Exploring the Potential of a Brain Therapy Model for Parkinson’s

brain therapy

For my PhD research, I wanted to examine in more detail the processes by which humans move from traumatic injury, like traumatic brain injury, to a place of well-being. My clinical experience led me to consider two things that people drew upon.

I found that, firstly, they drew upon cognitive processes when recovering from trauma. Secondly, the recovery process was helped by the relationship between the injured and those who are deemed healing practitioners. I witnessed a special kind of relationship that directly affects healing.

It is this healing relationship that became the focal point for my PhD. But I never let go of my deep belief in neural plasticity and our ability to cultivate our own neural sprouting. Little did I know then that I’d be applying healthy doses of brain therapy fertilizer to my own neural branches in fighting the progression of Parkinson’s disease.

Parkinson’s is complex in presentation, and it’s difficult to find a set of symptoms along with their progression that fits anything more than about half of the disease population. It’s been frustrating trying to advance my own cerebral rehab in the face of unclear guidelines. Whatever brain activities I choose each day are going to affect my brain health. To decide which brain activities are best, I need some clear brain therapy guidelines.

In my columns, I’ve written about creating a wellness map. This is a metaphor for brain therapy. Much of what I have written is tied to a brain model based on functional neuroanatomy — the connections between the prefrontal cortex and the thalamus. This relationship is illustrated in the following graphic:

(Graphic by Darcy Hoisington)

The graphic shows a “Grand Central Station” where sensory stimulus input comes in and gets routed back out to the appropriate destination. There are several “most popular” destinations: motor sequencing autopilot, making and carrying out plans, short-term and long-term memory, and actions or thoughts that are deemed to need more immediate attention, which often are emotion-laden.

Overseeing all of this is the open “conductor.” The conductor’s main responsibility is to make sure that the most important things get onto the tracks leaving the station before the less important things. The theory proposed here is that scenario-looping breakdowns, a malfunctioning autopilot, and exaggerated stimuli input are happening with information coming out of the station. This is information that got on the tracks without conductor intervention.

This theory proposes that these “conductor-Grand Central Station malfunctions” are major contributors to Parkinson’s symptoms. If we can decrease the effects of scenario-looping breakdowns, the malfunctioning autopilot, and exaggerated emotional stimuli, then the effects of Parkinson’s disease should be reduced.

The second part of this theory states that the conductor is still able to direct traffic out of the station. In addition to this, neural plasticity is a process that’s still available in the senior years of life, albeit more slowly. The conductor resides in the front part of our brain (frontal lobe) and is often referred to as “executive functioning.” I think that this term is too broad and lacks the specificity needed for me to design brain therapy. The success of my personal brain rehabilitation depends on my success with training the conductor. This is one of those frontiers of the exploration of wisdom.

I had been hesitant about putting such an immature theory into the public domain, but I was encouraged by a few short paragraphs in neurosurgeon Paul Kalanithi’s book, “When Breath Becomes Air.” He describes performing deep brain stimulation (DBS) on a Parkinson’s patient. In the middle of the procedure, the doctor needed to shift the electrode a few millimeters within the thalamus. The patient was complaining of intense mood surges that had no connection to context, but a small shift of the electric stimulus provided relief.

What intrigued me was that the stimulation of the thalamus triggered surges of exaggerated mood that had no link to the context. I’ve termed them SEM (surges of exaggerated mood) attacks. It was exciting to discover that a tiny shift in the electrode was all that was needed and — poof! — emotions were stable and tremor was reduced. I thought, “Perhaps I can train my brain to do its own natural version of DBS?”

I am just beginning this journey and would appreciate any thoughts. I look forward to hearing from you in the comments below.

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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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Blood Test May Help Predict Cognitive Decline in Parkinson’s, Study Shows

blood biomarkers of Parkinson's

A blood test may be able to predict early cognitive decline in people with Parkinson’s disease by measuring the length of chromosomal telomeres (the “tips” of chromosomes) in immune cells and the presence of inflammatory markers, a study shows.

The study, “Senescence and Inflammatory Markers for Predicting Clinical Progression in Parkinson’s Disease: The ICICLE-PD Study,” was published in the IOS Press Journal of Parkinson’s Disease.

Cognitive impairment is a well-known non-motor symptom of Parkinson’s disease. Biological markers identifying those at highest risk of early cognitive decline may help better predict disease progression of newly diagnosed Parkinson’s patients. 

Telomeres are a protective region of DNA at the end of each chromosome that facilitates proper genome replication. As people age, the ends of telomeres shorten with each cell division. Telomere shortening and dysfunction can also be indicators of disease processes in the brain.

However, studies that have used telomere length as a marker for Parkinson’s incidence and progression have reported conflicting results. 

Telomere shortening in humans can also trigger cellular senescence, a process characterized by the irreversible shutdown of cell division, and the release of pro-inflammatory signaling proteins and tumor-suppressor proteins such as p21 and p16

The senescence of different types of brain cells is associated with neurodegeneration and inflammation, and while the potential of both p21 and p16 as biomarkers for age-related diseases has been investigated, their use as markers for Parkinson’s disease progression and early cognitive decline has not been explored. 

Thus, researchers based at Newcastle University, in the United Kingdom, designed a three-year study to compare the length of immune cell telomeres isolated from newly diagnosed Parkinson’s patients and healthy controls over time. The team also examined whether blood-derived markers of cell senescence and inflammation are associated with cognitive and motor function. 

The authors previously published work in 2016 about the Incidence of Cognitive Impairments in Cohorts with Longitudinal Evaluation-Parkinson’s Disease (ICICLE-PD) study, which found that inflammatory markers in the blood measured at diagnosis were linked to more rapid cognitive and motor decline.

Continuing this line of investigation, the team studied 154 newly diagnosed Parkinson’s patients who had been part of the ICICLE-PD study, along with 99 age- and gender-matched control subjects. The average age of both groups was around 67 years. 

The participants were assessed at 18-month intervals in which demographic information, blood samples, and cognitive and clinical data were collected. The average telomere length in immune cells and senescence markers p21 and p16 were measured at two time points, baseline and 18 months. An additional five inflammatory markers were also included from the first ICICLE-PD study.

The results revealed that Parkinson’s patients had significantly shorter telomere length at baseline compared to controls, and their telomere length shortened faster over the 18-month period. 

Over 36 months of follow-up, 11 Parkinson’s patients (15.5%) developed dementia. They had significantly shorter telomeres at baseline and at 18 months, compared to those without dementia.  

Significantly lower levels of p21 were found in Parkinson’s patients compared to controls at baseline, and there was no difference in change with time. The differences between the levels of p16 at baseline or the rate of change over time was not statistically significant. However, unexpectedly, higher p16 levels at baseline predicted slower motor and cognitive decline over 36 months. 

The examination of the five inflammatory markers found significantly higher levels of pro-inflammatory signaling proteins TNF-alpha and interleukin-10 in the Parkinson’s group than in the controls. 

A baseline composite inflammatory score based on all five markers found a significant difference between the groups as well. This score was able to predict cognitive decline at 36 months, consistent with the first ICICLE-PD study.

“In summary, our study demonstrates that telomere lengths at baseline and 18 months were lower in [Parkinson’s disease] patients compared to age-matched healthy controls with shorter telomere length at baseline and at 18 months also associated with development of dementia within 36 months,” the researchers wrote. 

“A baseline inflammatory score consisting of five different cytokines gave the best prediction for cognitive scores of [Parkinson’s disease] cases 3 years later, while lower p16 gene expression predicted a more rapid disease progression over the same period in relation to both cognitive and motor scores,” they added.

Of note, gene expression is the process by which information in a gene is synthesized to create a working product, such as a protein.

“The markers that we have identified need to be validated in further studies but could ultimately help with planning more targeted management for patients earlier in their disease course,” said lead investigator Gabriele Saretzki, PhD, in a press release.

“Furthermore, a better understanding of the biological changes that predict disease course has implications for possible future therapies for the disease,” she added.

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Table Tennis Program May Ease Motor Symptoms in Parkinson’s, Early Study Shows

table tennis, Parkinson's

Table tennis may offer benefits as a form of Parkinson’s physical therapy, according to a preliminary study that showed lessening of symptoms in patients who participated weekly in the sport for six months.

“Pingpong, which is also called table tennis, is a form of aerobic exercise that has been shown in the general population to improve hand-eye coordination, sharpen reflexes, and stimulate the brain,” study author Ken-ichi Inoue, MD, of Fukuoka University in Fukuoka, Japan, said in a press release. “We wanted to examine if people with Parkinson’s disease would see similar benefits that may in turn reduce some of their symptoms.”

The study will be presented at the American Academy of Neurology’s 72nd Annual Meeting in Toronto, Canada, taking place April 25 to May 1.

Parkinson’s disease is a neurodegenerative disorder, characterized by progressive loss of motor control. This loss stems from the death of neurons in the brain that create a neurotransmitter called dopamine. Dopamine is vital to communications between muscles and the central nervous system.

In the study, the researchers had 12 people with mild to moderate Parkinson’s play table tennis once a week for six months. Participants were 73 years old on average and had been diagnosed with Parkinson’s for an average of seven years.

First, the researchers tested them to assess the types and severity of their symptoms.

The 12 participants then each played a five-hour session every week. The sessions were designed specifically for Parkinson’s patients, by experienced table tennis players from the university’s sports science department. Sessions consisted of stretching exercises followed by table tennis exercises, all under the instruction of an experienced player.

Parkinson’s symptoms were evaluated again after three months and at the end of the study. At both assessment points, participants demonstrated significant improvements in speech, handwriting, getting dressed, getting out of bed, and walking. Participants reportedly improved in their efforts to get out of bed from requiring two attempts, on average, at the beginning of the study to needing one attempt by the end of the study.

Participants also showed significant improvements in facial expression, posture, rigidity, slowness of movement and hand tremors, all of which are common symptoms of Parkinson’s disease.

To measure neck muscle rigidity, the researchers scored each participant on a scale of increasing rigidity from zero to four. Participants received an average initial score of three, which fell to an average of two by the end of the study.

The only side effects reported during the study consisted of a backache in one patient and another in a patient who fell.

The study was limited by the small number of participants, not having a control group to compare results to, and having only one specialist assess all the patients.

While preliminary, the results are nonetheless encouraging, the researchers said.

“[T]hey show pingpong, a relatively inexpensive form of therapy, may improve some symptoms of Parkinson’s disease,” Inoue said. “A much larger study is now being planned to confirm these findings.”

Notably, this study is not the first time that table tennis has been used as therapy for Parkinson’s. Ping Pong Parkinson has its own program developed specifically for people with Parkinson’s and holds weekly meetups at their Pleasantville, New York, headquarters.

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CDNF Safe in Advanced Parkinson’s, Trial Results Show

Phase 3 trial analysis

Treatment with cerebral dopamine neurotrophic factor (CDNF), developed by Herantis Pharma, was safe and well-tolerated among patients with advanced-stage Parkinson’s disease, according to topline results from a Phase1/2 clinical trial.

The therapy also showed promise in measures of dopaminergic function in some patients.

CDNF is based on a protein naturally found in the blood and cerebrospinal fluid (CSF), the liquid surrounding the brain and spinal cord. Preclinical (in-lab) studies have shown that CDNF has both neuroprotective and neurorestorative properties in dopaminergic neurons — brain cells that produce the neurotransmitter dopamine, the chemical messenger missing in people with Parkinson’s disease.

Previous proof-of-concept studies have shown that CDNF could ease motor and non-motor symptoms of Parkinson’s disease, and could act as a disease-modifying therapy.

The Phase 1/2 clinical trial (NCT03295786) is testing the safety and tolerability of CDNF in 17 patients with advanced Parkinson’s disease.

In the trial’s first part, patients were randomly assigned to receive monthly infusions of either CDNF (medium or high dose) or a placebo for six months. Because CDNF cannot be delivered as a pill or injection — since the body will not transport it to the brain — a neurosurgeon implants a drug delivery system, provided by Renishaw, in patients’ brains.

The 15 patients who completed the first part of the study joined the trial’s extension phase, in which each of them — including those previously randomized to the placebo — will receive six doses of CDNF over six months. All patients will start on a low dose, which can be increased after an independent group of experts confirms there are no safety concerns associated with the therapy.

Results from the second part of trial are expected during the third quarter.

The study’s primary goal is to assess the safety and tolerability of CDNF and its delivery device, as well as the accuracy of surgical placement of the device.

Additional goals include CDNF’s early signs of efficacy, including its effect on the Unified Parkinson’s Disease Rating Scale (UPDRS) motor score, patient-reported outcomes, levels of different forms of alpha-synuclein in the blood and CSF and the levels of dopamine transporters (DaT) using positron-emission tomography (PET) imaging. DaT are proteins that regulate the flow of dopamine between nerve cells, and their levels are usually lower among those with Parkinson’s.

Topline results from the first part of the study now show that CDNF was safe and well tolerated. Patients who experienced serious side effects fully recovered, and these effects were considered to be unrelated to the treatment.

Certain serious side effects “were probably related to device surgery and the drug administration process,” and these steps have been improved to avoid future incidents, the company said.

In some patients, researchers observed promising responses in dopamine transporter PET imaging, which measures dopaminergic function.

“This first set of topline data provides a solid basis for the next part of the study and confirms the positive safety and tolerability profile of CDNF,” Pekka Simula, Herantis’ CEO, said in a press release.

The promising results seen in the trial’s first part have prompted plans for a future Phase 2 trial, which will assess the effects of longer treatment with CDNF in patients in an earlier stage of Parkinson’s disease. Patient enrollment is expected to begin in 2021.

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Dizziness May Be Non-Motor Symptom of Early Parkinson’s, Study Finds

dizziness may be early sign of Parkinson's

Dizziness — including sensations of fainting, imbalance, and vertigo — is common among Parkinson’s patients and may be a potential non-motor symptom of early-stage disease possibly associated with cognitive decline, a study has found.

Typically, dizziness episodes are short and frequent, lasting seconds to minutes and occurring several times per day or week.

The study, “Dizziness in patients with early stages of Parkinson’s disease: Prevalence, clinical characteristics and implications,” was published in the journal Geriatrics and Gerontology.

Parkinson’s disease is diagnosed when typical motor symptoms occur — including tremor, rigidity, balance, and walking problems — but several other motor and non-motor features that surface before that stage could help detect the disease earlier. Some of these non-motor symptoms include loss of the sense of smell, constipation, sleep disturbances, and depression.

“In real clinical settings, we frequently observe that patients with [Parkinson’s disease] complain of dizziness,” the researchers wrote.

Feelings of dizziness may include faintness, lightheadedness, vertigo, and imbalance, and its prevalence is reportedly between 48%–68% in patients with Parkinson’s.

Dizziness is a well-known side effect of dopaminergic medications used for Parkinson’s such as levodopa and dopamine agonists (substances that mimic the action of dopamine in the brain). These agents can lead to a type of low blood pressure that occurs when a person stands up (orthostatic hypotension), causing lightheadedness.

“However, we have observed that drug-naïve patients [who have never taken antiparkinson medications] (…) sometimes report dizziness,” the researchers noted.

In fact, some researchers propose that dizziness may be an early, or prodromal, symptom of Parkinson’s. Despite this hypothesis, little is known about the clinical features and implications of this potential symptom in Parkinson’s patients.

Therefore, a team of Korean researchers at Seoul National University Hospital set out to gather more information about the characteristics of dizziness, and its risk factors and association with early Parkinson’s.

They conducted a pilot study that analyzed data from 80 patients (mean age of 71.3 years) with early-stage Parkinson’s (disease duration of no more than five years), who had been followed at the hospital.

The characteristics of dizziness episodes, including their prevalence, frequency, duration, and type, were surveyed for each patient. Motor and non-motor symptoms (cognition problems, anxiety, depression, and fatigue) were evaluated using different validated scales, to identify risk factors linked to dizziness.

The results showed that out of a total of 80 patients, 46.3% (37 patients) experienced dizziness. Episodes were typically short and frequent, lasting seconds (40.5% of the patients) to minutes (54.1%), and occurring several times a day (48.6%) or week (35.1%).

The most common type of dizziness was presyncope (40.5%) — a sensation of fainting usually caused by a drop in blood pressure that results in insufficient blood flow to the brain — followed by non-specific type (29.7%), disequilibrium (24.3%), and vertigo (5.4%).

Dizziness had no association with demographics (age, sex, education, body mass index) or general parkinsonian parameters such as motor symptoms, disease duration, or levodopa equivalent daily dose.

Among the many scales for motor and non‐motor symptoms assessed, only a lower Montreal Cognitive Assessment score, representing patients’ cognitive health, was significantly associated with dizziness in those with early Parkinson’s — a mean score of 19.7 in patients with dizziness versus 22.5 in those without it.

In summary, the study showed a significant percentage of patients with early Parkinson’s disease experienced dizziness, suggesting that it could be regarded as one of the non-motor symptoms of the disease, and one that could be “associated with cognitive decline,” the investigators wrote.

The association of dizziness to lower cognitive scores was an unexpected finding for the team. A possible explanation is that a drop in blood pressure during presyncope would reduce blood flow to the brain, resulting in cognitive impairments later on. However, patients also had other forms of dizziness that were unlikely related to this effect, so more studies are needed to clarify this issue in the future.

“We hypothesized that longer disease duration or dopaminergic medication would be more related to the occurrence of dizziness, and that the majority of dizzy [Parkinson’s disease] patients would show the orthostatic type of dizziness. However, our results did not fully support these hypotheses,” the researchers said.

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Is Parkinson’s Disease Coming Out of the Shadows?

normal

We all want to feel that we have something we can depend on, something we can call “normal” in this fight against Parkinson’s disease. But Parkinson’s is anything but normal. 

You might have heard that each person with Parkinson’s wears the disease differently. How the disease manifests is unique to each individual. Not only do the symptoms vary according to the individual, the treatments can also differ. A therapy that seems to be working wonders for one person may not make the slightest difference to another. 

Snowflake diseases

Parkinson’s is sometimes referred to as a “snowflake disease” based on the fact that no two snowflakes are alike. The snowflake analogy describes how no two cases of Parkinson’s are the same.

In her column “Disabled to Enabled,” Jessie Ace discusses this, stating that, “MS is sometimes called ‘the snowflake disease’ because each case is unique.”

An autoimmune disease called myasthenia gravis, characterized by a weakening of voluntary muscles, also is referred to as a “snowflake disease.” With so many snowflakes falling under the guise of many different diseases, it is easy to get confused about what disease you have and how it should be treated.

Changing perspective

What used to be an “abnormal” and rare disease seems to be more commonplace. At least it can sometimes appear like that to me. One thing that isn’t common is the young age at which some people first show signs of Parkinson’s. What used to be considered an “old person’s disease” is being seen in younger people, too. 

As life expectancy increases, Parkinson’s may become more common. But what about the younger crowd — those with young-onset Parkinson’s disease? This group, which comprises those diagnosed before age 50, accounts for only 2 to 10 percent of those living with Parkinson’s in the United States. In rarer instances, Parkinson’s-like symptoms can appear in children and teenagers — a form of Parkinson’s called juvenile Parkinsonism.

Research has helped to improve and speed up the diagnostic process for this disease (however slow it may seem), and so it makes the “abnormal” chronic illness known as Parkinson’s disease seem more “normal.” But we need to move faster to raise awareness and help with fundraising efforts for research toward more advanced treatments. Or better yet, a cure for Parkinson’s to take it out of the running entirely.

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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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Selenium Mineral Levels Increased in Cerebrospinal Fluid of Parkinson’s Patients, Research Suggests

Selenium Mineral Levels

People with Parkinson’s disease may have higher levels of selenium — a mineral with antioxidant properties — in their cerebrospinal fluid, the liquid that surrounds the brain and spinal cord, a study suggests.

The research, “Selenium level does not differ in blood but increased in cerebrospinal fluid in Parkinson’s disease: a meta-analysis,” was published in the International Journal of Neuroscience.

Although the exact trigger for Parkinson’s disease still remains to be identified, research indicates that its causative mechanism involves genetics, ageing, deficiencies in mitochondria — cells’ powerhouses — and oxidative stress.

Oxidative stress is an imbalance between the production of harmful free radicals — toxic molecules that are the natural byproducts of ongoing biochemical reactions in the body — and the ability of cells to detoxify. It results in cellular damage.

Such molecular and cellular changes eventually lead to the progressive death of dopamine-producing neurons in Parkinson’s disease.

Selenium is a critical mineral that has antioxidant properties, is essential for brain health, and plays a role in immune functions as well as anti-cancer activity.

Despite its antioxidant properties, conflicting evidence exists in regard to the role selenium plays in Parkinson’s. Several studies have found higher selenium levels in people with the disease, compared with healthy individuals, but others have shown regular or decreased levels of selenium in this patient population.

Now, a team led by researchers at Zhengzhou University, in China, evaluated all available evidence regarding selenium levels in the blood and cerebrospinal fluid, known as CSF, in the context of Parkinson’s disease.

The investigators searched the records of three biomedical databases that included studies from 1995 up through October 2019, examining associations between selenium levels and Parkinson’s risk.

The team analyzed a total of 12 case-control studies, which involved 601 Parkinson’s patients (mean age 57.62 to 70 years) and 749 healthy people (controls).

Compared with the healthy controls, the Parkinson’s patients had significantly higher selenium levels in their cerebrospinal fluid, the results showed. No differences were found in blood selenium concentration between the two groups.

“We speculate that oxidative stress conferred by the pathogenesis [disease characteristics] of [Parkinson’s disease] can lead to higher selenium levels and increased antioxidant capacity as a protective mechanism,” the researchers said.

While the investigators said their “results are convincing,” they did report great disparity between the studies analyzed. Such heterogeneity could be due to several factors, the researchers said, including the distinct methods by which the studies selected participants and quantified selenium levels, and inadequate matching between patients and healthy controls in each study. In addition, some of the studies lacked an analysis that minimized potential confounding factors like age, gender ratio, treatment, and the presence of other diseases — all of which might affect selenium levels in the body, the researchers said. Moreover, the analyzed studies were carried out in dozens of countries.

In these types of meta-analyses, when researchers combine the results of multiple scientific studies, there is always the possibility of publication biases, the investigators noted. Such publication bias can occur because studies with significant, or positive, findings are more likely to be published than studies with negative findings. This means that any meta-analysis or literature reviews based on published data could potentially be biased as a result.

In this case, however, the team used a specific statistical test — called a Begg’s test — to assess for this type of asymmetry of data and found no significant publication bias.

The researchers concluded that Parkinson’s patients may have higher selenium levels in their cerebrospinal fluid. However, further study is necessary as this finding, although significant, was associated with great data heterogeneity, they said.

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New Parkinson’s Treatment Target – Drp1 Protein Linked to Sense of Smell – Found in Rat Model, Study Reports

Drp1 Protein Sense of Smell

A new potential target for treating Parkinson’s, a protein named Drp1, has been identified using a rat model of the disease, a study reported.

The target was found to play a central role in the underlying cause of the degeneration and inflammation of nerve cells in the olfactory bulb, the area responsible for the sense of smell. Losing the sense of smell is an early symptom of the progressive neurodegenerative disease. 

The study, “Drp1, a potential therapeutic target for Parkinson’s disease, is involved in olfactory bulb pathological alteration in the Rotenone-induced rat model,” was published in the journal Toxicology Letters.

One early non-motor symptom of Parkinson’s is a loss of the sense of smell. Before it appears in the brain, the toxic buildup of the protein alpha-synuclein — a hallmark of the condition — occurs in the olfactory bulb, which is the the neural structure located above the sinuses that’s responsible for the ability to smell. 

However, the underlying mechanism that leads to early-stage olfactory bulb impairment is unclear.

A common phenomenon in Parkinson’s is the improper functioning of the mitochondria, or the small structures within the cell that produce energy — the cells’ powerhouses. A protein called dynamin-related protein 1 (Drp1) regulates mitochondria dynamics, notably in the cell division process. Chemicals that target this protein have been shown to cause mitochondrial fragmentation leading to the loss of neurons. 

Mitochondrial fragmentation also is known to drive a pro-inflammatory response, a common characteristic of neurodegenerative diseases. 

This prompted researchers to investigate whether Drp1-mediated mitochondrial damage played a role in the impairment of the olfactory bulb. The team used a rat model in which Parkinson-like symptoms were induced by the infusion of rotenone, a mitochondria inhibitor.

To examine the effects of rotenone on the olfactory bulb, a group of rats were treated and compared with a group of untreated rats. In a second experiment, these two groups of animals were compared with a third group treated with a specific Drp1 inhibitor.

Compared with the untreated group, rats treated with rotenone lost more weight and displayed parkinsonian features such as poor motor coordination. The treated rats also had a characteristic depletion of dopamine — the chemical messenger or neurotransmitter produced by dopaminergic neurons that are progressively lost in Parkinson’s disease.

An examination of olfactory tissue under the microscope showed that the density of dopamine-producing neurons was significantly reduced in rotenone-treated rats compared with the untreated group. 

Rotenone triggered the activation of olfactory-specific astrocytes — star-shaped neuroglia or neural support cells — and microglia, a type of brain-specific immune cell. The accumulation of these cells was accompanied by a significant increase in the production of pro-inflammatory markers. 

An examination of the mitochondria in the control animals found typical rod-like shapes characteristic of healthy olfactory cells. In contrast, large numbers of mitochondria in the rotenone-treated group were small and damaged. 

Rotenone injection also caused a dramatic reduction of Drp1 outside of the mitochondria and a significant increase on the inside. 

Finally, the researchers found that adding a Drp1 inhibitor led to a significant reduction in the loss of dopaminergic neurons, increased the presence of healthy mitochondria, and blocked the production of pro-inflammatory markers. 

“In summary, the present findings demonstrate that Drp1-mediated mitochondrial fragmentation induced by rotenone injection participated in neuropathologic changes in the olfactory bulb,” the researchers concluded. 

They said further study needs to be done “to elucidate the network as well as focus on the aberrant mitochondrial dynamics to explore the mechanism.”

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Iron Levels in Brain May Predict Parkinson’s Severity and Cognitive Decline, Study Finds

iron levels and the brain

Likely cognitive decline, dementia risk, and the severity of motor symptoms in Parkinson’s disease might be tracked by measuring the amount of iron content in the brain, a study reports.

These finding were described in the study “Brain iron deposition is linked with cognitive severity in Parkinson’s disease,” published in the Journal of Neurology, Neurosurgery and Psychiatry. The work was developed at University College London (UCL).

A link between iron buildup, and both natural aging and neurodegenerative disorders like Parkinson’s, has been established in several studies. Apart from loss of dopamine-producing neurons, Parkinson’s is characterized by pronounced iron accumulation in two brain regions, the globus pallidus and the substantia nigra.

“Iron in the brain is of growing interest to people researching neurodegenerative diseases such as Parkinson’s and dementias,”  Rimona Weil, the study lead author, said in a press release. “As you get older, iron accumulates in the brain, but it’s also linked to the build-up of harmful brain proteins, so we’re starting to find evidence that it could be useful in monitoring disease progression, and potentially even in diagnostics.”

About 50% all of Parkinson’s patients develop dementia as their disease progresses, the study noted. This seems to be preceded by mild cognitive impairment, but measures to accurately track cognitive changes in Parkinson’s are few.

To evaluate if changes in iron levels in the brain relate to cognitive changes in Parkinson’s patients, researchers used a cutting-edge magnetic resonance imaging (MRI) technique called quantitative susceptibility mapping (QSM). QSM can easily detect variations in the content of brain iron, and in other substances such as fats or calcium.

A total of 100 people (52 men and 48 women; mean age, 64.5) with early to mid-stage Parkinson’s and no evidence of dementia, and 37 age-matched people without the disease serving as controls (16 men and 21 women; mean age, 66.1) were enrolled.

All underwent a QSM exam and had their cognitive skills assessed using the Montreal Cognitive Assessment (MoCA), a validated algorithm to assess the risk of cognitive decline in Parkinson’s.

Motor skills were also assessed using the Movement Disorders Society Unified Parkinson’s Disease Rating Scale part 3 (UPDRS-III), as were patients’ visuoperceptual abilities.

“Visual changes are also emerging as early markers of cognitive change in PD. Whether structural brain changes are more strongly linked with clinical risk scores or visual deficits before onset of dementia is not yet known,” the researchers wrote.

QSM exams found higher iron content in brain tissue of the prefrontal cortex and putamen of Parkinson’s patients compared to controls. The prefrontal cortex is involved in planning complex cognitive behavior and in personality expression and decision-making, while the putamen regulates body movement and influences learning.

Higher brain iron levels in the hippocampus (a region involved in learning and memory), and in the thalamus (involved in sensory signaling, motor activity and memory) were found to associate with poorer memory and thinking scores on MoCA.

Poorer visual function and higher dementia risk scores were related to greater QSM changes in three brain regions: the parietal, frontal and medial occipital cortices.

Poorer motor function also correlated with higher iron content in the putamen (a brain region involved in motor control), suggesting a more advanced disease stage. There were no signs of brain atrophy in either study group.

“[W]hole brain measures of iron content can be used to probe key clinical indices of disease activity, with cognitive performance related to hippocampal changes, dementia risk linked to increased brain iron in parietal and frontal cortices and motor severity co-varying with raised brain iron levels in the putamen,” the researchers wrote.

“Our results show that iron in the PD brain has an important relationship with clinical severity,” they concluded, as “[b]ehavioural changes, captured by clinical measures, often occur before consistent [brain] atrophy is seen.”

“It’s really promising to see measures like this which can potentially track the varying progression of Parkinson’s disease, as it could help clinicians devise better treatment plans for people based on how their condition manifests,” said George Thomas, a PhD student and the study’s first author.

Weil’s team is now following study participants to see how their disease progresses, and whether symptoms they develop, like dementia, correlate with measures of iron content in the brain.

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New Cellular Model Can Reconstruct Entire Process of Lewy Body Formation in Parkinson’s Disease, Study Says

Lewy body formation, Parkinson's

Scientists have developed a new cellular model that can help reconstruct the entire process of Lewy body formation — a key event that underlies neurodegeneration in Parkinson’s disease — and that could potentially be used to evaluate the effect of therapeutics on the toxic protein buildup observed during this process.

The study, “The process of Lewy body formation, rather than simply α-synuclein fibrillization, is one of the major drivers of neurodegeneration,” was published in PNAS.

Parkinson’s is a multisystem neurodegenerative disorder with motor and non-motor features caused by the death of midbrain dopamine-producing neurons. These nerve cells are thought to die as a consequence of the aggregation, or clumping together, of a protein called alpha-synuclein in small fiber-like, or insoluble fibril, structures known as Lewy bodies.

Although evidence indicates abnormal alpha-synuclein accumulation is essential for the development of Parkinson’s disease, not much is known about the molecular and cellular processes that control the transformation of healthy alpha-synuclein protein into insoluble fibrils and, consequently, their clumping into Lewy bodies.

To better understand these biological events at a genetic, molecular, biochemical, structural, and cellular level, researchers at the Brain Mind Institute in Lausanne, Switzerland, tracked the development of Lewy bodies from beginning to end.

They began by using mouse primary neurons grown in lab dishes. They then added a small amount of alpha-synuclein fibrils that would be used as “seeds” that grew by recruiting neuron-produced alpha-synuclein.

“This approach has proven incredibly useful in modeling the formation of alpha-synuclein aggregates linked to diseases like Parkinson’s,” study senior author Hilal Lashuel, PhD, said in a press release.

Scientists usually monitor cell cultures for two weeks, but Lashuel’s team decided to go beyond that time limit. Twenty-one days after seeding, the team observed Lewy body-like inclusions in approximately 22% of the neurons.

These lab-grown Parkinson’s-related structures shared between 15%-20% of their protein content with “natural” Lewy bodies, which, given the slower growth rate in the laboratory versus the human brain, is an encouraging finding.

Importantly, the Lewy-body-like clump structures had not appeared by the usual two-week cutoff point, highlighting the need to prolong the experiments to observe features characteristic of neurodegeneration.

“Time, being patient and using a swiss army knife analytical approach is all that was required,” Lashuel said.

The formation of Lewy bodies involved a complex interplay between alpha-synuclein fibrillization, protein modifications, and interactions between alpha-synuclein clumps and membranous organelles, including mitochondria, which produce energy for cells.

In addition, the researchers found that Lewy body formation — rather than simply alpha-synuclein fibril accumulation — were the major drivers of neurodegeneration, since these structures disrupted cellular functions such as energy production, and compromised nerve cell communication by changing the properties of synapses, or the junctions between nerve cells that allows them to communicate.

Formation of Lewy bodies does not occur simply through the continued formation, growth, and assembly of alpha-synuclein fibrils “but instead arises as a result of complex [alpha-synuclein] aggregation-dependent events that involve the active recruitment and sequestration of proteins and organelles over time,” the researchers wrote.

“Our results generally agree with recent findings reported on Lewy bodies from Parkinson’s disease brains,” Lashuel said. “But while previous studies only offered snapshots of fibril evolution, our model can reconstruct the entire process of Lewy body formation, making it a powerful platform for elucidating the relationship between fibrillization and neurodegeneration in Parkinson’s and other diseases, and to screen for novel potentially disease modifying therapies.”

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