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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Is Parkinson’s Disease a Bully?

bully

Sherri Journeying Through

We have all heard of them, and many of us, in one way or another, have encountered them. Some of us (hopefully, with regret) have been one. Who am I talking about? 

Bullies

They intimidate us and physically hurt us. They embarrass us, taunting us with their words. We fear that they’ll defeat us.

What do bullies have to do with Parkinson’s disease?

Parkinson’s is a bully with a capital “B.” It teases and taunts us, telling us that we are no longer useful. It tries to convince us that we no longer serve any purpose. This disease can tempt us to give up, to surrender to its cruel clutches. 

Embarrassment is one way Parkinson’s tries to steal our dignity and pride. And it often wins. We forget as we struggle through each day that others don’t understand us: our movements, speech, and forgetfulness. We can take those misunderstandings personally.

Drooling, shaking, a quiet voice, and a masked face are symptoms that may have become “natural” to those of us with the disease. But no matter how “natural” these have become, we’re still embarrassed by them because of others’ reactions when we’re out in public.

Parkinson’s whispers its ugly lies, saying you are no longer of value

If anything, you have more value. You have developed an empathy that many others don’t possess. You can relate better to those who are battling other diseases, those who are in pain, feel alone, and need hope. People who are fearful receive your undivided attention. Of course, having this disease may not be your preferred method of acquiring such character traits.

In a recent documentary video on Facebook, television host and producer Mike Rowe said, “To feel bullied is to feel helpless.” While Parkinson’s disease is a bully with a capital “B,” we don’t need to feel helpless. Instead, we should feel hopeful. Why? We are becoming better and strong enough so we don’t allow Parkinson’s taunting to get the best of us. And for me, that’s a huge plus.

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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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MRI Technique Helps Distinguish Between Parkinson’s and Progressive Supranuclear Palsy, Study Reports

MRI technique

A specific magnetic resonance imaging (MRI) measure can accurately predict the development of eye movement abnormalities, helping to identify patients who develop progressive supranuclear palsy with parkinsonism (PSP-P) after an initial diagnosis of Parkinson’s, a study shows.

The study, “Refining initial diagnosis of Parkinson’s disease after follow‐up: A 4‐year prospective clinical and magnetic resonance imaging study,” appeared in the journal Movement Disorders.

A clinical diagnosis of Parkinson’s may be inaccurate in the early stages of the disease, when its characteristic motor symptoms are not fully manifested. PSP-P has a similar clinical presentation to idiopathic Parkinson’s (of unknown cause), including bradykinesia (slowness of movement), limb rigidity, and tremor, leading to difficulty in differentiating between the two.

Recent diagnostic criteria defined probable PSP-P as vertical gaze abnormalities (VGA) — difficulty in moving the eyes up and/or down — associated with levodopa‐resistant parkinsonism, a term for neurological disorders that cause movement problems similar to those of Parkinson’s. However, patients with PSP-P may never develop VGA, meaning the prevalence of this disorder could be underestimated.

MRI has been a helpful tool to diagnose PSP and to predict the appearance of gaze abnormalities in people with PSP-P. A new version of the Magnetic Resonance Parkinsonism Index (MRPI), named MRPI 2.0, has shown high accuracy in distinguishing cases of Parkinson’s from those of PSP-P. The MRPI can be used in MRI studies to predict the presence of PSP in patients with clinically unclassifiable parkinsonism.

However, studies on the clinical features of PSP-P in patients initially diagnosed with Parkinson’s are still lacking.

To address this, researchers in Italy followed a group of 110 individuals — 73 of whom were men, with a mean age at examination of 62.9 years, and a mean disease duration of 4.4 years — with probable or possible Parkinson’s and 74 healthy individuals used as controls over four years.

The investigators conducted annual clinical evaluations to assess the appearance of VGA without early postural instability, which strongly suggests PSP‐P. MRI scans were performed at the beginning of the study and at the end of the follow-up period.

They also evaluated whether MRPI 2.0 helped predict the development of PSP-P in patients initially diagnosed with Parkinson’s.

At the start, 21 of 40 individuals with possible Parkinson’s and all 70 individuals with probable Parkinson’s were responsive to levodopa. Of all the patients, 100 retained their initial diagnosis, and 10 (9.1%) developed VGA and had their diagnosis changed to PSP-P, nine of whom only showed a moderate response to levodopa.

Specifically, all 10 patients whose diagnosis changed showed slowness of vertical saccades during follow-up, which refers to quick, simultaneous movements of both eyes that abruptly change the point of fixation. Vertical supranuclear gaze palsy (resulting from a cerebral impairment) in five patients was associated with higher imaging biomarkers values than slowness in vertical saccades. All 10 patients had at least three years of parkinsonism without postural instability.

All MRI measures — including MRPI and MRPI 2.0 — were significantly different between patients with Parkinson’s and those at PSP-P both at the start of the study and at the end of follow-up. At the beginning, MRPI 2.0 was the most accurate (100%) biomarker in predicting the appearance of VGA, “enabling [PSP-P] patients to be identified at the earliest stage of the disease,” according to the researchers.

Although the number of patients whose diagnosis was changed is small, the researchers said that their findings “demonstrate the usefulness of these new imaging biomarkers, and specifically of the MRPI 2.0, in predicting the development of VGA and the clinical evolution towards PSP phenotypes in patients with the initial diagnosis of [Parkinson’s].”

Most clinical variables — including motor function, assessed with the Unified Parkinson’s Disease Rating Scale–Motor Examination (UPDRS‐ME), and cognitive function, measured with the Mini-Mental State Exam — also showed a marked difference between the two groups at follow-up. However, clinical variables were less accurate than imaging biomarkers in predicting VGA.

Data further showed that disease progression was more signficant in patients with PSP‐P, as assessed with MRI and UPDRS‐ME.

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Iowa City is Next Stop for Parkinson’s Foundation’s Team Training Program

team training program

The Parkinson’s Foundation is bringing Allied Team Training for Parkinson’s (ATTP), its signature professional education program, to Iowa City, Iowa, on March 27-30.

The program is intended to help medical professionals from diverse disciplines learn the best techniques in Parkinson’s care. 

Using a dynamic team-based approach, the training program is geared toward physicians, physician assistants; nurses; social workers; nurse practitioners; and occupational, music, speech, and physical therapists.

The interactive curriculum is offered in partnership with the University of Iowa Hospitals & Clinics, a designated Parkinson’s Foundation Center of Excellence. These centers — there are 45 worldwide — have specialized teams made up of an array of healthcare professionals and others knowledgeable about the latest in Parkinson’s care.

“The Parkinson’s Foundation is committed to providing healthcare professionals with the latest research and best practices that improve care for people living with Parkinson’s disease,” John L. Lehr, president and CEO of the Parkinson’s Foundation, said in a press release.

He said attendees will learn how to provide personalized and patient-centered care, and at the right time, throughout the disease’s progression. The concept is based on the idea that because each patient experiences Parkinson’s differently, a diverse healthcare team fosters better symptom management.

Featuring a mix of online courses and an extensive in-person curriculum, the program offers continuing medical education credits and continuing education units to eligible participants. Led by an interdisciplinary faculty of senior movement disorder specialists, training includes interactive case presentations, care planning with patients and caregivers, discipline-specific and interdisciplinary team development sessions, and patient and caregiver panels.

“Building upon our strengths in providing world-class care for patients, and conducting leading-edge research, our support from the Parkinson’s Foundation is allowing us to expand our interdisciplinary care, to increase our community involvement and educational activities for other healthcare professionals and patients across Iowa, and to attain even greater heights in the treatment of everyone affected by Parkinson’s disease,” said Ergun Uc, MD, professor of neurology and director of the Division of Movement Disorders at University of Iowa Hospitals & Clinics.

By the end of the program, participants should be able to explain the complexity of Parkinson’s motor and non-motor symptom management for all disease stages, identify challenges with medication side effects, list six non-pharmacological management strategies for non-motor symptoms, discuss options available to support patients and their families, describe the complementary role of each discipline on their care team, and apply strategies for building inter-professional networks and community partnerships.

Since its 2002 inception, the ATTP has trained more than 2,000 healthcare professionals in the United States and Canada.

Future ATTP training includes the Medical University of South Carolina (fall 2019), Massachusetts General Hospital and Beth Israel Deaconess Medical Center (spring 2020), Struthers Parkinson’s Center (fall 2020), Oregon Health & Science University (spring 2021), and the University of Kansas Medical Center (fall 2021).

Visit this site for more information about the Iowa event, and to register. Registration fees are $500 per person; $450 per person for teams of three or more. Attendance is free for physician fellows and eligible students.

More information about the foundation’s professional educational programs is available here.

The Parkinson’s Foundation works to enhance patient care and advance research toward a cure. According to the organization, 60,000 U.S. residents are diagnosed with Parkinson’s each year.

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The Compassionate Warrior in the Battle Against Parkinson’s

compassionate

“C” is for compassion in my CHRONDI Creed, a warrior’s guide in the battle against Parkinson’s disease. It may seem odd to label a warrior as compassionate. Normally we picture the warrior as fierce, brave, courageous, and strong. We don’t often associate compassion with such an image. However, in the battle against chronic disease, being both a warrior and compassionate person has important benefits. The compassionate warrior brings a special set of armor and weapons.

Compassion is the mindset upon which the strength and courage of a warrior are set in motion. I have defined compassion as empathy plus wisdom; empathy is the ability to sense and hear the suffering of others, while wisdom is the ability to do something to reduce that suffering. Compassion is about the reduction of suffering in the world.

The first step to becoming a compassionate warrior is making a commitment to a life of compassion, or having a philosophy of compassion. The second step is to realize that you can change your behavior so that you contribute less to the suffering of those around you. The third step is realizing that you can act in a way that helps reduce the suffering of those around you without sacrificing your well-being. In fact, this path of the compassionate warrior promotes personal well-being.

The challenges of living with PD are many. The most obvious are the motor and coordination issues that impact every movement. There are also equally impactful emotional issues such as impulse control, grief, loss, depression, anxiety, and anger. Also included is a decreased ability to manage those emotions.

When the actions connected to these emotions spill out into life, the consequences can be costly and add to an already arduous chronic disease battle. The biggest contributor to human suffering is the objectification of the other person, which often happens when emotions overflow. This is where the practice of compassion plays an important role.

Practicing compassion is very much a scenario looping skill, and as such, it is good brain training for people with Parkinson’s. Without doing so directly, the practice of compassion helps us to moderate those emotions and decrease their consequences.

compassionate
(Graphic by Dr. C)

It may seem odd to say that acting compassionately has selfish benefits. That’s not the goal of compassion or its mindset, but those benefits are simply positive side effects. Compassion focuses on the other person. The skill at which a person can do this depends on their history with practicing compassion. You don’t have to be an expert to have it make a difference.

Practicing compassion at any level is good for relationships, and healthy relationships improve the quality of life for anyone with a chronic disease. The compassionate mindset is also one of gentleness, which can be (and should be) applied to self in healthy doses. Being a compassionate warrior does not mean we sacrifice our well-being for the sake of another. Two people in a rowboat, both manning the oars, makes the journey easier.

Compassion, after some practice, can move from contemplated action to the first action taken. It then becomes the first thought considered, which then becomes living as a compassionate warrior. I have been training as a compassionate warrior for decades, and PD has set me back. As a compassionate warrior, I continue to work as hard as any warrior would when preparing for battle. The compassionate warrior does this preparation along with meditation and a calm mind.

It is a commitment to a way of living that’s foundational for the other parts of the CHRONDI Creed. Additionally, the other parts of the CHRONDI Creed help to support this foundation to becoming a compassionate warrior against the chronic disease of Parkinson’s.

It is not easy to become a compassionate warrior in the battle against PD, but the benefits are worth the effort. What is your experience in applying compassion in your life?

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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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Behavioral, Metabolic Changes Linked to Sleep Restriction Could Foretell Parkinson’s, Animal Study Suggests

sleep restriction

Chronic sleep restriction alters movement, worsens cognitive dysfunction and induces changes in the levels of several amino acids — the building blocks of proteins — and other markers in rats with Parkinson’s, according to a new study.

According to researchers, these findings could enable the use of biomarkers to identify those at risk of developing the disease.

The study, “Chronic sleep restriction in the rotenone Parkinson’s disease model in rats reveals peripheral early-phase biomarkers,” was published in the journal Scientific Reports.

Non-motor symptoms of Parkinson’s typically appear years before significant loss of dopamine-producing neurons in the substantia nigra, an area of the brain key to motor control. One such symptom is impaired sleep. Both sleep disturbances and lifestyle-imposed sleep restrictions may contribute to cognitive decline and produce detectable alterations in the body.

However, it remains unclear whether sleep disturbances constitute a risk factor for developing Parkinson’s disease.

An international team of researchers from Brazil, the U.K. and the Netherlands used the rotenone-induced rat model of Parkinson’s disease to evaluate if chronic sleep restriction triggers metabolic changes, cognitive impairment, and changes in the circadian rhythm (the body’s internal clock).

When injected into the substantia nigra, rotenone, an agrochemical, induces similar changes to those seen in early Parkinson’s, including excessive daytime sleepiness, rapid eye movement (REM) sleep behavior disorder, insomnia, and disruption of spontaneous sleep.

The results revealed that, unlike rotenone, sleep restriction for 21 days (six hours per day) — by soft tapping or gently shaking the cage, or gently disturbing rats’ sleeping nest — did not induce loss of dopamine-producing nerve cells.

Animals subjected to sleep restriction did not show the decreased levels of locomotor activity (movement) observed in  rats injected with rotenone, as assessed using the open field test, which is an experimental test used to evaluate animals’ general locomotor activity levels, anxiety, and willingness to explore.

The object recognition task, which evaluates memory by measuring the time animals spend on a new object, revealed that sleep restriction aggravated rotenone-induced cognitive dysfunction. Sleep recovery for 15 days reversed rats’ memory deficits.

Sleep restriction also impaired the animals’ circadian rhythm, as they showed reduced activity during the first 75 minutes after lights-off (the night period  when rodents become more active) at weeks 2 and 3.

The investigators subsequently looked at biochemical alterations in blood plasma using two metabolic profiling approaches called global 1H nuclear magnetic resonance (NMR) spectroscopy and targeted liquid chromatography/mass spectrometry (LC/MS).

Sleep restriction increased plasma levels of amino acids leucine, isoleucine, valine, ornithine (reportedly increased in Parkinson’s), arginine, lysine, alanine, proline, phenylalanine (a precursor of dopamine) and carnitine, as well as 15 different phospholipids, which is a type of fat that is a key component of cellular membranes.

In contrast, sleep restriction lowered the levels of creatinine (a product of muscle metabolism), acetylcarnitine (a form of the amino acid L-carnitine), and kynurenine (a byproduct of the amino acid L-tryptophan and previously implicated in Parkinson’s), among other molecules.

When combined with rotenone, sleep restriction increased plasma concentrations of most of the same amino acids and also of 54 phospholipids, while decreasing creatinine and forms of amino acids such as acetylcarnitine. Sleep recovery completely eliminated the changes induced by sleep restriction and rotenone regarding these molecules.

A statistical analysis then revealed that the concentrations of isoleucine, leucine and kynerunine were different when comparing animals on sleep restriction to controls. Concentration of the amino acid methionine correlated with rats’ activities.

NMR data additionally showed rotenone alone induced higher levels of circulating triglycerides and lipoproteins as well as LDL cholesterol (the “bad” cholesterol). In contrast, sleep restriction alone did not alter biochemical parameters.

Combined with rotenone, sleep restriction led to a more pronounced increase in amino acids levels, including phenylalanine and tryptophan, whose metabolism has been found altered in early-stage Parkinson’s patients. Sleep recovery again eliminated these changes.

“If combined, our results bring a plethora of parameters that represents reliable early-phase [Parkinson’s] biomarkers which can easily be measured and could be translated to human studies,” researchers wrote. Identifying who is at risk of developing the disease “has the potential to improve therapeutic strategies and possibly delay or attenuate the onset of symptoms,” they added.

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ProMIS Neurosciences Develops Antibodies Targeting Toxic Forms of Alpha-Synuclein

ProMIS Neurosciences

ProMIS Neurosciences has identified several antibody candidates that specifically target the toxic forms of alpha-synuclein, a key component of Lewy bodies that underlie the development of Parkinson’s disease.

In vitro (in the lab) studies have shown that ProMIS’s antibody candidates for Parkinson’s disease have a high specificity for toxic forms of alpha-synuclein without binding to non-toxic essential forms of the protein. Moreover, these antibody candidates prevent the spreading (propagation) of toxic forms of alpha-synuclein.

“In preclinical studies, ProMIS antibody candidates showed a high degree of selectivity for only the toxic forms of alpha-synuclein in a side-by-side comparison with other alpha-synuclein targeting antibodies that are currently in development,” James Kupiec, MD, ProMIS chief medical officer, said in a press release.

Alpha-synuclein plays a key role in a healthy brain, regulating the release of synaptic vesicles — “bubbles” — filled with chemical neurotransmitters (chemical messengers). The synapse is the junction between two nerve cells that allows them to communicate. This regulation occurs when alpha-synuclein is in its healthy state, i.e., arranged in a tetramer — four units of the protein wrapped around each other.

In Parkinson’s disease, alpha-synuclein’s 3D structure is altered (misfolded) promoting its aggregation into clumps and causing the death of dopamine producing-nerve cells. These cells are responsible for releasing the neurotransmitter dopamine, a critical neurotransmitter that regulates brain cell activity and function.

Traditional methods for generating antibodies are unable to specifically target the neurotoxic forms of proteins like alpha- synuclein. ProMIS Neurosciences developed a technology to design candidate antibodies that bind only to the toxic forms of misfolded proteins. That means these antibodies’ effectiveness is better and is linked with lower side effects.

“We used our proprietary discovery platform to generate several antibody drug candidates for Parkinson’s disease that precisely target only the toxic forms of alpha-synuclein,” Kupiec said.

“Selectivity represents the essential feature of a successful antibody therapy, for it is critical that treatment not hinder normal forms of alpha-synuclein that play an important functional role in the brain,” he added.

ProMIS Neurosciences’ lead antibody candidate, PMN310, being developed as a potential treatment for Alzheimer’s disease, was shown to attack only toxic forms of a protein linked to the disease — amyloid beta — and not normal forms. This investigational therapy is expected to enter Phase 1 clinical trials in 2019.

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L‐DOPA Treatment Prevents Age-related Iron Accumulation, Mouse Study Finds

iron accumulation

Levodopa (L-DOPA) therapy is neuroprotective and prevents age-related iron accumulation in the substantia nigra, a brain region involved in Parkinson’s disease.

The study with that finding, “L-DOPA modulates brain iron, dopaminergic neurodegeneration and motor dysfunction in iron overload and mutant alpha-synuclein mouse models of Parkinson’s disease,” was published in the Journal of Neurochemistry.

L-DOPA is sill the primary pharmacological treatment for Parkinson’s disease motor symptoms. However, while the therapy provides symptom relief immediately following the onset of motor symptoms, during later stages of the disease certain non L-DOPA-responsive symptoms emerge that contribute to the rapid decline in quality of life.

Conflicting evidence also suggests the therapy may further damage dopamine-producing neurons due to the overproduction of reactive oxygen species, a molecular phenomenon known as oxidative stress.

Oxidative stress is an imbalance between the production of free radicals and the ability of cells to detoxify them. These free radicals, or reactive oxygen species, are harmful to the cells and are associated with a number of diseases, including Parkinson’s disease.

Several studies have established an association between iron build-up and both aging and neurodegenerative disorders like Parkinson’s disease. Apart from loss of dopamine-producing neurons, Parkinson’s also is characterized by pronounced iron accumulation in two brain regions: the globus pallidus and the substantia nigra.

It has been suggested that free iron molecules can induce dopamine oxidation and thus contribute to Parkinson’s disease development. Nonetheless, the exact mechanism of iron-induced dopaminergic degeneration is still unclear.

“Considering the substantial conflicts in the literature regarding whether L -DOPA is either neurotoxic or protective, and that [iron] has multiple well-established roles in both normal [dopamine] metabolism and neurotoxic oxidation,” researchers from the University of Melbourne, Australia, examined the effects of L -DOPA administration in three mouse models of Parkinson’s disease.

Mice fed with an iron solution from 10 to 17 days of age — mimicking early-life iron overexposure to accelerated age-related accumulation; a mouse model of Parkinson’s disease which over-expresses human A53T mutation (hA53T) in the alpha-synuclein protein, mimicking disrupted dopamine metabolism; and a mouse model combining these two experimental paradigms, i.e., hA53T transgenic iron-fed mice.

Animals were given L-DOPA in their drinking water from three to eight months of age. Researchers analyzed the therapy’s effect on brain iron levels, nerve cell numbers and motor function prior to the equivalent onset of clinical symptoms, in comparison to mice fed with clioquinol spiked food for the same period of time.

Clioquinol is a compound that binds to iron molecules suppressing their (harmful) chemical activity. Studies demonstrate clioquinol is beneficial in animal models of three neurodegenerative disorders: Alzheimer’s disease, Parkinson’s disease and Huntington’s disease.

Results revealed L-DOPA did not increase neurotoxicity in any of the mouse models and prevented age-related iron accumulation in the substantia nigra, much like clioquinol.

In addition, researchers observed a potential neuroprotective effect, as in both the iron overload and the hA53T mouse models L-DOPA treatment significantly reduced iron levels in the substantia nigra, decreased protein carbonyls (biomarkers of oxidative stress), and prevented neurodegeneration.

“Chronic L -DOPA treatment showed no evidence of increased oxidative stress in [normal mice] midbrain and [normalized] motor performance, when excess [iron] was present,” researchers wrote.

Additionally, L-DOPA did not increase protein oxidation levels in hA53T mice, with or without excess iron accumulation in the substantia nigra, and showed evidence of neuroprotection.

At eight months, total iron levels did not increase in hA53T mice that did not receive L-DOPA, suggesting the mutant alpha-synuclein does not itself trigger harmful iron accumulation.

“When challenged with excess [iron] during a critical window of neurodevelopment [10-17 days of age], hA53T mice showed the expected increase in nigral [iron]. Interestingly, excess [iron] did not worsen or accelerate neuropathology,” researchers wrote.

Similar to clioquinol, L -DOPA was able to mitigate oxidative damage from excessive iron accumulation. This effect was not as pronounced in hA53T expressing mice, which are more susceptible to oxidative damage from iron exposure.

These findings suggest that alpha-synuclein dysfunction could be behind iron-mediated dopamine oxidation, with the latter being an early sign of parkinsonian neurodegeneration.

“We found no evidence in any of our model systems that L-DOPA treatment accentuated neurodegeneration, suggesting [dopamine] replacement therapy does not contribute to oxidative stress in the Parkinson’s disease brain,” researchers concluded.

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Vitamin A Supplement Fails to Protect or Treat Rats in Parkinson’s Disease Model, Study Says

retinol and neurons

Vitamin A, or retinol, given as an oral supplement did not prevent the loss of dopamine-producing neurons or lessen motor deficits in a rat model of Parkinson’s, a study reports.

Results also showed that retinol lowered levels of inflammatory markers in the blood and did not cause oxidative damage in the liver, but its use changed in potentially harmful ways the activity of inflammatory cells in the brain of rats without Parkinson’s.

The research, “The effects of retinol oral supplementation in 6-hydroxydopamine dopaminergic denervation model in Wistar rats,” appeared in the journal Neurochemistry International.

In the central nervous system, retinol (a type of vitamin A) plays diverse roles, including neuronal differentiation during embryonic development and long-lasting communication between neurons (nerve cells) in a key brain area involved in memory, the hippocampus.

Although in vitro (in the laboratory) and in vivo (with animal models) studies have reported that retinol has antioxidant and cell protective effects, and suggested a link between vitamin A deficiency and cognitive decline in Alzheimer’s, the use of retinol in prevent neurodegenerative disorders has not been fully explored.

To assess dietary retinol in Parkinson’s, researchers used a rat model in which a neurotoxin called 6-hydroxydopamine (6-OHDA) is injected into the brain’s substantia nigra, inducing the death of dopamine-producing nerve cells. This mimics hallmark changes in advanced Parkinson’s, leading to similar motor deficits.

The animals were given a form of retinol (retinyl palmitate, 3000 IU/kg per day, which is equivalent to 900 μg/day in an adult) orally over 28 days, followed by 6-OHDA injection. Their motor coordination, degree of neuroinflammation, and the content of dopaminergic neurons in the substantia nigra were then assessed.

As retinol supplements are also reported to have toxic effects, the scientists also looked systemic inflammation, liver toxicity, oxidative stress, and mutagenicity, or a toxic agent’s ability to cause mutations.

Data first showed no changes in 6-OHDA-induced oxidative stress or mutagenicity in the liver – the major organ in retinol storage – in treated animals. Retinol use also prevented a rise in blood levels of TNF-alpha and interleukin (IL)-1beta – two key mediators in the inflammatory response – in rats with Parkinson’s.

But retinol use did not protect against the loss of dopaminergic neurons and did not significantly ease motor deficits in the animal model. The rats’ motor function was tested 15 days after 6-OHDA injections.

In the substantia nigra, retinol administration was able to prevent the activation of microglia — key immune cells in the brain — but not of astrocytes, cells whose various functions include a role in the formation of the blood-brain barrier and response to injury.

However, rats without Parkinson’s-like disease (no 6-OHDA injections) and treated with retinol showed increased astrocyte activation. These cells can both work with and inhibit microglia, to boost or block neuroinflammation, the researchers said.

“These results, altogether, suggest that oral supplementation with retinol does not protect against dopaminergic toxicity in the [substantia nigra] and may disturb astrocytes and microglia functional homeostasis,” they concluded.

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Parkinson’s Foundation Will Gather Experts to Study Cannabis as Disease Therapy

Cannabis

These days, people with Parkinson’s disease tend to ask their doctors more questions about cannabis than any other subject; yet, few physicians have adequate answers for them.

So says a new survey announced by the Parkinson’s Foundation, which plans a conference on that subject next month in Denver.

The March 6-7 meeting will bring together about 40 top scientists, clinicians, physicians and marijuana industry executives, said James Beck, MD, the foundation’s chief scientific officer.

“There’s never been anything quite like this before,” Beck told Parkinson’s News Today by phone from his New York office. “Not a lot is known when it comes to Parkinson’s and medical marijuana. Our goal is to outline what we know and what we don’t know, what might be useful for Parkinson’s and what might not be useful.”

Cannabis2
Boxes of “Healer” CBD/THC cannabis drops await distribution at the Kind Therapeutics medical marijuana cultivation facility in Hagerstown, Maryland. (Photo by Larry Luxner)

He added: “Medical marijuana may have its utilities for treating some symptoms, but it isn’t a silver bullet.”

The survey, conducted jointly by the Parkinson’s Foundation and Chicago’s Northwestern University, found that 80% of Parkinson’s patients have used cannabis, and that 95% of neurologists have been asked to prescribe medical marijuana. But only 23% of doctors have ever received formal education on the subject.

In addition, 52% of the 56 experts who responded to the 73-item online survey took a neutral position on cannabis use with their patients, 9% discouraged its use, and 39% encouraged it.

“Having worked as a clinician for the past decade in Colorado — a state at the forefront of medical marijuana use — it is clear that people with Parkinson’s and their families are intensely interested in the potential of marijuana and cannabinoids in helping manage symptoms and other aspects of the disease,” Benzi Kluger, MD, a professor at University of Colorado Hospital and co-chair of the upcoming conference, said in a press release. “To date, there is more hype than actual data to provide meaningful clinical information to patients with Parkinson’s.”

Kluger wrote a review, “The Therapeutic Potential of Cannabinoids for Movement Disorders,” that was published in early 2015 in Movement Disorders.

Also presenting at the conference is A. Jon Stoessl, MD, co-director of the Djavad Mowafaghian Centre for Brain Health at the University of British Columbia in Vancouver.

“In order to move the field forward, we need to determine which cannabinoids are likely to be beneficial or harmful, whether people with Parkinson’s are at risk from side effects, what we are hoping to treat, and how to conduct informative clinical trials,” Stoessl said.

Finding answers

The Parkinson’s Foundation, founded in 1957, now has 120 full-time staffers and an annual budget of $33 million. It represents the roughly one million Americans with Parkinson’s, which now ranks as the second most common neurogenerative disease after Alzheimer’s.

Beck
James Beck, MD

Beck said his nonprofit hopes to “develop a path to understanding formulations of cannabis and the pharmacology behind it” for the benefit of Parkinson’s patients everywhere. Scientists have isolated more than 60 cannabinoids, including tetrahydrocannabinol (THC), the main psychotropic compound, and cannabidiol (CBD), a non-psychoactive chemical with potential therapeutic properties.

“What one buys over the counter is not consistent from batch to batch. It’s not produced in a regulated way,” Beck told us. “The weed that people may smoke today is 10 times more potent than what baby boomers were smoking in the ‘60s and ‘70s. It’s a natural product, and things like what ratios CBD and TCH should be are fundamental questions. We’ll have experts suggest what might be best.”

At the moment, 33 states and the District of Columbia have declared medical marijuana legal; that’s up from 20 states only four years ago. In D.C. and 10 states — Alaska, California, Colorado, Maine, Massachusetts, Michigan, Nevada, Oregon, Vermont and Washington — recreational use is also allowed.

Cannabis1
Baby marijuana plants thrive at the Kind Therapeutics cannabis cultivation facility in Hagerstown, Maryland. (Photo by Larry Luxner)

“The problem is that the federal government still considers it illegal, and that makes it difficult for researchers,” Beck said. “As we move forward to what’s likely to be a more permissive environment, we want to ensure that as legislation changes, we have a clear plan to move forward with research.”

Cannabis may be useful for several non-motor symptoms such as anxiety and weight loss associated with advanced Parkinson’s, he said, as well as for pain and stiffness.

“However, people with Parkinson’s can have cognitive impairment; some have psychosis and paranoia, and balance issues,” warned Beck, noting that falls constitute the leading cause of death for Parkinson’s patients. “Cannabis can lower blood pressure, which can lead to lightheadedness and falls, as well as hallucinations and paranoia, which may exacerbate the situation. It can also cause fuzzy thinking.”

A recent report, “Special Issue: Cannabis in Medicine,” that was published in the European Journal of Internal Medicine, concluded that cannabis reduces spasticity — muscular stiffness or involuntary spasms — in MS patients.

And data from two trials in Italy and the Czech Republic support the idea that Sativex, developed by Britain’s GW Pharmaceuticals, is effective in treating moderate-to-severe spasticity. The oromucosal spray is a formulated extract of the cannabis sativa plant and has earned approval in Australia, Canada, Israel and more than a dozen European countries.

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