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Rescuing Activity of Specific Neurons Improved Motor Function in Parkinson’s Mice

neurons

Rescuing the activity of neurons in the subthalamic nucleus — part of a brain region that controls movement — lessens motor dysfunction in a mouse model of Parkinson’s disease (PD), according to a recent study.

The “study argues that the loss of this intrinsic activity promotes abnormal synchronization and motor dysfunction in Parkinson’s disease,” Mark Bevan, PhD, the study’s senior study author, said in a press release. Bevan is a professor of physiology at Feinberg School of Medicine, Northwestern University.

The study, “Maladaptive Downregulation of Autonomous Subthalamic Nucleus Activity following the Loss of Midbrain Dopamine Neurons” was published in the journal Cell Reports.

The glutamatergic subthalamic nucleus (STN) is part of the basal ganglia, a brain region that controls movement and impulse control, and one of the key sites affected in Parkinson’s disease. Composed mainly by glutamate-producing neurons, in Parkinson’s models the firing of these neurons is decreased.

Of note, glutamate is a key excitatory neurotransmitter — chemicals that nerve cells use to send signals to other cells. Excitatory signaling from one nerve cell to the next makes the latter cell more likely to fire an electrical signal. Inhibitory signaling makes the latter cell less likely to fire.

Loss of dopamine-producing neurons, a hallmark of Parkinson’s disease, causes neurons within the STN to develop abnormal, synchronized activity, which results in impaired motor function.

Researchers at Northwestern University used a mouse model of Parkinson’s disease to investigate the mechanisms that lead to the abnormal activity of neurons within the STN.

“We first determined the mechanisms that cause STN neurons to adapt to the loss of dopamine by slowing their autonomous pacemaking activity,” said Eileen McIver, PhD, the study’s first author.

They found that loss of dopaminergic neurons resulted in lower activity “in the motor territory of the STN.” They then found that the cause for this abnormal activity was an increased activity of neurons in the basal ganglia carrying the D2 receptor. (The D2 receptor has the capacity to regulate the levels of dopamine by inhibiting the release of this neurotransmitter.)

This trigger increased the activity of an ‘indirect’ pathway” of the basal ganglia leading to additional chemical changes — activation of NMDA glutamate receptor and ATP-sensitive potassium channels — that ultimately reduced the firing of STN neurons.

Rescuing the activity of STN neurons using designer receptors exclusively activated by designer drugs (DREADDs) rapidly improved motor function in Parkinson’s mice. DREADDs are a class of engineered proteins that allow the targeted delivery of a receptor protein to specific cells.

“Within ten minutes of injecting the designer drug to activate DREADDs in the STN, we saw a symptomatic improvement,” McIver explained. Overall, these findings “provide proof-of-concept for the use of tools like DREADDs as a therapeutic approach in Parkinson’s disease,” he said.

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Coupling of Brain Electrical Signals May Be Parkinson’s Biomarker, Way to Improve Deep Brain Stimulation, Study Suggests

cross-frequency coupling electrical signals

The coupling of electrical signals in the brain — as it responds to levodopa and is associated with motor improvements — may provide ways to better assess the clinical state of people with Parkinson’s disease, and improve the efficacy of deep brain stimulation (DBS), according to new research.

The researchers say coupling patterns may enable broader insight into Parkinson’s, and have potential use as a biomarker.

The study, “Distinct subthalamic coupling in the ON state describes motor performance in Parkinson’s disease,” appeared in the journal Movement Disorders.

The human brain displays repetitive patterns of neural activity, or electrical pulses, due to the communication between brain nerve cells (neurons). These are called brainwaves.

Measuring a type of electrical pulses called local field potentials (LFPs) from the subthalamic nucleus (STN) — a brain region hyperactive in Parkinson’s patients — has shown the existence of frequency bands, or wave oscillations, that correlate with motor impairment and respond to medication.

The interactions between high- and low-frequency brain waves — cross-frequency coupling — also has been increasingly studied. This is particularly evident in unmedicated patients. Yet, what these interactions mean is still scarcely understood.

A team at the University of Houston addressed how these bands are changed by medication, as well as their coupling, via a 24-hour monitoring period that included three trials. Those trials involved nine people (seven men, ages 39-70 years) with idiopathic Parkinson’s, meaning the disease with no known cause. The participants underwent local field potential recording three weeks after deep brain stimulation of the subthalamic nucleus. The recordings were then correlated with motor improvements over three treatment cycles.

Clinical and behavioral assessments were made within 30 minutes prior to taking levodopa, which controls Parkinson’s symptoms. Similar evaluations were then done within 30 minutes after the participants said they felt the medication kicking in, in terms of motor function (verbal on state).

Specifically, the clinicians used the Unified Parkinson’s Disease Rating Scale to assess numerous symptoms: hand and foot tremors (item 20); upper and lower extremity rigidity (item 22); and finger tapping, hand open and close, hand pronation and supination — which means flipping the palm face up or face down — and leg agility (items 23–26).

A computer-based task also was used, with a keyboard. Participants had to press the left and right arrow keys sequentially and as fast as possible, for 30 seconds, using the index and middle fingers. The total number of keypresses was then analyzed.

The results showed that bradykinesia — slowness of movement — and keyboard scores differed between “off” and “on” states, meaning the periods before and after taking levodopa and regaining motor control. However, these responses did not correlate in all patients. Two patients showed eased bradykinesia yet minimal-to-no improvement in the performance of the keyboard task.

The data also showed distinct peaks across different bands. In the off state, the activity of low-beta (13-22Hz) and high-frequency oscillations (200-300Hz) was higher than normal. It was either suppressed, or shifted to a different frequency, after taking levodopa. Among other findings, six patients also showed a peak in the gamma range (50–200 Hz).

The investigators also found that, in the off state, the amplitude or signal strength of high-frequency oscillations was coupled with a specific parameter — called phase — of low-beta bands in all participants.

After the transition to the on state, this coupling shifted to a different subset of beta bands (22-30Hz) and high-frequency oscillations (300-400Hz). It also was linked with more pronounced improvements in the keyboard task scores. Only two patients failed to show this coupling after taking levodopa. That could be due to suboptimal dose, the team said.

Overall, the findings show that cross frequency coupling also exists in treated patients. “So in effect we have ‘cleared coupling’s name’ and showed the frequencies involved in coupling impacts whether its effects are negative or positive,” Musa Ozturk, the study’s lead author, said in a press release.

“Together with the differences in the ON-state coupling according to the degree of motor improvement, our observations suggest that [cross-frequency coupling] patterns provide a broader insight into [Parkinson’s], and have potential utility as a biomarker for the clinical state of patients,” the researchers said.

One potential application is deep brain stimulation.

“We can now make the closed-loop stimulator adaptive to sense a patient’s symptoms, so it can make the adjustments to the fluctuations in real time, and the patient no longer has to wait for weeks or months until the doctor can adjust the device,” said Nuri Ince, PhD, the study’s senior author.

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MS Medicine Copaxone May Have Benefits in Parkinson’s Disease, Mouse Study Finds

Copaxone

Treatment with Copaxone (glatiramer acetate), an FDA-approved medicine for multiple sclerosis, can restore motor function and biochemical markers in a mouse model of Parkinson’s disease, according to a recent study.

The findings, “Glatiramer Acetate Reverses Motor Dysfunction and the Decrease in 9 Tyrosine Hydroxylase Levels in a Mouse Model of Parkinson’s Disease,” were published in Neuroscience.

Parkinson’s disease, the second-most prevalent neurodegenerative disease of the elderly (after Alzheimer’s disease), is characterized by the gradual loss of muscle control, sometimes accompanied by cognitive deficits. It is mainly caused by the gradual loss of dopaminergic neurons in the substantia nigra, a region of the brain responsible for controlling body movements.

Unfortunately, so far, there are no treatments that effectively reduce or reverse degeneration of dopaminergic neurons associated with Parkinson’s disease.

“Glatiramer acetate (GA, also known as Copaxone), which is currently an FDA approved drug used in the treatment for multiple sclerosis, has been shown to directly dampen the pro-inflammatory response within the brain, in both mouse models of multiple sclerosis/experimental autoimmune encephalomyelitis and Huntington’s disease,” the researchers wrote.

Scientists set out to examine the therapeutic potential of Copaxone, an immunomodulatory drug, in the treatment of Parkinson’s disease.

In doing so, researchers used a mouse model of induced-Parkinson’s disease, in which the disorder was triggered by treating animals with MPTP, a neurotoxin that induces brain inflammation, loss of dopaminergic neurons, and motor impairments, as seen in patients with the disorder.

Treatment with Copaxone after the onset of the disease reversed gait (walking) and grip impairments in MPTP-treated mice.

Investigators believe this was due to the remarkable recovery in the levels of tyrosine hydroxylase (TH), one of the enzymes that is responsible for the production of dopamine in the striatum (a region of the brain involved in motor coordination) following treatment with Copaxone.

In addition, researchers found the number of TH-positive neurons in the substantia nigra increased slightly, albeit non-significantly, in animals treated with Copaxone, compared to those treated with a vehicle solution (control) after MPTP induction.

This was also associated with an increase in the levels of brain-derived neurotrophic factor (BDNF) — a protein whose main function is to protect dopaminergic neurons — and a decrease in the levels of IBA1, a marker of glial cells’ over-activation caused by brain inflammation. Glial cells, also known as microglia, are nerve cells that support and protect neurons.

Moreover, the levels of non-phosphorylated alpha-synuclein (syn-1), a protein directly involved in Parkinson’s disease, in the midbrain and striatum dropped significantly after MPTP induction and gradually recovered to normal levels after treatment with Copaxone. The midbrain is the region that connects the spinal cord to the brain, and plays key roles in motor movement  and auditory and visual processing.

“In this study, we show that GA [Copaxone] treatment results in restoration of motor impairments and recovery of the nigrostriatal pathway, (…) while dampening the microglia response and restoring BDNF levels,” the researchers wrote.

“Of note, this study also tested GA after the full regimen of MPTP had been completed, a time point at which there is no further loss of TH within the striatum or substantia nigra, showing that GA is a potential neurorestorative agent that has significant translational value for patients with PD [Parkinson’s disease]. To our knowledge, we are the first to test GA in a true restoration animal model of PD, resulting in recovery of the nigrostriatal pathway, leading the way for repurposing of this FDA approved drug,” they added.

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Harnessing the Power of Music

Listening to music

A proud, black piano stands in my parents’ living room. It’s the foundation of our home. From behind the sleek mahogany panels, fury, sadness, and happiness express themselves without judgment. My operatic brother sings his troubles away. My mom, a lifelong piano teacher, often alludes to the power of music because it isn’t just a creative outlet. It’s a mood-setter. It establishes rhythm and dance. Therapists use it to explore cognitive and emotional turmoil. And it also facilitates social change.

“Powerful songs have always been the engine behind the greatest social movements — it is the marching soundtrack that unites the people and gives them focus and resolve, and it’s not limited to the U.S.,” Barrett Martin writes in HuffPost. “In 1970s Nigeria, Fela Kuti invented Afro Beat music as a way to protest the oil company regime of Nigeria. His song ‘Zombie’ became a global hit that railed against Nigeria’s military dictators. In South Africa, the indigenous Mbatanga music helped bring about the end of apartheid and it spread a message of peace and reconciliation in that nation.”

If music is powerful enough to inspire entire chapters of history, what else is it capable of doing?

Parkinson’s disease and music

Music is powerful for a number of reasons; listening to it releases dopamine and serotonin – neurotransmitters that decline in Parkinson’s patients. But a study published in 2008 suggests that learning how to play an instrument also develops motor skills and reasoning abilities. Children who learned to play an instrument exhibited more advanced motor and reasoning skills than children who didn’t learn to play an instrument.

That same study states that, “Parallels between music and language have been used to support the hypothesis that music training may strengthen verbal skills.” Since music may help to develop speech patterns, exploring sound offers a tangible solution to verbal decline. Changes in speech occur with the progression of Parkinson’s. But active participation in music challenges the progression of Parkinson’s disease. Rather than observing consistent loss, Parkinson’s patients can explore music as a source of development.

Singing and Parkinson’s disease

If you’re feeling particularly enthusiastic about singing, consider joining a Parkinson’s singing group. In the same way that music changed history for entire communities, Parkinson’s singing groups offer a sense of camaraderie that’s powerful in itself. Producing endorphins in those who participate, singing is both cathartic and constructive. And it even boosts the immune system.

A small 2012 study in Norway found that group music therapy positively affected five of six Parkinson’s patients. While speech patterns didn’t noticeably improve, a decline in speech also didn’t occur during the study. This suggests that group singing may slow the progression of speech-related outcomes for Parkinson’s patients.

Singing encourages focus on breath support, diction, volume, and emotion. Vocal strength and articulation can challenge many Parkinson’s patients. But singing reinforces some of the functions that otherwise degrade.

Moving forward

Parkinson’s disease is degenerative and continuously heartbreaking in its thievery, but there are ways you can use music to fight its progression. Whether you’re interested in listening to records, picking up an instrument, or using your good ol’ vocal cords to bring happiness into your life, music offers incredible benefits to those who explore it.

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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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Treatment with Intranasal Insulin May Improve Verbal Fluency and Motor Function, Early Study Shows

Intranasal insulin

Treatment with intranasal insulin — which is atomized into a spray and inhaled through the nose — may ease Parkinson’s disease-related cognitive impairment and motor symptoms without dangerously lowering blood sugar levels, according to a proof-of-concept trial.

The study, “Safety and preliminary efficacy of intranasal insulin for cognitive impairment in Parkinson disease and multiple system atrophy: A double-blinded placebo-controlled pilot study,” was published in PLoS ONE.

Insulin, which regulates sugar (glucose) levels in the blood, is known to have potent effects in the brain, including on cognition. Intranasal insulin treatment has been shown to increase functional connectivity in the brain in type 2 diabetes without changing serum glucose levels.

Evidence also indicates that intranasal insulin improves visuospatial (visual perception of the spatial relationships between objects) and verbal short-term memory in people with mild cognitive impairment due to Alzheimer’s disease.

Cognitive impairment is a common non-motor complication of Parkinson’s disease. However, the effects of intranasal insulin on this particular complication remain to be understood.

In this study, researchers from Harvard Medical School and University of Massachusetts designed a randomized, placebo-controlled, single-center Phase 2 trial (NCT02064166) to evaluate the effectiveness of intranasal insulin as a treatment for individuals with Parkinson’s and multiple system atrophy (MSA). The symptoms of MSA are similar to those seen in Parkinson’s, but the disorder has a quicker progression and a much shorter survival rate.

A total 14 patients, comprised of nine men and five women, were randomly assigned to receive 40 international units (IU) of intranasal insulin or saline once daily for four weeks. Nine individuals were included in the insulin group and the remaining six were allocated to the placebo group.

Participants were diagnosed and treated for Parkinson’s disease, with one subject in the insulin group also treated for possible multiple system atrophy.

During the trial, participants completed a screening visit, a baseline assessment, two follow-up visits, and an end-of-treatment assessment. Researchers performed neuropsychological testing, and evaluated patients’ motor function — using several disease severity scales and a walking test — and disease progression.

Participants kept taking their usual medications. The last intranasal insulin or placebo dose was given on the day of post-treatment assessment.

The intranasal therapy was safe and well-tolerated and there were no treatment-related side effects. Importantly, blood glucose levels remained normal in treated individuals.

Results revealed patients who received the insulin had better verbal fluency than those given the placebo. Compared with their pre-treatment assessments, individuals given insulin also had decreased disease severity and motor scores — indicating their motor symptoms were eased by treatment and that the Parkinson’s did not progress as fast.

Interestingly, the patient with probable multiple system atrophy, who was included in the insulin group, remained stable during the study and showed a tendency toward improvement of motor skills.

“Although this is a single case of INI [intranasal insulin] treatment in MSA [multiple system atrophy], it warrants further investigation as there are no therapies available to modify disease progression,” the researchers said.

No changes were observed in cognitive, depression, or gait assessments within and between groups.

“Our study provided preliminary data that suggested an improvement of functional skills after four weeks of daily INI [intranasal insulin] treatment that paves the way toward a larger cohort study to evaluate long-term safety and potential efficacy of intranasal insulin administration for potential treatment and prevention of functional decline in patients with Parkinson disease,” the study concluded.

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Study Identifies Biomarkers for Motor, Cognitive Decline in Early Parkinson’s

early Parkinson's biomarkers

Urate, a salt derived from uric acid, and homocysteine, an amino acid, may predict motor and cognitive decline in early Parkinson’s disease, researchers report.

The study with that finding, “Urate and Homocysteine: Predicting Motor and Cognitive Changes in Newly Diagnosed Parkinson’s Disease” was published in the Journal of Parkinson’s Disease.

Low levels of urate have been associated with a higher risk of developing Parkinson’s over the subsequent 15 to 20 years. Low urate plasma concentrations also have been linked to cognitive decline, including poorer performance in attention, executive, and visuospatial functions.

High levels of homocysteine — an amino acid produced by the body, usually as a byproduct of consuming meat — also has been reported to increase the risk of dementia in older adults, suggesting it may play a role in the development of Parkinson’s disease dementia (PDD).

Researchers at Newcastle University, London, England, examined the association between urate and homocysteine levels, disease progression and cognitive status over 4.5 years in early Parkinson’s disease.

A total of 154 recently diagnosed Parkinson’s patients (100 men and 54 women, mean age 66.4 years) and 99 age-matched control subjects (54 men and forty-five women, mean age 67.9 years) underwent medical assessment by a movement disorders specialist. Participants with Parkinson’s disease were evaluated in the “on” motor state (when medication is taking effect and has not worn off) and patients were able to move smoothly.

Data on disease duration, concurrent diseases, medications, smoking history, and alcohol consumption were collected.

Motor symptoms’ severity was quantified using the Movement Disorders SocietyUnified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III and the Hoehn and Yahr scale. Cognition was assessed using the Montreal Cognitive Assessment (MoCa).

Blood samples were drawn only at the study participants’ initial visit and screened for urate, homocysteine, red cell folate (to measure the body’s store of folic acid) and vitamin B12 (an essential nutrient mainly present in meat and fish). Participants were examined  four times: at the study’s initial visit (baseline) and then at 18, 36 and 54 months.

At the first visit, 73% of Parkinson’s patients were levodopa (L-DOPA) naïve, meaning they were not yet taking prescribed anti-parkinsonian medications. No significant differences were found between treated and levodopa naïve patients regarding serum urate and serum homocysteine levels.

Participants with Parkinson’s disease had significantly lower baseline urate concentrations (302.7 μmol/L) than healthy controls (331.4 μmol/L). This also was true after 18 and 36 months.

On the contrary, plasma homocysteine levels were significantly higher than those observed in healthy controls, both at baseline (11.1 vs. 9.6 μmol/L) and at 18 and 36 months.

Lower urate concentration and higher homocysteine levels were associated with worsening of motor function in early diagnosed Parkinson’s patients. However, only higher homocysteine levels at baseline correlated with worse cognitive scores over 4.5 years of follow-up.

The findings suggest both urate and homocysteine can be biomarkers that help predict motor function decline, while only homocysteine predicts cognitive changes in early Parkinson’s disease.

“These findings lend support to the hypothesis that oxidative stress may play a role in the pathophysiology of PD [Parkinson’s disease] and that motor and cognitive aspects of the disease may have overlapping but separate mechanisms,” researchers wrote.

Of note, 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.

“In addition to potential disease modification, our findings suggest that determining urate and homocysteine concentration at the outset may have a role in predicting patients with PD [Parkinson’s disease] at greater risk of decline in motor and cognitive function,” they concluded.

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Hydrotherapy Improves Balance, Mobility in Parkinson’s Patients, Study Reports

hydrotherapy

Hydrotherapy may provide significant balance and mobility benefits in patients with Parkinson’s disease compared to medication and land-based exercises, according to a review study.

The research, “The Effects of Hydrotherapy on Balance, Functional Mobility, Motor Status, and Quality of Life in Patients with Parkinson Disease: A Systematic Review and Meta-analysis,” was published in the journal PM&R.

Impairments such as muscle rigidity and tremor affect the balance and mobility of people with Parkinson’s. Combined with fear of falling, it promotes a sedentary lifestyle and reduces quality of life.

Water-based exercise is often prescribed to these patients, providing a safe environment that reduces the risk of falling. Prior studies have reported that hydrotherapy improves motor symptoms. However, the evidence about  hydrotherapy as a treatment strategy in Parkinson’s is scarce.

To address this gap, researchers conducted a systematic review of the available scientific literature and a meta-analysis — a type of statistical analysis that combines the results of various studies.

The scientists focused on hydrotherapy’s effectiveness on patients’ balance, mobility, quality of life and motor function.

For this purpose, the investigators searched seven online databases as well as unpublished or ongoing clinical trials from inception through December 2017. Nineteen studies were identified, of which eight were randomized controlled trials (RCTs). Overall, the studies had 484 participants, with a mean age ranging from 54 to 78 years and an average disease duration ranging from three to 10 years.

The studies had different designs, which included comparisons of hydrotherapy with land-based exercises or medications, combinations of hydrotherapy with land-based therapy, and assessments of low-intensity and muscular resistance water-based exercises.

Hydrotherapy could include balance training, stretching, strengthening, trunk mobility, and gait exercises. The sessions ranged from 40 to 60 minutes, one to five days per week, for three to 20 weeks, for a total of eight to 60 sessions. Water temperature was set between 28ºC (82ºF) and 34ºC (93ºF) in the 12 studies that reported this parameter.

All but two studies with available information on levodopa usage evaluated patients’ in the “on” phase, which refers to the period when this medication is effective and has not yet worn off.

The meta-analysis on balance and mobility included five RCTs, which had a total of 133 patients. The results showed that hydrotherapy with or without land-based exercises significantly improved both balance and mobility compared to land-based therapy or usual care with medication alone.

Three other studies not included in the meta-analysis due to lacking a control group also found significant benefits with hydrotherapy in balance. One RCT not included in the statistical comparison did not report differences with hydrotherapy and land-based therapy, while another showed that aquatic obstacles training is more beneficial for balance than traditional water-based exercises.

In turn, two RCTs not included in the respective analysis failed to show mobility improvements with hydrotherapy.

As for quality of life, an analysis of three RCTs with 76 patients showed no benefits with hydrotherapy compared to land-based treatment, which the researchers attributed to the small number of studies included. This also was observed in one RCT not included in the meta-analysis. In contrast, five other studies, including two non-randomized trials, found significant improvements with water-based treatment.

Results of a meta-analysis of five RCTs with 140 patients also did not reveal improvements in motor function in comparison to land-based exercise. This can be explained by patients having types of motor complications not expected to improve with hydrotherapy, the team said.

Of note, two other RCTs and a non-randomized trial also did not find different results with hydrotherapy compared to other approaches in motor function.

Overall, the scientists wrote, “hydrotherapy, combined or not with other therapies, may improve balance and functional mobility of patients with [Parkinson’s] when compared to land-based therapy alone or usual care.”

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Proper Nutrition May Prevent More Severe Motor Problems in Parkinson’s, Study Suggests

Parkinson's motor symptoms

Maintaining good nutritional status may protect Parkinson’s patients from greater motor impairments associated with weight loss, according to new research.

The study, “Untangling the relationship between fat distribution, nutritional status and Parkinson’s disease severity,” was published in the journal Aging Clinical and Experimental Research.

Prior research has reported that individuals with Parkinson’s experience weight gain and obesity at early stages of the disease, but weight loss and low body mass index (BMI) at later stages.

Malnutrition may be a contributing factor for weight loss in Parkinson’s, as a significant proportion of these patients are at risk of developing an inadequate nutritional status. Malnutrition may aggravate motor symptoms, which then may be associated with other complications, such as depression or cognitive decline.

A team of international researchers explored the link between Parkinson’s severity and obesity, focusing on whether excess fat was deposited at the hip and thigh areas (gynoid), or at the abdominal region (android). The investigators also assessed if nutritional status might alter the association between disease severity and fat distribution.

A total of 195 Parkinson’s patients (mean age 73.6, 124 men) were included, all admitted to a geriatric day hospital in Rome from January 2012 to December 2015. The participants underwent dual-energy X-ray absorptiometry to assess body composition, as well as determinations of body weight, height, and BMI.

Total abdominal and gynoid fat were evaluated, as were patients’ nutritional status, severity of motor symptoms, cognition, functional ability, and depressive symptoms.

The findings revealed that patients with better motor function were more likely men, more educated and had better cognitive function, mood, functional status, and nutritional status. Also, improved motor scores (as determined by the Unified Parkinson’s Disease Rating Scale part III ((UPDRS III)) correlated with higher total body fat, percentage of abdominal fat, trunk-leg and trunk-limb fat ratios, as well as abdominal-gynoid fat ratio.

However, after accounting for nutritional status, only the percentage of abdominal fat and trunk-leg fat ratio were still associated with UPDRS III scores. Further analysis revealed that a greater abdominal fat distribution was linked with less severe motor impairment, but only with patients with a Mini-Nutritional Assessment score lower than 23.5, which indicates risk for malnutrition or overt malnutrition.

“In other words, a good nutritional status might protect [Parkinson’s] patients from weight loss associated with disease severity,” researchers wrote.

At the same time, higher percentage of gynoid fat was associated with worse motor function in patients with a MNA score not lower than 23.5.

“The main result of our study is that nutritional status drives the association between total and regional adiposity [fat storage] and disease severity in Parkinson’s disease patients,” the team commented. “In this regard, the early detection of malnutrition or risk of malnutrition in subjects with [Parkinson’s] is warranted.”

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AXO-Lenti-PD Gene Therapy Shows Benefits in 2 Advanced Parkinson’s Patients in Phase 1/2 Trial

AXO-Lenti-PD

One-time treatment with the gene therapy candidate AXO-Lenti-PD led to improved motor function and was well-tolerated after three months in two patients with advanced Parkinson’s disease, according to early results of an ongoing Phase 1/2 clinical trial.

These findings are from the open-label, dose-escalation portion of the SUNRISE-PD study (NCT03720418), in which the patients received the lowest dose (4.2×106 TU) of Axovant’s AXO-Lenti-PD. The goal is to test the safety, tolerability, and efficacy of the potential treatment.

“These findings are highly encouraging, and we look forward to advancing to higher dose cohorts where we will explore the full clinical potential of AXO-Lenti-PD in patients with Parkinson’s,” Gavin Corcoran, Axovant’s executive vice president of research and development, said in a press release.

Patient enrollment is ongoing in the U.K. (yet to open in France) for a total of about 30 participants ages 48–70 who have been diagnosed with idiopathic Parkinson’s for at least five years. More information on contacts and trial locations is available here.

AXO-Lenti-PD uses a harmless virus-based system to deliver three genes that generate key enzymes — tyrosine hydroxylase, cyclohydrolase 1, and aromatic L-amino acid decarboxylase — for the production of dopamine, the neurotransmitter found at reduced levels in Parkinson’s patients. The gene therapy — delivered surgically directly into the brain — is aimed at restoring dopamine levels in the brain to provide long-lasting benefits with a single administration.

As measured with the physician-rated Unified Parkinson’s Disease Rating Scale (UPDRS) part III off score — assessed after levodopa washout to not throw off the results — the two patients experienced a 25-point improvement in motor function, which represents an average 42% change from the beginning of the study. Off time is when medication — namely levodopa — is not working optimally, and Parkinson’s motor and non-motor symptoms return.

The benefits were observed across all subparts of the UPDRS scale, with an overall improvement of 54.5 points, or 55% from before treatment. In UPDRS part II, which refers to activities of daily living, average improvements were 22 points, and in part IV, dealing with complications of therapy, the patients showed a seven-point improvement.

Data further showed a mean 18% improvement in dyskinesia — involuntary, jerky movements — determined with the Rush Dyskinesia Rating Scale on score, which measures functional disability during activities of daily living while on treatment with levodopa.

According to a patient-recorded diary, both patients had an improvement in on time with dyskinesia and troublesome dyskinesia, with average decreases from before treatment of 3.5 hours (or 57%) and 1.3 hours (85%), respectively.

Treatment with AXO-Lenti-PD was also associated with an average reduction of 208 mg (19%) in levodopa equivalent daily dose — the amount of levodopa with a similar effect as the medication taken — at three months. No serious adverse events were reported.

Results of a Phase 1/2 trial (NCT00627588) of ProSavin, the predecessor to AXO-Lenti-PD, had shown favorable safety and tolerability, as well as significant improvement in motor function, at four years of treatment in most patients.

Compared with ProSavin, preclinical data of AXO-Lenti-PD showed higher production of the crucial enzymes and a minimum fivefold greater potency in improving behavior and movement in an animal model of Parkinson’s disease.

“These early data support the safety of the lowest dose of AXO-Lenti-PD, similar to what was observed with the earlier generation construct, ProSavin, and also suggest substantially greater biological activity than the highest dose of ProSavin previously tested,” Corcoran said.

Roger Barker, one of the principal investigators in SUNRISE-PD, said the results suggest that AXO-Lenti-PD “has the potential to significantly improve motor function in patients with advancing Parkinson’s.”

He also said that given the mechanism of action of AXO-Lenti-PD and the experience with ProSavin, the scientists expected the main benefit to be in relieving the off state — “and the results so far are very encouraging in this regard.”

Axovant is now planning to proceed to the second dose group (1.4×107) after receiving positive feedback from the trial’s data monitoring committee. Dosing of the first patient in this second group is expected in the second quarter of this year.

“I am hopeful that this development program will translate into a significant new therapeutic option for patients with Parkinson’s,” said Baker, a professor of clinical neuroscience and honorary consultant in neurology at the University of Cambridge and Addenbrooke’s Hospital.

Axovant recently gave a presentation at the Cowen and Company 39th Annual Health Care Conference in Boston. A copy of the slides and link to a webcast can be found here.

In June 2018, Axovant obtained exclusive worldwide rights to AXO-Lenti-PD from Oxford BioMedica, which originally developed the gene therapy.

The post AXO-Lenti-PD Gene Therapy Shows Benefits in 2 Advanced Parkinson’s Patients in Phase 1/2 Trial appeared first on Parkinson’s News Today.

Forced Exercise Improves Mobility, Mood in PD Patient, Study Finds

Theracycle

A collaboration between Theracycle and Virginian Outpatient Therapy will replicate a forced exercise regimen on a motorized bicycle with evidence of easing Parkinson’s symptoms, including rigidity, loss of balance and tremor.

In a 2009 study conducted by the Cleveland Clinic, an eight-week program of forced exercise with a trainer on a stationary tandem bicycle — in which patients’ bodies move beyond the extent they can do so themselves — was compared to voluntary exercise on a stationary single bicycle. Ten patients (eight men) with mild to moderate idiopathic Parkinson’s were included, five patients in each group.

The results showed that the patients on forced exercise (mean age 58 years, disease duration 7.9 years) had a 35% improvement in motor scores — as assessed with the Unified Parkinson’s Disease Rating Scale (UPDRS; higher scores mean more impairment) — as well as improved control and coordination of grasping during a bimanual dexterity task. Such improvements were not observed with voluntary exercise, although both groups had greater aerobic capacity.

The benefits in rigidity, bradykinesia — slowness of movement — and hand dexterity were maintained four weeks after stopping forced exercise, in which the patients pedaled at a rate 30% greater than their preferred voluntary rate.

In 2018, Shirlea Hennessy, Virginian Outpatient Therapy’s assistant director of rehabilitation, replicated the Cleveland Clinic study in a Parkinson’s patient. The patient’s wellness program was supplemented with an hour of forced exercise on the Theracycle three times a week for eight weeks.

This approach led to an improvement in the UPDRS score from 36 to 6 in 12 weeks, loss of 10 pounds, more joy in daily activities — including tai chi, yoga, Bible study, and visits with his grandchildren — and regaining the confidence to drive.

“To see such substantial improvements in his mobility symptoms in as little as eight weeks was remarkable,” Hennessy, who is also a board-certified geriatric clinical specialist, said in a press release.

Similar to the 2009 study, the patient maintained his improvements for four weeks after stopping the program, “revealing that a little effort can go a long way in establishing greater freedom and independence,” Hennessy said. “That freedom and independence is all that [Parkinson’s] patients strive for as they face their diagnosis and symptoms.”

Peter Blumenthal, Theracycle’s CEO, said that “to see Virginian Outpatient Therapy replicate the Cleveland Clinic study with its own patient and produce equally impressive results is inspiring.”

Hennessy will keep implementing forced exercise with a Theracycle for Parkinson’s patients at the outpatient physical therapy provider and expects to see benefits across the board.

A recent survey conducted by Theracycle revealed that 80% of its customers had improved walking, balance, and gait. Also, 73% reported an improvement in overall mood and 64% had a reduction in tremors or involuntary movements. Full results of the survey can be found here.

“At Theracycle, we understand how life-changing forced exercise can be for [Parkinson’s] patients,” Blumenthal said. “We’re honored to make a positive impact on the lives of those living with [Parkinson’s].”

Besides Parkinson’s, Theracycle provides motorized exercise bicycles to ease symptoms of multiple sclerosis, paraplegia, stroke, Down syndrome, traumatic brain injury, and other degenerative neurological disorders.

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