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 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


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.

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


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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Researchers Evaluate Computer-based Therapy to Ease Fatigue, Improve Motor Function

motor function, nonpharmacological intervention

An ongoing pilot trial is evaluating a computer-based, non-pharmacological cognitive approach to improve motor function and ease fatigue in people with Parkinson’s disease.

Study protocol for a randomised pilot study of a computer-based, non-pharmacological cognitive intervention for motor slowing and motor fatigue in Parkinson’s disease,” appeared in the journal Pilot and Feasibility Studies.

Non-pharmacological therapies may offer effective alternatives to the complications and significant cost of dopaminergic treatment. A team of English researchers set out to develop an approach based on cognitive tasks to lessen fatigue and improve motor function in this patient population.

Advances in the understanding of the brain’s anatomy — such as links between motor and cognitive processes — and of Parkinson’s underpinnings provide the required scientific ground to develop such an approach. Also, previous work from the same team and other researchers had shown that people with Parkinson’s have an impairment in visuospatial tasks, such as mental rotation and mental grid navigation. These tasks were found to activate brain regions such as the supplementary motor area, typically involved in motor control.

Mental rotation is the ability to rotate mental representations of two-dimensional and three-dimensional objects and is related to the brain’s capacity for visual representation; mental grid navigation is the ability to compute a series of imagined location shifts in response to directional cues around a mental grid.

Prior work in 16 people with early-stage Parkinson’s showed improved motor performance after a visuospatial intervention task of mental grid navigation, as evidenced by faster mean onset and velocity. Such results, the team said, indicate that cognitive tasks with visuospatial processing can improve resilience to motor slowing and improve motor function. Such a strategy could become a low-cost option for patients and suitable for home use.

But before this intervention can be considered for a large-scale clinical trial, researchers needed to understand whether the computer-based cognitive training intervention (spatial grid navigation) could lead to significant motor benefits. They also wanted to see whether the improvements extend to aspects such as lessened rigidity and increased motor fluency.

The team designed a randomized single-blind (only patients are unaware of which intervention is expected to be beneficial) pilot study (ISRCTN1256549) to evaluate the feasibility of a larger-scale clinical trial. The trial set out to determine the usability of the devices used to capture movement and finger-tapping data. Tests of finger tapping are routinely conducted to assess bradykinesia, or slowness of movement, and may indicate motor fatigue.

Secondary objectives included assessing changes of at least five points in the Unified Parkinson’s Disease Rating Scale Part III (UPDRS-II) motor examination measure, as well as improvements in movement response times and eased motor fatigue over five 45- to 70-minute sessions involving sequential subtraction or spatial memory control tasks.

Patients were tested at home, at local hospitals or at Wales’ School of Psychology, Bangor University. They did not change their medication or other nonpharmacological regimens. Patients’ hand dominance was assessed before starting the study. Evaluations of quality of life, fatigue, sleep quality, and non-motor symptoms were conducted.

In finger tapping, each hand was tested separately, with the number of taps over 15 seconds and the time between taps analyzed. To evaluate measures of velocity and trajectory, patients held down a button on a response box for four seconds and then reached for a green circle on a screen as quickly and accurately as possible. Eighteen trials were conducted per hand. Action completion time, including movement initiation time and reaching time/velocity, were the primary outcome measures on this task.

The spatial grid navigation task includes an empty grid made up of nine squares, shown for 10 milliseconds. Then, a red start square is displayed for 2.5 seconds and participants are asked to memorize its position. A sequence of five screens is then shown, with two, three or four arrows that indicate movement of the red starting square. The participants must track the position of the red square based on the observed sequence.

At the end of the task, a blue target square is shown with a test grid. The patients then decide whether the position of the blue square matches that of the final position of the presented sequence.

“The results of this study will provide information regarding the feasibility of conducting a larger randomized control trial of non-pharmacological cognitive interventions of motor symptoms in  [Parkinson’s disease],” the researchers stated.

“The longer-term view is to develop an evidence-based, online or app-based platform that could be accessed by people in their own homes alongside other pharmacological or physical treatments to support maintenance of motor slowing and motor fatigue symptoms,” they said.

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Small Vessel Disease Linked to Severity of Motor Impairment in Parkinson’s Patients, Study Finds

small vessel disease

A disorder related to tiny blood vessels in the brain, known as cortical small vessel disease, is directly linked to worsening motor function in Parkinson’s disease, according to a recent study.

An additional association between modifiable vascular risk factors, in particular hypertension, and dementia highlights the need to manage these risk factors in Parkinson’s patients.

The study, “Impact of small vessel disease on severity of motor and cognitive impairment in Parkinson’s disease,” was published in the Journal of Clinical Neuroscience.

Symptoms of Parkinson’s disease can be affected by different risk factors — any attribute, characteristic, or exposure of an individual that increases the likelihood of developing a disorder or injury. Notably, issues with the heart and its blood vessels, or cardiovascular risk factors, have been shown to contribute to greater motor dysfunction in Parkinson’s disease.

In addition, disorders rooted in the brain’s blood vessels, or cerebrovascular pathologies, are linked with an increased prevalence of parkinsonian symptoms, such as motor dysfunction, and cognitive impairment in the elderly.

The relationship among cortical small vessel disease — an umbrella term covering a variety of abnormalities related to small blood vessels in the brain — cognitive decline, and dementia is well-established. Despite this, small vessel disease is not considered a significant cause underlying cognitive impairment in Parkinson’s, and it is not clear whether and to what extent its symptoms and progression contribute to Parkinson’s motor severity and cognitive impairment.

Some of the most concrete evidence for understanding the impact of comorbidities — the simultaneous presence of two chronic diseases or conditions in a patient — in Parkinson’s and other neurodegenerative diseases has been obtained through autopsies of patients’ brains.

By comparing the clinical information collected from patients, such as motor function and cognitive ability, during treatment with an autopsy report, doctors can better assess the link among risk factors, the course of Parkinson’s disease, and the severity of parkinsonian symptoms and dementia.

Cerebrovascular disease pathologies, such as small vessel disease, have only been assessed in a limited number of autopsy studies of Parkinson’s patients.

Now, researchers at the University of Sydney Medical School in Australia have studied the relationship among vascular risk factors and small vessel disease and the severity of motor impairment, cognitive dysfunction, and dementia in Parkinson’s patients. Vascular risk factors studied included stroke, heart disease, hypertension, diabetes, and cigarette smoking.

To do so, they examined clinical information from 77 autopsy-confirmed Parkinson’s patients who were similar in age, cause of death, and duration or severity of Parkinson’s disease.

The researchers then examined clinical information collected during patient visits to determine the severity of cognitive dysfunction and motor impairment. The severity of motor impairment and disease progression was determined using the Hoehn and Yahr scale, while the Clinical Dementia Rating was used to assess the severity of cognitive dysfunction and progression.

Of the 77 patients, 65 percent had advanced-stage dementia. The mean duration of Parkinson’s disease was 12 years for patients with and without dementia. Patients with dementia had more vascular risk factors than those without dementia, including stroke, heart disease, hypertension and diabetes, and a longer history of cigarette smoking.

Researchers observed that the severity of small vessel disease was related to the degree of motor impairment. They did not find a link between the severity of small vessel disease and the presence of dementia in these patients.

They also found a link between the severity of modifiable vascular risk factors and cognitive impairment in the autopsies of Parkinson’s patients. Among the vascular risk factors, only hypertension was linked with cognitive impairment and dementia.

“Modifiable vascular risk factors relate most to the severity of cognitive rather than motor impairment in Parkinson’s disease,” the researchers wrote. This emphasizes the importance “of a holistic approach to the treatment of PD  [Parkinson’s disease] including the potential for longterm cognitive benefits of early and aggressive management of vascular co-morbidities.”

“Our study suggests that neurologists treating patients with Parkinson’s disease should proactively manage their patient’s vascular risk factors, which may reduce gait and cognitive impairment, two of the main clinical features that undermine well-being and independence in patients with Parkinson’s disease,” lead study author Jillian Kril, PhD, said in a news article published in Neurology Today.

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Parkinson’s Gene Therapy Eases Motor Symptoms by Creating New Brain Circuits, Study Shows

AAV2-GAD gene therapy

An experimental gene therapy called AAV2-GAD, previously shown to improve motor function in Parkinson’s patients, works by creating new circuits in the brain involving motor regions, researchers have discovered.

Their findings were published in the study, “Gene therapy reduces Parkinson’s disease symptoms by reorganizing functional brain connectivity,” in the journal Science Translational Medicine.

Neurodegeneration in Parkinson’s disease begins with the gradual loss of dopamine-producing nerve cells in the substantia nigra, a region of the brain responsible for movement control. However, at symptom onset, several changes in connectivity and metabolism (set of life-sustaining chemical reactions) in distinct areas of the brain are present.

The subthalamic nucleus (STN), which is key in the regulation of the motor circuitry, is one of the areas of the brain affected by Parkinson’s, becoming hyperactivated. Surgical interventions in this area, such as deep brain stimulation, have been pinpointed as a good therapeutic target to ease motor symptoms.

AAV2-GAD, developed by Neurologix, consists of a modified and harmless adeno-associated virus (AAV) that transports and delivers the glutamate decarboxylase (GAD) gene — which has the instructions to produce GAD, a key enzyme in the production of GABA, the major suppressive messenger molecule in the brain. AAV2-GAD is delivered through a surgical procedure.

Results from previous Phase 1 (NCT00195143) and Phase 2 (NCT00643890) clinical trials have shown that the administration of the AAV2-GAD gene therapy directly into the STN region resulted in significant motor improvements in Parkinson’s patients, which were maintained for at least a year.

Despite the promising results of AAV2-GAD, the precise mechanisms behind it remained unclear.

Scientists hypothesized, however, that the local delivery of the GAD gene to induce the production of GAD and GABA would convert STN nerve cells to a suppressive state and reduce their hyperactivity, ultimately easing Parkinson’s motor symptoms.

Clinical responses in Parkinson’s disease can, in theory, arise from changes in the underlying abnormal disease network, development of new networks, a placebo effect, or a combination of all three.

Previous studies have shown that Parkinson’s patients show a disease-specific metabolic network — known as Parkinson’s disease-related covariance pattern (PDRP) — and that this pattern can be used as an objective and sensitive indicator of disease progression and that its reduction is strongly associated with motor improvements, assessed with the Unified Parkinson’s Disease Rating Scale (UPDRS).

Researchers at The Feinstein Institute for Medical Research, in Manhasset, New York, have now evaluated whether the motor improvements associated with delivery of AAV2-GAD to the STN were due to changes in PDRP or to other mechanisms.

They compared the brain metabolic networks of 36 Parkinson’s patients who participated in the previous double-blind, randomized, controlled Phase 2 trial: 15 in the AAV2-GAD group and 21 in the control group (sham surgery). These specialized brain scans were obtained at the beginning of the study, and six and 12 months after surgery.

“Current Parkinson’s disease therapies act on the abnormal disease network in the brain and often stop working over time as the body builds a tolerance,” David Eidelberg, MD, the study’s senior author and director of the Center for Neurosciences at the Feinstein Institute, said in a press release. “What we observed with AAV2-GAD therapy is quite the opposite.”

To the team’s surprise, AAV2-GAD did not change Parkinson’s abnormal brain circuitry, like current therapies, but instead promoted the formation of new brain networks connecting the STN to motor regions, which became mature one year after surgery.

Patients in the control group did not show this type of rewiring, and changes in UPDRS motor scores were found to be significantly associated only with the AAV2-GAD-specific brain metabolic network.

Data showed that while AAV2-GAD delivery to the STN did not act on the disease network, it induced the rewiring of key areas of the brain, compensating for the faulty circuitry and showing motor benefits for Parkinson’s patients.

The team noted that a larger Phase 3 trial is required to confirm these findings and the therapeutic effects of AAV2-GAD delivery to the STN, and that metabolic network analysis might be useful for evaluating therapeutic effectiveness in patients with neurological disorders in clinical trials.

“This latest work mapping the therapeutic benefit of AAV2-GAD gene therapy is a major next step to further refining therapies that combat the root causes of [Parkinson’s disease],” said Kevin J. Tracey, MD, Feinstein Institute’s president and CEO.

The post Parkinson’s Gene Therapy Eases Motor Symptoms by Creating New Brain Circuits, Study Shows appeared first on Parkinson’s News Today.

Eradication of Helicobacter pylori Infections Could Ease Gut Symptoms, Motor Dysfunction in Parkinson’s Patients, Study Suggests

Eradicating Helicobacter pylori infections could improve motor function, ease gut symptoms and increase levodopa’s effectiveness in Parkinson’s patients, according to a review study.
The research, “Stomaching the Possibility of a Pathogenic Role for Helicobacter pylori in Parkinson’s Disease,” was published in the Journal of Parkinson’s Disease.
While a small subset of Parkinson’s cases have genetic causes, most cases are sporadic, with unknown environmental causes. Gastrointestinal symptoms such as constipation precede motor complications, suggesting that the disease might start in the gut and subsequently spread to the brain along the brain-gut axis.
This has been observed in rats, where injection of alpha-synuclein fibrils — the major component of Parkinson’s characteristic Lewy bodies — into the gut induced Parkinson’s-related pathology.
Chronic infections with H. pylori affect half the world’s population and may cause gastritis, ulcers, and stomach cancer, as well as various gastrointestinal symptoms. A greater occurrence of ulcers in patients with Parkinson’s was first reported in 1961. More recently, a link between H. pylori and Parkinson’s has been shown, with consistent reports of higher risk for Parkinson’s in people infected with this type of bacteria.
The research team reviewed all major studies that discussed the possible link between H. pylori and Parkinson’s, which led to four key findings:

Having Parkinson’s increases by 1.5 to 3 times the risk of H. pylori infection.
H. pylori infection worsens motor function in Parkinson’s patients.
Eradication of H. pylori with triple therapy improved motor function in Parkinson’s patients compared to infected patients in clinical studies.
Eradication of H. pylori improved gut absorption and increased plasma levels of Parkinson’s gold-standard treatment levodopa in patients. Research had shown that H. pylori binds to levodopa, preventing it from reaching the brain and reducing its effectiveness

As for pathways linking this bacterial infection with Parkinson’s, the researchers provided three possible explanations besides impaired levodopa effectiveness. One explanation is that bacterial toxins produced by H. pylori or alterations to the body’s own molecules such as cholesterol can damage neurons.
The infection can also cause a massive inflammatory response in the stomach, which would become systemic, cross the blood-brain barrier (BBB) — a semipermeable barrier that protects the brain — and worsen Parkinson’s symptoms and pathology. H. pylori could also reach the brain by colonizing immune cells that cross the BBB themselves.
Finally, H. pylori may disrupt the normal gut microbial population, or microbiota, altering inflammatory mediators that predispose a person to Parkinson’s disease.
“Our conclusion is that there is a strong enough link between the H. pylori and Parkinson’s disease that additional studies are warranted to determine the possible causal relationship,” David J. McGee, PhD, the study’s lead author and a professor at the Department of Microbiology and Immunology, LSU Health Sciences Center-Shreveport, said in a press release.
Although current evidence suggests that “eradication of H. pylori or return of the gut microflora to the proper balance in [Parkinson’s] patients may ameliorate gut symptoms, L-dopa malabsorption, and motor dysfunction,” scientists still have little information on whether H. pylori infection “is a predisposing factor, disease progression modifier, or even a direct cause of [Parkinson’s]”, the authors wrote.
Specifically, future studies should explore the interactions of H. pylori with neurons and levodopa, the role of H. pylori toxins, how inflammatory responses to H. pylori may

Source: Parkinson's News Today