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Atrophy in Thalamus Linked to More Severe Non-motor Problems in Parkinson’s Patients

brain regions

People with severe non-motor symptoms related to Parkinson’s disease (PD) have a smaller thalamus compared to those with similar but mild to moderate symptoms, a brain imaging study suggests.

Sleeping and gastrointestinal problems are also tied to atrophy (shrinking) of the thalamus, a part of the inner brain known to process motor signals and to regulate consciousness, alertness, and sleep.

The study, “Sleep disturbances and gastrointestinal dysfunction are associated with thalamic atrophy in Parkinson’s disease,” was published in the journal BMC Neuroscience

Parkinson’s is marked by a progressive loss of coordination and movement. In addition to difficulties in movement (motor symptoms), it can cause a variety of non-motor symptoms such as sleep problems, depression, gastrointestinal and urinary problems, and difficulty thinking (cognitive impairment).

Techniques such as magnetic resonance imaging (MRI) help to diagnose PD through brain scans, and they can also help identify structural changes in the brain — like changes in thickness or volume — associated with its non-motor symptoms.

But the exact location of specific brain areas linked to non-motor symptoms is still unclear. 

Researchers recruited 41 patients diagnosed with idiopathic (unknown origin) PD at the Movement Disorders clinics at King’s College Hospital in London. All were analyzed through MRI brain scans.

None of these patients chosen showed signs of mild PD cognitive impairments or disease-related dementia, and they had no history of neurological or psychiatric disorders.

Patients were first assessed by medical staff using the Non-motor Symptoms Scale for PD (NMSS), then self-assessed using the Non-motor Symptoms Questionnaire (NMSQ). The Beck Depression Inventory-II (BDI-II) and the Hamilton Depression Rating Scale (HDRS) evaluated neuropsychiatric symptoms.

Motor symptoms stages were determined with the Hoehn & Yahr (H&Y) scale, general cognitive status was assessed using the Mini Mental Status Examination (MMSE), and quality of life (QoL) was measured by patients completing the 39-item PD Questionnaire (PDQ-39).

All were required to stop taking dopamine-related medications the night before the scans to avoid involuntary movements caused by side effects. 

Patients were then divided into two groups based on their NMSS scores. A total of 23 patients who scored 40 or below were considered to have mild to moderate non-motor Parkinson’s symptoms, while 18 who scored 41 or above were defined as severe. 

Results showed that, compared to those with mild to moderate symptoms, those with severe non-motor symptoms were older, had the disease longer, were using higher doses of medication, had higher H&Y scores, and reported a lower QoL. Severe non-motor PD patients also scored more poorly in the sleep and fatigue sections of the NMSS. 

MRI scans were taken, and the cortical (outer brain) thickness and subcortical (inner brain) volumes were calculated and compared with patient assessments.

Analyses revealed that the inner brain’s thalamus was significantly smaller in volume (thalamic atrophy) in PD patients with severe non-motor symptoms, compared to those with mild to moderate symptoms. 

Other areas of the inner brain, including the hippocampus, the amygdala, were similar between the two groups. No differences in the thickness of the outer brain were seen. 

Researchers then divided patients into two groups based on sleep/fatigue problems and gastrointestinal tract dysfunction. Compared to those without these problems, a smaller thalamus was significantly associated with sleep and gastrointestinal disturbances. 

“This is the first study showing an association between higher non-motor symptom burden and thalamic atrophy in PD. Among the non-motor symptoms, sleep/fatigue disturbances and gastrointestinal dysfunction were the non-motor symptoms that drove this correlation,” the researchers wrote.

The team, however, noted that further studies with larger numbers of PD patients are needed to confirm these findings, and use specific scales to measure nighttime and daytime sleep problems and tools that capture gastrointestinal dysfunction.

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Brain Networks May Dictate Likelihood of Developing Impulse Control Disorders in Parkinson’s, Study Finds

impulsivity, Parkinson's

The way the brain of a Parkinson’s disease patient is wired may help doctors predict if he or she will develop impulse control disorders following dopamine replacement therapy, a study finds.

The results, “The structural connectivity of discrete networks underlies impulsivity and gambling in Parkinson’s disease,” were published in the journal Brain.

The main cause of motor symptoms in Parkinson’s disease is a lack of dopamine (a key brain chemical) resulting from a loss of dopaminergic neurons in the substantia nigra, a brain area responsible for controlling voluntary muscle movements.

Higher doses of dopamine agonists — which act as a substitute for (or mimic) dopamine in the brain — and longer treatment periods have been shown to make Parkinson’s disease patients more prone to developing impulse control disorders, such as gambling, compulsive shopping, overeating, and compulsive sexual behaviors.

This impulsivity may be mediated by the patient’s inability to evaluate rewards appropriately or to inhibit inappropriate choices.

“Despite prior work suggesting that distinct neural networks underlie these cognitive operations, there has been little study of these networks in Parkinson’s disease, and their relationship to inter-individual differences in impulsivity,” the researchers noted.

To shed additional light on the matter, these investigators from the University of Queensland and QIMR Berghofer Medical Research Institute in Australia, evaluated microstructural changes in the brains of 57 Parkinson’s patients (19 women and 38 men; mean age of 62 years).

Using high-resolution diffusion magnetic resonance imaging, the team studied, on a microscopic and network-related level, how a patient evaluated rewards and inhibited responses, and how these were associated with dopamine replacement therapy.

Trait impulsiveness and compulsivity, disinhibition, and impatience were assessed by neuropsychological tests. Patients were also given access to a virtual casino, so that their explorative, risk-taking, or impulsive behaviors could be examined.

According to the researchers, “different components of impulsivity were associated with distinct variations in structural connectivity, implicating both reward evaluation and response inhibition networks.”

The reward system refers to a group of structures that are activated when a person is presented with rewarding or reinforcing stimuli (e.g. addictive drugs). Upon a rewarding stimulus, the brain increases the release of dopamine. Response inhibition refers to the ability to suppress behavior that is inappropriate or no longer required.

In the gambling scenario, larger bets were linked to greater connectivity within the reward evaluation network — more specifically, the nerve fibers connecting the ventral striatum and ventromedial prefrontal cortex.

The striatum is a crucial motor area that’s known to be damaged in Parkinson’s, while the prefrontal cortex is involved in planning complex cognitive behavior, and in personality expression and decision-making.

Patients who looked for alternative slot machines in the virtual casino had less connectivity within the response inhibition network. In addition, high-risk “double or nothing” bets were linked to reduced connectivity of the reward evaluation network.

“By combining data from brain imaging, behavior in the virtual casino, and the effect of dopamine-replacement medication, we were able to identify people who were susceptible to impulse-control behaviors,” Phil Mosley, MD, the study’s first author, said in a news release.

Although dopamine replacement therapy was effective for most of the study sample, around 17% (one out of six) of treated participants had trouble controlling their impulses.

“We found people who developed these addictive behaviors differed in the way their brain structure interacted with dopamine-containing medication, which gave rise to the impulsive behavior,” Mosley said.

“None of these people had a history of addictive behaviors before diagnosis and only developed them after they began treatment with dopamine-replacement medications,” he added.

These findings suggest that adapting a treatment regimen to minimize the side effects associated with dopamine agonists could potentially reduce the occurrence of these impulsive behaviors.

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Antiparkinsonian Medication Improves Learned Movement Production by Boosting Neuronal Connectivity, Study Finds

Antiparkinsonian Medication

Dopaminergic therapy may ease difficulties with gesturing and using tools in people with Parkinson’s disease by improving brain connectivity between the cognitive and motor regions, a study has found.

The study results, “Dopaminergic modulation of the praxis network in Parkinson’s disease,” were published in NeuroImage: Clinical.

Parkinson’s patients often have trouble performing skilled or learned movements that are crucial for daily living. Praxis is what scientists call this kind of cognitively directed motor action, while apraxia, generally speaking, refers to the difficulty itself, i.e., any disorder of learned movement.

“Although the neuronal basis of praxis functions has been comprehensively investigated in healthy individuals, functional imaging studies targeting these abilities including their impairments in clinical samples are still rare,” the researchers wrote.

Medical University of Vienna researchers studied the functional connectivity of the praxis network in individuals with mild-to-moderate Parkinson’s and at an increased risk for apraxia. They also investigated the influence of dopaminergic therapy on praxis function-related brain network.

For this purpose, a total of 13 Parkinson’s patients (seven men and six women, mean age of 60.23 years) and 13 healthy controls (seven men and 6 women; mean age of 56.77 years) underwent functional magnetic resonance imaging (MRI) and apraxia assessments.

Functional MRI measures the small changes in blood flow that occur with brain activity in response to stimuli or actions.

In the Parkinson’s group, all tests were performed twice: once with individually optimized dopaminergic medication (“on” state) and once without (“off” state).

None of the participants had trouble imitating gestures upon demonstration of object use, and none of the Parkinson’s patients showed apraxia-like symptoms. However, patients in the off period (without optimized symptom control by medication) performed significantly poorer in praxis assessments than controls.

Regarding functioning of the praxis-related brain network, patients in both states (on and off) displayed higher global efficiency than healthy individuals. Further analysis revealed that most of the communication within the network relayed to the bilateral supramarginal gyri, a portion of the brain that is thought to be involved in language perception and processing.

In addition, patients with optimized dopaminergic medication showed higher connectivity between praxis and motor areas, particularly between the supramarginal gyrus and the primary motor cortex, basal ganglia, and frontal areas, in comparison to subjects in the “off” state.

This improved communication “might facilitate the propagation of long-term representations of object-related actions to motor execution areas,” thus enabling the correct execution of the wanted movement.

The praxis network was confined to the left-brain hemisphere in the control sample, while in patients “off” therapy, but not in “on” individuals, the  network expanded to the right hemisphere.

Importantly, antiparkinsonian treatment seemed to normalize patients’ learned movement skills and related network connectivity, suggesting such therapy may support higher-order cognitive motor functions, at least in early stages of this neurodegenerative disorder.

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Investigational Azeliragon May Lessen Cognitive Decline in Mild Alzheimer’s Disease Patients with Type 2 Diabetes, Analysis Finds

Azeliragon, Alzheimer's, diabetes

The investigational therapy azeliragon decreased inflammation and lessened cognitive decline and dementia in patients with mild Alzheimer’s disease and type 2 diabetes, compared with a placebo, according to data from a subgroup analysis of the Phase 3 STEADFAST study.

The findings were described in the presentation, “Inflammatory Biomarkers, Brain Volumetric MRI, FDG-PET results in Patients with Diabetes in Azeliragon Phase 3 trial in mild Alzheimer’s Disease,” during the 14th International Conference on Alzheimer’s and Parkinson’s Diseases and related neurological disorders, March 26-31, in Lisbon, Portugal.

Previous studies have found that people with type 2 diabetes are more likely to develop Alzheimer’s disease. There are more than 400 million people with diabetes around the world who are at a higher risk of developing dementia.

Azeliragon is a small investigational molecule, developed by vTv Therapeutics, that inhibits a receptor protein thought to be involved in the development of Alzheimer’s, called the receptor for advanced glycation endproducts, or RAGE.

Binding of RAGE to its partner proteins, such as the advanced glycation endproduct (AGE), triggers a state of inflammation that can eventually lead to Alzheimer’s disease. Azeliragon binds to RAGE and prevents it from binding to these other proteins, and in this way, halts the underlying inflammatory process.

The Phase 3 STEADFAST (NCT02080364) study — two independent and identical placebo-controlled Phase 3 trials (A-Study and B-Study) — assessed the efficacy and safety of azeliragon to treat mild Alzheimer’s disease. Topline results announced back in 2018 revealed that the A-Study and the B-Study did not meet primary goals — improvements in cognition — and the clinical trials were stopped. However, subsequent post-hoc subgroup analyses have shown that certain groups experienced positive benefits.

The study recruited around 800 patients being treated with acetylcholinesterase (AChE) inhibitors and/or Namenda (memantine).

AChE inhibitors target the acetylcholinesterase enzyme, preventing it from breaking down acetylcholine, and cause an increase in the level and duration of the neurotransmitter’s acetylcholine activity. AChEs have been found to be an effective therapy for Alzheimer’s patients.

Participants were randomized to either 5 mg of azeliragon treatment or a placebo (sugar pill) taken orally once daily for 18 months. The therapy’s effectiveness was assessed using specific cognitive tests.

The study included a subgroup of Alzheimer’s patients with type 2 diabetes, as shown by a haemoglobin A1c (HbA1c) levels of 6.5% or higher at the start of the trial. HbA1c stands for glycated haemoglobin, and measures the levels of hemoglobin within red blood cells that gets attached to a sugar (glucose).

During the trial, the researchers measured the levels of RAGE-related biomarkers in the blood. Additionally, they evaluated patients’ brain volume using magnetic resonance imaging (MRI), both at the start of the trial and after 18 months.

The team also measured the brain’s metabolic activity using fluorodeoxyglucose positron emission tomography (FDG-PET) at the start of the trial and after 12 months and 18 months. In this imaging technique, FDG, a radioactive glucose compound, is injected directly into the blood. PET scans then measure the uptake of FDG in brain cells, which is an indicator of metabolic activity.

In total, the STEADFAST study recruited 56 patients with both Alzheimer’s and type 2 diabetes — 23 patients were randomized to the placebo group and 33 to the azeliragon treatment group. The clinical characteristics between the two groups were similar at the beginning of the trial.

The brain MRI and FDG-PET data showed a favorable trend for lower brain shrinkage, and the chambers within the brain that contain the cerebrospinal fluid (CSF) — called ventricles — were less enlarged in patients treated with azeliragon.

The uptake of the radiotracer in the FDG-PET scan showed that the metabolic activity of nerve cells in several regions in the brain was better preserved in patients treated with azeliragon.

Treatment also led to a decrease in inflammatory biomarkers associated with RAGE activation, including  interleukin (IL)-6, IL-12, interferon-gamma, among others.

These results add to previous data that showed azeliragon in Alzheimer’s patients with diabetes led to a statistically significant benefit of 3.5 points in the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) and of 0.7 points in the Clinical Dementia Rating Scale Sum of Boxes (CDR-sb, a scale for assessing dementia severity) compared with a placebo.

vTv is planning a follow-up study on mild Alzheimer’s disease patients with diabetes to further evaluate azeliragon’s effect on cognition.

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Study to Explore Art Therapy for Improving Visuospatial, Motor Function in Parkinson’s Patients

A new exploratory study intends to assess the benefit of art therapy in improving visuospatial function and gait in Parkinson’s disease patients.
The ExplorArtPD study (NCT03178786) is currently recruiting participants in New York City. More information on enrollment can be found here.
The study’s experimental protocol, “Visuospatial exploration and art therapy intervention in patients with Parkinson’s disease: an exploratory therapeutic protocol,” was published in the journal Complementary Therapies in Medicine.
Due to the variety of Parkinson’s motor and non-motor symptoms, including visuospatial dysfunction — loss of space orientation, motion perception, and target localization — effective treatments require multidisciplinary approaches involving physical therapy, occupational therapy, psychological support, family counseling, and palliative care.
When these approaches fail, complementary therapeutic strategies, such as art therapy, may hold potential to help patients restore functional independence and maintain their quality of life.
Although the source of visusospatial dysfunction in Parkinson’s is not fully understood, altered visual function has been consistently shown, with subsequent impaired ability to drive, read, and write, and increased anxiety and depression, as well as a greater risk of falls.
Given the lack of specific therapeutic strategies for visuospatial dysfunction associated with Parkinson’s disease, researchers at the Marlene and Paolo Fresco Institute for Parkinson’s and Movement Disorders at NYU Langone Health developed an art therapy intervention protocol that includes psychotherapy and art creation to address visuospatial dysfunction and psychological needs of Parkinson’s patients.
The study is aimed at determining the characteristics of visuospatial exploration and its neural basis as assessed by clinical and behavioral tests, neuropsychological inventories, eye tracking, gait analysis, and brain magnetic resonance imaging (MRI). Researchers also intend to assess the therapeutic impact of art therapy on visuospatial dysfunction and gait in Parkinson’s patients.
“According to our preliminary data [art therapy] appears to be a safe, non-invasive, reproducible modality of intervention that could be administered to [Parkinson’s] patients with potential ease of recruitment,” the authors wrote.
The study has an anticipated enrollment of 40 participants, 20 of whom will have a clinical diagnosis of Parkinson’s disease and a Hoehn and Yahr scale stage of 2-3 — stage 2 meaning symptoms on both sides of the body, but no balance impairment, and stage 3 referring to balance impairment and mild to moderate disease. They must also have no history of clinically active eye abnormalities, and be eligible to undergo brain MRI scans. Researchers will also include 20 age-matched participants without Parkinson’s disease who will serve as controls.
Parkinson’s patients will undergo open-label art therapy and assessments both before the completion of art projects (baseline) and after completion (follow-up), while control participants will only undergo baseline assessments. In patients with motor fluctuations, the assessments will be made in the “on” state, when motor disability is milder and assessments can be performed with a lower risk of physical or psychological fatigue.
Art therapy will consist of 20 consecutive sessions lasting 90 minutes each, approximately twice per week for a maximum of 14 weeks. It will be administered by credentialed professionals with a master’s degree in art therapy. The approach will favor group dynamics, mutual support, and encouragement through shared projects.

Source: Parkinson's News Today

First Parkinson’s Patient Treated with Insightec’s Incisionless Brain Therapy

Insightec

Insightec has treated the first patient in a pivotal study of its non-invasive ultrasound therapy, ExAblate Neuro, for patients with advanced Parkinson’s who have not responded to medication.

The device uses focused ultrasound and magnetic resonance imaging (MRI) to destroy a target deep in the brain — the Vim nucleus of the thalamus — through an intact skull. This area has been identified as responsible for causing Parkinson’s tremors. The MRI technology enables physicians to guide treatment planning and deliver thermal feedback in real-time monitoring.

The therapy aims to improve motor function and treat the characteristic involuntary movements of arms and legs, which may occur as a side effect of medication, and impair patients’ quality of life and ability to perform daily activities.

In July 2016, Insightec’s therapy become the first focused ultrasound device approved by the U.S. Food and Drug Administration (FDA) for the treatment of medication-resistant essential tremors with non-invasive thalamus destruction. In October 2017 the FDA granted approval to initiate the trial for these patients.

The trial (NCT03454425) evaluates the safety and effectiveness of the ExAblate System for the treatment of Parkinson’s motor features. It is currently enrolling patients who are 30 or older and have predominant motor disability from one side of the body. Insightec plans to recruit a total of 40 participants and expects to complete the research by December 2020.

“Building on the success of the incisionless focused ultrasound treatment for essential tremor, we are excited to extend its application to the debilitating effects of Parkinson’s,” Howard Eisenberg, MD, the study’s principal investigator and a neurosurgery professor at the University of Maryland School of Medicine, said in a press release.

Eisenberg is recognized as one of the nation’s top neurosurgeons and an expert on traumatic brain injury and the blood brain barrier.

“INSIGHTEC is committed to supporting focused ultrasound research, which is much less invasive than conventional surgery, and has the potential of improving the lives of people living with Parkinson’s,” said  Maurice R. Ferré, MD, CEO at Inisightec.

The company recently began a parallel Phase 3 trial (NCT03319485) of its MRI-guided focused ultrasound system for treating motor symptoms in Parkinson’s. It plans to recruit more than 100 patients with advanced idiopathic Parkinson’s not responding to available therapies. Patient enrollment is ongoing at sites in Maryland, New York, Ohio, Pennsylvania, and Virginia. More information is available here.

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Source: Parkinson's News Today

MRI-Focused Ultrasound Undergoing Phase 3 Clinical Trial for Parkinson’s Treatment

focused ultrasound

New technology that uses MRI-guided focused ultrasound to target areas of the brain affected by Parkinson’s disease and improve motor symptoms will be further tested in a pivotal Phase 3 clinical trial.

Led by the University of Maryland Medical Center (UMMC) and the University of Maryland School of Medicine (UMSOM), the randomized trial will assess the safety and effectiveness of the novel procedure. It is the final step before the U.S. Food and Drug Administration (FDA) will consider approving it as a nonsurgical treatment for  Parkinson’s.

“The goal of the focused ultrasound treatment is to both lessen the main symptoms of Parkinson’s disease, which include tremors, rigidity and slow movement, as well as treat the dyskinesia that is a medication side effect, so that less medication is needed,” Howard M. Eisenberg, MD, the trial’s lead investigator, said in a press release.  Eisenberg is a professor and the chair of neurosurgery at both UMSOM and UMMC.

Participants are currently being recruited for the new trial (NCT03319485), which follows a previous study where MRI-guided focused ultrasound led to a 62% improvement in upper-limb tremors, compared with 22% in the control group, in patients with tremor-dominant Parkinson disease who did not respond to other forms of therapy.

Findings were published in the study, “Safety and Efficacy of Focused Ultrasound Thalamotomy for Patients With Medication-Refractory, Tremor-Dominant Parkinson Disease: A Randomized Clinical Trial,” in the journal JAMA Neurology.

“The results of the pilot trial, so far, are very encouraging,” said Eisenberg about the first trial conducted in 2015 with 20 patients, the majority of whom were treated at UMMC.

With the new technology, clinicians direct ultrasound waves to a brain structure called the globus pallidus, which helps regulate voluntary movement, to destroy damaged tissue, decreasing the uncontrolled movements that characterize Parkinson’s disease.

Doctors use magnetic resonance imaging (MRI) to create a temperature map of the brain, giving them a real-time picture of the region they want to hit with the sound waves. They then raise the energy, directly targeting that area of the brain to destroy the tissue.

Patients are awake and alert the entire time in the MRI scanner, enabling them to give clinicians constant feedback. They are fitted with a helmet through which the energy is converted into sound waves, which are then targeted to the globus pallidus. The approach is noninvasive, meaning there is no surgery or radiation treatment involved.

Current therapies to lessen movement and coordination problems in Parkinson’s patients include levodopa (sold under the brand name Dopar, among others), which is the most common. Patients with advanced Parkinson’s may undergo surgery, known as deep brain stimulation, to implant micro-electrodes in the brain that help control tremors, rigidity and dyskinesia (abnormal, uncontrolled, involuntary movement).

“For people with Parkinson’s disease and other movement disorders such as essential tremor, focused ultrasound is an appealing alternative to deep brain stimulation because it does not involve more invasive surgery,” said Paul S. Fishman, MD, PhD, professor of neurology at UMSOM and a neurologist at UMMC.

Enrollment in the study is approximately 80 to 100 participants, and the inclusion criteria were designed to include a wider population of Parkinson’s patients. Sponsored by InSightec, the trial is recruiting participants in the U.S. at the University of Maryland Medical System, Maryland; Weill Cornell Medicine, New York; and The Ohio State Wexner Medical Center, Ohio.

“University of Maryland Medicine is a world leader in pioneering MRI-guided focused ultrasound to become a new standard of care for treating many devastating brain diseases including Parkinson’s, essential tremor and glioblastoma, an often deadly type of brain cancer,” said E. Albert Reece, MD, PhD, MBA, vice president of medical affairs at the University of Maryland and dean of UMSOM.

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Source: Parkinson's News Today