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Melatonin Levels in Parkinson’s Patients May Be Linked to Non-motor Symptoms

melatonin

Alterations in the levels of melatonin — the hormone that controls sleep-wake cycles — circulating in the blood are associated with certain non-motor symptoms of Parkinson’s disease, namely sleep disturbances, gastrointestinal issues, and heart problems.

The study with that finding, “Elevated Plasma Melatonin Levels Are Correlated With the Non-motor Symptoms in Parkinson’s Disease: A Cross-Sectional Study,” was published in the journal Frontiers in Neuroscience.

Melatonin is a hormone produced by the pineal gland, a small pea-shaped gland in the brain that regulates sleep. Higher levels of this hormone are usually present at night.

In addition to its main role in regulating the body’s internal clock (circadian rhythm), melatonin also controls the production of other hormones, helps regulate the body’s internal temperature, and influences cognitive performance and mood.

Although some studies have reported that patients with Parkinson’s have altered levels of melatonin that possibly are associated with their motor symptoms and other disease features, the findings have been inconclusive.

To explore the possible relationship between melatonin levels and non-motor symptoms of Parkinson’s, researchers now measured the levels of melatonin circulating in the blood of 61 patients with Parkinson’s (average age 62.4 years) and 58 age and sex-matched healthy individuals (controls).

Within the Parkinson’s group, 14 patients had cardiovascular symptoms (23%), 42 had gastrointestinal dysfunction (68.9%), and 51 had sleep disorders (83.6%).

Blood samples were collected in the dark, or under a dim light, following a 12-hour overnight fasting period in all study participants. Melatonin levels were determined by enzyme-linked immunosorbent assay (ELISA), a commonly used test that allows researchers to measure the levels of specific molecules using an enzymatic reaction.

Non-motor symptoms of Parkinson’s were assessed in all patients using the Hamilton Anxiety Rating Scale, the Hamilton Depression Rating Scale, the Parkinson Disease Sleep Scale, the Epworth Sleepiness Scale, and the Non-Motor Symptoms Scale for PD.

Disease severity also was evaluated in all patients using the Unified Parkinson’s Disease Rating Scale and the Hoehn and Yahr Staging scale.

Statistical analyses were used to identify possible relationships between melatonin levels and Parkinson’s non-motor symptoms and disease severity.

Researchers found that, compared to healthy individuals, patients with Parkinson’s had higher levels of melatonin circulating in their blood (19.40 versus 12.82 picograms per milliliter (pg/mL)).

Within the overall Parkinson’s population, there was a significant negative correlation with melatonin levels and levodopa equivalent doses, meaning lower levels of melatonin were associated with higher levodopa dosages.

This suggested that “the increased plasma melatonin level in PD patients may be related to the degeneration of dopaminergic neurons and the use of dopaminergic drugs,” the researchers wrote.

Likewise, among Parkinson’s patients, lower melatonin levels were associated with heart problems, sleep disturbances, and gastrointestinal issues.

”This finding suggests a potential underlying link between plasma melatonin levels and the non-motor symptoms in PD [Parkinson’s disease] patients,” the researchers wrote.

No relationships between hormone levels and other non-motor symptoms of the disease, including sexual and urinary dysfunction, memory impairments, hallucinations, and mood changes, were found.

Also, no link was found between melatonin levels and disease severity.

“Current research indicates that circadian rhythm dysfunction is associated with the clinical manifestations of PD, and changes in melatonin levels are associated with the non-motor symptoms in patients with PD,” they wrote.

“The relationship between melatonin and PD still needs further research, which is also valuable for exploring biomarkers for early diagnosis of PD,” they added.

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ANVS401 Improves Colonic Motility in Mouse Models of Early Parkinson’s

mouse study ANVS401

Investigational therapy ANVS401 (also known as Posiphen) reversed gastrointestinal dysfunction linked to early Parkinson’s in two mouse models of the disease.

Results of the study, “Translational inhibition of α-synuclein by Posiphen normalizes distal colon motility in transgenic Parkinson mice,” were published in the American Journal of Neurodegenerative Disease.

Parkinson’s disease is characterized by aggregates of alpha-synuclein in the nervous system, particularly in dopamine-producing neurons in the brain. How these aggregates form in the first place, however, is not fully understood.

One proposed hypothesis is that the aggregates don’t initially form in the brain, but in the enteric nervous system (ENS) — the nervous system of the gut.

This is supported by the fact that gastrointestinal dysfunction can occur decades before the onset of motor symptoms. Common gastrointestinal symptoms include dysphagia (difficulty swallowing), gastroparesis (slow movement of the stomach muscles), longer gut transit time (time between ingestion of food and its excretion as feces), constipation, and difficulty with defecation.

ANVS401, developed by Annovis Bio (previously known as QR Pharma), is an oral medication that stops the production of alpha-synuclein protein. It does so by binding to SNCA mRNA — a molecule that serves as a template for protein production — and preventing it from being translated into alpha-synuclein by the cell’s protein-making machinery. (Translation is the process by which the genetic information contained within a gene, in this case SNCA, gives rise to a protein.)

Previous in vitro studies in human and rodent nerve cells have shown that ANVS401 can reduce alpha-synuclein protein levels in those cells. However, no preclinical studies of the effects of ANVS401 in animal models of Parkinson’s disease existed.

Now, researchers at the University of California San Francisco, in a study funded by the Michael J. Fox Foundation, tested the effectiveness of ANVS401 to reverse gastrointestinal dysfunction in two mouse models of SNCA-associated early Parkinson’s disease. 

“What we have here is a very early model of PD [Parkinson’s disease], where alpha-synuclein accumulates in the enteric nervous system and causes defects in gut motility,” the researchers wrote.

The team also studied ANVS401’s pharmacokinetics and pharmacodynamics — how the body affects a medicine and the interactions between the body and a medicine. 

The results showed that in both mouse models, ANVS401 prevented slowing in colonic motility (the amount of time it takes for material to move through the colon). This positive effect was kept for at least nine weeks after ANVS401 treatment was stopped.

“This may be indicative of the time it takes α [alpha]-synuclein to accumulate and cause gastrointestinal dysfunction,” the researchers wrote.

However, whole gut transit time — the time it takes for food to leave the stomach and go through the small bowel and colon  — was not changed by ANVS401 treatment. The weight of the mice also remained unchanged.

Importantly, while lower doses of ANVS401 (10 mg/kg) reduced the levels of alpha-synuclein in the gut of mice treated for 21 weeks, higher doses (50 and 65 mg/kg) reduced alpha-synuclein levels in the brain of mice treated for a much shorter period of time (21 days).

This suggests that ANVS401 acts over a longer period of time in the gut and may help researchers calculate its appropriate dose to be used in future clinical trials so the treatment can “be effective, and less probable to cause side effects.”

Overall, the data “are in agreement with the ability of Posiphen to reach the nervous system, and its mechanism of action, the translational inhibition of α [alpha]-synuclein,” the researchers wrote.

“ANVS401 lowered levels of α[alpha]-synuclein and normalized gut motility in two transgenic animal models of PD [Parkinson’s disease]. Together, these data are very exciting and provide strong support for moving forward in our development of ANVS401,” Maria Maccecchini, PhD, CEO of Annovis Bio said in a press release.

Annovis Bio now is planning a multi-center, randomized, double-blind, placebo-controlled Phase 2a trial evaluating the safety and tolerability of ANVS401 in patients with early Parkinson’s disease.

The compound already is being tested in a Phase 2 clinical trial (NCT02925650), called DISCOVER, in people with early stage or probable Alzheimer’s disease.

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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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