When it comes to multiple sclerosis (MS), you probably know that the immune system plays a role in attacking the nervous system. But what if your blood vessels also played an important role? In this interview, we dive into the fascinating link between vascular dysfunction and MS with insights from Dr. Jonathan Pansieri. From how the blood-brain barrier is disrupted, to how impaired blood flow can worsen inflammation, we explore how vascular issues could be affecting your journey with MS. Understanding this link could open new doors on treatment strategies and offer fresh hope to patients living with this complex disease.
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Table of Contents
Introduction – Who is Dr. Jonathan Pansieri?
I am Dr Jonathan Pansieri, neuroscientist in the Medical Science Division of the University of Oxford, and a fellow from the UK-MS society. I am 36 years-old, living with my partner who is also a scientist in the Department of Surgery focusing on prostate cancer. I am a dog person, so I would love to have 2 big dogs in the near future, but I will need to adapt my schedule for that! If there is something else to say about me, as a French citizen, I miss so much the lovely French pastries that I’m trying to make my own croissant and pain au chocolat, but despite 5 years of training now, I definitely need to improve my skills, it is such a disaster so far…
Personal motivation for your career choice?
Since 2014, my research journey was revolved around unraveling the complexities of neurodegenerative diseases like Alzheimer’s and Parkinson’s. I’ve been deeply involved in developing diagnostic and treatment strategies, from designing nanoparticles for imaging to understanding the dynamics of toxic faulty proteins called amyloids. In late 2019, I realised that inflammation more than neurodegeneration is a pivotal phenomenon in all brain diseases and may be the key to develop efficient therapies, early in the disease course.
Therefore, this prompted a shift of knowledge development in the MS field, where inflammation plays a predominant role. Now, a significant portion of my research is dedicated to investigating vascular impairment in MS and identifying therapeutic targets that could not only halt the disease but also potentially prevent it. In my lab, we have made substantial strides in understanding MS, and I’m hopeful that our findings will pave the way for better outcomes for those living with MS in the coming years. This mission fuels my passion and drives my path forward.
Vascular dysfunction Impact on MS
How much do we currently understand about the vascular dysfunction that influence the severity and outcome of multiple sclerosis?
Our understanding of how vascular problems influence the severity and progression of MS has come a long way, though there’s still much to learn. The most obvious sign of vascular impairment in MS is the breakdown of the so-called blood-brain barrier (BBB), a protective and hermetic shield that normally keeps toxic substances and immune cells out of the brain. BBB gets leaky in MS, allowing inflammatory cells to flood the brain and spinal cord, sparking inflammation that damages neurons and activating inflammatory pathways in a vicious circle, from early to end stages of MS.
Nowadays, if two theories are hypothesised, called “inside-out” with signals coming from the brain to the blood vessels and recruiting immune cells, and “outside-in” coming from the vascular system to the brain, there is no doubt that vascular dysfunction in MS is not just a side effect but a key player in driving the disease’s progression. By disrupting blood flow, allowing immune cells into the brain, and fueling inflammation, these vascular issues directly affect how severe MS becomes and how it progresses over time.
How challenging is it to establish a clear connection between vascular dysfunction and the way MS presents in an individual?
Establishing a clear connection between vascular issues and how MS manifests in an individual is extremely challenging, mainly because MS is so varied in its presentation and progression.
First, the disease’s heterogeneity is a huge hurdle. MS can range from mild symptoms to severe motor dysfunction, with some cases progressing rapidly while others move more slowly. This variability makes it tough to determine how much vascular dysfunction contributes to each individual case.
Second, the genetic background plays a key role. With over 200 genetic risk factors identified, it’s clear that some patients are more genetically prone to immune and vascular dysfunction than others. Add in environmental factors like EBV infection or smoking, and the picture gets even more complicated. The way these genetics and environmental factors interact with vascular health is still not fully understood.
Third, the vascular pathology in MS isn’t consistent. Some lesions show clear signs of vascular dysfunction, while others are sparser, and depends on the inflammatory state of the lesion itself. This patchiness makes it difficult to draw direct links between vascular damage and specific symptoms.
Lastly, our current diagnostic tools, while advanced, still have limitations. Imaging can reveal BBB disruption, but these findings don’t always correlate with how severe the disease is in individual patients. For example, someone with BBB leakage might have mild symptoms, while others with severe symptoms show little evidence of vascular issues on scans.
Despite these challenges, the field is moving towards a breakthrough, especially combining the cutting-edge technologies (such as genetics, proteomics but also clinical imaging and AI) these last five years, with more longitudinal studies. It’s just a matter of time, I believe, before we crack the code.
Are there specific markers of vascular dysfunction that have been consistently linked to more severe forms of MS?
I would say that rather than universal markers today, there are indeed several promising markers of vascular dysfunction that warrant further investigation, particularly in relation to severe forms of multiple sclerosis (MS). One standout candidate is fibrinogen, a clotting factor that has emerged as a key player in the pathology of progressive MS. Fibrinogen not only deposits around and outside MS lesions but also promotes inflammation by activating immune cells. This creates a vicious cycle of inflammation and neurodegeneration that can persist for decades, contributing significantly to disease severity. Studies have shown that increased fibrinogen deposition correlates with heightened neuroinflammation and worse clinical outcomes in progressive MS, making it a crucial area for further research and drug design.
Moreover, our preliminary findings regarding iron accumulation in the spinal cord are particularly intriguing. We observed a gradient of abnormal iron deposition from the lumbar to the cervical spinal cord, mirroring the clinical phenotype of MS, where symptoms often escalate from the lower to the upper limbs. This discovery not only deepens our understanding of MS pathology but also opens new avenues for targeted therapies aimed at mitigating iron-related damage in the CNS.
By continuing to explore these markers, we and others can potentially develop strategies that not only elucidate the mechanisms behind MS but also pave the way for novel therapeutic interventions tailored to fight vascular dysfunction and its effects on disease progression.
The Role of Microglia in MS
What role do microglia play in the development and progression of MS, and how do they interact with genetic factors?
Microglia are specialised resident immune cells of the central nervous system, which play regulatory and inflammatory functions in the brain, acting as both protectors and potential aggressors. Basically, if their role is primarily to be the police of the brain by clearing cellular debris and initiate repair processes, they can become rogue and their over-activation lead to the aberrant release of pro-inflammatory cytokines and chemokines. This results into inflammation and tissue damage in early stages of MS. In progressive forms of MS, microglia promote chronic inflammation through cytokines production and oxidative stress as few examples, which contributes to neuronal death and other neurodegenerative mechanisms such as axonal loss.
This view is the classical consensus about microglia.
However, Recent research from us and others challenges the simplistic view of microglia as simply „good“ or „bad.“ We now understand that both pro-inflammatory and anti-inflammatory microglia can coexist, especially in the context of MS. Importantly, people with the HLA-DRB1*15 genetic risk factor exhibit microglial dysfunction that hampers their protective abilities, resulting in greater neuronal damage. To go a little bit deeper, HLA-DRB1*15 encodes for a specific type of major histocompatibility complex (MHC) class II molecule, which is involved in presenting toxic molecules to immune cells. In the context of people with MS carrying HLA-DRB1*15 allele, it is possible that dysfunction in MHCII exacerbates neuronal death by absence of protection from microglial response rather than exacerbated inflammation.
How could targeting microglia potentially lead to new therapeutic approaches for MS, based on our growing understanding of genetics?
I believe our evolving understanding of microglia opens exciting and real possibilities for new MS treatments. Therapies could aim to restore the balance between harmful and protective microglia, enhancing their beneficial effects while reducing inflammation. By improving how microglia present antigens, we can potentially strengthen their immune regulation, leading to better protection for neurons. Further, insights into genetic factors, especially regarding individual risk profiles, can inform personalised therapies. The development of new small molecules and biologics could finely tune microglial responses, promoting healing and neuroprotection. Even more and taking into account the heterogeneity of MS, we can’t exclude that some drugs with disappointing results so far, are actually efficient but in a subset of people with MS.
In other hand and linked to what previously mentioned, it is important to note that microglia are closely linked to the vascular system and the dysfunction of the BBB in MS. This relationship creates a complex interplay where microglial activation can influence vascular integrity, and vice versa. Understanding these interconnected mechanisms is crucial for developing targeted therapies, especially given the heterogeneity of MS, where addressing both microglial and vascular dysfunctions may significantly improve the quality of life for people with MS.
Additionally, I want to mention that microglia are not only relevant for treatment but also diagnosis and monitoring. The relevance of translocator protein (TSPO) imaging in this context cannot be overlooked. TSPO is a marker of neuroinflammation and microglial activation, making it a valuable tool for diagnosis, assessing disease activity and monitoring therapeutic responses. This can assist in differentiating between active and inactive lesions, providing insights into disease activity. By employing TSPO imaging, we can gain insights into the dynamics of microglial activation and their interaction with the vascular system, enabling us to tailor treatments more effectively.
Potential Applications of Genetic Research
With the increasing knowledge of the genetic basis of MS, how might this influence the development of new treatment strategies?
Well, as we delve deeper into the genetic basis of MS, we are obviously discovering exciting opportunities for new treatment strategies. However, it’s essential to have a systematic and targeted approach, and to be cautious about how we interpret this information. The growing knowledge of MS genetics—highlighting key markers like HLA-DRB1*15, or others such as dysferlin SNPs, and AQP4—promises to transform our treatment strategies. By leveraging this information wisely, we can definitely improve patient outcomes and enhance the quality of life for those living with MS.
For instance, HLA-DRB1*15 is a well-established risk factor that already allows us to tailor treatments specifically to individual patients based on their genetic profiles. Conversely, dysferlin SNPs is quite new, and may point to new therapeutic targets by revealing unique pathways involved in MS progression, but still need further investigations. In the meantime, AQP4 is particularly relevant in conditions like neuromyelitis optica, which can mimic MS symptoms, therefore needs to be taken cautiously.
Despite this criticism I make, what I see as the most influential use of these genetic data, is to help us and neurologists to identify patients who are at higher risk for more severe forms of the disease. By recognizing genetic diversity, we can refine how we classify MS subtypes, leading to targeted treatments that cater to the specific needs of different individuals.
MS, Dementia, and Alzheimer's
What commonalities exist between multiple sclerosis, dementia, and Alzheimer's disease in terms of their underlying genetic and pathological mechanisms?
MS, AD and dementia are all chronic neurodegenerative diseases that progress with age, leading to significant disability and a decline in quality of life. While they may differ in their specific symptoms and time courses, they often share common features, such as cognitive decline seen in 40 to 70% of people with MS and even more common obviously in AD and dementia.
Pathologically, these diseases reveal disturbing patterns: vascular dysfunction, abnormal microglial responses, and neuronal loss are common threads woven into the fabric of each condition. This shared landscape suggests that the brain’s inflammatory response plays a crucial role in their development and progression, even if the specific underlying mechanisms and affected brain areas may differ.
One interesting commonality is the involvement of aquaporin-4 (AQP4). In MS, AQP4 is associated with immune cell dysfunction, contributing to neuroinflammation and exacerbating disease symptoms. In Alzheimer’s, AQP4 plays a dual role, not only in promoting neuroinflammation but also in facilitating the accumulation of toxic amyloid plaques, which are harmful to neurons. This highlights a fascinating link between the two diseases, indicating that they may share similar pathways related to inflammation and cellular dysfunction.
Furthermore, genetic factors like HLA-DRB1*15 in MS and HLA-DRB1*13 in Alzheimer’s show how certain genetic variations can influence susceptibility and progression in both diseases. This connection emphasizes the potential for cross-disease insights; studying the genetic underpinnings of one condition could shed light on the other.
How do these diseases differ in their impact on the brain, particularly in the context of neurodegeneration and immune system involvement?
That is indeed an important question! As previously said, these diseases share common features but essentially, while MS is defined by its inflammatory processes and immune-mediated damage, Alzheimer’s disease is characterised by its relentless neurodegeneration and the gradual cognitive decline.
MS is often considered the quintessential inflammatory disease of the brain. Basically, the immune system mistakenly attacks the myelin sheath protecting the tubes called axons where electric and chemical signals goes back and forth between neurons, leading to inflammation and neurodegeneration. This inflammatory response results in a variety of neurological symptoms in people with MS, such as fatigue, motor and sensory deficits, and cognitive changes. As a result, MS presents with distinct inflammatory lesions in the brain and spinal cord, reflecting its nature as an immune-mediated (and not auto-immune) disorder.
In contrast, Alzheimer’s disease is recognized as the quintessential neurodegenerative disease. While inflammation does play a role in AD, the primary pathology is centered on the progressive loss of neurons and synapses, particularly in regions of the brain crucial for memory and cognitive function such as the hippocampus. This degeneration is characterized by the accumulation of amyloid-beta plaques and tau tangles, which disrupt communication between neurons and ultimately lead to cell death. The immune system’s response in AD is more of a secondary reaction to this neurodegeneration, rather than the driving force as seen in MS.
Could breakthroughs in the treatment or understanding of one of these diseases potentially offer insights or benefits for treating the others?
In fact, yes! Very recently, we made a surprising discovery using post-mortem brain tissues: amyloid-beta and tau tangles, the notorious culprits in AD, are significantly reduced in the brains of people with MS. This finding reveals that MS brains show less amyloid accumulation throughout the aging process, which may be a game-changer for AD research.
This opens up exciting new avenues to explore the role of amyloid in MS and how it affects disease severity. We need to investigate what mechanisms are at play that lead to this decreased amyloid and tau burden in MS cases, particularly its impact on cognitive decline. If we can identify a specific phenotype in MS that effectively clears these toxic plaques or uncover MS-related factors that inhibit amyloid accumulation, it could hold critical implications for developing future treatments for Alzheimer’s disease. In short, breakthroughs in understanding MS could shine a light on new strategies for tackling Alzheimer’s and vice versa!
Quickfire Q&A Session
Complete the sentence: "For me, multiple sclerosis is...."
For me, multiple sclerosis is a complex challenge that highlights the delicate balance between the immune system, neuroinflammation, and neurodegeneration. My mission is to unravel the disease’s mysteries, exploring the chicken-and-egg dynamics to ultimately help those living with this incurable condition.
What development would you like to see in the field of multiple sclerosis in the next 5 years?
I would like to see a significant shift toward personalised medicine in the field of MS. In a perfect world, this means not only to carefully developing treatments tailored to individual genetic profiles, but also to redefine what we call MS.
In my field, I hope for advancements in our understanding of the interplay between inflammation and neurodegeneration. It is of absolute priority in basic research to consider specific microglial subpopulations and targeting their roles and not their entity as “immune cells”, to enhance their protective functions while mitigating harmful inflammation. I also expect to see more innovative therapies that address vascular dysfunction in MS, recognizing its pivotal role in the disease progression.
Finally, I believe we are at the crossroads where we need to follow the right path, between the emerging technologies and the mistakes we made in the past fifty years. These mistakes, in both AD and MS, may inform us about cross-pollination of ideas which could lead to groundbreaking discoveries that improve the lives of people living with MS, moving us closer to effective therapies and, hopefully, a cure.
Farewell
Finally, what message of hope or encouragement would you like to share with the listeners?
To everyone living with MS, I want to emphasize that you are not alone in this journey, and I guarantee you the absolute commitment of doctors and researchers with all of you. The research community is actively working to understand the complexities of MS, and significant strides are being made every day. There is more than hope on the horizon—new treatments are being developed, and advances in personalised medicine is evolving when I’m writing this sentence. We are increasingly recognising the importance of inflammation and vascular health in MS, and this knowledge is guiding us toward more effective interventions.
Stay hopeful and engaged; in my practice, your experiences and voices are vital in shaping research. Together, we are making progress, and I believe that brighter days are ahead for all individuals living with MS. Keep pushing forward; we are in this fight together!
How and where can interested people follow your research activities?
As an academic, I’m always dedicated to share our progresses with both the research community and individuals living with progressive MS. In addition, we regularly host patient information days in Oxford to present the latest in clinical care, symptom management, and research advancements, so stay tune!
You can also follow my work on Twitter (@group_deluca and @JPansieri), where I share insights and updates (though I wish I could share more!). Additionally, you can connect with me on ResearchGate (https://www.researchgate.net/profile/Jonathan-Pansieri) and LinkedIn (https://www.linkedin.com/in/jonathan-pansieri-11887bb5/), where I’m always open to discussions. Thank you all for your support—let’s keep pushing forward together!
Many thanks to Jonathan for the exciting interview and also to all his colleagues working on the project. It sounds very promising.
See you soon and try to make the best out of your life,
Nele
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