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Specific BDNF Mutation May Be Linked to Higher Risk of Cognitive Impairment in Parkinson’s, Study Suggests

BDNF gene mutation

One amino acid change in the brain-derived neurotrophic factor (BDNF) gene, which provides instructions for a protein important to neuronal survival, may be associated with cognitive impairment in Parkinson’s disease patients, a study has found.

The study, “BDNF Val66Met polymorphism and cognitive impairment in Parkinson’s disease—a meta-analysis,” was published in the journal Neurological Sciences.

BDNF protein is produced inside brain cells and is crucial for their function as well as supporting their growth and protecting them against premature cell death. When its coding sequence is changed, this can have a major impact on brain cell outcomes.

Previous studies have suggested that one specific BDNF gene mutation called Val66Met that results in the change of a valine (Val) by a methionine (Met) at position 66 — both amino acids, also known as the protein’s building blocks — could be linked to cognitive impairment in Parkinson’s disease. However, there is no consensus on the relevance of this genetic mutation on outcomes of Parkinson’s patients.

Chinese researchers searched for available literature on this matter, and analyzed pooled data from six studies involving a total of 1,467 patients with Parkinson’s disease. These studies had been carried out in Italy, Spain, Poland, Brazil, Belgrade (Serbia), and the Netherlands.

Results revealed a significant association between the Val66Met BDNF mutation and risk of Parkinson’s disease-related cognitive impairment. Patients who had two copies of the BDNF gene with methionine (mutated version) were found to have a 3.82 times higher risk of developing cognitive impairment than those who had two BDNF copies with valine (non-mutated version).

However, it’s worth mentioning that the studies in this analysis only included Caucasian study samples, so these results should not be generalized to other ethnicities.

Parkinson’s disease affects people of all races and ethnicity worldwide. Some studies indicate that neurodegenerative disorders affect more white people than any other ethnicity, but a solid conclusion cannot be drawn from available research as they tend to vary widely regarding diagnostic criteria, sample sizes, and methodology.

“Future studies should verify our findings in larger populations, particularly in other ethnicities,” the researchers wrote.

Still, the team believes that this study provides evidence that mutated BDNF “may be associated with increased risk of cognitive impairment of Parkinson’s disease, at least among Caucasians.”

In addition, this Val66Met change in the BDNF sequence should be studied in different Parkinson’s patients presenting tremor dominant or postural instability gait disorders. Further understanding of the impact of genetics on the long-term outcomes of these patients “may better guide clinical treatments and judge the prognosis,” they said.

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Low Levels of Substance P in Saliva May Help Predict Swallowing Problems, Study Suggests

substance P dysphagia

Low levels in saliva of a molecule called substance P may help predict the development of swallowing problems in people with Parkinson’s disease, a small pilot study in Germany found.

Since this molecule works as communication signal between nerve cells in the body, this discovery suggests that impaired substance P activity may be an important contributing factor in the  development of this Parkinson’s complication.

The study, “Substance P Saliva Reduction Predicts Pharyngeal Dysphagia in Parkinson’s Disease,” was published in the journal Frontiers in Neurology.

The progression of Parkinson’s disease is associated with the loss of movement control, including control over muscles in the face, mouth, and throat. This can lead to speech problems and swallowing difficulties, which are known medically as dysphagia.

Such swallowing difficulties can severely affect a person’s ability to sustain healthy eating practices without needing additional support.

“Parkinson’s-related dysphagia affects the oral, pharyngeal and the esophageal phase of swallowing and occurs in all stages of the disease,” the researchers said.

However, this complication may remain undetected during early stages of Parkinson’s in many patients, which may prevent early diagnosis and timely care, they said.

Previous studies have shown that levels of the neurotransmitter substance P are reduced among elderly Parkinson’s patients who have aspiration pneumonia. This suggests that substance P may be involved in the underlying mechanism of the normal swallowing and cough reflex in the throat’s inner tissues, called the pharyngeal mucosa.

To learn more, German researchers explored the role of substance P in the progression of pharyngeal dysphagia in people with Parkinson’s.

The study enrolled 20 patients; half showed signs of swallowing difficulties. Researchers collected saliva samples from all patients and analyzed the levels of substance P.

Participants who did not have pharyngeal dysphagia were slightly younger, had Parkinson’s for fewer years, and also showed fewer signs of motor impairments caused by the disease as compared to patients with the complication. However, these differences were minor, and the groups were considered to be at similar disease stages.

The results showed that patients who did not have swallowing problems had 1.8-fold higher levels of substance P than those with dysphagia.

“Our findings could be another indication that, in early stages, loss of substance P containing neurons in the pharyngeal mucosa may lead to pharyngeal hyposensitivity and merely incipient pharyngeal dysphagia,” the researchers said.

Additional studies are warranted to further understand the role of substance P in Parkinson’s disease progression, the researchers said. They also recommended that further studies be done to evaluate substance P’s potential as a biomarker for early dysphagia.

Future research also should address the potential use of capsaicin — an active compound in chili peppers known to stimulate the release of substance P — as strategy to target the sensory system within the swallowing network of nerve cells, they added.

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High Levels of Inflammatory Biomarker Evident in Patients, Study Says, But Cause-Effect Unknown

c-reactive protein inflammation

Parkinson’s disease patients have “significantly elevated” levels of c-reactive protein, an acute-phase biomarker for inflammation in the body, according to a recent literature review.

It remains to be understood, however, if c-reactive protein is a risk factor for this neurodegenerative disorder, or if the disease itself triggers an inflammatory response.

The study, “C-reactive Protein and Risk of Parkinson’s Disease: A Systematic Review and Meta-analysis” was published in Frontiers in Neurology.

Chronic neuroinflammation is a hallmark of Parkinson’s disease (PD). Studies have suggested that inflammatory processes may contribute to disease risk and progression, although this biological response is unlikely to be the primary cause of neuronal death.

Evidence indicates that high c-reactive protein (CRP) levels are strongly correlated with the inflammatory process. Indeed, some studies suggest a link between CRP and chronic inflammatory and neurodegenerative disorders, such as cardiovascular disease, Alzheimer’s disease, or Parkinson’s.

Although some population-based studies have explored the relationship between c-reactive protein levels and Parkinson’s risk, results so far have been contradictory.

That led researchers at the First Affiliated Hospital of Guangxi Medical University, in China, to analyze all available studies regarding c-reactive protein levels in the serum, plasma, blood, and cerebrospinal fluid — the liquid that surrounds the brain and spinal cord — in Parkinson’s patients.

Investigators searched the records of seven life sciences, biomedical or medical databases — three of them Chinese — up through October 2018, examining associations between c-reactive protein levels and Parkinson’s risk.

The team analyzed a total of 23 case-control studies published between 2009 and 2018, which involved 2,646 Parkinson’s patients (mean age 63.6–73.2) and 1,932 controls. Disease duration ranged from 3 months to 9.8 years.

Whether studies used standard or more sensitive immunoassays — a procedure used to measure certain immune-related proteins or substances — c-reactive protein concentration in whole blood, serum, and cerebrospinal fluid was found to be significantly, and consistently, higher in Parkinson’s patients than in healthy controls.

Other factors, such as the patient’s medication use or other accompanying diseases, also may affect c-reactive protein levels, the researchers said.

Although the findings indicate a link between c-reactive protein levels and Parkinson’s, it is still unknown whether this “measurable” biochemical inflammation contributes to, or is a consequence of, Parkinson’s-related neurodegenerative mechanisms.

“[T]here is growing evidence that support an association between neuroinflammation and the initiation and progression of PD pathophysiology,” the researchers wrote.

“The results of this review only suggested a correlation between CRP levels and PD, but could not completely delineate whether inflammation plays a causal role in PD, or if PD leads to inflammatory processes,” they concluded.

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Having a Heart, Lung, Kidney, or Bone-Marrow Transplant May Lower Risk of Developing Parkinson’s

transplant

People who have had kidney, heart, lung, or bone-marrow transplants are less likely to develop Parkinson’s disease than the general population, research suggests.

The study, “Transplant and risk of Parkinson disease” was published recently in Parkinsonism & Related Disorders

Chronic neuroinflammation is a hallmark of Parkinson’s disease with studies suggesting that inflammatory processes contribute to disease risk and progression, although such biological response is unlikely to be the primary cause of neuronal death. That is why researchers suspect that reducing inflammation in the brain has the potential to slow neurodegeneration.

Anti-rejection drugs, also known as immunosuppressant medications, inhibit the immune system’s activity and reduce overall inflammation in the body, including the central nervous system.

Patients who undergo organ transplants usually are given these types of medicines to lower their body’s ability to reject the transplanted organ.

“Because inflammation may play a role in the pathophysiology of PD [Parkinson’s disease], it is possible that immunosuppressants could reduce the risk” of the disease, researchers wrote.

A team led by Washington University School of Medicine in St. Louis researchers investigated the risk of Parkinson’s disease in relation to tissue transplant. This same team had shown previously that individuals taking selected immunosuppressants had a lower risk of Parkinson’s disease than the general population Medicare beneficiaries who were studied.

In the most recent study they assessed Medicare beneficiaries (age 66–90 years) data from 2004 to 2009 and identified 89,790 Parkinson’s disease cases. For the control group, researchers selected a 0.5% random sample of all Medicare beneficiaries included in the study period, totaling 118,095 subjects.

History of kidney, heart, lung, bone-marrow, pancreas or cornea transplant was then registered. There were 278 transplants in the Parkinson’s sample and 302 in the control group.

Statistical analysis revealed patients who underwent transplants had a 37% lower risk of developing Parkinson’s than the general Medicare population.

“Overall, patients who had undergone tissue transplant more than five years prior to PD [Parkinson’s disease] diagnosis or reference had lower risk of PD,” researchers wrote.

This correlation was consistent for kidney, heart, lung, and bone-marrow transplants. Liver or corneal (the transparent layer that makes up the front of the eye) transplant was not linked to Parkinson’s disease risk.

When adjusting for underlying cause of the transplants, such as valvular heart disease, diabetes with renal complications, or chronic hepatitis infection, organ transplant remained inversely correlated with Parkinson’s risk. However, the association with kidney transplant became statistically non-significant.

“This study provides evidence that tissue transplant may be associated with a lower PD [Parkinson’s disease] risk, warranting further investigation to identify factors that mediate this relationship, including a potential effect of immunosuppressive therapy on PD risk,” researchers concluded.

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Subjective Cognitive Decline Could Help Predict Parkinson’s Dementia, Study Contends

cognitive decline

Subjective cognitive decline in Parkinson’s disease could predict the development of dementia. As such, a suitable cognitive screening test could help provide an accurate diagnosis and prognosis.

The study with those findings, “Subjective cognitive decline and progression to dementia in Parkinson’s disease: a long-term follow-up study,” was published in Journal of Neurology.

Even during the early stages of disease, mild cognitive impairment can affect non-demented Parkinson’s patients, and is considered a risk factor for the development of dementia (PDD).

In fact, the prevalence of PDD increases as the disease progresses: from 28% after five years of evolution to 80% after 20 years of the disease.

Subjective cognitive decline — self-reported acquired difficulties with cognitive functioning — is common in the elderly and can be used as a predictor of dementia. In Alzheimer’s disease, subjective cognitive decline has been linked to disease-related tissue/molecular changes and a higher risk for dementia development. However, the predictive value of this type of cognitive status impairment has not been demonstrated yet in Parkinson’s disease.

Scientists from the University of La Laguna, Spain, investigated the neuropsychological profile of subjective cognitive decline in Parkinson’s disease and explored which components could better predict the development of PDD. The team also compared different screening tests to assess subjective cognitive complaints.

A total of 43 Parkinson’s patients and 20 healthy subjects were subjected to neuropsychological examination using a battery of cognitive tests. All patients were being medicated for Parkinson’s and were evaluated during their “on” state — when they are responding to medication and have reduced symptoms.

Subjective cognitive decline was diagnosed using two distinct approaches. A semi-structured interview in which the patient provided his/her subjective opinion on his/her attention, memory, spoken language, naming, written language, visuospatial skills and executive functions; diagnosis was considered when the patient had at least one cognitive complaint. Additionally, a subjective cognitive decline diagnosis also was established on the basis of the interview question concerning memory complaint.

For a mild cognitive impairment diagnosis, investigators followed the criteria proposed by the Movement Disorder Society (MDS)

Based on the results of the interview and on the MDS Task Force criteria, patients were diagnosed as having either subjective cognitive decline or mild cognitive impairment. Of the 43 patients, 13 (30.2%) were diagnosed with subjective cognitive decline, 22 (51.2%) with mild cognitive impairment and 8 (18.6%) had no subjective cognitive complaints. Difficulties in naming and memory were the most frequent cognitive complaints.

Based on memory complaints alone 10 patients (23.25%) were diagnosed with subjective cognitive decline. Interestingly, 10 of the 22 (45.45%) who had been diagnosed with mild cognitive impairment reported no memory complaints.

Mild cognitive impairment subjects performed poorer in the processing speed (the time it takes a person to do a mental task), executive functions (a set of mental skills that helps with organization and regulation), visuospatial skills, memory, and language domains, compared to the other groups.

There were no significant differences between healthy participants (controls)  and Parkinson’s disease patients with subjective cognitive decline in any of the neuropsychological measures.

The team also assessed how many patients diagnosed with subjective cognitive decline progressed to dementia after a mean follow-up of 7.5 years. Fifty percent of mild cognitive impairment patients, 33.3% of individuals diagnosed with subjective cognitive decline, and 14.3% of patients without subjective cognitive complaints developed dementia, which was found to be associated with a poor performance in verbal and visuospatial memory and naming at the beginning of the study.

Additionally, both the language and memory domains were good predictors of dementia development.

“These results are highly relevant for future investigations and also for clinicians: the [subjective cognitive decline] assessment is frequently the first step of cognitive examination and can influence future decisions (e.g., to administer a screening test or a comprehensive neuropsychological assessment),” researchers wrote.

“Assessments that do not include procedures to adequately explore cognitive complaints may underestimate the proportion of [Parkinson’s-related subjective cognitive decline] and, therefore, [mild cognitive impairment] and thus misclassify patients as [Parkinson’s disease] with normal cognition, especially when brief cognitive examinations are chosen,” they concluded.

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Genetic Variant Predetermines Risk of Cognitive Decline in Parkinson’s, Research Suggests

genetic variant

Researchers have found that Parkinson’s patients whose cognitive ability is intact, but who have a specific genetic variant, have significantly less gray matter in the regions of their brain that are related to dementia.

The study with that finding, “Reduced gray matter volume in cognitively preserved COMT 158Val/Val Parkinson’s disease patients and its association with cognitive decline,” was published in Brain Imaging and Behavior.

Several mutations in the COMT gene have been associated with the risk of developing Parkinson’s disease. This gene provides instructions for making catechol-O-methyltransferase (COMT), an enzyme that helps break down certain chemical messengers like dopamine.

The most common alteration in the DNA sequence that makes up the COMT gene is the Val158Met mutation in which a valine (Val) is replaced by a methionine (Met) at position 158. Val and Met are both amino acids, also known as the protein’s building blocks.

Every individual has two copies of each gene, one inherited from each parent. Therefore, a person can have two Val’s in the same position at both COMT gene copies (also known as the Val/Val genotype), a Val in one gene and a Met in the other (Val/Met genotype), or two Met’s (Met/Met genotype). Scientists use the word “genotype” to describe a person’s genetic constitution.

Changes in COMT’s molecular structure, lead to high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzymatic activity.

The Val158Met mutation in the COMT gene has been associated with an increased risk of cognitive decline in Parkinson’s disease, particularly in people with greater COMT activity. When this happens, there is too much neurotransmitter degradation, thus leading to reduced levels of dopamine and affecting basic brain functions such as motor coordination and memory.

Evidence suggests a correlation between cognitive impairment, one of Parkinson’s non-motor features, and reduced gray matter volume.

The brain is composed of gray and white matter. The first consists of cell bodies — the control center of neurons — while the latter is made up of nerve cell projections, known as axons or fibers, connecting distinct parts of gray matter.

A Spanish team of researchers used magnetic resonance imaging (MRI), a non-invasive imaging technology, to investigate a possible structural brain compromise in Parkinson’s patients with highly active COMT activity that could explain their increased risk for subsequent cognitive impairment.

The study included 120 newly diagnosed Parkinson’s patients with normal cognition (who were not previously treated for the disease) and 48 healthy controls from the Parkinson’s Progression Markers Initiative database.

Results showed that there was a widespread, significant reduction in cerebral gray matter volume in patients with the Val/Val genotype. They observed alterations in the fronto-subcortical and posterior-cortical brain regions, where motor and cognitive functions originate.

Gray matter volume at some of the identified regions was associated with cognitive decline in a four-year follow-up period, suggesting that gray matter volume reduction during the early stages of disease predisposes Val/Val patients to cognitive impairment.

Nonetheless, gray matter volume analysis at one-year follow-up was not increased in Val/Val subjects, in comparison to Val/Met and Met/Met participants, indicating a somewhat stable atrophy in the Val/Val subset and that those brain changes might already be present prior to diagnosis.

The team believes their research “sparks the need to further characterize the association between a modified COMT enzymatic effect and a structural brain compromise in the early stages of [Parkinson’s disease].”

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Older IBD Patients Show Increased Risk for Parkinson’s Disease, Study Suggests

IBD risk factor

Older patients with inflammatory bowel disease (IBD) are more likely to develop Parkinson’s disease than those without the condition, a meta-analysis suggests.

Whether the same association exists for younger patients — ages 59 or younger — remains to be determined, according to the researchers.

The study, “Older patients with IBD might have higher risk of Parkinson’s disease,” was published in the journal Gut.

The chronic activation of pro-inflammatory mechanisms, which occurs in autoimmune conditions, has been increasingly recognized as a critical contributor of neurodegenerative disorders.

Studies suggest that this may happen due to the “gut-brain axis” — the two-way communication between the nervous system and the intestine that monitors gut function and links certain regions of the brain to intestinal functions, such as immune activation or intestinal permeability.

In line with the findings, some studies have already reported that patients with IBD — an autoimmune condition characterized by chronic inflammation of the gut — are 22-41% more likely to develop Parkinson’s than those without IBD.

However, a case-control study that examined Medicare data from 89,790 Parkinson’s cases and 118,095 population-based controls suggested that IBD actually reduced the risk for Parkinson’s by 15%.

To clarify this association, a team at Sichuan University in China reviewed all studies investigating the link between IBD and risk of Parkinson’s. Five studies met the inclusion criteria defined by the team, including a total of 9,174,766 participants.

Overall, IBD patients did not have a significantly higher risk of Parkinson’s than reference individuals, nor did patients with ulcerative colitis or Crohn’s disease — the two main forms of IBD — when examined individually.

However, patients 60 years or older were found to have a 32% higher risk of developing Parkinson’s. Patients 50 years or younger did not show this association, the researchers said.

“Our meta-analysis showed that patients with IBD did not have an increased risk of PD; however, subgroup analysis with cohort studies showed that they might be associated with increased risk of PD,” the researchers wrote.

“Age has been regarded as an important risk factor for Parkinson’s disease,” they added, but the findings suggest that “age at IBD diagnosis might be a risk factor of Parkinson’s disease.”

Interestingly, the team found that some studies reported medication-related side effects in the IBD population that resembled parkinsonism in the older population.

“It is necessary to take it into consideration whether older people will take more medications, and whether these medications lead to a higher risk of Parkinson’s also needs further studies to verify in the future,” they said.

Additional well-designed observational studies are still warranted to further explore the risk of Parkinson’s disease within the younger IBD population, the team noted.

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Mutations on NUS1 Gene Can Significantly Raise Person’s Risk of Parkinson’s, Study Reports

NUS1 mutations

Mutations affecting the NUS1 gene are linked to a significantly increased risk — 11 times higher — of developing Parkinson’s disease, study shows.

The study, “Coding mutations in NUS1 contribute to Parkinson’s disease,” was published in Proceedings of the National Academy of Sciences.

Although exact triggers of Parkinson’s disease remain unclear, aging, and environmental and genetic factors are believed to be major culprits.

SNCA was the first gene to be linked to the development of Parkinson’s. Since its discovery in 1997, scientists have attempted to find other genes that may also play a role.

Chinese researchers conducted a detailed genetic analysis of samples collected from 39 patients with early-onset Parkinson’s disease, their parents, and 20 unaffected siblings, aiming to detect de novo mutations associated with the disease.

A de novo mutation is a genetic alteration evident for the first time in one family member as a result of a mutation in the egg or sperm of a parent, or a mutation that arises in the fertilized egg itself during early development. A child with a de novo (new) mutation will develop the associated disease, while his parents or siblings will not.

Researchers identified 12 genes carrying de novo mutations — MAD1L1, NUP98, PPP2CB, PKMYT1, TRIM24, CEP131, CTTNBP2, NUS1, SMPD3, MGRN1, IFI35, and RUSC2. These genes are known to be expressed in two brain regions affected in Parkinson’s disease, called the stratum and substantia nigra, and could be functionally relevant to early-onset Parkinson’s.

Biologic network analysis showed that all the identified genes may share similar biological functions, and act together to increase the risk of developing Parkinson’s.

Patients did not have any other genetic variants previously associated with the disease.

Next, researchers explored the presence of rare mutations in these 12 genes in samples collected from 1,852 patients with sporadic (non-familial) Parkinson’s disease and 1,565 healthy volunteers. In this secondary screening, no significant alterations were found with exception of the NUS1 gene.

To confirm this finding, the team performed a detailed analysis of the NUS1 gene in a larger number of samples (3,237 patients and 2,858 controls). Similar to the previous analysis, Parkinson’s patients carried NUS1 mutations that were not present in the (healthy) control samples.

The presence of NUS1 variants, and consequent lower levels of the gene, were associated with a 11.3 times higher risk of having Parkinson’s disease.

Researchers also examined the role of the NUS1 gene in vivo, by deleting the equivalent gene — which shares 44% similarly with the human NUS1 — in a fly model (Drosophila). They observed that this deletion induced the loss of dopamine-producing nerve cells and, consequently, lower brain dopamine levels — two main hallmarks of Parkinson’s disease.

“These data … suggest that NUS1 plays important roles in dopamine neurons and that the loss of NUS1 could lead to neuronal dysfunction that is related to Parkinson’s disease,” the researchers wrote.

“[D]e novo mutations could contribute to early onset PD [Parkinson’s disease] pathogenesis and identify NUS1 as a candidate gene for PD,” they concluded.

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Appendix Removal Early in Life Reduces Risk of Developing Parkinson’s, Study Shows

appendix, Parkinson's risk

The healthy human appendix contains Parkinson’s disease-related alpha-synuclein aggregates, and removing the organ early in a person’s life reduces the risk of developing the disease, a study has found.

The study, “The vermiform appendix impacts the risk of developing Parkinson’s disease,” was published in Science Translational Medicine. The work was led by researchers at the Center for Neurodegenerative Science at the Van Andel Research Institute in Michigan.

“Our results point to the appendix as a site of origin for Parkinson’s and provide a path forward for devising new treatment strategies that leverage the gastrointestinal tract’s role in the development of the disease,” Viviane Labrie, PhD, an assistant professor at Van Andel and senior author of the study, said in a press release.

In the brains of Parkinson’s patients, there is a buildup of a protein called alpha-synuclein that forms clumps known as Lewy bodies. These clumps are toxic and lead to neuronal death.

“Gastrointestinal (GI) dysfunction is a common nonmotor symptom of PD [Parkinson’s disease], often preceding the onset of motor symptoms by as many as 20 years,” the researchers wrote.

In addition, it has been shown that neurons innervating the intestines of Parkinson’s patients contain aggregated alpha-synuclein.

“Accumulation of alpha-synuclein in the GI tract not only may contribute to the nonmotor symptoms of PD but also has been hypothesized to contribute to PD pathology in the brain,” the researchers said.

Studies have revealed the existence of many alpha-synuclein aggregates in the appendixes of early-stage and established Parkinson’s patients, as well as in neurologically intact subjects.

The appendix — a worm-like organ that sticks out of the large bowel in the lower right side of the abdomen — helps the immune system detect and eliminate harmful microorganisms, while regulating the gut’s bacterial composition.

In this study, researchers investigated whether this tiny organ contributes to Parkinson’s disease risk.

They analyzed two separate, yet complementary, epidemiological data sets: the nationwide Swedish National Patient Registry (SNPR) and the Parkinson’s Progression Markers Initiative (PPMI).

The SNPR contains information on 1.6 million individuals with a follow-up period of up to 52 years. Investigators identified all individuals who had had an appendectomy (surgical removal of the appendix) from 1964 to 2015 and obtained data on their surgical procedure, year of birth, year of surgical procedure, sex, geographic location (municipality), and, when applicable, date and cause of death. For each patient who underwent an appendectomy, there were two control participants who had not had their appendix removed matched in year of birth, sex, and geographic area.

This data-set analysis revealed that appendix removal was associated with a 19.3% lower risk of developing Parkinson’s than controls. Parkinson’s was diagnosed in 1.17 out of every 1,000 patients who had an appendectomy compared with 1.4 per 1,000 in the general population.

The surgery had the greatest impact on those living in rural areas, with a significant 25.4% reduction in Parkinson’s risk, indicating that removal of the appendix might influence environmental risk factors for the disease. Interestingly, no appendectomy-related benefit was observed in the urban area sample.

“The age of PD diagnosis was, on average, 1.6 years later in individuals who had an appendectomy occurring 20 or more years prior than in cases without an appendectomy. We also observed a significant delay in age of PD onset in individuals with an appendectomy 30 or more years prior, but a limited size in this longer latency group precluded further analysis,” the scientists said.

Researchers then looked at the PPMI data set, which contained detailed information about Parkinson’s diagnosis, age of onset, and other demographic factors, as well as the genetic information of 849 patients.

The team chose to focus on individuals who had their appendix removed at least 30 years before being diagnosed with Parkinson’s, because the early-stage phase of Parkinson’s can last for decades before an accurate diagnosis.

Results showed that age at disease onset was significantly delayed by 3.6 years in those who had undergone an appendectomy (54 individuals, representing 6.4% of the Parkinson’s sample), compared with those who had not.

Disease occurrence was not linked to immune disorders not affecting the gastrointestinal tract, nor was it related to the surgical event itself.

Once a Parkinson’s diagnosis had been established, there were no differences in symptom severity between people with and without a history of appendectomy, suggesting the appendix can potentially impact disease mechanism before the clinical onset of symptoms.

The team then explored the interaction between the appendix and environmental/genetic Parkinson’s risk factors. They reported that the surgical procedure delayed the age of onset in subjects with a family history — meaning those with one or two family members with Parkinson’s — but had no effect in individuals without a family history of the disease.

Importantly, those with a mutation in the LRRK2GBA, or SNCA gene — which are common in hereditary Parkinson’s cases — did not benefit from the appendectomy, indicating that removal of the appendix may be more protective against environmental causes of Parkinson’s rather than genetic ones.

Tissue analysis showed that the mucosa and neurons within the healthy human appendix were filled with aggregated alpha-synuclein. Such accumulation was evident in all age groups, including subjects younger than 20.

Although appendixes of both people with and without Parkinson’s contained disease-prone forms of alpha-synuclein that tend to aggregate rapidly, the Parkinson’s group’s “diseased” protein content was higher than that of the control group.

“We were surprised that pathogenic forms of alpha-synuclein were so pervasive in the appendixes of people both with and without Parkinson’s. It appears that these aggregates — although toxic when in the brain — are quite normal when in the appendix. This clearly suggests their presence alone cannot be the cause of the disease,” Labrie said.

Next, the scientists will search for which appendix-related factor(s) may contribute to Parkinson’s disease.

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High Cholesterol Levels May Protect Against Parkinson’s Disease, Study Suggests

cholesterol, Parkinson's risk

High levels of blood cholesterol may decrease the risk of men developing Parkinson’s disease, according to a large-scale clinical study.

The study, “Higher serum cholesterol and decreased Parkinson’s disease risk: A statin‐free cohort study,” was published in the journal Movement Disorders.

High blood cholesterol, in particular, low-density lipoprotein cholesterol (LDL-C), is a well-established risk factor for coronary disease and stroke. Human and animal studies suggest it may also play a role in the risk of Parkinson’s, although, so far, the data remains controversial.

To explore the association between high cholesterol levels over time and Parkinson’s risk, researchers reviewed the clinical records of 261,638 individuals collected from the medical databases of Maccabi Health Services, the second largest health maintenance organization in Israel.

The study covered all patients, ages 40 to 79, who had undergone at least two cholesterol evaluations between 1999 and 2012 (the study period) and who did not receive statins, which are cholesterol-lowering agents.

During the study period, 746 patients were diagnosed with Parkinson’s disease, 70% of which were definite cases. Disease incidence rates increased with age for both men and women, ranging from 0.06% in men and 0.04% in women at ages 40-44 to 4.8% in men and 3% in women at ages 75-79.

At the beginning of the study, total cholesterol and LDL-C levels were similar among men and women and were slightly higher than optimal standard values. In fact, one-third of the participants had LDL-C levels above 140 mg/dL, the level at which statin therapy is usually recommended, according to clinical guidelines.

Analysis of one-year lagged clinical data revealed that total cholesterol levels greater than 180 mg/dL and LDL-C higher than 110 mg/dL were associated with a reduced risk of Parkinson’s disease in statin-free middle-age men and elderly women.

In men ages 50 to 69, higher total cholesterol levels were associated with an 18-29% reduced risk of Parkinson’s, whereas high LDL-C levels were linked to a 20-28% reduced risk.

In women ages 70 to 74, a similar protective association was reported, but with lower impact. Higher total cholesterol levels were linked to a reduced risk of up to 7%, and high LDL-C levels correlated with a 2-12% reduced risk of Parkinson’s.

“Although our findings could not determine whether decreased cholesterol alone causes PD or whether cholesterol and Parkinson’s disease share a common cause, they strongly imply relevance for clinical practices and health policies,” the researchers wrote.

Additional long-term studies are necessary to “further elucidate the favorable range of cholesterol levels and its changes throughout life that could affect Parkinson’s disease,” they concluded.

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Source: Parkinson's News Today