Devices to Record the Progression of PD


The progression of Parkinson’s disease (PD) is unique to every person, with different early, middle, and late-stage symptoms. However, this view of PD progression may be an artifact of limited data rather than an accurate description. We need new ways of measuring PD symptoms as they change over time. We have the technology to create new devices that people can use over an extended period, across multiple settings and severity of “off periods.”

I see progression as a change in the intensity and duration of “bad” days and off periods. Many longitudinal studies investigate the progression of PD (for example, the rate of progression in exercise), but it is hard to find studies that measure changes in response to treatment. Devices discussed in this column might change that.

Better measurement of PD progression begins with a few assumptions. First, subtle, early motor symptoms will appear before more obvious symptoms, such as tremors or bradykinesia. Second, early motor symptoms will be inconsistent and episodic. Third, we have the technology to build mobile monitoring devices.

I recently read that a patient being evaluated for “internal tremors” showed no signs of tremor during a physical examination of his bare feet. However, once he put his socks and boots on, an astute clinician observed the left bootlace swinging in such a way that, when measured, fit the PD pattern of a tremor. In other words, while the patient didn’t exhibit tremor during a visual examination of his bare feet, his shoelace reflected an underlying tremor!

A shoelace is not going to be a reliable measuring device, but it proves that slight motor changes that are difficult to detect do exist. I’ve designed two possible motor symptom detection devices: a mobile swing monitor (MSM) and a fine motor skills test (FST). Both devices would record and monitor movement fluctuation over time and across settings in daily life over 10 or so days. Both devices use sensors to track and record movement through three dimensions.

The MSM uses five “movement in 3D space” sensors — one on each wrist, one on each ankle, and one on the belt — with recording hardware for all five. Worn for several days, like a Holter monitor, the MSM would map the sway of the arms, legs, and body over time and across settings. The MSM is very similar in appearance to wearable training weights, which can measure the slightest variations in body movement. Wearable training weights are used by Olympic and World Cup judges to evaluate Shaun White’s amazing snowboard flips and twists.

The FST, illustrated in the graphic below, has a 3D monitor in the “soda can” receptor where the block is inserted. Similar to the game “Operation,” the patient must remove objects from openings in the receptor without setting off the buzzer. The warning light goes off when the sensor plate is touched.

The FST will measure how the person adjusts position and control while using fine motor skills. The FST uses a 3D monitor and four independent, pressure-sensitive plates that record when the patient fails to insert the block and when the block is aligned. The plates can be positioned at different widths using an adjustable difficulty setting, making it harder to insert the block without touching the plates.

Fine skills motor test, designed by Dr. C. (Photo by Dr. C)

Data gathered by these two devices may provide patients and medical professionals with more accurate clinical data about motion, tremors, and fine motor skills over a greater period. They could demonstrate the progression of intensity and duration of bad days and off periods and serve as the beginning of a database on PD progression.

Many people are excited about using technology to provide outcome measures. As we know, technology is not being utilized in offices with patients to help understand the progression of PD. But hopefully, that will change.

If these devices are already being tested in the home of PD patients, sign me up!


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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Understanding What Parkinson’s Progression Means to Each Patient


Every day following the ruin of stagnation, it seems that I have progressed from early Parkinson’s to a moderate stage of the disease. But I can’t be sure. Many other factors, including stress, injuries, medication changes, and aging, could be making it look and feel worse. To appease my quandary, I dove into the internet, searching for elucidation about Parkinson’s progression.

We watched as Michael J. Fox and Muhammad Ali were changed by the disease. Granted, their Parkinson’s symptoms were dramatic: Their body movements gradually became less fluid, the tremors more pronounced. Over time, the movement challenges became more noticeable, signifying progression. The Parkinson’s community uses the terms “early,” “middle,” and “late” stage to describe progression. It mostly makes sense and matches what medical providers identify with patients. But it doesn’t help me in my search for well-being possibilities.

Progression for me is more than “early,” “middle,” or “late.” I accept that the disease will cause changes in me and my life. But it would be helpful for my wellness map if some of the pitfalls could be marked, “Danger ahead!” or, “Here’s a list of supplies,” to get me through the hardest parts of my chronic disease journey. Being well-prepared is an essential part of wellness success. The progression of Parkinson’s is not about stages — except in a general way. Rather, it means having some idea about what can be done to slow the progression, or, failing that, how to recognize when progression is happening. Useful information about progression would help guide us through what is sometimes a tortuous journey. It might make the trip easier.

Chatting with the Parkinson’s community reveals the entrenched idea that progression is unique to each person. It would be helpful if our understanding of progression could provide for each patient more details than, “It’s unique to everyone, and you will know when you get there.” So what’s holding up progress toward understanding disease progression?

Medical professionals determine Parkinson’s progression by a system involving a physical exam, patient report, and sometimes a standardized measurement tool or questionnaire. That system fails when all that we are told about progression is, “You’ll know it when you get there.” We need better information from early Parkinson’s stages to understand progression to middle and beyond. Data from the existing collection system is insufficient to give a clear understanding of what progression means to each patient.

I recently read an article in which the authors discuss the merits of the retropulsion test to evaluate postural instability in Parkinson’s. The three methods are: “(1) the pull test as described in the MDS-UPDRS scale; (2) using an unexpected shoulder pull, without prior warning; and (3) the push-and-release test.” Although the test is considered the gold standard, the authors state that “the outcome can vary considerably due to variability in test execution and interpretation.”

The authors state that the test fails to predict future falls, explaining that falling results from the “complex interplay between gait, balance, cognitive decline and environmental factors, and the retropulsion test captures only part of that.”

It is difficult to spot early symptoms during a short office visit once every three to six months. Increasing the speed of care by reducing the duration of clinic appointments has not improved healthcare for this ailing columnist. It hinders the ability of the healthcare practitioner to get to know the patient better and increases the chance of the latter being categorized as “that patient with Parkinson’s.” The provider can’t see all the effects of the chronic disease, even with a longer visit.

We have good and bad days, on and off periods, and life circumstances — all of which make data collection on Parkinson’s progression from a 15-minute office visit problematic. It makes sense that early diagnosis and proper treatment should make a difference in progression. As far as I can tell, no adequate longitudinal studies exist that describe variation in progression as a result of treatment, or lack thereof. This applies even to exercise, my favorite Parkinson’s treatment to slow progression, and the effects of stress as my “most need to avoid” situation to prevent speeding up the progression.

In the next column, I will offer a possible solution to the Parkinson’s progression research problem. 


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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Neurofilament Light Chain Levels May Be Useful Biomarker for Disease Progression in Parkinson’s, Study Finds

Neurofilament light chain

Levels of neurofilament light chain (NfL) — a protein found in blood plasma — may be a useful biomarker of disease progression for Parkinson’s, a study says.

The study, “Blood NfL: A biomarker for disease severity and progression in Parkinson disease,” was published in the journal Neurology.

A hallmark feature of Parkinson’s disease is the progressive degeneration of brain cells, which can happen at varying rates in different people. As such, researchers have focused on discovering a biomarker of neurodegeneration that could be used to predict the course of the disease for each individual patient.

The protein neurofilament light chain (NfL) is a key component of axons — myelinated nerve segments responsible for the transmission of nerve signals — and the main byproduct of nerve cell degeneration.

In other chronic neurodegenerative disorders — including amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), inherited peripheral neuropathy, Alzheimer’s dementia, and frontotemporal dementia — studies have reported that the levels of NfL in blood plasma were abnormally high, suggesting its usefulness as a marker of neurodegeneration.

In the case of spinal muscular atrophy (SMA), a genetic neurodegenerative disorder that affects motor neurons, the phosphorylated neurofilament heavy subunit (pNF-H) — a key component of motor nerve cells — is also being investigated as a potential biomarker of neurodegeneration.

In this study, researchers from the National Taiwan University and their collaborators set out to investigate if plasma levels of NfL could also be associated with disease progression in people with Parkinson’s disease.

To that end, they carried out a prospective longitudinal study in which they followed 116 patients with Parkinson’s, 22 people with multiple system atrophy (MSA) — a rare neurodegenerative disorder — and 40 healthy individuals (controls).

Plasma levels of NfL were measured in all study participants using an electrochemiluminescence immunoassay — a technique that allows researchers to measure the levels of a protein of interest based on an electrochemical reaction. Researchers noted that the testing required just a blood sample from each participant.

Those who had Parkinson’s performed motor and cognitive tests at the beginning of the study, and at a mean follow-up interval of three years. The Unified Parkinson’s Disease Rating Scale (UPDRS) Part III and the Hoehn-Yahr scale were used to evaluate the progression of motor symptoms, while the Mini-Mental State Examination (MMSE) was used to assess the progression of cognitive symptoms.

Results showed that plasma levels of NfL were much higher among those with MSA (35.8 pg/mL), compared with those with Parkinson’s (17.6 pg/mL), and controls (10.6 pg/mL).

However, in patients with Parkinson’s, NfL levels were higher among those who had dementia and among those with severe motor impairments (advanced Hoehn-Yahr stage).

Correlation analyses revealed there was a modest association between NfL levels and UPDRS Part III (motor) scores.

Another statistical analysis performed after a mean follow-up of 3.4 years — and normalized for participants’ age, sex, disease duration and baseline symptoms, or symptoms at the start of the study — revealed that higher levels of NfL at baseline were linked to a higher risk of disease progression in patients with Parkinson’s. This was true for either motor or cognitive symptoms.

“Our results suggested that the plasma NfL level could serve as a noninvasive, easily accessible biomarker to assess disease severity and to monitor disease progression in PD,” the researchers said.

“Future large longitudinal follow-up studies that incorporate other biomarkers such as neuroimages are needed to strengthen the possible prognostic role of blood NfL levels in PD progression,” they added.

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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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