How gum disease could lead to Alzheimer's

January 26, 2019    By Maria Cohut

In a new study, researchers have found that a bacterium largely responsible for gum disease also contributes to the development of Alzheimer's disease.

According to data from the National Institute of Dental and Craniofacial Research, 8.52 percentof adults between 20 and 64 years of age in the United States have periodontitis (gum disease).

Gum disease is a widespread problem that can lead to more negative outcomes, from tooth loss to an increased risk of cancer.

Now, emerging evidence suggests that one of the bacteria involved in periodontitis could also contribute to the accumulation of toxic proteins in the brain, which scientists have associated with the development of Alzheimer's disease.

These findings have emerged from a new study in mice that researchers from Cortexyme, Inc., a pharmaceutical company that aims to develop new therapeutics for Alzheimer's disease, have conducted.

The results of the research — whose lead author is Dr. Stephen Dominy, Cortexyme co-founder — appear in the journal Science Advances.

"Infectious agents have been implicated in the development and progression of Alzheimer's disease before, but the evidence of causation hasn't been convincing," notes Dr. Dominy.

The bacterium that boosts brain toxicity

The researchers zeroed in on one bacterium — Porphyromonas gingivalis — which is a Gram-negative oral anaerobe that drives the development of gum disease.

P. gingivalis, the researchers note, also appears in the brains of people who doctors have diagnosed with Alzheimer's disease, which left the investigators intrigued.

When looking at a mouse model, the team found that infection with P. gingivalis led to greater production of beta-amyloid in the rodents' brains.

Beta-amyloid is a marker of Alzheimer's disease in the brain; in this neurodegenerative condition, the toxic protein accumulates in excess, forming into plaques that disrupt normal communication between brain cells.

The researchers also looked at gingipains, the toxic enzymes of P. gingivalis. They found that — both in human brains and in mouse models — they could associate high gingipain levels with the presence of two other proteins that scientists have already linked with the development of Alzheimer's: tau and ubiquitin.

In both in vivo and in vitro models, gingipains exacerbated tau toxicity, the investigators explain. However, once they settled on gingipains as a clinical target, the team was able to start developing strategies to counteract their effects.

A promising clinical target

Thus, Dr. Dominy and associates went on to design a series of small molecule therapies blocking the activity of P. gingivalis gingipains.

In experiments on mouse models, the researchers eventually identified a compound called "COR388" as the most effective gingipain inhibitor. COR388 was able to reduce the presence of P. gingivalis in the brain after infection with this bacterium, and it lowered neuroinflammation.

The compound also stopped the production of toxic beta-amyloid and had a protective effect on neurons in the hippocampus, the brain area that is largely responsible for memory-related processes.

"Now, for the first time, we have solid evidence connecting the intracellular, Gram-negative pathogen, [P. gingivalis], and Alzheimer's pathogenesis while also demonstrating the potential for a class of small molecule therapies to change the trajectory of disease," declares Dr. Dominy.

"Despite significant funding and the best efforts of academic, industry, and advocacy communities, clinical progress against Alzheimer's has been frustratingly slow," adds study coauthor Casey Lynch.

"

The Science Advances publication sheds light on an unexpected driver of Alzheimer's pathology — the bacterium commonly associated with chronic periodontal disease — and details the promising therapeutic approach Cortexyme is taking to address it with COR388."

Casey Lynch

COR388 is already under trial, and the researchers have reported that, so far, volunteers — both healthy individuals and people with a diagnosis of Alzheimer's disease — have reacted well to this compound.

The Cortexyme team is looking to organize a larger clinical trial, testing the effect of COR388 in people with mild to moderate Alzheimer's disease some time this year.

https://www.medicalnewstoday.com/articles/324298.php?utm_source=newsletter&utm_medium=email&utm_country=US&utm_hcp=no&utm_campaign=MNT%20Daily%20Full%20%28non-HCP%20US%29%20-%20OLD%20STYLE%202019-01-26&utm_term=MNT%20Daily%20News%20%28non-HCP%20US%29

What Are the Health Benefits of a Rocking Chair?

Jenny Good    January 2019

Without a doubt, we live in a high-tech world. It seems a new gadget for promoting better health comes along every day; but according to Life Span, a simple rocking chair can improve your health and increase overall well-being. While using a rocking chair won't provide the fitness training of an aerobic workout, the activity may improve your health in some significant ways.

Increased Well-Being of Dementia Patients

Rocking Chair Therapy reports that a study conducted at the University of Rochester reveals an increase in the psychological well-being of nursing home residents with severe forms of dementia. The study suggests rocking causes a release of endorphins that elevates the mood of dementia patients, in addition to relieving pain. Study leader Nancy. M. Watson, PhD, RN, director of Center for Clinical Research on Aging, noted that rocking has long been known to soothe infants, and it seems to provide the same therapeutic benefit for adults.

Decreased Need For Medications

Watson explained that rocking causes a reduction in anxiety and depression among seniors, and reported a decreased need for anxiety and depression medication in those who she observed. Because these medications sometimes come with harmful side effects, rocking may prove a more tolerable option for some people dealing with these conditions.

Increased Balance

The motion of rocking stimulates the body to maintain balance, resulting in greater balance capabilities. Greater balance is especially useful in older individuals, who face an increased risk of injury by falling.

Improved Muscle Tone

Rocking provides a way to tone the leg muscles of those who cannot tolerate weight-bearing exercise. Rocking brings a safe activity to people who live an otherwise sedentary lifestyle. Although rocking does not make up for strength-training exercises such as lifting weights, it may be a valuable strengthening option for those unable to perform more strenuous activities.

Soothes Colic Symptoms

Rocking mimics the movement the baby felt inside the mother's womb. Rocking a baby who suffers from colic reduces crying episodes and promotes sleep. Rocking also might promote restful sleep in babies not diagnosed with colic disorder.

Eases Arthritis and Back Pain

ADK Rocking Festival reports that President John F. Kennedy used a rocking chair to help relieve back pain, as prescribed by his doctor. According to the festival website, rocking helps prevent pain signals from traveling from the back to the brain. The site also claims that rocking can significantly improve pain from arthritis.

https://www.livestrong.com/article/146843-what-are-the-health-benefits-of-a-rocking-chair/

BETTER AND ANIMAL-FREE EXPERIMENTATION THANKS TO NERVOUS SYSTEM-ON-A-CHIP

Posted by Frans van Beveren | Jan 25, 2019 | Tags: TU/e

SNEAK PREVIEW OF TH FUTURE

Together with six partners, The Eindhoven University of Technology will develop a nervous-system-on-a-chip. This will enable medicines to be tested accurately and will eliminate the need to test on animals. The project is supported by the EU with a grant of almost 7 million euros.

With the nervous-system-on-a-chip (NoC), new drugs against Parkinson’s disease can be tested. For exmple by investigating the transport of specific proteins that travel through the nervous system, which are associated with Parkinson’s disease.

The partners in the research group called CONNECT all contribute differently. This allows the University of Luxembourg to grow cells in a specific form, which are able to mimic specific human brain cells well. The University of Sheffield is mainly concerned with the biological development of the relevant type of nerve cells. KU Leuven has experts in the optical analysis of nerve cells and Erasmus MC is an expert in electrophysiological analysis. AALTO University helps with the choice of materials and electrodes for the NoC while the Oxford Parkinson Disease Center has a bio-bank with cells from Parkinson’s patients for testing. The TU/e researchers bring all of these aspects together, through the design and realization of the NoC.

During the first experiments, the cells will be specially cultivated, but in the future, cells from Parkinson’s patients could become available. If all these experiments are successful, it will open the door to personalized medication, so patients will have to take ineffective drugs much less often. The development of new medicines can also be drastically accelerated. This is desperately needed, given that an average drug has a development time of 10 to 12 years and costs about 1.6 billion euros.

https://innovationorigins.com/better-and-animal-free-experimentation-thanks-to-nervous-system-on-a-chip/

Manufacturer adds new grades to medical product portfolio

January 25, 2019

Hamilton Precision Metals and SMP Wallingford, two of the six business that comprise AMETEK Specialty Metal Products (SMP), have added two new Titanium strip grades to their product portfolio for medical applications.

The companies claim the new grades, 9 and 23, allows for manufacturing of smaller devices that enable safe, external re-charging for a range of neuromodulation and neurostimulation therapy applications.

Having developed a proprietary production process for both Ti grades, the two AMETEK facilities are now able to produce a thin strip that ultimately offers external charging capabilities for implanted medical devices when incorporated to the external shell. This new production technology involves a cold rolling and annealing process that yields titanium strip with outstanding microstructure characteristics and formability properties.

Hamilton and SMP Wallingford will be exhibiting at the MD&M West on 5 February at the Anaheim Convention Center in Anaheim, California.

Matt Lappen, product manager for SMP Strip Business, said: “Our new Titanium strip grade products are set to make a major contribution to the treatment of Parkinson’s disease, sleep apnea and chronic pain without the use of opioids. We’re very excited to be a part of this ground-breaking therapeutic advance.

”https://www.medicalplasticsnews.com/mpn-north-america/manufacturer-adds-new-grades-to-medical-product-portfolio/

No Effect of Levodopa on Parkinson's Progression

 Sue Hughes     January 25, 2019

Use of levodopa in early Parkinson's disease does not have any disease-modifying effect, either beneficial or detrimental, a new study suggests.

"There was no difference in Parkinson's symptoms or levodopa side effects at 80 weeks in those patients who started taking the drug at week 1 and those who started at week 40," senior author Rob de Bie, MD, PhD, University of Amsterdam, the Netherlands, told Medscape Medical News.

"This suggests that levodopa does not have any effect on disease progression — either positive or negative."

He explained that patients and physicians can be reluctant to start levodopa because there is a fear that prolonged use may be associated with faster disease progression, a wearing off of efficacy, or increased side effects.

"But our data give us reassurance that levodopa does not increase disease progression," he said.

"This should have a big impact on clinical practice," he added. "Patients can now start taking levodopa with confidence whenever they need to control symptoms without the worry that it may be having an adverse effect. The disease will still progress, and the levodopa may need to be used more frequently, but this does not appear to be related to past use of the drug."

The study was published online January 24 in the New England Journal of Medicine.

In an accompanying editorial, Susan Bressman, MD, and Rachel Saunders-Pullman, MD, MPH, Icahn School of Medicine at Mount Sinai, New York City, say this trial supports current practice.

"There is no evidence that early initiation of levodopa slows progression of the disease; on the other hand, there is no reason to delay therapy when it is clinically indicated. The results of the current trial, taken together with those of other trials, support treatment that is guided by clinical need and that uses the lowest dose that provides a satisfactory clinical effect," they write.

In their article, de Bie and colleagues explain that levodopa is the main treatment for Parkinson's disease but that physicians may delay initiating treatment for various reasons, including concern about the induction of dyskinesias. However, almost all patients ultimately receive levodopa to control motor symptoms.

They note that an earlier study provided mixed results on the effect of levodopa on disease progression.

The ELLDOPA study compared levodopa with placebo for 40 weeks. Patients who received the drug had fewer symptoms at 2 weeks after stopping the treatment than those who had been receiving placebo, suggesting that levodopa may slow the progression of Parkinson's disease or have a prolonged effect on symptoms.

However, neuroimaging data from that trial suggested either that levodopa had the detrimental effect of accelerating the loss of dopamine nerve terminals or that it modified the striatal dopamine transporter.

The investigators suggested that one way of distinguishing a possible disease-modifying effect of levodopa from an effect on symptoms would be to conduct a delayed-start trial. In the first phase, patients would receive either the active drug or placebo. A difference between the groups at the end of this phase may be the result of an effect on symptoms, or it may be a disease-modifying effect, or both.

During the second phase, both groups would receive the active drug, and persistent differences between the groups at the end of this phase could be presumed to be the result of a disease-modifying effect, because the effects of the drug on symptoms at that time would be the same in both groups.

The current study, known as LEAP, had such a design. In the LEAP trial, 445 patients with early Parkinson's disease were randomly assigned to receive either levodopa (100 mg) plus carbidopa (25 mg) three times per day for 80 weeks (early-start group) or placebo for 40 weeks followed by levodopa/carbidopa for 40 weeks (delayed-start group).

The mean Unified Parkinson's Disease Rating Scale (UPDRS) scores at baseline were 28.1 in the early-start group and 29.3 in the delayed-start group. The change in UPDRS score from baseline to week 80 was −1.0 points in the early-start group and −2.0 in the delayed-start group, a nonsignificant difference, which the authors say implies that levodopa had no disease-modifying effect.

Secondary outcomes supported this conclusion. Progression rates in the second phase of the trial did not show a benefit to the early-start group. In addition, no significant differences were observed between the groups with respect to the rates of dyskinesia and levodopa-related fluctuations, which suggests that the patients in the early-start group were not negatively affected by their longer exposure to levodopa, the researchers say.

The dose of levodopa (100 mg three times per day) in combination with carbidopa (25 mg three times per day) that was used in the trial was chosen as a compromise between higher doses, which are associated with a greater risk for side effects, and lower, less effective doses.

Whether higher doses of the drug, longer periods of administration, or initiation of the drug at later stages of the disease could alter the course of Parkinson's disease warrants evaluation in future trials, the authors state.

In their editorial, Bressman and Saunders-Pullman point out that 39% of patients initially allocated to receive placebo in the study actually started taking levodopa in the first phase because of the need for symptom relief. Although results of a per-protocol analysis that included only patients who completed their originally assigned treatment were similar to the results of the intention-to-treat analysis, the trial was probably insufficiently powered to allow firm conclusions, they say.

They add that trials of disease-modifying agents for the treatment of Parkinson's disease are underway.

"The potential for identifying effective disease-modifying agents and for advancing the field beyond the conundrum of early use as compared with later use of levodopa is promising," they conclude.

The LEAP trial was supported by grants from the Netherlands Organization for Health Research and Development, Parkinson Vereniging (a Dutch patient organization), and Stichting Parkinsonfonds and Stichting Parkinson Nederland (Dutch funding organizations for Parkinson's disease research). de Bie receives grant support from GE Health and Medtronic. 

N Engl J Med. Published online January 23, 2019. Abstract, Editorial

https://www.medscape.com/viewarticle/908247#vp_2

Inhibitory Processing Remains Intact in Parkinson’s Patients, Study Suggests

 JANUARY 25, 2019 BY JOANA CARVALHO 

The ability to block out irrelevant information when asked to recognize and name objects, known as inhibitory processing, remains intact in patients with Parkinson’s disease, a study has found.

The study, “The Suppression of Irrelevant Semantic Representations in Parkinson’s Disease,” was published in the journal Frontiers in Human Neuroscience.

Previous studies have shown that Parkinson’s disease might affect inhibitory processing in the brain. However, this is still a debatable subject in the scientific community, since the severity and type of impairments are highly varied among patients and studies.

“The lack of agreement concerning inhibitory processing in PD [Parkinson’s disease] is readily manifest in the literature concerning … the variety of lexical-semantic tasks including verbal fluency, semantic priming [saying words related to the prime word given, for example, wolf in reply to dog], and confrontation naming [naming a picture],” the researchers wrote in the study.

To study this, these researchers from the University of Queensland in Australia set out to investigate whether patients with Parkinson’s disease were able to block out inappropriate or irrelevant information when naming a picture.

They used an object-based priming technique, in which participants were asked to name a red image and ignore a green image in a set of 144 superimposed images. The 144 images were then divided into three categories — identical, related and unrelated — containing 24 image pairs of primes (visual stimulus) and probes (patients’ choice).

“The green distractor image in the prime stimulus was identical to the red image in the subsequent probe stimulus in the identical condition [e.g. both representing a dog], semantically related to the red probe image in the related condition [e.g. both representing objects], or semantically unrelated in the unrelated condition [e.g. the green prime image showing an animal and the red probe image showing an object],” the researchers said.

The study enrolled 16 patients with Parkinson’s disease and 13 age-, sex- and education-matched healthy individuals used as controls.

Interestingly, both Parkinson’s patients and healthy controls took longer to name target images that were identical to the prime distractor image than they took to name target pictures that were unrelated to the distractor image. “This result suggests the presence of a negative priming effect across both groups,” the researchers wrote.

No significant differences in naming response time were found between related and unrelated image pairs in both groups. Likewise, no differences were observed in the magnitude of this negative priming effect in the two groups.

“The PD group performed similarly to controls across all conditions in terms of naming latency, demonstrating that the retrieval of an object’s name was slowed when that same item had previously been ignored,” the researchers wrote.

“These results suggest that inhibitory mechanisms related to the processing of visual-semantic stimuli may be largely intact in PD. Further investigation using paradigms that strictly control for the influence of lexical-semantic input and output is required in order to elucidate the integrity of such mechanisms,” they concluded.

https://parkinsonsnewstoday.com/2019/01/25/inhibitory-processing-remains-intact/

Study Explores Parkinson’s Effect on How Brain Represents Tool Embodiment

JANUARY 25, 2019 BY JONATHAN GRINSTEIN 

A new way to understand and study how the brain represents tool embodiment — the physical actions for using tools — was proposed in a new research article.

The study recommends methods for understanding Parkinson’s disease signs and symptoms relating to the brain’s ability to represent motor output, which can aid in the diagnosis, treatment, and monitoring of neurological conditions.

The research article, “Defective Tool Embodiment in Body Representation of Individuals Affected by Parkinson’s Disease: A Preliminary Study,” was published in Frontiers in Psychology.

People have the capacity to use tools for acting in the environment. For example, they can use a rod because something is out of reach; the tool helps them get an object that would otherwise be unreachable. To do so, the human brain takes the object into account as if it were part of the body; when using a rod, the brain represents the hand as if it were the tip of the rod — the brain “embodies” the tool.

This ever-changing representation of the body, derived from all sensory input around the body that the brain uses to plan and execute actions, has been termed the “body schema.” Although there is increasing research on understanding the body schema and tool embodiment in healthy individuals, the body schema is thought to be affected in several pathological conditions. These include people with neurological diseases affecting motor control or spinal cord injury, as well as amputees who use a prosthesis. Yet there is little known about the body schema and tool embodiment in Parkinson’s disease, a neurological disease characterized by sensory and motor symptoms affecting motor action.

To understand how the body schema is affected by neurological disease, researchers from the Istituto Auxologico Italiano and the University of Turin, Italy, studied tool embodiment in Parkinson’s disease patients.

The study included 14 people affected by Parkinson’s disease and 18 healthy controls. The researchers had the participants use a rod to point toward a far target and studied the accuracy and how long it took for the patients to point toward the target before and after they had spent time training with the rod.

They also investigated changes in the brain’s estimation of arm length through a test called the Tactile Estimation Task. In this task, participants estimated the distance between two tactile stimuli presented simultaneously on the arm. If the rod is correctly embodied, the arm should be represented from its base to the tip of the rod, and, consequently, the distance between the two might be perceived larger than the actual gap.

All patients were tested when their symptoms were efficiently managed by Parkinson’s medicine, or “on” state of medication.

After tool-use training, control participants’ behaviors completely changed: they were slower to perform movements after training to try to hit the target. More specifically, after training, healthy individuals reported a higher value of deceleration — when individuals are nearest to the target after having achieved peak of velocity of movement. However, such differences did not emerge in the Parkinson’s participants. Researchers did not observe any differences in estimation of arm length before and after the tool-use training in either Parkinson’s or control participants.

These results suggest possible difficulties in the tool embodiment process for Parkinson’s patients. The lack of changes in these participants before and after training possibly reflects the absence of effective tool embodiment into the body schema. This study proposes a new way to understand Parkinson’s signs and symptoms in terms of how they affect a patient’s body schema.

“This study suggests a novel way to conceive Parkinson’s sensory motor signs and symptoms: the disease might affect the tool embodiment in cognitive body representation, as a possible secondary effect of altered plasticity of body schema, since the sensory and motor symptoms, or altered multisensory integration process due to the degeneration of dopaminergic neurons in the basal ganglia,” researchers stated.

“Tool embodiment in body representation can extend the potentiality of individual’s action; however, if deficient, it might have remarkable consequences and implications on motor behavior, specifically in those clinical conditions like Parkinson’s, in which the body and action are primarily affected by symptoms,” they said.

https://parkinsonsnewstoday.com/2019/01/25/study-explores-parkinsons-effect-on-how-brain-represents-tool-embodiment/

Cognitive Impairment Tests to Assess Dementia Risk Can Be Easier, Study Shows

JANUARY 24, 2019 BY CATARINA SILVA IN NEWS.

A shorter, simpler version of testing to diagnose mild cognitive impairment in Parkinson’s disease is just as effective as a lengthier evaluation at predicting the risk of developing Parkinson’s disease dementia, a report shows.

The study, “Risk of Parkinson’s Disease Dementia Related to Level I MDS PD-MCI,” was published in Movement Disorders.

Both cognitive decline and dementia are recognized as non-motor complications of Parkinson’s with significant clinical impact. Evidence suggests that mild cognitive impairment is a risk factor for Parkinson’s disease dementia (PDD).

The International Parkinson and Movement Disorder Society (MDS) has formulated two levels of criteria for diagnosing Parkinson’s-related mild cognitive impairment. Levels 1 and 2 differ in their methods of assessment, level of diagnostic certainty, and extent of clinical characterization.

Level 1 is comprised of a simpler, shorter series of cognitive tests, while level 2 entails a more extensive neuropsychological evaluation.

One study has shown that using level 2 criteria to assess mild cognitive impairment — which considered age, sex, years of education, depression and the severity of motor symptoms — can be effective at confirming an increased risk of patients developing dementia.

The University of Amsterdam researchers evaluated the prognostic value of testing mild cognitive impairment, using level 1 criteria as indicators of PDD.

“Comprehensive neuropsychological testing is not always possible because of time, cost, or patients’ inability to cooperate with a long assessment,” they said.

Looking at eight international studies, totaling 1,045 patients, they analyzed demographic and clinical data including age, sex, years of education, disease duration and neuropsychological examinations, based on the Unified Parkinson’s Disease Rating Scale (UPDRS) part III (motor tests), the Movement Disorder Society (MDS)-UPDRS III score, the Hoehn and Yahr scale (used to measure symptom progression), and an indicator of patient depression.

Level 1 criteria were applied, with one test of each of the five cognitive domains: attention, executive function— the ability to manage and organize thoughts, actions, and feelings — memory, visuospatial function, and language.

Survival analysis evaluated how each factor contributed to the risk of PDD.

In an initial evaluation, 17% of the patients were diagnosed with mild cognitive impairment. Median follow-up was 2.8 years and 151 out of the 1,045 (14.4%) patients developed dementia.

Only 9% of those without cognitive impairment at the beginning of the study developed dementia during follow-up, compared to 77% in the mild cognitive impairment group.

Worse performance in level 1 testing was associated with a higher risk of developing PDD dementia.

The evaluation also revealed that increasing age, male sex, and the severity of Parkinson’s motor symptoms independently heighten this risk.

Importantly, the study found that both levels of criteria had similar discriminant ability, meaning that the less extensive level 1 testing was effective at determining PDD risk.

Researchers also reported that level 1 criteria identified fewer mild cases, and associated them with relatively higher risk ratios, which they said could be attributed to the rating system used.  Level 1 criteria measures greater cognitive decline, when using the same cutoff as level 2 criteria.  For example, in level 1, at least two out of five tests need to show impairment, compared to at least two out of 10 tests in level 2

“In conclusion, level I PD-MCI [mild cognitive impairment] criteria classification, based on a brief neuropsychological assessment, confers an independent contribution to the hazard of PDD while taking age, sex, education, PD motor sign severity, and depression into account. This finding supports the role of level I PD-MCI as a risk factor for PDD,” they wrote.

https://parkinsonsnewstoday.com/2019/01/24/tests-mild-cognitive-impairment-dementia-risk-easier-study-says/

Gut Bacteria Affect Metabolism of Parkinson’s Therapy Levodopa, Study Shows

JANUARY 24, 2019 BY CATARINA SILVA IN NEWS.

Levodopa, one of the main medicines used to treat Parkinson’s symptoms, can be converted into dopamine by gut bacteria, researchers report.

The findings might explain why levodopa treatment is less effective in some patients.

The study, “Gut bacterial tyrosine decarboxylases restrict levels of levodopa in the treatment of Parkinson’s disease,” was published in Nature Communications.

Parkinson’s disease is characterized by low levels of dopamine, a chemical brain messenger essential for neurons involved in movement control.

In terms of treatment, patients cannot take dopamine directly, as the compound is broken down by the body before it reaches the brain. Levodopa crosses the blood-brain barrier and is taken up by dopaminergic neurons, which convert the chemical into dopamine, which helps manage disease-related motor symptoms.

Studies have suggested that gut bacteria can affect treatment effectiveness in several diseases; particularly in Parkinson’s, the amount of levodopa that reaches the brain varies among patients.

“It is well established that gut bacteria can affect the brain,” assistant professor in microbiology Sahar El Aidy, PhD, and this study’s lead investigator, said in a press release. “There is a continuous chemical dialogue between gut bacteria and the brain, the so-called gut-brain axis.”

However, it remains to be explained if inter-patient variations in gut bacteria composition and functionality contribute to treatment response fluctuations in Parkinson’s disease patients who require a higher daily treatment dosage regimen.

Researchers from the University of Groningen in The Netherlands analyzed the effect of levodopa metabolizing bacteria in the middle section of the small intestine (jejunum), where levodopa is absorbed.

Using rat jejunum bacteria samples, researchers saw that an enzyme called tyrosine decarboxylase, which normally converts tyrosine into tyramine, also efficiently converted levodopa to dopamine in the gut. Enterococcus bacteria, commonly found in the intestines, were responsible for such enzymatic activity.

To understand if they could somehow inhibit levodopa’s conversion, the Dutch team “fed” the bacteria with a high concentration of the amino acid tyrosine, the main substance that tyrosine decarboxylase acts on, but tyrosine’s abundance did not prevent levodopa’s metabolization.

As part of their treatment regimen, Parkinson’s patients are given a decarboxylase inhibitor, like carbidopa, to block peripheral metabolism of levodopa to dopamine, allowing a greater concentration of levodopa to reach the brain.

Scientists studied the effect of human decarboxylase inhibitors, including carbidopa, benserazide, and methyldopa, on the bacterial tyrosine decarboxylase. None of the tested inhibitor compounds blocked levodopa’s enzymatic transformation.

“It turned out that, for example, the inhibitor carbidopa is over 10,000 times more potent in inhibiting the human decarboxylase,” said El Aidy. This could be due to species-specific changes in carbidopa’s chemical structure, indicating that a more effective levodopa treatment could be achieved by co-administration of tyrosine decarboxylase inhibitor targeting both human and bacterial forms of the enzyme.

“[C]ommonly applied inhibitors of human DOPA [levodopa] [tyrosine] decarboxylase in levodopa combination therapy do not inhibit bacterial TDC [tyrosine decarboxylase] dependent levodopa conversion, implying levodopa/carbidopa (levodopa) combination therapy for PD [Parkinson’s disease] patients would not affect the efficacy of levodopa in situ [locally] by small intestinal bacteria,” researchers wrote.

These findings confirm the gut bacteria’s ability to influence local levels of levodopa treatment and suggest that the presence of tyrosine decarboxylase could reduce the amount of levodopa available in the bloodstream of Parkinson’s patients.

To test the latter hypothesis, investigators analyzed stool samples from patients who were on a normal or high dose of levodopa. They reported a strong positive correlation between the relative abundance of the bacterial gene encoding for tyrosine decarboxylase and the need for a higher levodopa/carbidopa treatment dose, as well as with disease duration.

To further understand the concept that the amount of tyrosine decarboxylase in jejunum’s bacteria affects bloodstream levels of levodopa/carbidopa and dopamine, scientists orally administered levodopa plus carbidopa to 18 wild-type (healthy) rats and analyzed animals’ blood 15 minutes after administration (time point when levodopa is at its higher concentration in rats).

Results showed that higher abundance of bacterial tyrosine decarboxylase in the rats’ jejunum decreased plasma levels of levodopa. The ratio between dopamine and levodopa/carbidopa levels in the small intestine positively correlated with bacterial enzyme amount.

Researchers then treated 10 rats with a subtype of Enterococcus bacteria known asEnterococcus faecalis that did not have the tyrosine decarboxylase gene and compared their levodopa/carbidopa plasma levels with 10 other rats that were given wild-type (normal, positive for the tyrosine decarboxylase gene) Enterococcus faecalis cells.

As expected, animals treated with wild-type cells had significant lower plasma levels of levodopa/carbidopa than the ones treated with mutant cells.

“Collectively, our data show that levodopa conversion by bacterial [tyrosine decarboxylase] in the small intestine should be considered as a significant explanatory factor for the increased levodopa/carbidopa dosage regimen required in a subset of [Parkinson’s disease] patients,” researchers wrote.

“This is considered to be a problem for Parkinson’s disease patients, because a higher dose will result in dyskinesia, one of the major side effects of levodopa treatment,” El Aidy said, referring to the involuntary, jerky movements patients experience.

https://parkinsonsnewstoday.com/2019/01/24/gut-bacteria-affect-parkinsons-therapy-levodopa-metabolism-study-shows/