New evidence sheds light on how Parkinson's disease may happen

June 14, 2018, Baylor College of Medicine

Dr. Hugo Bellen. Credit: Baylor College of Medicine

Researchers at Baylor College of Medicine and Texas Children's Hospital have identified unexpected new key players in the development of an early onset form of Parkinson's disease called Parkinsonism. These key players are ceramides, a family of lipid molecules that are found within cell membranes. The researchers propose that ceramides are the linchpin that connects previously identified cellular defects and genes independently known to be associated with Parkinson's disease and suggest a mechanism that can lead to the condition. The findings, published in the journal Cell Metabolism, could result in novel strategies to prevent or treat the condition in the future.

"Numerous genes have been associated with Parkinson's disease or Parkinson-like diseases; nevertheless, there is still little understanding of how these genes cause these conditions," said corresponding author Dr. Hugo Bellen, professor of molecular and human genetics and neuroscience at Baylor College of Medicine and an investigator at the Howard Hughes Medical Institute. "In this work, we have identified new contributors to the disease that we propose can provide a connection between previously unconnected genesand cellular defects observed in these diseases."

"When I joined the laboratory of Dr. Bellen, I decided to work on the human PLA2GA6 gene. Mutations in this gene cause neurodegenerative disorders, including Parkinsonism," said first author Dr. Guang Lin, postdoctoral associate in molecular and human genetics at Baylor. "The PLA2G6 gene encodes a phospholipase, an enzyme that modifies a type of fats called phospholipids. Phospholipids are major building blocks of our nervous system, but they have not been well characterized. We thought that we ought to investigate what this phospholipase was doing in these diseases."

Lin and his colleagues developed a fruit fly model of the human condition by knocking out the fly equivalent of the human PLA2GA6 gene, called iPLA2-VIA, which the researchers determined is expressed in neurons and probably other types of cells. These mutant fruit flies lived about one third of the lifespan of normal flies and presented with cellular characteristics similar to those observed in humans with mutations in PLA2G6 gene.

"Confirming previous results by other researchers, we also observed that fruit flies without the iPLA2-VIA gene were healthy when they were young and presented with age-dependent neurodegeneration," Lin said.

In addition, the researchers looked for the first time at the effects of the mutation on two other measurements: bang sensitivity and the workings of the visual system. Bang sensitivity refers to the response of the fruit flies to mechanical stress. They observed that while normal fruit flies have no bang sensitivity, meaning they recover immediately from impact, flies lacking iPLA2-VIA gene take longer to recover; they were paralyzed for some time after the impact, indicating problems with their nervous system.

To determine the workings of the visual system, the researchers conducted electroretinograms to measure the electrical responses of photoreceptors, neurons that sense light, in the eyes at different times during the life of the adult fruit flies. They found progressive loss of electrical activity in the mutant flies, findings that once again show a defect in the nervous system of these flies.

"We further carried out electron microscopy studies to take a closer look at the structure of neurons. We discovered that in the sick flies, the photoreceptors had many inclusions, lump-like structures, in their membranes, which are a symptom that something is wrong. The inclusions were absent in normal cells," said Bellen, who also is a member of the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital. "We also found structural malformations in most of the mitochondria, which is often a feature of Parkinson's disease, as well as dramatic enlargement of lysosomes, intracellular structures involved in the recycling of membranes and other cellular components. Altogether, these results indicated that the iPLA2-VIA gene is important to maintain proper membrane structure and shape."

A surprising finding

"Because the fly iPLA2-VIA gene encodes a phospholipase, an enzyme that modifies phospholipids, we expected that flies lacking the iPLA2-VIA gene would have changes in the phospholipids, providing a connection with the structural and functional defects we observed in the flies," Bellen said. "Surprisingly, our analysis showed that the phospholipids were normal. We did not anticipate this."

Then, what was abnormal?

The researchers looked at many types of lipids and found that the amounts of almost all the ceramides—lipids that are important for membrane structure and function—were increased in flies lacking the iPLA2-VIA gene. This suggested that the gene plays a role in the pathway that produces ceramides.

"We tested the effect of desipramine and myriocin, two drugs that block ceramide synthesis, on fruit flies lacking the iPLA2-VIA gene," Bellen said. "As expected, both drugs led to decreased amounts of ceramides in the cells. Interestingly, mutant flies treated with the drugs also presented with less neurodegeneration, less bang sensitivity, improved electoretinograms and less alterations in the lysosomes when compared with mutant flies not treated with the drugs."

Digging deeper into these results, the researchers looked into the processes cells use to reuse and to recycle ceramide-derived lipids present in cell membranes. Cells both reuse and recycle these lipids to keep a balanced supply in cell membranes. Cells reuse these lipids via intracellular trafficking mediated by the retromer. Retromers can identify these lipids, extract them before they are recycled and bring them back to membranes. Lipids that are not reused in this way are transported to the lysosomes where they are broken down into ceramides, which are then incorporated into membranes of the cells. The increased levels of ceramide stiffen the membranes. This further disrupts the function of the retromer, leading to more lipid shuttling to the lysosomes where they are broken down to produce more ceramides. This creates a positive-feedback loop that causes ceramides to accumulate and leads to neurodegeneration.

The results of their investigations revealed clues suggesting that ceramide balance is disrupted in flies lacking the iPLA2-VIA gene. These mutant flies have decreased levels of Vps35 and Vps26, proteins in retromers that are essential for their function. The researchers found that normally the iPLA2-VIA protein binds to Vps35 and Vps26 and this binding enhances retromer function. Lacking iPLA2-VIA protein results in less Vps35 and Vps26 and causes the disruption of retromer function, suggesting that the iPLA2-VIA protein stabilizes retromers and their function, which was not known before.

"These observations led us to predict that if retromers are defective, then lysosomes would have extra work and should expand, and this is what we observed," Bellen said. "All the approaches we tested that improved retromer function also resulted in an improvement of the defects we observe in fruit flies lacking the iPLA2-VIA gene. Interestingly, mutations in the vps35 gene also cause Parkinson's disease."

Bellen and his colleagues confirmed these results in vertebrate neurons grown in the lab.

In addition, the researchers found that having high levels of alpha-synuclein, a hallmark of Parkinson's disease in vertebrate neurons, leads to retromer dysfunction, lysosomal expansion and ceramide accumulation. Interestingly, these defects triggered by excess alpha-synuclein also were reduced by treatment with the same drugs that improved the defects observed in fruit flies lacking the iPLA2-VIA gene.

Altogether, this work provides new evidence suggesting connections between new and previously identified pieces known to be associated with the Parkinson's disease puzzle and suggest a mechanism that can lead to the condition.

"We show that loss of phospholipase PLA2G6 leads to ceramide accumulation, defects in retromer function, progressive lysosome expansion and, finally, to progressive neurodegeneration with characteristics in common with those observed in Parkinson's disease. And the same drugs that interfere with ceramide synthesis also ameliorate the condition. We also found a place for alpha-synuclein in the disease puzzle," Lin said.

"We think that our work is important because it points to a potential mechanism leading to Parkinsonism and perhaps Parkinson's disease," Bellen said. "We propose that loss of phospholipase PLA2G6 or a reduction in Vps35 causes a disruption of retromer function that creates an insidious stress for the cell and is potentially at the root of these conditions. If retromer function is disrupted, neurons are not able to reuse some ceramide-derived lipids, and more of them travel to the lysosomes, which have to work harder over time and hence start expanding.

 Also, as ceramide-derived lipids are shuttled to the lysosomes to produce ceramides, the cell builds up ceramides, which redistribute to the cell membranes and membranes of other organelles, such as mitochondria, disrupting the membranes' functions. We propose that the pathway becomes gradually and increasingly disturbed because of the stiffening of membranes by intercalating ceramides, which creates progressively more stress as well as mitochondrial dysfunction that eventually would lead to Parkinsonism and Parkinson's disease in the long term."

More information: Cell Metabolism (2018). DOI: 10.1016/j.cmet.2018.05.019 

Journal reference: Cell Metabolism

Provided by: Baylor College of Medicine 

https://medicalxpress.com/news/2018-06-evidence-parkinson-disease.html

Does Taming Killer Astrocytes Spare Neurons in Parkinson’s Disease?

Marzia Maria Lecchi  

• University of Milano-Bicocca 
• Posted: 14 Jun 2018 

13 Jun 2018

Activated microglia contribute to neurodegenerative diseases, and recent work suggests they do that, at least in part, by riling up normally protective astrocytes to attack and kill neurons. Can preventing astrocytes from going bad block the disease? Possibly, says a study in the June 12 Nature Medicine. Seulki Lee, Ted Dawson, and Han Seok Ko, all at Johns Hopkins Medical School in Baltimore, find that in two mouse models of Parkinson’s disease, a diabetes drug prevents the accumulation of toxic synuclein protein in the brain, restores normal movement, and prolongs survival. That was no surprise—similar glucagon-like peptide 1 receptor (GLP-1R) agonists are being tested in clinical trials for Parkinson’s disease. However, when the investigators probed the drug’s mechanism, they found it inhibited microglia activation, and prevented the production of inflammatory cytokines that turn astrocytes into killers.

The new study suggests astrocytes could directly mediate the toxicity of synuclein fibrils in Parkinson’s disease. These angry astrocytes have been implicated in other neurodegenerative diseases, and the results raise the possibility that blocking them could offer a therapeutic approach to multiple conditions.

Co-first authors Seung Pil Yun and Tae-In Kam did not intend to study astrocyte activation. Instead, their goal was to understand how a novel GLP-1R agonist worked in mouse models of Parkinson’s disease. Several GLP-1R agonists are approved for treating Type 2 diabetes, in which they ease insulin resistance and normalize glucose metabolism. In the brain, GLP-1R agonists improve glucose metabolism too, while also stimulating neurogenesis and neuron survival, and quelling inflammation. In a small, Phase 2 study, the GLP-1R agonist exenatide slowed symptomatic progression in people with PD (Aug 2017 news). 

In the new study, the researchers first evaluated the activity of NLY01, a long-lived, brain-penetrant GLP-1R agonist developed in Lee’s lab, in two mouse models of PD. In one, mice got injections of preformed α-synuclein filaments into the midbrain. One month later, when synuclein pathology was starting to spread, the researchers began twice-weekly subcutaneous injections of NLY01 or vehicle. After five months, NLY01 had reduced synuclein pathology and dopaminergic neuron loss, and normalized dopamine levels in the mid-brain. The mice showed nearly normal motor function, including running, climbing, grooming, and rearing behaviors. In the second model, in mice expressing the human A53T α-synuclein mutant A53T, NLY01 prolonged the animal’s lifespan by nearly three months, concomitant with a reduction in synuclein pathology at death.

How did the compound work? At the time, Dawson was collaborating with Ben Barres and Shane Liddelow, then at Stanford University in Palo Alto, California, to study astrocyte activation by microglia. They discovered that microglia-derived inflammatory cytokines Il-1α and TNF, along with the complement protein C1q, convert resting astrocytes to a destructive phenotype they called A1 (Jan 2017 news). These inflammatory astrocytes release an unknown factor that participates in dendritic pruning and ultimately causes neuronal death. 

Liddelow and colleagues had found markers of A1 astrocytes in disease tissue from people with PD, AD, Huntington’s disease, ALS, and MS, and more recently showed they mediated tau toxicity in animal models (Sep 2017 news). Dawson knew that GLP-1R agonists inhibit microglia activation, and wondered if they might save neurons by stopping A1 conversion in response to synuclein. “We did the experiments on a lark, and they turned out to be correct,” he told Alzforum.

Mainly Microglia. 

GLP-1R predominantly colocalizes with the microglial marker Iba-1 in the substantia nigra, supporting a glial locus of action for NLY01 in PD.  [From Yun et al., Nature Medicine, 2018.]

To make the case, they first evaluated the effects of NLY01 on isolated microglia, astrocytes, and dopaminergic neurons in culture. NYL01, they found, failed to protect isolated neurons from the toxic effects of α-synuclein fibrils, suggesting that the drug did not act directly on neurons. Microglia in the midbrain expressed more GLP-1R receptors than neurons, and the receptor levels were increased 10-fold in microglia in PD brain tissue, so they tested the effect of NYL101 on those cells. In culture, synuclein triggered activation of microglia, and release of IL-1α, TNFα, and C1q. Conditioned media from synuclein-treated microglia induced A1 markers on astrocytes, which then killed cultured neurons. 

However, microglia treated with NYL101 failed to release the cytokines, induce A1 astrocytes, or cause neuronal death. Besides NYL01, neutralizing antibodies to Il-1α, TNF, and C1q also eliminated the microglia’s ability to induce A1 astrocytes and neuron death.

The investigators tracked similar events in vivo, where α-synuclein fibril injection or the A53T mutant induced microglia activation, expression of Il-1α, TNF, and C1q RNA, and appearance of complement C3d, a marker for A1 astrocytes (see image). All were inhibited by NLY01. Taken together, the results indicate that microglia-induced astrocyte conversion contributes to neurodegeneration in response to synuclein fibrils, Dawson said.

Can You C3? Injection of mice with synuclein fibrils (top) induces expression of the A1 marker complement 3D (green) in GFAP-positive astrocytes (red, and merged images). Mice who also received NLY01 have fewer C3-positive astrocytes (bottom panels). [From Yun et al., Nature Medicine, 2018.]

“This gives another rodent model of an additional neurodegenerative disease, driven by another protein, but showing the same microglia cascade leading to astrocyte activation and neuronal cell death,” said Liddelow, who is now at New York University. “We had hypothesized this would be a common response, and that seems to be panning out,” he told Alzforum.

Patrik Brundin, Van Andel Research Institute, Grand Rapids, Michigan, called the work a transformative breakthrough, and clinically relevant. But, he said, a few details are puzzling. “It’s a little bit unexpected that the cell death following exposure to synuclein aggregates is so heavily mediated via A1 astrocytes,” he said. “We know from previous work that synuclein is toxic to dopamine neurons in culture. Here, they report that death is heavily dependent on microglia activating astrocytes, and then astrocytes secreting this unknown neurotoxic factor.” Brundin also wondered why NLY01 appeared to decrease the extent of synuclein deposits. “Is that due to protection from the enigmatic neurotoxic factor? It’s unclear why that would reduce spread,” he said.

The work is important for PD researchers because previous preclinical studies with the diabetes drugs came solely from toxin-based PD models, said Thomas Foltynie, University College London. Foltynie ran the initial trials of exenatide for PD, and is planning a Phase 3, pending funding. “Showing the treatment is neuroprotective in two synuclein-based models is important in building confidence that this will help in human PD,” he told Alzforum. He said the study also suggests a potential biomarker for GLP-1R agonist trials, where investigators could monitor microglial activation with PET imaging. At the same time, Foltynie cautions, mice do not always reflect what happens in humans, and the results need to be validated in people first.

NLY01 is on a fast track to human testing. Several of the authors co-founded a company that received funding a month ago and plans to conduct a Phase I tolerability and safety study in healthy volunteers this year, with the goal of a Phase 2 in Parkinson’s disease in 2019.

GLP-1 R agonists are also of interest in AD, where insulin signaling in the brain goes awry and diabetes is a risk factor for disease. One agonist, liraglutide, improved brain glucose metabolism in people with AD (May 2016 news). Will that translate to cognitive benefits? That question is being tested in an ongoing multicenter trial in London. Lee told Alzforum his group is testing NLY01 in animal models of AD.—Pat McCaffrey

https://www.alzforum.org/news/research-news/does-taming-killer-astrocytes-spare-neurons-parkinsons-disease

Treatment Options For Nightmare Disorder in Adults

June 14, 2018
Source: AASM.

A variety of treatment options may be effective for nightmare disorder in adults, according to a position paper from the American Academy of Sleep Medicine (AASM).

Nightmare disorder involves repeated occurrences of nightmares that cause clinically significant distress or impairment. It affects approximately 4 percent of adults, occurring in isolation or as part of other disorders such as PTSD, and it can significantly impair quality of life. Nightmare disorder also can exacerbate an underlying mental illness, such as depression or anxiety. NeuroscienceNews.com image is in the public domain.

The position paper reports that image rehearsal therapy is useful for the treatment of nightmare disorder and nightmares associated with post-traumatic stress disorder (PTSD). Image rehearsal therapy is a technique that involves altering the content of a nightmare by creating a new set of positive images and rehearsing the rewritten dream scenario while awake.

Although evidence was less clear for other treatments, the task force found that a variety of interventions may be used for the treatment of nightmare disorder, including cognitive behavioral therapy, hypnosis, and several prescription medications. In contrast, the task force concluded that the anti-anxiety medication clonazepam and the antidepressant venlafaxine are not recommended for the treatment of nightmare disorder.

“Helpful treatment options are available for adults who are experiencing distress due to nightmares,” said lead author Dr. Timothy Morgenthaler, professor of medicine at Mayo Clinic in Rochester, Minnesota. “The judgment and expertise of a knowledgeable clinician are essential to ensure appropriate treatment selection and effective management of nightmare disorder.”

A task force developed the position paper based on their clinical expertise and a qualitative assessment of the available evidence. The paper was approved by the AASM board of directors and is published in the June 15 issue of the Journal of Clinical Sleep Medicine.

Nightmare disorder involves repeated occurrences of nightmares that cause clinically significant distress or impairment. It affects approximately 4 percent of adults, occurring in isolation or as part of other disorders such as PTSD, and it can significantly impair quality of life. Nightmare disorder also can exacerbate an underlying mental illness, such as depression or anxiety.

“The first step to get help for nightmares is to discuss this concern with a doctor, who may refer you to an accredited sleep center for a comprehensive sleep evaluation by a board-certified sleep medicine physician,” said AASM President Dr. Douglas Kirsch. “Effectively treating nightmare disorder can improve sleep quality, resulting in less daytime sleepiness and improved alertness.”

The position paper includes the following position statements. Positions of “recommended” and “not recommended” indicate that a treatment option is determined to be clearly useful, or ineffective or harmful, for most patients. Positions of “may be used” indicate that the evidence or expert consensus is less clear, either in favor, or against the use, of a treatment option:

• The following therapy is recommended for the treatment of PTSD-associated nightmares and nightmare disorder: image rehearsal therapy.
• The following therapies may be used for the treatment of PTSD-associated nightmares: cognitive behavioral therapy; cognitive behavioral therapy for insomnia; eye movement desensitization and reprocessing; exposure, relaxation, and rescripting therapy; the atypical antipsychotics olanzapine, risperidone and aripiprazole; clonidine; cyproheptadine; fluvoxamine; gabapentin; nabilone; phenelzine; prazosin; topiramate; trazodone; and tricyclic antidepressants.
• The following therapies may be used for the treatment of nightmare disorder: cognitive behavioral therapy; exposure, relaxation, and rescripting therapy; hypnosis; lucid dreaming therapy; progressive deep muscle relaxation; sleep dynamic therapy; self-exposure therapy; systematic desensitization; testimony method; nitrazepam; prazosin; and triazolam.
• The following are not recommended for the treatment of nightmare disorder: clonazepam and venlafaxine.
• The ultimate judgment regarding propriety of any specific care must be made by the clinician, in light of the individual circumstances presented by the patient, accessible treatment options, and resources.

The task force also identified a need for more randomized controlled trials and well-designed comparative efficacy trials to allow for further evaluation of treatments for nightmare disorder.ights at night, and try to get as much light by day as possible.

About this neuroscience research article

Source: AASM 

Publisher: Organized by NeuroscienceNews.com.

Image Source: NeuroscienceNews.com image is in the public domain.

Original Research: Open access research for “Position Paper for the Treatment of Nightmare Disorder in Adults: An American Academy of Sleep Medicine Position Paper” by Timothy I. Morgenthaler, MD; Sanford Auerbach, MD; Kenneth R. Casey, MD, MPH; David Kristo, MD; Rama Maganti, MD; Kannan Ramar, MD; Rochelle Zak, MD; Rebecca Kartje, MD, MSHI, MBA in Journal of Clinical Sleep Medicine. Published June 2018.

doi:10.5664/jcsm.7178 

---

Abstract

Position Paper for the Treatment of Nightmare Disorder in Adults: An American Academy of Sleep Medicine Position Paper

Introduction

Nightmare disorder affects approximately 4% of adults, occurring in isolation or as part of other disorders such as posttraumatic stress disorder (PTSD), and can significantly impair quality of life. This paper provides the American Academy of Sleep Medicine (AASM) position regarding various treatments of nightmare disorder in adults.

Methods

A literature search was performed based upon the keywords and MeSH terms from the Best Practice Guide for the Treatment of Nightmare Disorder in Adults that was published in 2010 by the AASM. The search used the date range March 2009 to August of 2017, and sought to find available evidence pertaining to the use of behavioral, psychological, and pharmacologic therapies for the treatment of nightmares. A task force developed position statements based on a thorough review of these studies and their clinical expertise. The AASM Board of Directors approved the final position statements.

Determination of Position

Positions of “recommended” and “not recommended” indicate that a treatment option is determined to be clearly useful or ineffective/harmful for most patients, respectively, based on a qualitative assessment of the available evidence and clinical judgement of the task force. Positions of “may be used” indicate that the evidence or expert consensus is less clear, either in favor or against the use of a treatment option. The interventions listed below are in alphabetical order within the position statements rather than clinical preference: this is not meant to be instructive of the order in which interventions should be used.

https://neurosciencenews.com/adult-nightmare-disorder-9346/

Researchers Identify New Gene Associated with Parkinson’s Disease, Dementia

JUNE 13, 2018 BY MARTA FIGUEIREDO 

Mutations in the LRP10 gene are associated with the development of neurodegenerative diseases with Lewy bodies formation, such as Parkinson’s disease, Parkinson’s dementia and dementia with Lewy bodies, according to a recent study.

The study, “LRP10 genetic variants in familial Parkinson’s disease and dementia with Lewy bodies: a genome-wide linkage and sequencing study,” was published in The Lancet Neurology.

Abnormal deposits of the protein alpha-synuclein in the brain results in the formation of Lewy bodies and, eventually, nerve cell death. Lewy body formation affects chemicals in the brain whose changes can lead to Parkinson’s disease, Parkinson’s dementia, and dementia with Lewy bodies.

Mutations in specific genes — namely SNCA and LRRK2 — have been linked with inherited forms of these diseases. However, most patients do not have mutations in these genes. This suggests that additional genes may be responsible for Lewy bodies formation in these neurodegenerative disorders.

Several international researchers in collaboration with the International Parkinsonism Genetics Network analyzed patients’ data from clinical centers in Netherlands, Italy, Taiwan, Portugal, Brazil, the U.K., and Sweden.

By analyzing the genome (the total genetic material of an organism) of 10 relatives from an Italian family with a history of familial Parkinson’s disease and no mutations in known disease-causative genes, LRP10 was revealed as a potential culprit associated with the disease.

This gene was analyzed in 660 unrelated individuals diagnosed with Parkinson’s disease, Parkinson’s disease dementia or dementia with Lewy bodies from centers in those seven countries, and in 645 individuals with no indication of neurodegenerative diseases as a control group.

This analysis identified eight additional LRP10 mutations (in eight distinct patients) that potentially could be associated with these diseases.

When studying brain samples (autopsy-derived) from three patients with different LRP10 mutations, the researchers observed an elevated presence of Lewy bodies, strengthening the link between LRP10 mutations and the generation of these detrimental structures.

Three of the eight mutations severely impaired the production of the LRP10 protein, four affected protein stability, and two affected protein localization, suggesting that impaired LRP10 function may be a common mechanism behind the development of these diseases.

The LRP10 gene gives origin to the low-density lipoprotein receptor-related protein 10 (LRP10), which is involved in the cellular uptake of fat molecules.

LRP10 was found to localize in vesicle-like structures associated with proteins already known to be involved with alpha-synuclein accumulation and Parkinson’s disease, again stressing its involvement in Lewy body-associated diseases.

“Our work shows that LRP10 variants are implicated in Parkinson’s disease, Parkinson’s disease dementia, and dementia with Lewy bodies, and are associated with a severe burden of Lewy pathology [disease] in the brain,” researchers wrote.

Additional studies on the LRP10 protein function and its interaction with other proteins may potentially point to new biomarkers and therapeutic targets of these neurodegenerative diseases.

https://parkinsonsnewstoday.com/2018/06/13/researchers-id-new-gene-associated-with-parkinsons-disease-dementia/

When the Rain Falls and Hope Is Renewed

June 13, 2018  In Columns, Journeying Through Parkinson's Disease

 - 

a column by "Sherri Woodbridge."

Today it is raining here in Oregon, the state where many believe it rains all the time. But you know what’s good about so much rain? Everything stays green. All year. Sometimes, I know, it can seem depressing (and it is for some). But not today. Today it’s raining and … it’s a beautiful day.

• The birds are still singing. Nothing stops them. Even in the rain, they find something to sing about.
• There are jillions of puddles to jump in. And that’s exactly what my grandkids would do. And love it. They even get Grammy to do it, too.
• The leaves on the trees and bushes are always a bright, spring-green clean.
• The air smells fresh (for those who can smell).
• The flowers’ roots are always refreshed.

I remember a time when there was no rain. I lived in Northern California during the big drought. You could only water landscape once a week. You couldn’t wash your car. Residents were asked to cut back on laundry washing and shorten showers. Energy-saving faucets were stocked in hardware stores and signs saying, 

“If it’s yellow, let it mellow. If it’s brown, flush it down,” were selling like hotcakes. Drought-tolerant landscape was in big demand. People were trying to conserve water everywhere they could. And in that conservation, things began to die. Lawns and shrubbery were replaced by often less colorful species, guaranteed to survive the heat with less water. Kids were disheartened when summer sprinkler fun ceased. Guys with an obsession for washing their trucks weekly were frustrated by the new policies set in place.

No rain meant saying no to many other things. River rafting. Skiing. The list could go on and on. We longed for the days when rain would come. We prayed for days for the rain to fall.

One day, the skies clouded over and there was a hint of hope. The hope turned to joy when the drops began to fall from the sky. People opened their front doors and walked out into the uncommon liquid sunshine and danced. The rain fell as a wet welcome to a thirsty and dry community.

This past winter seems to have hung around in many different ways:

• The wet is becoming intolerable. But let’s face it — before long, the popular complaint will be that it’s intolerably hot.
• Medications that once worked wonders aren’t so wonderful anymore.
• Falls are more frequent and frustration is growing over what else will begin to increase with this debilitating disease — whatever it is.
• Concentration levels are falling, speech is getting more difficult to understand, and memory is gone.

Do you not know? Have you not heard? It is raining, but a new day is coming. It may even, for some, feel like a drought-infested summer in their spirits, where they are longing for rain. Take heart — a day is coming when there will be no more pain. No more tears. No more sorrow. A new day, when we will run with new feet, hug with new arms, and smell the beautiful roses with brand new noses. A day is coming when these days of discontent will have been OK because we were never made for this world anyway.

We are taught to be content in all things, and for the most part, we should be. However, having a hint of discontentment can also be good if you believe there is something better, and the best is yet to be. I don’t want to get so settled here that I forget to remember there is something better coming. 

I don’t want to get so comfortable that I forget this earth is not my final resting place. I want to remember that at any moment, my Prince is going to ride in on a white horse and take me Home. My discontentment and sorrow will be that I didn’t share that hope when it was raining or was hopelessly dry in someone’s life. Because without that hope, there really isn’t anything more to this life than living and dying, and that hope then becomes hopelessness.

It’s raining here today, but in the past week, my hope has been restored in many ways, and the sunshine is burning bright and warm within me. God has not forgotten. He has not failed us.

We are not home yet. Thank God — we are not home yet.

***

Note: Parkinson’s News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The opinions expressed in this column are not those of Parkinson’s News Today or its parent company, BioNews Services, and are intended to spark discussion about issues pertaining to Parkinson’s Disease. 

https://parkinsonsnewstoday.com/2018/06/13/parkinsons-when-rain-falls-hope-is-renewed/

Sleep Problems in Parkinson’s Traced in Study to 2 Mutations That Alter How Nerve Cells Work

JUNE 13, 2018 BY JOSE MARQUES LOPES, PHD

Mutations in two specific genes affect how nerve cells work in the brain, disrupting sleep patterns in Parkinson’s patients, a new study suggests, and recommends a way of possibly treating this disease symptom.

The research, “ER Lipid Defects in Neuropeptidergic Neurons Impair Sleep Patterns in Parkinson’s Disease,” appeared in the journal Neuron.

Non-motor symptoms of sporadic and familial Parkinson’s include difficulties sleeping, such as insomnia, nightmares, and restless sleep. These disturbances can occur years before Parkinson’s hallmark loss of dopamine-producing neurons and motor symptoms, and cannot be treated with dopaminergic therapy. The reasons for such disturbed sleep patterns in Parkinson’s patients, however, remains unknown.

parkin and pink1 are well-studied Parkinson’s-related genes, both broadly expressed in the brain. When they don’t function as they should, specific points of excessive contact among brain cells seem evident, the study reported, including among mitochondria — tiny cell structures that produce energy, working as the cell’s power plant. Patients with mutations in either parkin or pink1 are known to have disturbed sleep patterns.

Researchers studied these two genes in nerve cells generated from both patients’ stem cells and fruit flies, to better understand reasons for the troubled circadian — the 24-hour body rhythm – and sleep patterns in Parkinson’s patients.

Although no major defects in mitochondria or neurons were observed, results revealed that parkin and pink1 mutations led to overly abundant contact sites between mitochondria and the endoplasmic reticulum (ER) — a cellular structure particularly important in the production, folding, modification, and transport of proteins.

These contact sites caused an abnormal transfer of lipids (fats), which destroyed a component of the cell membrane (called the phosphatidylserine) with well-known implications  on cognitive function and aging. The loss of phosphatidylserine, in turn, disrupted the production of vesicles that transport chemicals when nerve cells communicate and control circadian rhythms.

“Our data here suggest that understanding the basic cell biology is key,” the scientists wrote. Specifically, these alterations were found in neurons derived from a brain area called hypothalamus, which regulates sleep and wakefulness. Mutations in either gene affected the necessary increase in vesicle secretion that takes place in the brain in the hours preceding dawn, the researchers noted.

Importantly, the investigators found that feeding animals with phosphatidylserine restored the production of vesicles and eased sleep pattern disturbances.

They noted that excessive ER-mitochondrial contacts have also been reported in Alzheimer’s, amyotrophic lateral sclerosis, Huntington’s, all of which are characterized by sleep disturbances and a disrupted circadian rhythm.

However, as in Parkinson’s, little is known about sleep pattern defects in these disorders. “Our study now provides a new direction that can be tested in the context of those diseases as well,” they wrote.

And it may be of clinical relevance to patients, the researchers said, noting that their work further supports evidence that sleep impairments in Parkinson’s have a different pharmacology than its motor symptoms, which are due to dopamine loss.

“It is also important to note that the disordered circadian rhythmicity and sleep patterns are caused by neuronal dysfunction and not neurodegeneration, which implies that it can be corrected, as we show here in flies by the addition of [phosphatidylserine] to the food,” the researchers wrote.

https://parkinsonsnewstoday.com/2018/06/13/parkinsons-sleep-problems-traced-to-two-mutations-that-alter-how-nerve-cellls-work-in-study/

Diagnosis of neurodegenerative diseases through eye movements

June 13, 2018   Universidad Politécnica de Madrid

A new robotic system developed by UPM researchers and AURA Innovative Robotics Company can help diagnose neurodegenerative diseases such as dementia and Parkinson's through the analysis of eye movements.

OSCANN Desk is a non-invasive technology developed by researchers from Universidad Politécnica de Madrid (UPM) and the company AURA Innotive Robotics, led by Cecilia García Cena that with a simple, fast test can provide data about brain function through the measurement of eye movements.

This new system is in the phase of clinical trial authorized by the Spanish Agency of Medicines and Medical Devices in six Spanish hospitals and, thanks to techniques of imaging processing and machine learning, its results will allow doctors to early diagnose neurodegenerative diseases and carry out customized treatments.

The diagnosis process of a neurodegenerative disease takes time since symptoms are complex to assess in the early stages of the disease. Besides, there are symptoms that are common to other neurodegenerative diseases such as tremors. High rates of diagnostic uncertainty make objective tests necessary to achieve an accurate medicine in which each patient receives information, prognosis and appropriate treatment.

The physiological process in medicine explains the eye movements. Accurately measure these movements would provide real-time information about how the brain is working at that moment. From this premise and in order to achieve an early diagnosis of neurodegenerative diseases, researchers from Centre for Automation and Robotics (CAR) CSIC-UPM and AURA Innovative Robotics Startup Company have developed OSCANN desk, an assistant medical device that through techniques of image processing and machine learning is able to accurately assess the eye movements.

Thanks to this new tool, doctors will have objective data of the brain functioning that, along with other clinical data, will enable accurate early diagnosis of the disease.

The test is conducted in a health care center with no need for a second doctor's appointment. The patient sits comfortably in a chair and the device is adapted to his anatomy to precisely measure the eye movement. The patient looks at stimuli that appear on a monitor, and each test lasts about a minute.

The clinical tests allowed researchers to develop models of pathologies, and by applying machine learning techniques, similarities and differences are analyzed among over 500 variables of eye movement. Likewise, the progress of certain symptoms can be objectively measured. This will help doctors to make a diagnosis and customize the treatment.

Today, the tests are applied to Alzheimer's, Parkinson's, mild cognitive impairment, diverse dementias, multiple sclerosis, and others. Additionally, researchers are collaborating on other clinical studies such as those for autistic spectrum disorders, epilepsy, diabetes, alcoholism, migraines, depression and bipolar disorder. This tool is being used in six hospitals that are national reference centers in pathologies.

In the near future, OSCANN Desk will be working in HM Hospitals, specifically in the Memory Disorders Unit of HM CINAC located at the Hospital Universitario HM Madrid.

Provided by: Universidad Politécnica de Madrid

https://medicalxpress.com/news/2018-06-diagnosis-neurodegenerative-diseases-eye-movements.html