Phase 1 Trial to Explore RDN-929’s Safety in Treating Brain Diseases by Protecting Synapses

Treat Neurodegenerative Diseases

Rodin Therapeutics has started a Phase 1 clinical trial to explore the safety of its synthetic compound, RDN-929, to treat neurodegenerative diseases, including Alzheimer’s and Parkinson’s, by protecting synapses.

The trial (NCT03668314), is designed to assess the safety, tolerability, pharmacokinetics — how the body affects a medicine — and pharmacodynamics — the interactions between the body and a compound — of single and multiple ascending doses of RDN-929 in approximately 92 healthy adult volunteers.

The study, conducted in the Netherlands, is currently recruiting participants.

“We’re thrilled to be in the clinic with our lead compound, which represents a novel approach to treating neurodegenerative diseases such as Alzheimer’s,” Adam Rosenberg, president and CEO of Rodin, said in a press release.

“This Phase 1 trial is an important milestone for us as we advance an ambitious clinical strategy,” Rosenberg said.

The study is divided in three parts. In the first part, researchers will randomly assign 48 adult participants to receive a single administration of one of six ascending doses of RDN-929, or a matched placebo.

Part two will select 12 healthy elderly subjects (ages 55–80) from the first group, who will undergo two crossover treatment periods, separated by a washout period of at least seven days for the medication to clear their system. In the first period, participants will receive a single dose of RDN-929 selected based on data from part one, either while fasting or with food. This will be followed by a second administration of a single dose of RDN-929, with the fasting or food status reversed.

The last part of the trial will explore multiple ascending doses of RDN-929 in up to four groups of eight healthy elderly subjects (at least three of each gender). The doses will be selected by an independent safety review committee, upon an interim safety analysis and approval by the ethics committee.

Researchers here will administrate once daily RDN-929 or placebo for 12 days. Escalation to the next higher dose will be based upon a review of the safety and tolerability data.

RDN-929 is a synthetic compound developed to selectively inhibit the histone deacetylase (HDAC)-CoREST complex. This complex is known to be involved in preventing the expression of certain neuronal genes.   RDN-929 is designed to rebalance neuronal genes’ levels, strengthen brain cell communication (synaptic function), and promote the formation of new synapses.

Gene expression is the process by which information in a gene is synthesized to create a working product, like a protein. Synapses are the junctions between two nerve cells that allow them to communicate; synaptic plasticity refers to the ability of synapses to strengthen or weaken over time.

Preclinical data has shown that RDN-929 is both effective and suitable for long-term treatment. Rodin believes that its compound may represent a new way of treating over 100 brain disorders that are characterized by synaptic loss and dysfunction, referred to as synaptopathies.

“We believe that directly targeting and strengthening synapses will lead to meaningful improvements in clinical symptoms, and we are hopeful that this approach can help patients across a broad range of disease severities,” Rosenberg stated.

Rodin is also sponsoring an ongoing, non-therapeutic clinical trial (NCT03577262) to explore the performance of a new radioactive tracer, designed to measure synaptic density in the living brain using positron emission tomography (PET) scans.

Data from these two studies will provide useful information to plan future clinical trials of RDN-929 in patients with Alzheimer’s, Parkinson’s, frontotemporal dementia, and other synaptopathies.

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The ABCs of Parkinson’s: ‘M’ is for Musings on Mumbling

mumbling

Sherri Journeying Through

If you asked me which symptom of Parkinson’s disease (PD) is the most annoying, I may reply, “My soft voice.”

I have always had a soft voice. Perhaps I have always had Parkinson’s disease! I have had a diagnosis of the disease a much shorter amount of time than when my symptoms initially began, in high school. It wasn’t until after my diagnosis, however, that people began telling me to, “Speak up!”, “Quit mumbling,” or, “You talk too softly.”

Too many times since my diagnosis, I have replied to those statements with my own feelings of frustration. 

“I am speaking up!” I will state.

“Well, I can’t hear you. Maybe you should yell,” they have retorted.

“I am yelling!” I scream, unaware that the decibel of “yelling” I feel I am projecting in volume is nowhere close to what they hear.

Since I have started meeting with a group of other people with Parkinson’s for a boxing class, I have seen a different side to the mumbling factor.

I often would ignore those who would tell me I am speaking too softly. I would mutter to myself that perhaps they are the ones who need some help hearing. But then, little by little, I was beginning to feel as if people were just downright ignoring me when I would say something. Then I started boxing and realized there are other people in the class similar to me. People who trip. People who have tremors. People who mumble.

Mumbling? Saying something quietly in such a way that it makes it difficult for others to hear you. Usually, it’s intentional. The hard thing for people with PD? We are perceived as mumbling when, in fact, we think we are talking normally. We truly do believe that we are talking loudly enough. Unfortunately, that often is not the case.

A few people with PD have explained it as:

“No one listens to me anymore.” –Shirley

“… my struggle with my voice has been the most challenging, caused me more heartache and frustrations.” –Mike

“People talk over me as if I am not talking.” –Mary

Parkinson’s disease can cause a soft voice/speech (known as hypophonia), which makes it difficult for others to hear those who experience it. Not all people with PD will struggle with speech difficulties, but for those who do, it can be extremely frustrating and can cause embarrassment, leading you to avoid socializing with others. 

If you have speech problems while living with Parkinson’s, you may want to look into the Lee Silverman Voice Treatment LOUD, a method that has shown improvements in voice and speech quality. In the meantime, sing. Loudly. It’s been known to help strengthen the muscles. And try to force yourself to speak loudly when talking. No mumbling. No muttering. No giving up. 

***

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.

The post The ABCs of Parkinson’s: ‘M’ is for Musings on Mumbling appeared first on Parkinson’s News Today.

Caffeine Plus Coffee Compound Linked to Serotonin Help Protect Brain from Toxic Damage, Mouse Study Says

coffee and its compounds

Two compounds found in coffee — caffeine and EHT, a fatty acid molecule derived from serotonin — work together to protect the brain from damage induced by alpha-synuclein, a study in mice reported.

The study, “Synergistic neuroprotection by coffee components eicosanoyl-5-hydroxytryptamide and caffeine in models of Parkinson’s disease and DLB,” was published in PNAS.

Parkinson’s disease is characterized by alpha-synuclein aggregates. When this protein clumps, it gives rise to small fibrils that accumulate inside brain cells, producing small inclusions called Lewy bodies. These structures are highly toxic and often cause irreparable damage to affected nerve cells, slowly killing them.

Previous studies have shown that alpha-synuclein is abnormally hyperphosphorylated — a chemical modification in which a phosphate group is added to the protein — in the brain of patients with Parkinson’s. This is caused by the lack of activity of the protein phosphatase 2A (PP2A), an enzyme responsible for removing phosphate groups from alpha-synuclein.

Of note, alpha-synuclein phosphorylation is known to occur in Parkinson’s disease, and is thought to be a critical step in disease progression as it enhances alpha-synuclein’s toxicity —possibly by increasing the formation of alpha synuclein aggregates.

Interestingly, studies also report that Eicosanoyl-5-hydroxytryptamide or EHT — a fatty acid molecule found in coffee — promotes the activation of PP2A. In transgenic (or genetically engineered) mice, it was able to reverse the symptoms of phosphorylation to produce large quantities of alpha-synuclein.

The chemical serotonin, a neurotransmitter, is known to serve as a “feel-good” chemical in the brain, influencing a person’s sense of well-being and happiness.

“Considering epidemiologic and experimental evidence suggesting protective effects of CAF [caffeine] in PD [Parkinson’s disease], we sought, in the present study, to test whether there is synergy between EHT and caffeine in models of [alpha]-synucleinopathy,” the researchers wrote.  “[A]mong patients with early PD, the amount of CAF consumption does not impact the rate of progression of the disease, and decaffeinated coffee has been found to be protective in Drosophila models of PD, raising some question about the protective effect of only CAF among the numerous other compounds in coffee.”

Researchers treated alpha-synuclein transgenic mice (SynTg) — which overexpress alpha-synuclein in nerve cells — with either higher doses of caffeine and EHT separately, or with lower doses of both compounds for six months.

SynTg mice treated with caffeine and EHT had lesser accumulation of hyperphosphorylated alpha-synuclein in the brain, which was linked to higher levels of active PP2. These animals also  maintained neuron integrity and function, had lower brain inflammation, and performed better on behavioral tests.

Investigators found the same therapeutic benefits when they used the combined treatment in another mouse model of alpha-synucleinopathy, in which animals were injected with pre-formed fibrils of alpha-synuclein (alpha-Syn PFF).

In both animal models, however treatment with either caffeine or EHT alone failed to produce the same positive effects.

“These findings suggest that these two components of coffee have synergistic effects in protecting the brain against [alpha]-synuclein−mediated toxicity through maintenance of PP2A in an active state,” the researchers wrote.

“As we begin to unravel the polypharmacology of the micronutrients in commonly consumed botanical extracts such as coffee, it seems likely that it will be possible to optimize their composition to enhance efficacy so as to provide widely available, inexpensive, and effective therapeutics for the prevention and treatment of neurodegenerative diseases such as PD, DLB [dementia with Lewy bodies], PSP [progressive supranuclear palsy], and AD [Alzheimer’s disease],” they concluded.

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New Neurodegeneration Challenge Network Puts Focus on Causes of Parkinson’s, Other Disorders

Neurodegeneration Challenge Network

A new network launched by Facebook CEO Mark Zuckerberg and his wife, Priscilla Chan, will unite leading investigators from various biomedical fields, as well as biologists and physicians, in gaining insight into why neurodegenerative disorders such as Parkinson’s occur.

The Chan Zuckerberg Initiative’s (CZI) Neurodegeneration Challenge Network will focus on neurodegenerative diseases as a group of disorders that share common features — and possibly future cures.

”Neurodegenerative disorders, including Alzheimer’s, Parkinson’s, Huntington’s disease and ALS, are a class of diseases that affect millions of people worldwide,” CZI science program officer Katharine Brose said in a press release. “Meanwhile, the causes of most degenerative diseases are only partly understood, and there still are no effective therapies to cure, prevent or even treat most of these disorders.”

Research projects were selected in a competitive process. Grantees include 17 early-career investigators and nine collaborative teams. Each team — seven from the U.S, one from Sweden, and one from Belgium — will receive $1.05 million.

The Belgian team, led by Patrik Verstreken, PhD, plans to develop a new chip to study how Parkinson’s works. He will work alongside researchers Wim Vandenberghe, MD, PhD, and Dries Braeken, PhD.

”We will produce human neuronal microcircuits that are relevant to Parkinson’s disease on a multi-electrode array chip,” Braeken said. “This chip will be used to measure electrophysiological changes between neuronal circuits of cells obtained from healthy people and from an extensive collection of Parkinson’s patients.”

The 2D chip is needed to form a 3D human-relevant model for brain function and disorder.

Verstreken said he hopes to “print” small parts of the human brain on a unique chip, allowing scientists access to brain tissue from healthy individuals and patients. He explained that the technology can be used to monitor disease progression and to look for potential solutions.

”While we will develop this chip using tissue from Parkinson’s patients, the same technology can be used to create better models for Huntington’s disease or any other neurodegenerative disease, for that matter,” Vandenberghe said.

Years of research notwithstanding, there remains much about Parkinson’s and related diseases that scientists don’t yet understand.

“By supporting these nine interdisciplinary collaborations and generating shared tools, resources and platforms, we hope to inspire a new approach to tackling neurodegenerative disease — one that leverages the combined power of basic science and technology to accelerate progress toward clinical goals,” Brose said.

Zuckerberg is Facebook’s co-founder and CEO. Chan is a pediatrician and philanthropist. Founded by Zuckerberg and Chan in 2015, the CZI aims to use technology to solve some of the world’s toughest problems. Its focus areas are science, education, justice, and opportunity.

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Merger of New Mexico Parkinson’s Coalition, PMDAlliance Expected to Improve Patient Services

PMDAlliance merger

The recent merger of the New Mexico Parkinson’s Coalition (NMPC) and national nonprofit Parkinson & Movement Disorder Alliance (PMDAlliance) is expected to significantly boost support services for Parkinson’s patients in the New Mexico area, according to the organizations.

“I’m a firm believer in mergers when the organizations share similar missions and are compatible in their purpose and goals,” Sarah Jones, CEO of PMDAlliance, said in a press release. “Bringing everything under one virtual roof creates exponential benefit. It saves money and allows us to serve more people in need.”

As a result, the organizations expect a fourfold increase in the programs offered to patients with Parkinson’s and other movement disorders in New Mexico.

The coalition website states that “the tough decision was made knowing that there would be new, innovative programs and support brought to New Mexico as well as funds to hire a community engagement manager,” adding that more patients will have access to education, exercise programs, and events.

These improvements in services will be expanded to include smaller areas in the state rather than being limited to larger cities such as Albuquerque, Santa Fe, and Las Cruces.

“Working collaboratively, we can expand our reach in New Mexico, including extending services to our Native American neighbors and rural communities,” said Karen St. Clair, a former coalition board member. “PMDAlliance is passionate about services, just as the coalition is. By merging we can allocate more resources to service delivery instead of administration.”

Next year, the PMDAlliance will bring to the state educational events such as a support group for leadership training, a retreat for caregivers and their partners, and a program that focuses on new medical treatments.

The NMPC will be folded into the PMDAlliance umbrella, although it will continue to co-brand — using both organizations’ logos — until the transition is complete in about eight months, St. Clair said in a phone interview with Parkinson’s News Today. After that, its website will discontinue. The coalition was formed the year after the American Parkinson’s Disease Association’s decision in 2013 to leave New Mexico.

Operating nationwide but with no brick-and-mortar base, PMDAlliance provides educational workshops for organization leaders and those affected by movement disorders. Its overall mission is to improve patients’ lives.

According to the Parkinson’s Foundation, about 60,000 U.S. residents are diagnosed with Parkinson’s annually.

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Taking a Careful Look at Apathy: It Could Be Motor Hesitation

apathy

Depression is often associated with Parkinson’s disease (PD), as is apathy. But there may be a subtle difference between the two. At the risk of oversimplifying, let’s define depression as a state of sadness and loss of interest, and apathy as an apparent lack of motivation. Put sadness and low motivation together and the result looks like someone who has stopped enjoying life. But linking the two together may be a mistake when PD is involved because what looks like a lack of motivation may be the result of motor hesitation and difficulty with set shifting (changing from one motor activity to another). I have seen this motor hesitation in my own life. I feel stuck; not because of a lack of desire but rather an inability to move. It requires a careful examination to recognize the difference.

In a previous column, I talked about scenario looping breakdowns in connection to freezing — a common PD motor symptom. Apathy with PD folks may be linked more to scenario looping breakdowns than to a mood disorder. With PD it speaks to the “unwillingness” to act. But with a breakdown in scenario looping, it may appear as the unwillingness to act when it is actually a form of freezing due to an organic neurological condition. Combine this with the “flat affect face” or facial masking that can come with PD and it can appear to the observer as apathy. A careful look may reveal that often it is not. It is a manifestation of scenario looping breakdowns.

Scenario looping is the brain’s ability to loop through scenarios, exchanging possible actions or responses, until the best course has been determined. This happens with use of language and with motor actions. In every case, the scenario has a starting point. If there is no external cue from the environment to get started, we call that spontaneous initiation; an example is engaging in speech with your partner. You wouldn’t always want to wait until your partner speaks first or provides an external cue. In a normal relationship, each person will often initiate speech spontaneously without external cueing. Patients who have damage to areas of the brain responsible for scenario looping will frequently have problems with spontaneous speech. Does this mean that they are apathetic?

Spontaneously starting a new motor sequence may be difficult for some PD patients. Another example: My partner wants me to put up a new curtain rod. This involves a series of motor tasks: getting the tools and step stool, removing the old curtain rod, and using small screws. These actions involve the use of fine motor skills which are always difficult for those with PD. The curtain rod has been leaning against the wall for a week. Is it apathy that prevents me from engaging in the task? Is it fear? It doesn’t feel that way. It feels like a physical resistance to move my body in the direction of that given sequence of motor actions. PD patients often have motor action hesitancy, and this may be misinterpreted as apathy. In a chapter of “Parkinson’s Disease: Diagnosis and Clinical Management,” Lisa M. Shulman and Mackenzie Carpenter say that great care needs to be taken when ascribing the symptom of apathy to a PD patient, and that more research is necessary.

I need to be taking that careful look, to be clear in my mind that this is motor hesitancy. Doing so will ensure that scenario looping breakdown does not become apathy in my mind, or in the minds of those who care for me. There is a risk of mentally interpreting the motor resistance as “he doesn’t care.” The distinction is very important, and I spend time in mental contemplation making the distinction clear. Muscle hesitancy and difficulty with initiating motor sequences is not apathy. Understanding the difference between apathy and scenario looping breakdown is an opportunity to reframe and enlighten. Taking the time to contemplate on the difference is time well spent.

Write a comment and tell me if you see a difference between apathy and muscle initiation in your own life. Do you have suggestions on how to use this distinction to improve your quality of life?

***

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.

The post Taking a Careful Look at Apathy: It Could Be Motor Hesitation appeared first on Parkinson’s News Today.

Taking a Careful Look at Apathy: It Could Be Motor Hesitation

apathy

Depression is often associated with Parkinson’s disease (PD), as is apathy. But there may be a subtle difference between the two. At the risk of oversimplifying, let’s define depression as a state of sadness and loss of interest, and apathy as an apparent lack of motivation. Put sadness and low motivation together and the result looks like someone who has stopped enjoying life. But linking the two together may be a mistake when PD is involved because what looks like a lack of motivation may be the result of motor hesitation and difficulty with set shifting (changing from one motor activity to another). I have seen this motor hesitation in my own life. I feel stuck; not because of a lack of desire but rather an inability to move. It requires a careful examination to recognize the difference.

In a previous column, I talked about scenario looping breakdowns in connection to freezing — a common PD motor symptom. Apathy with PD folks may be linked more to scenario looping breakdowns than to a mood disorder. With PD it speaks to the “unwillingness” to act. But with a breakdown in scenario looping, it may appear as the unwillingness to act when it is actually a form of freezing due to an organic neurological condition. Combine this with the “flat affect face” or facial masking that can come with PD and it can appear to the observer as apathy. A careful look may reveal that often it is not. It is a manifestation of scenario looping breakdowns.

Scenario looping is the brain’s ability to loop through scenarios, exchanging possible actions or responses, until the best course has been determined. This happens with use of language and with motor actions. In every case, the scenario has a starting point. If there is no external cue from the environment to get started, we call that spontaneous initiation; an example is engaging in speech with your partner. You wouldn’t always want to wait until your partner speaks first or provides an external cue. In a normal relationship, each person will often initiate speech spontaneously without external cueing. Patients who have damage to areas of the brain responsible for scenario looping will frequently have problems with spontaneous speech. Does this mean that they are apathetic?

Spontaneously starting a new motor sequence may be difficult for some PD patients. Another example: My partner wants me to put up a new curtain rod. This involves a series of motor tasks: getting the tools and step stool, removing the old curtain rod, and using small screws. These actions involve the use of fine motor skills which are always difficult for those with PD. The curtain rod has been leaning against the wall for a week. Is it apathy that prevents me from engaging in the task? Is it fear? It doesn’t feel that way. It feels like a physical resistance to move my body in the direction of that given sequence of motor actions. PD patients often have motor action hesitancy, and this may be misinterpreted as apathy. In a chapter of “Parkinson’s Disease: Diagnosis and Clinical Management,” Lisa M. Shulman and Mackenzie Carpenter say that great care needs to be taken when ascribing the symptom of apathy to a PD patient, and that more research is necessary.

I need to be taking that careful look, to be clear in my mind that this is motor hesitancy. Doing so will ensure that scenario looping breakdown does not become apathy in my mind, or in the minds of those who care for me. There is a risk of mentally interpreting the motor resistance as “he doesn’t care.” The distinction is very important, and I spend time in mental contemplation making the distinction clear. Muscle hesitancy and difficulty with initiating motor sequences is not apathy. Understanding the difference between apathy and scenario looping breakdown is an opportunity to reframe and enlighten. Taking the time to contemplate on the difference is time well spent.

Write a comment and tell me if you see a difference between apathy and muscle initiation in your own life. Do you have suggestions on how to use this distinction to improve your quality of life?

***

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.

The post Taking a Careful Look at Apathy: It Could Be Motor Hesitation appeared first on Parkinson’s News Today.

Chinese Herbal Medicine Can Ease Brain Inflammation and Protect Neurons, Mice Study Reports

Chinese medicine and Parkinson's disease

A concoction made from several Chinese herbal medicines helped reduce brain inflammation and promoted nerve cell survival in a mouse model of Parkinson’s disease, a study finds.

The study, “Curative Anti-Inflammatory Properties of Chinese Optimized Yinxieling Formula in Models of Parkinson’s Disease,” was published in Evidence-Based Complementary and Alternative Medicine.

Parkinson’s disease is characterized by the gradual loss of dopaminergic neurons in the substantia nigra — a region of the brain responsible for movement control — together with brain inflammation caused by the over-activation of glial cells, which are cells that support and protect neuronal cells, and are more reactive and proliferative than neurons.

“In PD [Parkinson’s disease], neuroinflammation (…) mediated primarily by microglial activation can directly cause DAN [dopaminergic neurons] damage,” the researchers stated. Therefore, finding a way to reduce brain inflammation and prevent glial over-activation “could be an effective method for treating PD.”

The Optimized Yinxieling Formula (OYF), a Chinese concoction of eight different plants, has been used orally to treat patients with moderate and severe psoriasis, an autoimmune disease that affects the skin, characterized by itchy or sore thick patches with silvery scales. The effectiveness of OYF comes from its anti-inflammatory properties, scientists say.

A team of Chinese researchers investigated OYF to treat brain inflammation in a mouse model of Parkinson’s disease. The team found that the herbal medicine successfully blocked the production of pro-inflammatory cytokines (molecules that mediate immune responses) and reduced overall inflammation in mouse glial cells that were activated and cultured in a laboratory dish (in vitro).

As expected, animals treated with MPTP (a neurotoxin that induces Parkinson’s symptoms) showed glial over-activation and poor performance on different behavioral tests. However, when these animals were injected with OYF, glial over-activation was blocked and motor impairments greatly reduced.

To pinpoint the molecular mechanisms responsible for the positive effects of OYF, researchers compared the transcriptome of animals treated with OYF to those receiving a saline solution (control group). The transcriptome is the group of all RNA molecules produced from active genes in a cell or tissue.

Transcriptomic analysis identified 16 signaling pathways responsible for immune system regulation that were highly active in mice treated with OYF. In addition, OYF use lowered the activity of 15 other signaling cascades involved in inflammatory response, “suggesting that the physiological effects of OYF involve key roles of immune and inflammation regulations.”

“[O]ur data showed that OYF can inhibit microglial activation and suppress secretion of proinflammatory cytokines, which collectively protects DAN [dopaminergic neurons] from immune-mediate death,” the researchers said.

“This study suggests that OYF can be used as an effective anti-inflammatory treatment in PD mouse model, providing a novel perspective for the treatment and prevention of PD patients, although more studies of clinical trials in PD might be necessary,” they concluded.

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Key Parkinson’s Brain Area Implicated in Memory Loss, Study Suggests

substantia nigra, memory

Neurodegeneration in the substantia nigra, a critical area of the brain involved in Parkinson’s, leads to memory deficits, according to a study that explored the effects of levodopa on a rat model of the disease.

Findings of the study, titled “Implication of nigral dopaminergic lesion and repeated L-dopa exposure in neuropsychiatric symptoms of Parkinson’s disease,” also illustrated the key role dopamine plays in memory. It was published in the journal Behavioral Brain Research.

Similar to motor symptoms, loss of dopamine-producing neurons in the substantia nigra — a brain area implicated in motor function — has been proposed as the cause of neuropsychiatric manifestations in Parkinson’s disease. This has been shown in animal models, in which bilateral lesion of the substantia nigra (which selectively affects this region only) resulted in anxiety- and depression-like behaviors, as well as motivational, memory and social interaction deficits.  A study in rats also reported psychosis-like behavior in animals subjected to bilateral lesion.

Prior research has shown that chronic dopamine replacement therapy (DRT) — which compensates for the lack of dopamine and represents the standard treatment for different Parkinson’s motor symptoms — leads to impaired ability of neurons to fine-tune their responses in animals and is associated with Parkinson’s-related neuropsychiatric disorders in patients.

After lesion of the nigrostriatal pathway — including the substantia nigra and the dorsal striatum — DRT led to compulsive behavior in animals, which was associated with cellular alterations in brain regions involved in cognitive/affective information processing. Progressive degeneration of the brain’s nigrostriatal pathway — one of the four major dopamine pathways in the brain, involved in production of movement — is a characteristic event in Parkinson’s.

While chronic administration of levodopa worsened lesion-induced anxiety and depression in rats, lesioned primates showed psychotic-like behavior only after dopaminergic treatment.

Biotrial Pharmacology researchers have now evaluated the impact of substantia nigra neurodegeneration, repeated exposure to dopaminergic medication, and the combination of both on the development of neuropsychiatric symptoms of Parkinson’s. The team hypothesized that repeated exposure to levodopa could promote brain remodeling and avoid cognitive-like and affective-like deficits.

The team used a rat model based on bilateral substantia nigra injection of a toxin called 6-hydroxydopamine, which induces selective lesions of specific dopaminergic neurons that do not provoke motor deficits.

A subgroup of animals was repeatedly administered with levodopa (20 mg/kg per day) and benserazide (5 mg/kg daily) via under-the-skin injection over 10 consecutive days (chronic exposure), starting 10 days after partial substantia nigra lesion. Benserazide is an inhibitor of an enzyme called DOPA decarboxylase, which converts levodopa into dopamine.

Behavioral tests were started three weeks after the lesions. These included assessments of spontaneous locomotor activity; forelimb voluntary movement with the stepping test; anxiety-like behavior with the elevated plus maze, in which increased time spent on an open arm correlates with greater anxiety; social interaction, as indicated by the amount of time spent in active non-aggressive social behavior with another rat; memory through novel object recognition; and amphetamine-induced hyperlocomotion (AIH), used to assess responses to psychostimulants.

All animals (both with and without chronic levodopa exposure) received single acute injections of levodopa (12.5 mg/kg)/benserazide (15 mg/kg) before the elevated plus maze and novel object recognition tests.

Results revealed that, in contrast to preserved motor function, lesioned rats showed a significant memory deficit as well as anxiety-like behavior. Social interaction and AIH were unchanged. These animals also demonstrated a 48% decrease in the number of dopaminergic cells within the substantia nigra, whose extent did not correlate with the memory and anxiety results.

Researchers found that a single injection of levodopa/benserazide reversed the memory deficit, but not the anxiety-like behavior. According to the scientists, this suggests that dopaminergic pathways “were less directly involved in lesion-induced anxiety-like behavior.”

Chronic administration of levodopa did not change the results seen in lesioned rats (not chronically exposed), which was contrary to the team’s hypothesis. The investigators attributed this finding to having induced a partial lesion. Studies in more severely injured animals and with longer administrations of levodopa would be of interest, they believe.

The results in the memory test indicate “a not previously clearly identified critical role in cognition for the [substantia nigra],” and illustrate “the critical role of [dopamine] in this behavioural outcome,” the researchers wrote.

According to the team, the findings are in accordance “with clinical data suggesting that a panel of non-motor impairment including cognitive deficit and anxiety may be used as prodromal (early) markers of early stages of [Parkinson’s].”

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Defective Activity of GCase Enzyme Linked with Neurodegeneration in Parkinson’s, Mouse Study Finds

GCase study

Impaired activity of the enzyme glucocerebrosidase (GCase), which is responsible for breaking down and recycling cell waste, boosts neurodegeneration and accumulation of alpha-synuclein in Parkinson’s, according to a new mouse study.

The research, “Development and biochemical characterization of a mouse model of Parkinson’s disease bearing defective glucocerebrosidase activity,” was published in the journal Neurobiology of Disease.

Mutations in both copies (homozygous) of the GBA1 gene are responsible for the development of Gaucher disease, a disorder characterized by impaired activity of GCase — an enzyme responsible for the breakdown of a lipid, called glucosylceramide, inside cells.

If occurring in only one gene copy (heterozygous), mutations in GBA1 do not cause Gaucher, but are considered the most relevant risk factor for Parkinson’s after reaching advanced age. Nearly 10 percent of patients with sporadic Parkinson’s disease have heterozygous GBA1 mutations, showing more severe cognitive decline and a slightly younger age of onset compared to those without such mutations.

A link between the hallmark Parkinson’s protein alpha-synuclein and GCase has been suggested by the observation of a mutant form of this enzyme in Lewy bodies (protein clumps mainly formed by aggregates of alpha-synuclein). Also, prior studies have shown that inhibiting GCase activity boosts alpha-synuclein accumulation and activation of cells called microglia, a sign of neuroinflammation seen in patients with Parkinson’s disease.

Researchers at the IRCCS Mondino Foundation, in Italy, aimed to better understand the association between GCase deficiency and Parkinson’s. Specifically, they explored whether a partial defect in GCase comparable to that caused by heterozygous mutations in GBA1 (with approximately 50 percent of residual GCase activity) may increase the effects of MPTP, a widely used neurotoxin to cause Parkinson’s in animal models.

The team developed a model with partial deficiency of GCase activity caused by chronic (28 days) administration of low doses of CBE — a GCase inhibitor — in mice injected with MPTP for five days.

They then determined brain GCase activity, degeneration of dopamine-producing neurons in the nigrostriatal pathway, alpha-synuclein levels, and neuroinflammation. Of note, progressive degeneration of the brain’s nigrostriatal pathway — one of the four major dopamine pathways in the brain, involved in production of movement — is a characteristic event in Parkinson’s.

The results showed that a CBE dose of 50 mg/kg of body weight caused GCase activity reduction in the cerebral cortex similar to that seen in Parkinson’s patients with heterozygous GCase mutations.

The team then found that, although not statistically significant, pre-treatment with this CBE dose boosted MPTP-induced neurodegeneration in the striatum. This was assessed by the amount and signal of tyrosine hydroxylase — the enzyme that mediates the production of the dopamine precursor L-DOPA — as well as by the number of neurons containing this enzyme.

“Our results confirm the concept that GCase dysfunction renders nigrostriatal neurons more susceptible to neurodegeneration,” researchers wrote.

Also, using both CBE and MPTP was able to cause a significant increase in the number of dopamine-producing neurons expressing alpha-synuclein in the substantia nigra, leading to the initiation of the process of alpha-synuclein primary aggregation. Of note, the substantia nigra is a brain region that contains dopaminegic neurons, which are lost as a consequence of Parkinson’s disease.

In turn, microglia was markedly activated by either CBE or MPTP within the substantia nigra. Co-administration of these two compounds did not promote further activation, which the investigators attributed to all microglia cells already being activated by each compound separately.

“Overall, we believe this model may be used as an additional tool to study the biochemical processes underlying pathophysiology [changes of normal physiological functions associated with disease] characterizing [Parkinson’s] in the presence of GCase defects,” researchers wrote.

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