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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Specific Area of Brain Involved in Motor Issues, Slow Thinking in Parkinson’s, Mouse Study Shows

area of brain

Nerve cell damage in a specific area of the brain impairs motor function and slows thought, both of which are symptoms of Parkinson’s disease, a mouse study finds.

The study, “Loss of glutamate signaling from the thalamus to dorsal striatum impairs motor function and slows the execution of learned behaviors,” was published in NPJ Parkinson’s Disease.

Parkinson’s disease is caused by the progressive loss of brain nerve cells — in particular, those that produce dopamine, a molecule essential for nerve cell communication — as well as the abnormal accumulation of alpha-synuclein-containing Lewy bodies that induce nerve cell damage.

While a hallmark of Parkinson’s disease is the loss of dopamine-producing nerve cells in a brain area called the substantia nigra, known to be involved in motor function, increasing evidence shows that other areas of the brain are also impacted both at Parkinson’s onset and throughout the course of the disease.

Nerve cells in the substantia nigra send dopamine signals to the dorsal striatum, a region of the brain also involved in the control of movement. The loss of dopamine signaling in Parkinson’s disease leads to dorsal striatum dysfunction and to the motor problems seen in Parkinson’s patients.

However, the dorsal striatum also receives signals from other areas of the brain, such as the thalamus, which relays motor signals to the dorsal striatum through glutamate, another signaling molecule. The thalamus is also known to play a crucial role in memory, executive function, and attention.

Several studies have reported that Parkinson’s patients present with Lewy bodies, loss of nerve cells, and changes in the structure and activity of the thalamus.

These data suggest that nerve cell damage in the thalamus may be involved in the development of Parkinson’s symptoms.

Researchers have now evaluated whether the disruption of glutamate-dependent thalamus signaling to the dorsal striatum results in the cognitive and motor deficits characteristic of Parkinson’s.

The team generated genetically modified mice that allowed the induction of loss of glutamate signaling specifically between the thalamus and the dorsal striatum. A battery of motor and behavioral tests were performed in these mice to assess motor function, visuospatial function, executive function, attention, and working memory.

Modified mice showed significant motor coordination deficits, compared with healthy mice, suggesting that impaired thalamus-dorsal striatum signaling is involved in motor deficits.

In addition, while the disruption of thalamus-dorsal striatum signaling did not result in an apparent cognitive impairment, these mice took longer to process cues and new environments and were slower at carrying out tasks than healthy mice.

These results suggest that the loss of glutamate signaling between the thalamus and dorsal striatum led to slower processing reaction times, which resemble “bradyphrenia, the slowness of thought that is often seen in patients with PD and other neurological disorders,” the researchers wrote.

Slow thought can cause bradykinesia — slowness of movements or difficulty moving the body quickly on demand — which is also a symptom of Parkinson’s.

The team noted that the results highlight the involvement of glutamate-producing nerve cells in the thalamus that signal to the dorsal striatum in behaviors of mice that resemble slowness of thought and movement, indicating that the loss of function of these cells contribute to cognitive and motor deficits in Parkinson’s disease.

This may explain why some of the Parkinson’s therapies that target dopamine signaling have limited therapeutic effects in terms of patients’ cognitive function.

The researchers added that new therapies acting on other communication molecules besides dopamine are needed to target cognitive symptoms, and that their genetically modified mice may serve as a model to test those approaches.

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Source: Parkinson's News Today