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Shifted microbial composition across the prodromal and early stages of α-synucleinopathy. a Principal coordinates analysis (PCoA) of microbial communities across control (n = 108), RBD-FDR (n = 127), RBD (n = 170), and early PD (n = 36) based on Bray–Curtis distance matrix at the genus level. The label of each group indicates group centroid. Boxplots along the axes of PCoA showed the distributions of PCoA1 and PCoA2 between groups. The white line in the box represented median values, while the lower and upper boundaries represented the first and third quartiles, respectively; whiskers extend up to values within 1.5 times of the interquartile range; outliers are plotted as individual points beyond the whiskers. Statistical differences were analyzed using ANOVA (two-sided test) with post hoc test. P values for multiple testing were adjusted by applying Benjamini–Hochberg method. b Principal coordinates analysis of microbial communities between groups with 70% confidence ellipse. The significance of inter-group differences in overall microbial composition was calculated by PERMANOVA with adjustment of age and sex (permutation = 99,999, two-sided test, based on Bray–Curtis distance matrix at the genus level). R² indicated the inter-individual variation explained by grouping factors in PERMANOVA test, and P values for pairwise comparisons were adjusted by applying Benjamini–Hochberg method. RBD REM sleep behavior disorder, RBD-FDR first-degree relatives of patients with RBD, PD Parkinson’s disease, PERMANOVA permutational multivariate analysis of variance, ns not significant. Credit: Nature Communications (2023). DOI: 10.1038/s41467-023-38248-4

Scientists at The Chinese University of Hong Kong have found that the gut microbiome holds Parkinson’s disease markers and may indicate a method of early diagnosis.

In the study, “Gut microbiome dysbiosis across early Parkinson’s disease, REM sleep behavior disorder and their first-degree relatives” published in Nature Communications, the research team looked for correlations in the gut microbiota between comorbid pathologies to see if they could find a causal link.

REM sleep behavior disorder (RBD) causes people to physically act out their dreams while sleeping. RBD affects around 40% of patients with Parkinson’s disease (PD), which is also a condition of unintended movements. Patients with RBD are even more likely to acquire PD at some point. The partial overlap in conditions raises interesting questions, and researchers looked to the gut for answers.

In recent years growing knowledge around the gut-brain connection and the relationship between neurological pathologies and microbiota populations has inspired researchers to focus more attention on the role the gut plays in overall human health. While causal relationships are not always clear, correlations between pathologies and microbiota profiles can be strikingly similar across patients with shared diagnoses.

Parkinson’s is characterized by the abnormal aggregation of a presynaptic neuronal protein in the central nervous system (spine and brain), alpha-synuclein (α-syn). While this had been considered causal to the pathology, the authors cite studies offering increasing evidence that α-syn pathology has already occurred in the enteric nervous system (neurons embedded into the walls of the gastrointestinal system).

Following the related symptom progression backward, RBD is considered the most specific precursor signal of Parkinson’s. Patients with RBD report having an increased prevalence of constipation and increased phosphorylated α-syn immunostaining in their enteric nervous system. Parkinson’s patients with RBD features also exhibit these increased constipation and enteric α-syn histopathology effects compared to those without RBD, suggesting a distinct subtype of Parkinson’s disease that reflects a gut-brain link of α-synucleinopathy.

Isolated RBD symptoms not yet meeting the diagnostic criteria for RBD might reflect a precursor stage of RBD. A recent study reported that the first-degree relatives of RBD patients had increased constipation, and a spectrum of RBD features from isolated RBD symptoms diagnosed RBD. The clustering suggests to researchers that RBD relatives might be a group of susceptible individuals at a much earlier stage of α-synucleinopathy of RBD and ultimately at risk of Parkinson’s.

The researchers performed a cross-sectional microbiome study across prediagnoses and early stages of the diseases along with controls and RBD relative to disentangle the associations of gut microbiota with the progression of α-synucleinopathy.

The study found gut microbiota compositions significantly altered in early PD and RBD compared with controls and the relative cohort. In RBD patients, the overall microbiota composition shifted closer to those with early Parkinson’s.

Random forest modeling identified 12 microbial markers, including depletion of butyrate-producing bacteria and an overabundance of Collinsella, Desulfovibrio, and Oscillospiraceae UCG-005. The profile produced a signal distinct enough to distinguish RBD from controls reliably with machine learning assistance. These findings suggest that Parkinson’s-like microbiota profile changes occur at the early stages of RBD-related Parkinson’s when RBD first develops.

Another interesting find was the depletion of butyrate-producing bacteria and enrichment of pro-inflammatory Collinsella in RBD relatives, a group that had not yet shared any of the other tell-tale signatures in the microbiota, hinting at a pre-precursor signal that needs further investigation.

The study finds markers for pathology pre-symptom progression of Parkinson’s disease and REM sleep behavior disorder, highlighting the potential role of gut microbiota in the pathogenesis of α-synucleinopathy. The observations open the door for future research to go beyond the correlations and seek the early causative path of both diseases in hopes of discovering what could be a pre-clinical diagnostic intervention to prevent Parkinson’s from developing in the first place.

Researchers have long explored how music affects the mind. For example, can listening to music boost academic performance, alleviate depression or help kids become better learners? Several studies have shown that music can influence our ability to think, learn and remember – and even connect with the people around us.

One fascinating area of research is how people with Alzheimer’s disease and other types of dementia can benefit from music. This question is especially compelling in the face of sombre statistics: the Alzheimer Society of Canada reports that 564,000 Canadians live with dementia; 15 years from now, that number is expected to surpass 930,000.

Alzheimer’s disease and other types of dementia can cause memory problems that affect day-to-day activities, difficulties with language, changes in mood and behaviour, disorientation in time and place, and other effects. As dementia progresses, cognitive and functional abilities continue to decline, and eventually the person loses the ability to communicate verbally. There is not yet a cure for Alzheimer’s disease or several other kinds of dementia, but you can take steps to reduce your risk.

Music and the brain

The effects of dementia are devastating to individuals and their families. Researchers are keen to find ways to ease its symptoms and restore abilities and memory. A few studies on music and dementia have shown promising findings, including:

• The area of the brain associated with musical memory tends to be least affected by dementia. People can often recall music from their teens and 20s.
• Music appreciation is one of the last cognitive skills to be affected by dementia.
• Music therapy may help reduce cognitive decline and enhance quality of life.
• Music may improve the memory of people with dementia. In one study, test subjects performed better on memory tests when they listened to classical music.
• The emotional content of music can bring back emotional memories.
• Music can reduce anxiety, depression, stress and agitation.
• Singing can increase brain activity. One study found that participating in small group music sessions improved the cognitive abilities of people with moderate to severe dementia.
• Personalized music and memory therapy may improve symptoms and reduce the usage of anti-anxiety and anti-psychotic medications in people living with dementia.
• Researchers are studying whether music could help people with dementia learn new things and form memories.

The power of a playlist

In 2014, the documentary Alive Inside drew worldwide attention to Music & Memory, a non-profit organization that brings music to people with cognitive and physical challenges in hundreds of nursing homes and other care facilities in Canada and other countries. In the poignant film, people with dementia become animated and lucid when given iPods loaded with personalized music from their younger days. (Watch the video of one resident, Henry, that went viral before the film’s release.)

Alive Inside explores music’s potential to revitalize people with dementia by evoking emotions and memories. The film also shows how music can help people reconnect and socialize with others. In care facilities that have adopted the Music & Memory program, participants are happier and more social; relationships among participants, families and staff members deepen; and there are fewer behavioural issues.

Starting the music

• If you have a loved one with dementia, here are some ideas for connecting with them through music:
• People with dementia may become agitated, aggressive or anxious. Soothing music can help calm or lighten their mood.
• When creating playlists, look for songs with special meaning for your loved one, such as favourite tunes from their teenage years. If you need ideas, ask family members for input (they may also appreciate the opportunity to help).
• Start with something gentle and play it softly. To avoid overstimulation, turn off the TV and other sources of noise.
• Enjoy music with your loved one by listening to songs together, singing, playing instruments or dancing.
• Music can evoke negative emotions and memories as well as positive, happy ones. When playing music for someone with dementia, watch how they react. If they appear to be enjoying it – singing, humming, tapping their feet – that’s a good sign. But if they become uncomfortable or upset, take a break and try again another time, with different songs.

There are plenty of reasons your skin may become inflamed, dry, red, or flaky. It can be the result of cold weather, an allergic reaction, or even stress. But if your irritated skin persists, you may have a condition called plaque psoriasis, which is marked by scaly, swollen patches of skin. Like eczema, rosacea, or keratosis pilaris, psoriasis is generally a life-long, chronic skin condition, so it’s imperative that you know how to treat the symptoms. To learn more about the common skin disease, we tapped Dr. Alexis Parcells, a New Jersey-based, board-certified plastic surgeon and owner of Parcells Plastic Surgery.

What is psoriasis?

Psoriasis is an autoimmune disease that causes your skin to be in a constant or near-constant inflammatory state. Instead of your immune system only attacking outside aggressors, like bacteria or viruses, your T cells attack healthy skin cells, causing the skin to become inflamed. From there, your skin cells mature faster and turn over at a quicker rate than normal, explains Parcells. For perspective, your skin cells normally turn over every month, but the skin cells on someone with psoriasis can turn over every three to four days. Because the skin can’t shed fast enough to keep up, “the skin ends up piling up on itself and it starts to become thicker and causes itching, burning, and stinging sensations,” Parcells says. Both males and females of any race can have psoriasis, and the onset of symptoms most commonly begins between ages 15 and 25.

What causes psoriasis?

You will only experience psoriasis if you have the autoimmune disease. This differs from, say, eczema, which you can experience if you have a lack of protein in the skin or from environmental triggers only, like cold weather. However, there are triggers that cause psoriasis to flare up, such as stress, infections (such as an upper respiratory infection), or injuries to the skin, like a sunburn, bug bite, or scratch.

Psoriasis is not contagious and thought to be hereditary, as about a third of people with psoriasis also have a relative with the disease, according to the National Psoriasis Foundation.

How can you identify psoriasis on your skin?

To diagnose psoriasis, you’ll want to see a dermatologist, who will evaluate and possibly biopsy the skin to confirm the condition. But while it’s always wise to see a doctor when there are changes to your skin, you may not run to your dermatologist every time you experience flaky or red skin. To help you determine whether your skin irritation could be psoriasis, and therefore should be treated by a doctor, you can look for certain characteristics and take inventory of your routine.

Psoriasis most commonly appears as plaque, or raised red patches with white or silver-looking scales, around the knees, elbows, and scalp. The patches of irritated skin may burn or feel tender or thick to the touch. You’ll also want to take note of any pain, stiffness, or swelling in the joints, as about one in three people with plaque psoriasis also develop psoriatic arthritis, according to the National Psoriasis Foundation.

Skin irritation, psoriasis included, can come as a result of a change in routine, such exposing the skin to new products (think: skincare lotions and potions, laundry detergent, or clothing). If this happens, first try getting back to the basics and only using gentle, fragrance-free products on the skin. If it gets better, you may have only experienced a mild skin irritation. If it gets worse or doesn’t go away, it could be a sign of a psoriasis flare and you’ll want to see a doctor for treatment.

To help your dermatologist, take photos of the skin while it’s irritated and consider keeping a log of possible triggers and any patterns you notice among the flare-ups (including things like whether they happen during the busiest times at work when you’re most stressed).

How do you treat plaque psoriasis?

The first step to treating psoriasis is consulting your doctor. “There are creams and lotions, depending on how severe the case is, so that’s why it’s important that, if it is psoriasis, you have a physician who is prescribing treatment for you,” Parcells says.

For a mild case, you may be able to treat it at home with colloidal oatmeal or unscented epsom salt baths, which will relieve itchy skin and soothe joint pain for psoriatic arthritis, respectively. For the former, try the Aveeno Soothing Bath Treatment, which claims to cleanse, moisturize, and relieve sensitive, itchy skin. For the latter, choose a soak that’s unscented, like the Solimo Epsom Salt Soak, to avoid further skin irritation while you soothe your joints. After a bath, Parcells recommends applying a thick cream while the pores are still dilated from the warm water. For this, go with the Cerave Moisturizing Cream that contains hyaluronic acid to hydrate the skin and ceramides to protect the skin barrier. For a more emollient ointment that seals in moisture and adds a protective layer over the skin, try the Eucerin Original Healing Cream.

For more moderate cases, your doctor may recommend you use a prescription topical steroid cream to control the irritation. And if you experience a heightened flare-up, Parcells says they may recommend applying the cream at night and covering it with a layer of plastic wrap to “keep the environment moist and allow the medication to penetrate properly.”

Severe cases may be treated with an oral “biologic” medication that suppresses the immune system to reduce the effects of the skin disease. Parcells says that patients won’t be on biologics for long periods of time, as the idea is to calm a severe flare-up and then, with a physician monitoring, taper the medication down to see how your body adjusts and responds.

Regardless of how severe your psoriasis is or the treatment you’re seeking, you should keep your skincare routine simple, with gentle, non-irritating formulas that are free of fragrance and acids. If you’re tempted to physically or chemically exfoliate away the thick or flaky skin, don’t, as this may only speed up the cell turnover process and worsen the problem.

How do you treat scalp psoriasis?

Given that the skin on your scalp is different from that on your body, you’ll want to take a different approach to treating psoriasis in this area. Your doctor may want to prescribe you a wash or ointment for the scalp or they may direct you toward an over-the-counter option, like the MG217 Psoriasis Medicated Conditioning 3% Coal Tar Shampoo, which claims to treat psoriasis and dandruff by softening and removing scales and slowing the turnover of skin cells with salicylic acid and coal tar, respectively.

Can you cure psoriasis?

There is no cure for psoriasis, but it is manageable with counsel from a doctor and treatment. Not treating the condition may only cause it to grow more uncomfortable. “You should be empowered to seek treatment and there are affordable ways to improve your symptoms,” Parcells says. “We’re all human, we’ve all got skin conditions, and don’t feel ashamed by it.”

Effective therapies for neurodegenerative diseases like Alzheimer’s are urgently needed. But developing new drugs is difficult, time-consuming, and expensive, with a high risk of failure. Strategic partnerships can help biotech companies manage costs and access the latest technologies to drive innovation and advance novel therapy ideas.

A serious unmet medical need

Finding treatments for neurodegenerative disorders such as Alzheimer’s disease is one of today’s largest unmet medical needs. Around 50 million people worldwide have some form of dementia, and numbers are expected to almost double every 20 years. 

“Brain disease poses the third-largest health burden globally and deserves a suitable research focus,” said Fraser Murray, CEO of Pandeia Therapeutics, a biotech developing drugs for Huntington’s disease.

Developing effective therapies is difficult, as neurodegenerative disease profiles are heterogeneous, and despite following many leads over the last decades, researchers don’t fully understand the underlying pathophysiologies. Clinical trials testing drugs against Alzheimer’s and other neurodegenerative diseases are lengthy and complex and often lack robust biomarkers. 

One theory for Alzheimer’s: limited success

Most scientists agree that two proteins in the brain – beta-amyloid and tau – are involved in Alzheimer’s disease. The amyloid hypothesis proposes that abnormal levels of beta-amyloid protein form plaques between neurons in the brain, disrupting cell function. Then, tau accumulates and forms neurofibrillary tangles inside the neurons, blocking their transport system. 

Why these proteins accumulate, how they relate to each other, and what other factors are involved remains not fully understood. Most efforts to develop therapies have focused on this hypothesis and failed. Many experts question the amyloid hypothesis because plaques and tangles have also been found in people with no dementia symptoms. 

Therefore, some researchers believe we need to investigate causative mechanisms more widely to develop alternative ways to treat Alzheimer’s disease.

For example, Alzheimer’s is known to cause low-level inflammation in the brain, so treating inflammatory processes could be an option. Changes in the brain’s insulin levels, heart and blood vessel health, and hormones may also play a role in Alzheimer’s disease, and researchers are exploring these avenues for Alzheimer’s drug development too. 

Looking for new targets and genetic links

With the help of new technologies, researchers are shifting their search for new genetic links and therapeutic targets beyond beta-amyloid. As of May 2021, there were 152 clinical trials assessing 126 new agents for the treatment of Alzheimer’s disease worldwide. 

Small molecules and biologics, such as monoclonal antibodies, oligonucleotides, and cell therapies are all under investigation. Mechanisms vary and include preventing the build-up of disease-causing proteins, suppressing specific transcription factors, expressing therapeutic proteins, and using stem cells to replace damaged brain cells. 

Astrocytes are one example of a new approach. “Astrocytes have been overlooked in drug discovery and are potentially an untapped source of new targets. Astrocytic processes are fundamental to central nervous system homeostasis, and their dysfunction is both a consequence and cause of neurodegeneration,” explained Jamie Bilsland, CSO of AstronauTx, a UK biotech that is taking this alternative approach to fighting Alzheimer’s disease.

Current treatments only fight the symptoms of Alzheimer’s disease and may only have a temporary beneficial effect. Novel treatment strategies are aimed at disease modification, to delay, or prevent the onset of Alzheimer’s disease, but these require biomarkers to identify which people will develop Alzheimer’s and might benefit from therapies. 

One promising biomarker and therapeutic target is the aggregatin protein, which attaches to amyloid-beta. Various RNA regulators could also be biomarkers or therapeutic targets. Genomic and transcriptomic studies comparing Alzheimer’s disease and healthy states will advance this area and further the understanding of the disease pathology. 

The genetic links to Alzheimer’s disease are mostly undefined and are likely multi-factorial. Some risk genes are known, but how and when they cause disease is still not understood. Nevertheless, research continues to correlate genetic data with Alzheimer’s disease patient samples and brain scans. 

Because multiple factors seem to be involved in the pathophysiology of Alzheimer’s disease, a one-target one-molecule approach for its treatment has been ineffective so far. Researchers are therefore investigating multipotent molecules that address more than one target at the same time, so-called multi-target directed ligands (MTDLs). 

MTDLs come with several advantages, including increased efficiency, reduction of drug-drug interactions, and a simplified drug regimen for Alzheimer’s patients. A key issue of MTDLs researchers are still working on is how to optimize the efficacy of one drug on two or more different targets.

However, despite the large variety of therapeutic approaches in the global pipeline, the failure rate for drugs targeting Alzheimer’s disease remains high. There is a desperate need for new hypotheses and strategies, as well as tools to test these hypotheses, in pre-clinical discovery, translational studies, and clinical trials.

Sophisticated end-to-end solutions to advance Alzheimer’s research

How can small or emerging biotech companies advance their innovative hypotheses? For example, through strategic partnerships with global solutions providers, such as WuXi AppTec, biotechs can gain access to the latest technologies and expertise. 

WuXi AppTec provides an extensive collection of high-quality R&D and manufacturing services. 

“We have built an open, enabling platform to support any organization involved in drug discovery, across all modalities, from target identification and validation all the way to commercial manufacturing,” explained Dave Madge, Vice President at WuXi AppTec. 

“The expertise we have developed and the facilities we have built give our collaborators access to the tools they need when they need them. This provides rapid, timely, and economical access to technologies and accelerates our collaborators’ discovery programs.” 

The company’s in vitro hit-finding platform accelerates drug discovery by leveraging a broad suite of technologies to deliver novel, tractable, chemical matter. Diverse platforms, such as affinity selection mass-spectroscopy, DNA-encoded library screening, fragment screening, and biochemical screening, ensure that a suitable assay technology is available for all target types. 

These assays are enabled by extensive protein production and cell-line development capabilities and further supported by orthogonal assay techniques, such as biophysics and visualization of ligand-protein interactions by x-ray crystallography. Sophisticated computational chemistry, virtual screening, and machine learning platforms inform and accelerate discovery programs.

WuXi AppTec provides a fully integrated solution for medicinal chemistry, in vitro and in vivo biology, and drug metabolism pharmacokinetics studies to rapidly transform screening hits into clinical candidates.

The platform also includes induced pluripotent stem cell-derived cell lines, disease models, and patient-derived cell lines, as well as a variety of sophisticated animal models for Alzheimer’s, Parkinson’s disease, encephalomyelitis, and amyotrophic lateral sclerosis. 

“As our understanding of genomics and biological pathways expands, human diseases, once thought untreatable, are well within our realm of intervention,” said Kris Rutten, Director at WuXi AppTec. 

“Large molecule drugs like peptides, oligonucleotides, bispecific antibodies, and proteolysis targeting chimera’s – PROTACs – are emerging new modalities that are generating a big buzz in the world of drug development. Our integrated platform fully supports these new modalities from early hit finding campaigns through lead generation and candidate selection.”

Alzheimer’s disease drug development has faced limited success so far, but as researchers combine new technologies and strategic partnerships, the expectation is that they can accelerate innovation and improve outcomes in the future.