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Parkinson’s May Originate From Alpha-Synuclein Migrating From the Gut, Rat Study Shows

gut Parkinson's alpha-synuclein

New experimental evidence collected from rats shows that alpha-synuclein — the protein that causes Parkinson’s disease — can travel from the intestines to other organs, such as the heart and brain.

These findings, reported in the study “Evidence for bidirectional and trans-synaptic parasympathetic and sympathetic propagation of alpha-synuclein in rats,” provide further support to the hypothesis that the development of Parkinson’s disease is directly linked to the intestinal system.

The study was published in Acta Neuropathologica.

A hallmark feature of Parkinson’s is the progressive degeneration of brain cells due to the accumulation of toxic clumps of alpha-synuclein, called Lewy bodies.

Prior work in postmortem human brains has shown that the misfolded protein primarily accumulates in brain areas controlling movement, which explains the characteristic motor symptoms associated with the disease. But that work also revealed the protein’s accumulation in the vagus nerve – which connects the brain to the gut.

This led to the theory that Parkinson’s progression could require communication between the gut and the brain.

To further explore this association, researchers from Aarhus University and its clinical center, in Denmark, conducted a new study in rats. The team used rats that were genetically modified to produce excessive amounts of alpha-synuclein, and which were susceptible to accumulating harmful versions of the protein in nerve cells. Human alpha-synuclein or an inactive placebo was injected into the small intestines of these rats.

With this approach, the investigators found that both groups of rats — those injected with alpha-synuclein or placebo — had high levels of the protein in the brain. However, only those injected with alpha synuclein showed Parkinson’s characteristic clump build-up patterns, which affected the motor nucleus and substantia nigra in the brain.

“After two months, we saw that the alpha-synuclein had travelled to the brain via the peripheral nerves with involvement of precisely those structures known to be affected in connection with Parkinson’s disease in humans,” Per Borghammer, an Aarhus University professor and the study’s senior author, said in a press release written by Mette Louise Ohana.

“After four months, the magnitude of the pathology was even greater. It was actually pretty striking to see how quickly it happened,” Borghammer said.

Alpha-synuclein also was found to accumulate in the heart and stomach, which suggests a secondary propagation pathway. That pathway likely is mediated by the celiac ganglia, which are abdominal nerve bundles that innervate the gastrointestinal tract.

A recent study conducted by researchers at Johns Hopkins University School of Medicine revealed similar data, but in mice. The Hopkins team also found that, when they injected an altered form of alpha-synuclein in the intestine of mice, it would first accumulate in the vagus nerve and subsequently spread throughout the brain.

With the findings from the new study, researchers now have more detailed evidence on how the disease most likely spreads.

This may put the scientific community one step closer toward developing more effective medical strategies to halt the disease, Borghammer said.

“For many years, we have known that Parkinson patients have extensive damage to the nervous system of the heart, and that the damage occurs early on. We’ve just never been able to understand why. The present study shows that the heart is damaged very fast, even though the pathology started in the intestine, and we can continue to build on this knowledge in our coming research,” he said.

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The Top Things I Learned in Parkinson’s Summer School

Summer School

Laurie K. Mischley, a naturopathic doctor, assembled approximately 60 people with Parkinson’s for a conference at Bastyr University’s Seattle campus in August. The six-day “summer school” included lectures, exercise classes, and nutrition advice designed to improve each patient’s experience with Parkinson’s and possibly slow progression. Those in attendance provided blood, urine, breath, hair, and stool samples for analysis. The data gathered were used to tailor science-based, real-world strategies for each student to implement at home.

Mischley is the principal investigator in the research study “Complementary & Alternative Medicine Care in Parkinson’s Disease,” which analyzes patient experiences. This study tracks medication, dietary, and nutrition habits, as well as supplement use and other selected behaviors of people with Parkinson’s, and will correlate those factors with disease progression. For many years, Mischley has treated only patients with Parkinson’s.

Mind and movement classes were offered at 8 a.m. and 1 p.m. daily. Classes in yoga, qi gong, meditation, the Feldenkrais Method, and high impact, to name a few, were led by personal trainers, certified instructors, or physical therapists. The whole teaching staff was experienced in movement techniques that are tailored for people with Parkinson’s.

Following are my top takeaways from the conference and the teachings of Mischley. Consult your doctor before making any changes to your health regimen.

1. Step outside my comfort zone

Mischley stressed the importance of doing new, different, and challenging activities. They help us build new neural pathways, which may help slow disease progression. During the week, we were offered sessions in drumming and singing — activities that are not in most people’s comfort zones.

2. Taking prescription drugs is not enough

Socialization and support groups, exercise, diet, and dietary supplements are extremely important.

At one of the meals, I spooned rice onto my tray rather than my plate. While trying to fix the mess I’d made, I looked around and saw faces filled with empathy rather than annoyance and impatience. Many of us with Parkinson’s deal with clumsiness and the “dropsies” on a daily basis. Being surrounded by people who understand Parkinson’s symptoms can be quite comforting.

Self-isolation does not help depression (a possible Parkinson’s symptom). I know that I need to socialize more, but sometimes fatigue (my worst Parkinson’s symptom) gets in the way.

I have long believed that exercise is key to staving off disease progression. Mischley’s recommendation is five to seven days per week of movement activity, some of it intense enough to elevate the heart rate (e.g., it should be difficult to talk while walking at a brisk pace). Amplitude training and task-specific exercises should also be included.

Flavonoid consumption might be neuroprotective. Hence, Mischley recommends including plenty of dark berries and several cups of green tea in the daily diet.

A plant-based diet (no dairy) is the way to go.

3. Disease progression may be slowed with some supplements

Mischley recommends the following to potentially slow disease progression:

  • Glutathione: intranasal is better than capsules, but much more expensive;
  • CoQ10: has mitochondrial/cellular protection properties;
  • Turmeric/curcumin: curcumin exhibits antioxidant and anti-inflammatory properties, crosses the blood-brain barrier, and may be neuroprotective;
  • DHA: has anti-inflammatory properties.

4. Absorption of nutrients and medications is important

Just taking medications and vitamins is not enough. The body must properly absorb them. Even though I was taking a lot of supplements (B, D, omega-3 fatty acids), my lab results showed that I was deficient in these substances, which may indicate that my body is not properly absorbing them. I have always felt that the carbidopa/levodopa (C/L) I was taking did not really help my symptoms. Perhaps my body was not absorbing that medication properly, either.

A suggested way to optimize C/L absorption is to take nonbuffered vitamin C, such as Emergen-C, with medication. CDP-choline  and a digestive enzyme supplement were also recommended to possibly improve nutrient and medication absorption.

5. People with Parkinson’s typically show common nutrient deficiencies

Through her research, Mischley has found that there is some commonality in out-of-range lab test results among people with Parkinson’s:

* I was out of range in these areas

Most standard blood test panels do not include testing for any of the above.

6. There is no ‘magic pill’ that addresses all symptoms or progression

Mischley compares Parkinson’s to a boat with a lot of holes in it. There is no one plug that will fix all the leaks, but rather a platter of plugs. Plus, we all need to find our own way. What works for some may not work for others.

It takes a lot of trial and error to figure out a personalized strategy. However, I have faith that there is a “cocktail” of remedies that will work for me. Attending Parkinson’s Disease Summer School has helped me take the first step by giving me the tools and information I need.

***

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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Boosting Levels of Molecule in Brain Slows Parkinson’s Progression and Eases Symptoms, Animal Study Finds

animal model study

A molecule called GM1 ganglioside may protect the brain against the molecular changes associated with Parkinson’s disease progression, and may one day directly treat its neurodegenerative processes, according to an early study.

The study, “GM1 Ganglioside Modifies α-Synuclein Toxicity and is Neuroprotective in a Rat α-Synuclein Model of Parkinson’s Disease,” was published in Scientific Reports.

GM1 ganglioside is a component of the cell membrane and has long been considered a master modulator of the nervous system because of the many functions it regulates.

Parkinson’s patients have lower-than-usual levels of GM1 ganglioside within the substantia nigra, a brain region that’s severely damaged in Parkinson’s.

In lab experiments, GM1 ganglioside was found to protect against the aggregation of alpha-synuclein protein, the main component of Parkinson’s hallmark Lewy bodies. Specifically, GM1 ganglioside did not allow acetylated alpha-synuclein to form harmful clumps or aggregates within the cells. Acetylated (with an added acetyl group) alpha-synuclein has been shown to more effectively induce intracellular clustering in nerve cells, compared to the unchanged form of alpha-synuclein.

This suggests that problems with GM1 may somehow contribute to the vulnerability and degeneration of dopamine-producing neurons seen in Parkinson’s disease.

Using a rat model of Parkinson’s, researchers for this study investigated the extent to which GM1 ganglioside could protect against alpha-synuclein toxicity and the development of Parkinson’s-related molecular and behavioral changes.

A single injection of an adeno-associated viral vector (AAV) carrying a copy of human mutant alpha-synuclein was administered into the substantia nigra of rats, leading to protein aggregation and the degeneration of dopaminergic neurons, a decrease in dopamine levels within the striatum (another motor control brain center that’s affected by Parkinson’s), and behavioral problems.

Some rats were then randomly assigned to daily GM1 ganglioside injections (30 mg/kg) beginning 24 hours after AAV-alpha-synuclein administration and lasting for six weeks (early start group). Others were given the daily GM1 ganglioside injections (30 mg/kg) three weeks after the AAV-alpha-synuclein, and lasting for five weeks (delayed start group).

Results showed that GM1 ganglioside protected against loss of substantia nigra dopamine-releasing neurons and striatal dopamine levels, and reduced alpha-synuclein clumping. Importantly, the delayed start of GM1 ganglioside reversed motor deficits that had appeared in this animal group, suggesting the therapy was able to restore their motor function.

“When we looked in the brains of these animals, not only did we find we could partially protect their dopamine neurons from the toxic effects of alpha synuclein accumulation, we had some evidence that these animals had smaller and fewer aggregates of alpha-synuclein than animals that received saline injection instead of GM1,” Jay Schneider, PhD, a professor in the department of pathology, anatomy and cell biology at Thomas Jefferson University and first author of the study, said in a press release.

Scientists believe the low brain levels of GM1 ganglioside seen in Parkinson’s may facilitate the formation of harmful alpha-synuclein clumps.

“By increasing GM1 levels in the brains of these patients, it would make sense that we could potentially provide a slowing of that pathological process and a slowing of the disease progression, which is what we found previously in a clinical trial of GM1 in Parkinson’s disease patients,” Schneider said. Results of that university-sponsored trial (NCT00037830) in 77 patients, concluded in 2010, supported its potential as a disease-modifying treatment.

Schneider’s team is now focused on finding out what other effects GM1 ganglioside might have on alpha-synuclein.

“It’s important to understand how GM1 is working because there might be other ways we could manipulate GM1 levels in the brain to have a beneficial effect,” he added.

According to the researchers, GM1 has the potential to be a treatment that directly impacts “the underlying disease processes in [Parkinson’s disease] and that can slow neuronal cell death and symptom progression,” protecting dopamine neurons from dying “as well as rescue and restore function to damaged but viable neurons.”

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Molecule May Halt Parkinson’s Progression, Study Using New Mouse Model Finds

anle138b molecule

A molecule called anle138b was able to reduce toxic alpha-synuclein aggregates, or clumps, in the brain — a key event linked to Parkinson’s — and reverse motor symptoms associated with the disease in a novel Parkinson’s mouse model.

The study, “Depopulation of dense α-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson’s disease model,” was published in Acta Neuropathologica. The work was funded by the charity Parkinson’s UK.

Many neurodegenerative disorders involve aggregation of misfolded (harmful) proteins in the brain. Parkinson’s is characterized by a buildup of the protein alpha-synuclein in the brain, which forms clumps known as Lewy bodies that damage and kill nerve cells, or neurons.

Anle138b has been shown to reduce toxic protein accumulation and delay disease progression in models of multiple system atrophy, Alzheimer’s disease and Parkinson’s.

Investigators from the University of Cambridge now evaluated the effects of anle138b in a new mouse model of Parkinson’s disease.

Although this molecule had previously been shown to reduce the clumping of proteins in other Parkinson’s models, the team wanted to understand its potential to treat the condition during its natural progression. To that end, they created a new mouse model that mimics the way alpha-synuclein gradually accumulates in specific areas of the brain, impairing neuronal communication and resulting in motor alterations.

The animals were nine months old before treatment initiation — around 46 human years. At the start of the treatment, the mice already showed low levels of dopamine in their striatum, a brain region involved in voluntary movement control that is severely affected in Parkinson’s. This reduction was associated with the onset of motor symptoms, including changes in gait that resembled some of the early motor symptoms seen in individuals with the disease.

However, the animals’ substantia nigra, another brain region involved in motor function that is also affected by the disease, had not yet been significantly damaged. Mice striatal (meaning “of the striatum”) and nigral (meaning “of the substantia nigra“) dopamine-producing neurons also exhibited alpha-synuclein aggregation.

Starting at nine months of age, mice were treated with anle138b for three months. Treatment reduced alpha-synuclein clumps, restored dopamine levels in the brain, and prevented dopaminergic nerve cell death. This was accompanied by gait improvements, suggesting that anle138b can effectively reverse, or at least halt, Parkinson’s progression.

These results indicated that “there is a window of time when it is possible to prevent [dopaminergic] neuronal death, even when striatal [dopaminergic] release is already impaired,” the researchers said. This means that if anle138b is given early on — before advanced nerve cell death — it may reduce  alpha-synuclein aggregates, potentially halting Parkinson’s progression.

“Our study demonstrates that by affecting early alpha-synuclein aggregation with the molecule anle138b in a novel transgenic mouse model, one can rescue the dopaminergic dysfunction and motor features that are typical of Parkinson’s,” Maria Grazia Spillantini, professor in the department of clinical neurosciences at the University of Cambridge, and the study’s lead researcher, said in a press release.

“The evidence from this early stage study builds on our understanding of how alpha-synuclein is involved in Parkinson’s and provides a new model that could unlock future treatments,” added Beckie Port, research manager at Parkinson’s UK.

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

caudate involvement

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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#AANAM – Promising Blood Pressure Medicine Fails to Slow Parkinson’s Progression, Trial Results Show

Dynacirc study

In contrast to what was observed in mice, a hypertension medicine called Dynacirc (isradipine) failed to slow Parkinson’s disease progression in humans, according to Phase 3 clinical trial results.

However, “the study did not fail,” according to Tanya Simuni, MD, who presented “A Phase 3 study of isradipine as a disease modifying agent in patients with early Parkinson’s disease (STEADY-PD III): Final study results” during the 2019 American Academy of Neurology Annual Meeting in Philadelphia. Instead, the study’s negative results are important to understand how to fine-tune future approaches for effective treatments, Simuni said.

Belonging to a class of medications called calcium channel blockers, Dynacirc is used to treat high blood pressure (hypertension). The medicine relaxes blood vessels so the heart does not have to pump as hard, ultimately reducing blood pressure. Importantly, Dynacirc can penetrate the central nervous system and reach the brain, where it needs to exert its effects.

A preclinical study demonstrated that upon treatment with Dynacirc dopaminergic neurons — those that are lost as a consequence of Parkinson’s — had levels lower of oxidative stress than those of untreated mice, suggesting the medicine could have a protective role against oxidative stress damage.

Oxidative stress is an imbalance between the production of free radicals and the ability of cells to detoxify them, resulting in cellular damage as a consequence of high levels of oxidant molecules. Importantly, the molecular phenomenon has been implicated in the degeneration of dopamine-producing neurons.

Researchers believe dynacirc can protect neurons by blocking calcium channels on the surface of dopaminergic nerve cells. Normally these cells are continuously flooded with calcium, fueling cells’ powerhouses (mitochondria), which ends up contributing to harmful oxidative stress and, consequently, nerve cell death.

STEADY‐PD III was a 36-month, Phase 3, placebo‐controlled study (NCT02168842) assessing the effectiveness of Dynacirc 10 mg daily (two daily 5 mg doses) in 336 participants with early Parkinson’s disease who were not receiving dopaminergic therapy.

Participants were assigned randomly to receive Dynacirc or placebo for three years. Subjects had to complete 12 in-person and four telephone visits, during which researchers evaluated patients’ motor, neuropsychiatric, and cognitive skills. Blood and urine samples also were collected.

There were a total of 68 serious adverse events among treatment groups, six of which were deemed possibly related to treatment.

Although considered safe and well-tolerated, the treatment failed to slow progression of Parkinson’s disability. Researchers believe this may have been due to several reasons, including late intervention or inappropriate dosing, as the dose was selected based on tolerability and may not have effectively blocked the desired calcium channels.

Another hypothesis is that this target might not be the leading cause of human Parkinson’s development, or that a single target may not be sufficient to treat or slow disease progression.

“Unfortunately, the people who were taking isradipine did not have any difference in their Parkinson’s symptoms over the three years of the study compared to the people who took a placebo,” Simuni said in a press release. “Of course, this is disappointing news for everyone with Parkinson’s disease and their families, as well as the research community.”

“However, negative results are important because they provide a clear answer, especially for the drug that is commercially available. We will all continue to work to find a treatment that can slow down or even cure this disease,” she added.

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Low Levels of Substance P in Saliva May Help Predict Swallowing Problems, Study Suggests

substance P dysphagia

Low levels in saliva of a molecule called substance P may help predict the development of swallowing problems in people with Parkinson’s disease, a small pilot study in Germany found.

Since this molecule works as communication signal between nerve cells in the body, this discovery suggests that impaired substance P activity may be an important contributing factor in the  development of this Parkinson’s complication.

The study, “Substance P Saliva Reduction Predicts Pharyngeal Dysphagia in Parkinson’s Disease,” was published in the journal Frontiers in Neurology.

The progression of Parkinson’s disease is associated with the loss of movement control, including control over muscles in the face, mouth, and throat. This can lead to speech problems and swallowing difficulties, which are known medically as dysphagia.

Such swallowing difficulties can severely affect a person’s ability to sustain healthy eating practices without needing additional support.

“Parkinson’s-related dysphagia affects the oral, pharyngeal and the esophageal phase of swallowing and occurs in all stages of the disease,” the researchers said.

However, this complication may remain undetected during early stages of Parkinson’s in many patients, which may prevent early diagnosis and timely care, they said.

Previous studies have shown that levels of the neurotransmitter substance P are reduced among elderly Parkinson’s patients who have aspiration pneumonia. This suggests that substance P may be involved in the underlying mechanism of the normal swallowing and cough reflex in the throat’s inner tissues, called the pharyngeal mucosa.

To learn more, German researchers explored the role of substance P in the progression of pharyngeal dysphagia in people with Parkinson’s.

The study enrolled 20 patients; half showed signs of swallowing difficulties. Researchers collected saliva samples from all patients and analyzed the levels of substance P.

Participants who did not have pharyngeal dysphagia were slightly younger, had Parkinson’s for fewer years, and also showed fewer signs of motor impairments caused by the disease as compared to patients with the complication. However, these differences were minor, and the groups were considered to be at similar disease stages.

The results showed that patients who did not have swallowing problems had 1.8-fold higher levels of substance P than those with dysphagia.

“Our findings could be another indication that, in early stages, loss of substance P containing neurons in the pharyngeal mucosa may lead to pharyngeal hyposensitivity and merely incipient pharyngeal dysphagia,” the researchers said.

Additional studies are warranted to further understand the role of substance P in Parkinson’s disease progression, the researchers said. They also recommended that further studies be done to evaluate substance P’s potential as a biomarker for early dysphagia.

Future research also should address the potential use of capsaicin — an active compound in chili peppers known to stimulate the release of substance P — as strategy to target the sensory system within the swallowing network of nerve cells, they added.

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Heel, Toe: Walking with Mindfulness

walking

Slow Is the New Fast Jean Mellano

Mindfulness isn’t difficult, we just need to remember to do it.” — Sharon Salzberg

The ability to walk is something many of us, myself included, have always taken for granted. Now that I have Parkinson’s disease (PD), something that used to come as a matter of course to me is starting to deteriorate. PD has adversely affected my left side more than my right side. I find myself tripping more, since I tend to drag my left foot.

Walking now requires my conscious thought

Going for a walk is now more of a mindful task than an exercise for me. I find it much more therapeutic to focus on how I walk and be in the present moment than to think about the future and how my PD may progress. With each step I take, I concentrate on repeating to myself, “Heel, toe.”

My stride analysis

When there was snow on the ground, I decided to compare my walking steps when I did not focus on saying “heel, toe” with those from when I did. My footprints in the snow were very telling, so I took a photograph. On the left side of the photo are my steps when I was not thinking about my stepping patterns. You might notice that both feet show a bit of a drag in the snow. On the right side of the photo, as I moved forward, I really focused on flexing both of my feet and having my heel strike first. There are no signs of drag on either foot.

Am I putting too much thought into this?

Years of training to improve as a dancer and a cyclist have made analysis of my body movements come quite naturally to me. Whether it was improving my pedal stroke for more cycling power or perfecting my balance to do pirouette turns, I learned to be mindful and to be in touch with how my body was performing. Now I must use that skill to help myself be more attentive when I walk.

My neurologist says I tend to overthink things. I believe our greatest strengths can also be our greatest weaknesses. Sometimes, I do overthink, to the point of getting paralysis by analysis. However, I believe that mindful analysis of my PD symptoms (including my walking technique) is critical in helping me to create different ways of doing things that at one time (before PD) used to come as second nature to me.

Do not dwell in the past, do not dream of the future, concentrate the mind on the present moment.” — Unknown

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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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Parkinson’s Gene Variant May Affect Gene Expression, Disease Progression, Study Suggests

A Parkinson’s disease genetic risk variant, called rs1109303, might have a direct impact on the expression of nearby genes INPP5K and CRK, influencing disease risk and progression, a study suggests.
The study, “Parkinson’s Disease Risk Variant rs1109303 Regulates the Expression of INPP5K and CRK in Human Brain,” was published in Neuroscience Bulletin.
Parkinson’s disease, the second most prevalent neurodegenerative disorder in the elderly, affects 1-2% of people over the age of 65 worldwide, and is characterized by the gradual loss of muscle control, sometimes accompanied by cognitive deficits.
Previous large-scale genome-wide association studies (GWAS) identified several genes that increase a person’s predisposition toward developing Parkinson’s, including SNCA, MAPT, NUCKS1, the HLA region, GAK, BST1, GBA, WNT3, RIT2, and LRRK2. GWAS are studies based on a method that scans the genome (all of the genes present in our DNA) looking for specific types of genetic alterations found more frequently in people with a particular disease.
Besides genetic risk factors, studies have reported that uric acid (urate) levels in blood serum may also contribute to increasing an individual’s susceptibility to Parkinson’s.
In 2015, a GWAS study found a direct association between urate levels and the rs1109303 risk variant, which is located within the noncoding sequence — regions that do not encode protein sequences — of the INPP5K gene.
At the time, scientists were convinced that the rs1109303 variant might influence disease progression by affecting the expression of nearby genes, namely MYO1C, PITPNA, SLC43A2, and CRK. Gene expression is the process by which information in a gene is synthesized to create a working product, like a protein. However, at the time, they did not pursue this line of investigation further.
Now, researchers in China have gone back to the original hypothesis drawn in 2015 and set out to investigate whether the rs1109303 risk variant could regulate the expression of nearby genes INPP5K, MYO1C, PITPNA, SLC43A2 and CRK.
The team analyzed multiple large-scale expression quantitative trait loci (eQTL) data sets, including a total of 22 human brain and 34 non-brain tissue samples from healthy donors and patients with neurological disorders. Expression quantitative trait loci are specific locations within the genome that contain genes encoding for traits that can be measured in a quantitative way.
The first eQTL data set from the Brain eQTL Almanac (Braineac) included 10 eQTL data sets from 10 brain regions of 134 healthy individuals.
The second eQTL data set from the Genotype-Tissue Expression (GTEx) database included a total of 449 donors — healthy individuals (94%) and subjects with neurological diseases (6%) — with a total of 7,051 samples from 44 different tissues.
And the third eQTL data set included whole blood data from three different studies involving 5,311, 2,116 and 5,257 individuals.
Analysis of the Braineac data set showed that the rs1109303 variant was associated with an increase in the expression of the CRK gene in the occipital cortex — the visual processing center of the brain.
In the GTEx data set, the rs1109303 variant was linked to an increase in the expression of INPP5K in the anterior cingulate cortex — an area of the brain that plays a role in regulating blood pressure and

Source: Parkinson's News Today

Parkinson’s Subtypes Share Early Psychiatric Features, But Diverge as Disease Progresses, Study Suggests

motor subtypes

In the early stages, three motor subtypes of Parkinson’s disease share similar psychiatric and cognitive features, with the distinct psychiatric profiles associated with each type only appearing as the disease progresses, a study suggests.

The study, “Psychiatric profile of motor subtypes of de novo drug-naïve Parkinson’s disease patients,” was published in the journal Brain and Behavior.

Parkinson’s disease is a diverse neurodegenerative disorder with distinct motor and non-motor symptoms. It is already known that different motor subtypes of the disease evolve with different clinical courses and prognoses.

Parkinson’s can be divided into three main clinical subtypes according to the predominant motor features: tremor-dominant, where tremor is a predominant symptom of the disease; akinetic-rigid or postural instability gait difficulty, characterized by stiffness or inflexibility of the muscles; or mixed, with no prevailing motor features.

Patients diagnosed with akinetic-rigid usually show a faster disease progression and are at higher risk of developing disability and dementia. On the other hand, progression of the tremor-dominant form is slower and associated with less cognitive decline, visual hallucinations, and depression.

These differences are attributed to lower dopamine levels in the brains of akinetic-rigid patients than in those with the tremor-dominant subtype.

Italian researchers studied the psychiatric, cognitive, and motor profiles of these three Parkinson’s subtypes in early, untreated Parkinson’s patients. They used untreated patients to avoid bias of the medication effect.

They included 68 newly diagnosed Parkinson’s patients, of whom 39 were akinetic-rigid, seven were mixed, and were 22 tremor-dominant. The participants underwent a complete assessment of psychiatric symptoms, including depression, anxiety, and apathy; cognitive issues, such as memory, language, attention; and motor features.

No differences were observed among the three Parkinson’s subtypes in any of the psychiatric and cognitive variables assessed. Researchers hypothesize that psychiatric differences among the three motor subtypes are not present in the very early stages of the disease, suggesting that a possible differentiation emerges only over the progression of the disease and potentially with its interaction with dopaminergic replacement therapy.

“This idea is widely supported by the literature on PD patients with longer disease duration and under antiparkinsonian treatment showing greater cognitive deterioration and psychiatric symptoms in AR patients,” the authors wrote.

“The evolution of psychiatric features is not predictable based on early motor presentation and regular follow-ups are needed to investigate their different possible progression,” they concluded.

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Source: Parkinson's News Today