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Imaging Technique Finds Key Neurons in Brain Interact, May Support More Targeted Treatments

nerve cell communication

Two key types of brain nerves cells affected by Parkinson’s disease — cholinergic neurons and dopaminergic neurons — communicate and interact via signaling systems, researchers were able to “see” using a new imaging approach.

This beneficial neuron-to-neuron interaction, confirmed through the novel approach in a rat model of the disease, also supported further work on targeted treatments for Parkinson’s, including a potential gene therapy.

Their study, DREADD Activation of Pedunculopontine Cholinergic Neurons Reverses Motor Deficits and Restores Striatal Dopamine Signaling in Parkinsonian Rats,” was published in Neurotherapeutics.

Parkinson’s is a progressive neurodegenerative disease, meaning that it steadily worsens as neurons die over time. One of its hallmarks is the loss of dopamine — a neurotransmitter crucial for coordinating movement and regulating mood — that occurs when dopaminergic neurons in a brain structure called the substantia nigra malfunction and die.

Cholinergic neurons — those that produce the neurotransmitter acetylcholine — are nerve cells found in the pedunculopontine nucleus (PPN) of the brain. They are also implicated in Parkinson’s, since in post mortem studies of patients’ brain tissue a significant amount of these cells are found dead.

Researchers had previously used used a harmless virus to deliver a genetic modification to cholinergic neurons in a rat model of Parkinson’s disease. This technique is called designer receptors exclusively activated by designer drugs (DREADDs), and consists of a class of engineered proteins that allow researchers to hijack cell signaling pathways in order to look at cell-to-cell interactions more easily.

The animals were then given a compound designed to activate the genetic ‘switch’ and stimulate the target neurons. After treatment, almost all animals had recovered and were able to move.

Now, this same research team used positron emission tomography (PET), a brain imaging technology, together with DREADDs to selectively activate cholinergic neurons in the brains of diseased rats and look at how other brain cells responded.

They found that stimulating cholinergic neurons led to the activation of dopaminergic neurons in the rat brain, and dopamine was released.

This means that cholinergic activation restored the damaged dopaminergic neurons. The parkinsonian rats appeared to completely recover — they were able to move without problems and their postures returned to normal.

“This is really important as it reveals more about how nerve systems in the brain interact, but also that we can successfully target two major systems which are affected by Parkinson’s disease, in a more precise manner,” Ilse Pienaar, PhD, a researcher at the University of Sussex and Imperial College London and study author, said in a press release.

“While this sort of gene therapy still needs to be tested on humans, our work can provide a solid platform for future bioengineering projects,” Pienaar added.

This new technique has several advantages over deep brain stimulation (DBS), a surgical procedure that sends electrical impulses to the brain to activate the neurons.

Deep brain stimulation can help to relieve some Parkinson’s symptoms, but is invasive and has had mixed results. Some patients show improvements while others experience no changes in symptoms or even a deterioration. This may be due to therapy imprecision, as DBS stimulates all types of brain nerve cells without a specific target.

This study sought to address the selectivity issue by looking at the activation of one type of cell in a specific part of the brain to get a better understanding of how other parts might be influenced.

“[T]he current data could allow for designing medical approaches capable of improving the ratio between desirable and undesirable outcomes and leaving nonimpaired functions intact. For example, specific genetically defined neurons … could be targeted to treat motor symptoms of [Parkinson’s], without inducing a cognitive detriment, and vice versa,” the researchers wrote.

“For the highest chance of recovery, treatments need to be focused and targeted but that requires a lot more research and understanding of exactly how Parkinson’s operates and how our nerve systems work,” Pienaar said. “Discovering that both cholinergic and dopaminergic neurons can be successfully targeted together is a big step forward.”

The researchers concluded, “[t]his study supports the hypothesis that it is the cholinergic neuronal population, projecting from the PPN, which delivers some of the clinical benefits associated with PPN-DBS.”

Pienaar and colleagues collaborated with Invicro, a precision medicine company, for this study. Lisa Wells, PhD, a study co-author on the study and Invicro employee added, “It has been an exciting journey … to combine the two technologies [DREADD and PET] to offer us a powerful molecular approach to modify neuronal signaling and measure neurotransmitter release. We can support the clinical translation of this ‘molecular switch’ … through live imaging technology.”

This work may make possible more selective and more effective treatment alternatives to deep brain stimulation.

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Changes in Neuronal Communication Linked to Falls and Freezing of Gait in Parkinson’s, Study Finds

neuronal communication changes, Parkinson's motor symptoms

Parkinson’s disease-related falls and freezing of gait — when patients are unable to move their feet forward when trying to walk — are associated with changes in a specific type of neuronal communication in different brain regions, a study reports.

The study, “Cholinergic system changes of falls and freezing of gait in Parkinson disease,” was published in Annals of Neurology.

Many people with Parkinson’s disease will experience falling and freezing of gait, which tend to become more frequent as the disease progresses. In some cases, symptoms cannot be controlled with dopaminergic therapy, suggesting that non-dopamine mechanisms contribute to Parkinson’s disease motor symptoms.

Previous studies have shown that the brainstem (region that connects the brain to the spinal cord) and basal forebrain (important in the production of acetylcholine) regions with degenerated acetylcholine-releasing neurons projecting to the thalamus and cerebral cortex are associated with falls and slow gait speed in Parkinson’s patients.

Acetylcholine is a brain chemical (neurotransmitter) released by nerve cells to send signals to other cells (neurons, muscles, and glands). The thalamus is involved in several important processes, including consciousness, sleep, and sensory interpretation; the cerebral cortex plays a key role in memory, attention, perception, awareness, thought, language, and consciousness.

Scientists have also observed reduced dopaminergic nerve terminals in the striatum, reduced cholinergic (meaning “acetylcholine-releasing”) nerve terminals in the cortex, and more severe beta-amyloid accumulation in Parkinson’s disease “freezers” compared with “non-freezers.”

The striatum coordinates multiple aspects of cognition, including both motor and action planning; the cholinergic system contains nerve cells that use acetylcholine to propagate a nerve impulse, and has been associated with a number of cognitive functions, including memory, selective attention, and emotional processing.

University of Michigan researchers hypothesized that distinct patterns of cholinergic projection system changes in the brain are associated with freezing of gait and falls in Parkinson’s patients.

The team examined and performed [18F]FEOBV positron emission tomography (PET) scans on 94 Parkinson’s patients (72 men and 22 women) with a history of falling and “freezing.” Most subjects were taking dopamine agonists, carbidopa-levodopa or combinations of both.

[18F]FEOBV is a radioactive marker that selectively binds to the vesicular acetylcholine transporter (VACht) that loads acetylcholine into synaptic vesicles — sac-like structures in neurons that store chemical messengers before releasing them into the gap between nerve cells (synapse), enabling neuronal communication.

A PET scan is a non-invasive imaging technique to visualize metabolic processes in the body. Before the scan, [18F]FEOBV is administered via injection; doctors wait for the radiotracer to be distributed throughout the body, and then scan the patient to detect and quantify the patterns of its accumulation in the body.

Because the marker binds to VACht, scientists use it to quantify active cholinergic nerve terminals in the brain.

“Participants were asked about a history of falling. A fall was defined as an unexpected event during which a person falls to the ground. The presence or absence of (freezing of gait) was based on clinical examination and directly observed by the clinician examiner,” according to The Movement-Disorder Society Sponsored-Unified Parkinson’s Disease Rating Scale (MDSUPDRS), the researchers wrote.

They reported that 35 participants (37.2%) had a history of falls, and 15 (16%) had observed freezing of gait.

Compared with non-fallers, fallers had a significant decrease in VACht expression within the right thalamus, specifically in the lateral geniculate nucleus, which is the primary center for processing visual information. This suggests that the visual information processing required for walking around safely might be compromised in Parkinson’s patients with a history of falling.

On the other hand, patients with freezing of gait had significantly reduced VACht expression in the bilateral striatum and hippocampus — required for learning and memory — compared with non-freezers.

The team found that a history of falls was associated with cholinergic projection system changes that relay to the thalamus, while the neural signals behind freezing of gait transmit to the caudate nucleus — a brain region associated with motor processing.

They also found that Parkinson’s fallers had a lower density of thalamic cholinergic nerve terminals compared with non-fallers.

Freezing of gait was related to longer disease duration, more severe parkinsonian motor ratings, and higher levodopa levels.

These results suggest that changes in acetylcholine-mediated neuronal communication are linked to falls or freezing behavior, depending on the affected brain region.

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Changes in Specific Brainstem Nerve Cells Linked to Parkinson’s for First Time

brainstem cells

It’s widely accepted that Parkinson’s disease (PD) patients experience neuronal death in the brainstem. Now, for the first time, researchers report that the number of copies of mitochondrial DNA is increased in the surviving nerve cells within this area of the brain.

Interestingly, specific brainstem neurons had more alterations in their mitochondrial DNA.

“This is the only study to date to characterise mitochondrial DNA errors in cholinergic neurons, a neuronal population that is highly vulnerable to cell death in Parkinson’s disease patients,” Joanna Elson, PhD, a mitochondrial geneticist at Newcastle University, said in a press release.

The study resulted from a collaboration between Newcastle University and University of Sussex, both in the United Kingdom.

The team’s work, “Mitochondrial DNA xchanges in pedunculopontine cholinergic neurons in Parkinson disease,” was published in Annals of Neurology.

Mitochondria are our cells’ powerhouses, responsible for maintaining their health. Changes to the genetic composition of the mitochondria compromise its function and can lead to nerve cell death.

Mitochondrial DNA damage has been associated with both normal aging and neurodegeneration.

In a Parkinson’s scenario, studies have demonstrated that a specific brainstem region, known as the pedunculopontine nucleus (PPN), presents altered mitochondrial DNA.

PPN is thought to be involved in the initiation and modulation of gait and other stereotyped movements. As a result of Parkinson’s progression, these “behavioral functions” are affected.

Part of the PPN is made up of cholinergic neurons, meaning these cells produce the brain chemical acetylcholine and use it to communicate with other nerve cells. Cholinergic neuronal loss has been observed in Parkinson’s patients.

In this study, researchers isolated single cholinergic neurons from postmortem PPNs of Parkinson’s patients and aged controls. They then analyzed its mitochondrial DNA content.

Results showed that the number of copies and changes in mitochondrial DNA were significantly higher in the Parkinson’s group, compared to the control samples.

Moreover, the mitochondrial DNA of Parkinson’s patients changed by more than 60 percent, which has been associated with deleterious effects on mitochondria function.

The current results differ from other studies that have focused on other brain regions and cell types.

“Our study is a major step forwards in gaining an enhanced insight into the serious condition. Only by understanding the complexities of what happens in specific cell-types found in specific areas of the brain during this disease can targeted treatments for Parkinson’s disease be produced,” Elson explained.

“At present, treatments are aimed at the whole brain of patients with Parkinson’s disease. We believe that not only would cell-specific targeted treatments be more effective, but they would also be associated with fewer side-effects,” said Ilse Pienaar, PhD, a neuroscientist at Sussex University.

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Source: Parkinson's News Today