directly to the brain through a port placed behind the ear.

This part of the study showed that patients who received monthly doses of GDNF into their putamen — a brain region involved in movement control that’s deeply damaged in Parkinson’s — had a significant increase of dopamine levels in the brain compared to the placebo group. However, the apparent increase in dopamine levels were not reflected on patients’ clinical status.

“The spatial and relative magnitude of the improvement in the brain scans is beyond anything seen previously in trials of surgically delivered growth-factor treatments for Parkinson’s,” principal investigator Alan L. Whone, PhD, said in a press release. Whone is in Translational Health Sciences, Bristol Medical School, University of Bristol, and Neurological and Musculoskeletal Sciences Division, North Bristol NHS Trust, Bristol, UK,  “This represents some of the most compelling evidence yet that we may have a means to possibly reawaken and restore the dopamine brain cells that are gradually destroyed in Parkinson’s,” he said.

Using the same patient sample (41 subjects, ages 35–75) researchers further assessed the effects of continued (21 patients who had received GDNF) or new (20 patients who had received placebo) exposure to GDNF for another nine months in the open-label extension phase of the trial. Dosing followed the same protocol as before with GDNF infusion given every month.

Although all patients knew they were receiving GDNF, they remained oblivious to what their treatment in the previous study was.

The primary goal of the study was measure the percentage change from parent trial week zero to week 80 (or week 40, depending on the study group) in the “off” state Unified Parkinson’s Disease Rating Scale (UPDRS) motor score. As disease progresses, patients experience off periods more frequently. Such episodes are characterized by the reappearance or worsening of symptoms due to diminishing effects of levodopa therapy.

The treatment had no treatment-emergent safety issues, but all patients experienced at least one adverse side effect, including application site infection, headache, back pain, and uncontrollable muscle contraction (dystonia).

By 18 months (all participants had received GDNF), both groups showed a trend toward score reduction, indicating motor function improvement. GDNF also was found safe when administered over this length of time. However, there were no significant differences in off state UPDRS motor score between patients who received GDNF for 18 months and those who received it for nine months only (parent study placebo group).

Importantly, total off time and good-quality “on” time per day improved in both study groups.

In comparison to the beginning of the parent trial, mean total off time per day decreased by an average of 1.5 hours in patients who received GDNF throughout the whole study, and by 0.8 hours in the those who received placebo and GDNF. “Good-quality ON time increased by [an average of 1.6] hours in the GDNF/GDNF group and by [0.5] hours in the placebo/GDNF group,” researchers wrote.

“This trial has shown that we can safely and repeatedly infuse drugs directly into patients’ brains over months or years. This is a significant breakthrough in our ability to treat neurological conditions, such as Parkinson’s, because most drugs that might work cannot cross from the blood stream into the brain due to a natural protective barrier,” said senior author Steven Gill, honorary professor in neurosurgery at the University of Bristol, and designer of the GDNF delivery system (Convection Enhanced Delivery, CED).

“I believe that this approach could be the first neurorestorative treatment for people living with Parkinson’s, which is, of course, an extremely exciting prospect,” Gill stated.

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Holding On to Happiness, but Not Too Tightly

happiness

Life, liberty, and the pursuit of happiness. The H in the CHRONDI Creed refers to happiness. Happiness can be an elusive thing when battling a chronic disease like Parkinson’s. So many things can get in the way of experiencing happiness: pain, deep fatigue, irritability, the time consumed by the disease, and grief accompanying things stolen by the disease. Trying to hold on to even small moments of happiness is challenging. However, it is possible to experience moments of happiness in the face of chronic disease if one trains the brain to hold the moment gently — not too tightly.

Happiness is a state of mind and includes a broad range of phenomena, such as gratitude, inspiration, accomplishment, beauty, awe, laughter, compassion, tranquility, joy, love, exhilaration, ecstasy, and bliss. The experience of happiness can have a connection to one (or several) of these phenomena. Before you finish reading this column, let’s take a mental excursion together.

Visualize in your mind the last time you were happy and try to feel how you felt at that time. Try to hold the moment gently. Pause now to do that before reading on.

Were any of the above phenomena part of your memory? Remembering happiness is helpful in reminding us what it felt like and of what the experience may look like again. It can help us to see it in the smallest of moments throughout our lives. It is not a practice of grasping after happiness. Happiness is like a butterfly flitting from flower to flower. We take in the beauty and the rich, sensual experience and hold it gently in our mind. If we were to grasp the butterfly, we would destroy the experience.

Gently holding happiness without grasping is tied to a compassionate way of being. So much of our unhappiness is tied to grasping, to misperceptions, objectification, and poor communication in relationships. The practice of compassion is about experiencing the needs of others and then moving beyond suffering to a place of well-being. It is a shift in perception and out of suffering. Walking the path of the compassionate warrior is filled with happiness experiences accompanied by the knowledge of empathy, shifting perceptions, and shared well-being. Scrooge in Charles Dickens’ “A Christmas Carol” wasn’t happy until he experienced a shift in perception and became compassionate.

I don’t expect to experience happiness all the time. That’s just too unrealistic for where I am in my personal development as a compassionate warrior battling a chronic disease. I seek small moments each day, not by grasping for them but by looking for them, like looking at the butterfly, and then gently holding the moment in my mind. Then, I am very grateful for that moment and not sad when it naturally fades into the next experience as part of the day. This feeling of happiness is not induced by drugs or alcohol (which bring fake happiness and negative consequences). It is a happiness that comes from the practice of allowing the mind to experience both the large and small moments of happiness. I do my best to begin and end each day with a confirmation (a mantra or a prayer) of specific gratitude — not a statement of general gratitude but one aimed at something specific in my life. Gratitude is a way of holding the door open for those happiness moments.

Perhaps happiness brain training can be very helpful for those suffering from PD because of the link to dopamine production. I haven’t seen any research on this, but I find the practice to be quite helpful. What do you think? Are there methods you use to bring happiness into your life? Share them in the comments. Let’s pool together a collection of happiness tools for our readers.

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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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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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