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Changes in Gait, Cognition May Be Early Signs of Idiopathic Parkinson’s, Research Suggests

gait and Parkinson's

Changes in gait and cognition precede a diagnosis of idiopathic (without known cause) Parkinson’s disease, and may occur earlier than typical non-motor symptoms, a study has found.

The study, “Prediagnostic markers of idiopathic Parkinson’s disease: Gait, visuospatial ability and executive function,” was published in Gait & Posture.

Motor symptoms in idiopathic Parkinson’s disease (IPD) are identified relatively late in the disease course, reducing the odds of neuroprotective benefit from available treatment options. Identifying individuals during the prodromal (early) period that precedes motor symptoms could be of great use for clinical studies seeking new therapies to prevent or delay disease progression.

A team of French researchers sought to determine the existence of any subtle gait disorders or other signs that precede the diagnosis of IPD, based on data from a long-standing study of human aging across the adult lifespan: the Baltimore Longitudinal Study of Aging (BLSA).

Conducted by the National Institute on Aging (NIA) Intramural Research Program, the BLSA continuously enrolls healthy volunteers age 20 and older who are followed throughout their life independently of the development of age-related diseases.

Ten pre-diagnosed IPD patients (eight men and two women) and 30 healthy control subjects were chosen for this study.

Subjects were assessed for the disease approximately 2.6 years before diagnosis. Clinical examination included gait speed, spatio-temporal gait parameters, balance, upper-limb motor skills, neuropsychological profile, and non-motor symptoms.

In comparison to the control group, IPD patients had shorter step length and reduced gait speed in a usual gait speed testing condition. Despite also having shorter step length when testing maximum gait speed, no differences between the IPD and control samples were found in walking speed.

Moreover, patients had worse mental rotation ability (the ability to rotate mental representations of two-dimensional and three-dimensional objects, which is related to the brain’s capacity for visual representation), and impaired ability to name different examples that could be inserted into a category (for instance, naming all types of flowers one can think of in one minute).

Compared to control subjects, IPD patients had no changes in upper-limb motor function, no depression, no sleep disturbances, no urinary symptoms, and no orthostatic hypotension (when blood pressure suddenly drops when standing up quickly).

Researchers concluded that the observed “changes might serve as markers to improve the early detection of IPD patients, who could then benefit from pharmacological neuroprotection trials and/or prevention trials of lifestyle-related interventions in order to delay, or even prevent, clinical manifestations.”

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Low Doses of Herbicide and Lectins Led to Parkinsonism in Animals, Study Reports

pesticides and herbicides

Ingesting a once widely used herbicide called paraquat along with lectins — proteins in common foods that bind carbohydrates (e.g., sugars) — can lead to symptoms typical of Parkinson’s disease and known as parkinsonism, a study reported.

Importantly, this animal research provides a new preclinical model for testing treatments in forms of Parkinson’s disease influenced by environmental factors.

The study, “Ingestion of subthreshold doses of environmental toxins induces ascending Parkinsonism in the rat,” was published in the journal Parkinson’s Disease.

Parkinson’s development in people has been linked to both genetic and environmental factors. Researchers need to model how these factors cause the disease to discover treatments for patients with different types of Parkinson’s.

Previous studies have modeled how high levels of individual neurotoxins and external factors such as diet are linked to Parkinson’s. But individuals, over the course of a lifetime, are more likely to be repeatedly exposed to low doses of toxins, or a combination of toxins, whose disease-causing capacity may be enhanced by factors that include diet.

For example, paraquat — a neurotoxin and herbicide once in wide use and still in restricted use in the U.S. though banned in Europe — has been linked to Parkinson’s disease (ways it can be ingested include drinking water). But it has only been studied in isolation and at doses far beyond those commonly encountered. Similarly, lectins — sugar-binding proteins commonly found in legumes and grains — have been linked with rare forms of parkinsonism.

For these reasons, researchers at Penn State College of Medicine sought to understand and model how repeated exposures to low doses of toxins and external factors contribute to Parkinson’s development. They sought to demonstrate how exposure to common levels of paraquat and lectin can induce disease symptoms.

The researchers applied low-level doses of paraquat and lectins to rats daily for a week, and after a couple of weeks, checked for symptoms of parkinsonism. They tested the animals for motor function and for the production of a misfolded protein called alpha-synuclein that is linked with the development of Parkinson’s disease. They detected a decrease in motor function and in the number of dopaminergic neurons (those that produce the brain signaling chemical dopamine), the generation of misfolded alpha-synuclein, and other symptoms typical of parkinsonism.

To confirm that the symptoms spotted were related to parkinsonism, the researchers performed tests to see if known Parkinson’s treatments — levodopa — could reverse the observed symptoms.

“After observing that these animals did indeed show symptoms of Parkinsonism, we wanted to double check and make sure we weren’t looking at animals that had these symptoms for another reason,” Thyagarajan Subramanian, a study co-author and professor of neurology at Penn State College of Medicine, said in a press release. “We administered levodopa … [and] saw a return to almost normal types of motor responses, which was a clear indication that we were looking at some sort of Parkinsonism.”

Increasing evidence suggests that environmental neurotoxins or misfolded alpha-synuclein proteins are transported from the gut to the brain through the vagus nerve — the nerve that enables communication between the gut and the brain— this way damaging dopaminergic neurons in the substantia nigra, a major brain region affected in Parkinson’s disease.

“We were able to demonstrate that if you have oral paraquat exposure, even at very low levels, and you also consume lectins — perhaps in the form of uncooked vegetables, dairy or eggs — then it could potentially trigger the formation of this protein alpha-synuclein in the gut,” Subramanian said. “Once it’s formed, it can travel up the vagus nerve and to the part of the brain that triggers the onset of Parkinson’s disease.”

Interestingly, removing the vagus nerve before exposing the animals to paraquat and lectins protected them from parkinsonism.

The researchers plan to test whether medical treatments or dietary modifications can interfere with the transport of alpha-synuclein from the gut to the brain via the vagus nerve in this new model of Parkinson’s incorporating environmental factors.

They intend to test a substance called squalamine, which has been shown to remove alpha-synuclein from the gut and is now in clinical trials for treating Parkinson’s symptoms. 

“This study gives solid evidence that lectins, while in the presence of certain toxins, may be one potential culprit for the cause of Parkinsonism,” Subramanian said. “Additionally, this animal model can be a tool in the future to continue developing new medications and treatments for Parkinson’s disease.”

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Therapies Targeting LRRK2 Gene Could Benefit Broad Population of Parkinson’s Patients, Study Finds

LRRK2 gene

The LRRK2 gene may play an important role in nonhereditary Parkinson’s disease, not just the familial form as previously thought, researchers at the University of Pittsburgh School of Medicine​ have discovered.

“This discovery is extremely consequential for Parkinson’s disease because it suggests that therapies currently being developed for a small group of patients may benefit everybody with the disease,” J. Timothy Greenamyre, MD, PhD, the study’s senior author, said in a press release. Greenamyre is the Love Family Professor of Neurology at Pitt’s School of Medicine, chief of the movement disorders division at the University of Pittsburgh Medical Center, and director of the Pittsburgh Institute for Neurodegenerative Diseases.

These new findings were reported in the study, “LRRK2 activation in idiopathic Parkinson’s disease,” published in Science Translational Medicine.

Parkinson’s disease is a chronic and progressive neurodegenerative condition caused by the loss of dopamine-producing neurons in the substantia nigra, a brain region involved in the control of voluntary movements. It is estimated to affect 1 million people in the U.S. and up to 10 million worldwide.

There are two basic types of Parkinson’s: the familial hereditary form of the disease, which is associated with genetic mutations that make individuals more prone to develop Parkinson’s; and the idiopathic nonhereditary form of the disease, where the causes are unknown.

Genetic mutations in the leucine-rich repeat kinase 2 (LRRK2) gene — which provides instructions for making a kinase, a type of protein that regulates the function of many others — that cause an overactivation of the protein have been associated with the familial form of Parkinson’s.

However, researchers still do not know if the normal, nonmutated LRRK2 gene could also play a role in the idiopathic form of the disease.

To answer this, investigators set out to analyze the activity of LRRK2 in postmortem brain samples from patients with idiopathic Parkinson’s, who did not have genetic mutations in LRRK2, and healthy individuals from the same age group used as controls.

But studying LRRK2 is difficult because its levels in the brains of Parkinson’s patients are extremely low and hard to detect.

To overcome this, Greenamyre’s team took advantage of a technique called proximity ligation assay, which works by attaching special fluorescent molecules to LRRK2 that glow red when the protein is active, allowing researchers to spot them under a microscope.

Investigators found that LRRK2 activity was increased in dopamine-producing neurons from the substantia nigra of patients with idiopathic Parkinson’s, in comparison with healthy controls.

Interestingly, they observed the same trend in two different rat models of the disease, suggesting that LRRK2 overactivity seems to be important not only for patients with genetic mutations in LRRK2, but also for other individuals with the idiopathic form of the disease.

They then found that LRRK2 activity is linked to alpha-synuclein — a protein that accumulates inside nerve cells, producing small structures called Lewy bodies — that is considered a hallmark of Parkinson’s disease.

Using an animal model of Parkinson’s, they discovered that LRRK2 activation actually blocks the mechanism cells use to clear excessive alpha-synuclein, eventually leading to an abnormal buildup of the protein inside nerve cells.

Researchers then treated these animals with an investigational treatment intended for patients with familial Parkinson’s that works by blocking LRRK2 activity. Remarkably, they observed that the therapy was able to prevent both the accumulation of alpha-synuclein and the formation of Lewy bodies inside nerve cells.

These findings show that, regardless of genetic mutations, the LRKK2 gene plays a role in both types of Parkinson’s disease, indicating that LRRK2 inhibitors may be useful to treat patients with the idiopathic or familial form of the disease.

“We believe that LRRK2 inhibitors may be beneficial not only for the 3 to 4% of people with [Parkinson’s disease] who carry LRRK2 mutations but also for [idiopathic Parkinson’s disease] patients who do not carry LRRK2 mutations,” the authors wrote in the study.

In the future, Greenamyre’s team aims to investigate how LRRK2 overactivity can be prevented, as well as determining the underlying mechanisms that cause its activation in Parkinson’s patients.

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Source: Parkinson's News Today