Current Treatment Options for Multiple Sclerosis

Post by Meredith McCarty

The takeaway

MS is a degenerative disease that affects millions of people worldwide. Over the past several years numerous treatment options have emerged that can alleviate many MS symptoms and slow the progression of this disease significantly. 

What is Multiple Sclerosis (MS)?

MS is a neurological condition that affects the central nervous system (CNS), including the spinal cord and the brain. What makes this disease so complex is that individual outcomes can be unpredictable, with varying phases of disease progression and relapse among individuals. MS is commonly diagnosed in individuals experiencing cognitive problems, vision loss, numbness, or weakness, though the severity of symptoms vary greatly1. Most individuals with MS will experience periods of remission and relapse of symptoms, with different treatments that target the immune system offering therapeutic benefits. 

The hypothesized sources of the acute symptoms of MS are not only focal changes in brain pathology but also diffuse changes throughout the CNS. Focal changes include inflammation of the meninges (tissues that cover the surface of the brain and include arteries, veins, and lymphatic network), demyelination (destruction of the protective sheath surrounding neurons), and changes in the blood-brain barrier1,2. More widespread diffuse changes include neuron loss and overactivation of microglia (which support neurons in the brain)1,2. 

Current disease-modifying therapies

Most approved treatments for MS target the immune system. This is based on evidence that the acute symptoms of inflammation seen in MS are due to atypical immune system functioning. While various immune cells typically circulate through the bloodstream and target invasive or damaged cells for destruction, in MS, neuroinflammation within the CNS can lead to the accumulation of immune cells that instead attack otherwise healthy brain cells. Previously, this immune dysfunction has been thought to be caused by T-Cell action, however, treatments that target B-Cells have been found to have greater therapeutic benefit3. 

There are several disease-modifying therapies (DMTs) currently FDA-approved for MS treatment that have been shown to delay the progression of acute MS symptoms4. The mechanism of action of these DMTs is targeting B-cells for downregulation. Essentially, this is thought to slow the progression of damage to the CNS by directly targeting the immune system. These DMTs are administered either orally, intravenously (via an IV) directly and quickly, or into the hypodermis (the innermost layer of the skin), which leads to a slower absorption rate. Some research suggests different mechanisms of administration may alleviate some side effects due to the speed of the DMT reaching circulation, and the cost of treatment is also a consideration (whether it must be administered in a clinical setting4). These DMTs have been found to reduce the formation of new brain lesions, as well as MS relapse rates in many patients. They remain the most effective treatment method for MS.  

Progress in MS research

There is much current research into the underlying cause of MS, to uncover a cure for this disease. Interestingly, recent research has found that the Ebstein-Barr virus (EBV) is associated with an increased risk of developing MS. EBV is a B-Cell virus that may cause long-standing changes in B-Cells post-infection that could cause chronic inflammation in the CNS5. In healthy individuals, the number of EBV-infected cells is kept low via action by cytotoxic T-Cells that can identify these EBV-infected cells and eliminate them. If there is a deficit in the action of these cytotoxic T-Cells, this could lead EVC-infected cells to accumulate in the CNS. Indeed, a recent human study found clinical improvement in individuals with MS who were treated with cytotoxic T-Cells targeted against EBV-infected cells5.

Interestingly, research into the gut microbiome may offer clues into the cause of MS. Prior work has shown the gut microbiome (the bacteria and other microbes in the gut) plays an important role in immune regulation6. Some researchers theorize that an imbalance in the gut microbiome may lead to inflammation throughout the immune system, potentially playing a role in MS development and progression. Therapeutic strategies to regulate gut microbiome homeostasis may illuminate alternative treatments for MS. 

There is some debate as to whether a longer-lasting increase in chronic inflammation may be the cause of progressive MS symptoms over time, while more acute symptoms may be caused by focal infiltration of the CNS leading to acute inflammatory damage2. Future research into the complex interaction between the CNS and the immune system following cortical injury will offer novel insight into the progression of acute and chronic MS. Especially as current DMTs cannot pass the blood-brain barrier directly if it is undamaged, novel methods to allow therapeutic intervention within the CNS via direct route may offer promising treatment alternatives. There are exciting research studies and clinical trials underway that will help clarify the cause of MS. Through a greater understanding of the interaction between the immune system and the CNS, researchers will continue to fill the gaps in understanding this complex disease.

References +

Magliozzi R., Howell O. W., Calabrese M., Reynolds R. Meningeal inflammation as a driver of cortical grey matter pathology and clinical progression in multiple sclerosis. Nature Reviews Neurology. 2023. https://doi.org/10.1038/s41582-023-00838-7

Zuroff L. R.; Benjamins J. A.; Bar-Or A.; Lisak R. P. Inflammatory mechanisms underlying cortical injury in progressive multiple sclerosis. Neurosciences. 2021, 8, 111. http://dx.doi.org/10.20517/2347-8659.2020.35

Gelfand J. M., Cree B. A. C., Hauser S. L. Ocrelizumab and Other CD20+ B-Cell-Depleting Therapies in Multiple Sclerosis. Neurotherapeutics. 2017. https://doi.org/10.1007/s13311-017-0557-4

Cotchett K. R., Dittel B. N., Obeidat A. Z. Comparison of the Efficacy and Safety of Anti-CD20 B Cells Depleting Drugs in Multiple Sclerosis. Multiple Sclerosis Related Disorders. 2021. https://doi.org/10.1016/j.msard.2021.102787

Pender M. P., Csurhes P. A., Smith C., Douglas N. L., Neller M. A., Matthews K. K., Beagley L., Rehan S., Crooks P., Hopkins T. J., Blum S., Green K. A., Ionnides Z. A., Swayne A., Aftab B. T., Hooper K. D., Burrows S. R., Thompson K. M., Coulthard A., Khanna R. Epstein-Barr virus-specific T cell therapy for progressive multiple sclerosis. JCI Insight. 2018. https://doi.org/10.1172/jci.insight.124714

Altieri C., Speranza B., Corbo M. R., Sinigaglia M., Bevilacqua A. Gut-Microbiota, and Multiple Sclerosis: Background, Evidence, and Perspectives. Nutrients. 2023. https://doi.org/10.3390/nu15040942

Identifying Targets for Neuromodulation of PTSD

Post by Kelly Kadlec

The takeaway

In this study, the authors investigated the functional connectivity between brain regions of veterans with and without brain lesions to identify a neural circuit for Post-traumatic stress disorder (PTSD). They demonstrated the potential therapeutic benefits of targeting brain regions within this circuit using noninvasive neuromodulation.  

What's the science?

Post-traumatic stress disorder can result from the experience of a traumatic event or series of events and symptoms can include anxiety and depression. Despite its prevalence, traditional medication and psychotherapy treatments are often not effective, leading researchers to explore neuromodulation techniques such as transcranial magnetic stimulation (TMS). Unfortunately, one of the most commonly implicated regions in PTSD, the amygdala, is not accessible by TMS. Therefore, there is a need to identify alternative modulation targets. Recently in Nature Neuroscience, Siddiqi and colleagues investigated circuits involved in  PTSD in veterans and identified and demonstrated the medial prefrontal cortex (mPFC) as a potential target for TMS treatment of PTSD.

How did they do it?

First, the authors compared rates of PTSD in veterans with and without penetrating traumatic brain injury (TBI), and examined which lesioned brain areas were most associated with reduced rates of PTSD. Additionally, they used functional MRI (fMRI) to determine the functional connectivity (FC) of brain areas where lesions seemed to protect against PTSD. This connectivity was established by lesion network mapping, which relies on the connectome database of resting-state fMRI for 1,000 individuals. Then, they compared the patterns of FC found in veterans with TBI to those without TBI including a large cohort of veterans with PTSD.   

The authors then assessed whether neuromodulation of implicated brain regions resulted in changes in PTSD symptoms. First, they evaluated how TMS in regions identified by the connectivity results compared with TMS in other regions in terms of the ability to relieve PTSD symptoms. In addition, they evaluated how different types of modulation (i.e. inhibitory, excitatory) impacted PSTD symptoms.

What did they find?

First, the authors report that veterans with penetrative brain injuries had reduced rates of PTSD. In particular, individuals with damage to the amygdala were the most protected against developing PTSD. 

Next, the authors found that reduced functional connectivity between the mPFC, amygdala, and hippocampus, was associated with reduced PTSD symptoms. This ‘lesion-derived PTSD circuit’ was also validated in veterans without TBI by comparing FC in individuals with and without PTSD. They were able to further examine this circuit in individuals who had received TMS for PTSD in a previous study and found that, as hypothesized, a reduction in these patient’s symptoms was associated with a reduction in FC between the areas in this circuit. 

Finally, the authors validated the neural circuit they identified as a target for TMS-based treatment of PTSD by showing that TMS in regions within the circuit was more effective than TMS in other areas in reducing symptom severity. In addition, as predicted by the FC results, applying inhibitory modulation to these regions resulted in a decrease in PTSD symptom severity while applying excitatory modulation had the opposite effect.  

What's the impact?

PTSD can have a negative impact on the quality of life of individuals afflicted and current treatments are unfortunately limited in their efficacy. The findings in this study demonstrate the mPFC as a promising target for non-invasive neuromodulation and reduction of PTSD symptoms. Further, the results of this study present causal evidence for a critical neural circuit in PTSD.  

Access the original scientific publication here.

Can Alzheimer’s disease be prevented?

Post by Shireen Parimoo

Overview

Alzheimer’s disease (AD) is a neurodegenerative disorder that affects millions of older adults globally, with five million new cases every year. In the brain, AD is characterized by the accumulation of amyloid beta plaques and neurofibrillary tangles made up of misfolded tau proteins. These plaques and tangles accumulate in brain areas like the hippocampus that are important for memory, eventually leading to cell death and atrophying of affected regions. As a result, common cognitive impairments in AD include memory problems, diminished attentional and decision-making capacity, and loss of language abilities. Alzheimer’s disease also impacts mental health and day-to-day functioning as patients experience problems with sleep, depression, apathy, aggression, and psychosis. Although there is no known cure for AD, treatments currently exist to alleviate some of the cognitive symptoms of the disease.

Risk Factors for Alzheimer’s disease

One of the major risk factors for AD is genetic susceptibility. Normally, we inherit one copy of a gene - called an allele - from each parent.  A small subset of individuals with AD have early-onset or familial AD that they develop due to inherited gene mutations from one or both of their parents. Symptoms of early-onset AD generally begin in the 30s and 40s and quickly lead to deteriorating health and well-being. For most patients, however, symptoms of AD emerge later in life, around 65 years old. In these cases of sporadic AD, the apolipoprotein E (APOE) has been identified as a key genetic risk factor. Specifically, having one or two copies of the APOE-4 allele increases the risk of AD because it leads to higher levels of amyloid plaques in the brain. 
 
Besides genetic risk, many lifestyle and medical factors can also increase the risk of developing AD. For example, hypertension and elevated cholesterol levels are both associated with a higher risk of developing AD, as are obesity and diabetes. Research studies have also identified smoking, poor sleep, social isolation and loneliness, and chronic stress as lifestyle predictors of AD and cognitive decline later in life. Fortunately, many of these risk factors are modifiable, which means that it is possible to make lifestyle changes to lower the odds of developing AD.

The Importance of Lifestyle // Protective Factors

Protective factors are variables that - as the name suggests - protect against the risk of developing AD. As with risk factors, protective factors can be immutable or modifiable. A genetic protective factor, for instance, is the presence of two copies of the APOE-2 allele. Unlike APOE-4, the APOE-2 variant of the gene reduces the risk of developing AD. Interestingly, although genetic risk itself is not currently modifiable, studies show that there is an interaction between genetic and lifestyle factors, or in other words, between nature and nurture.
 
Fortunately, research studies over the past few decades have identified several modifiable lifestyle factors that have a protective effect against dementia and cognitive decline, even if there is a genetic risk for developing AD. This means that we can take measures to improve our brain health into our own hands and, at the very least, mitigate the rate of cognitive decline in older age.

1. Physical activity is an all-around protective factor against multiple conditions including AD and dementias. Exercising reduces blood pressure and proinflammatory activity, both of which are risk factors for AD. In the long term, physical activity also improves blood flow to the brain, which is important for brain health and functioning in general. Aerobic exercises like running, walking, and cycling increase neurotrophic factors in the brain, which are proteins that promote the growth, plasticity, and survival of neurons. The effects of exercise on the hippocampus in particular are well-documented. Both healthy older adults and AD patients who engage in physical activity have higher levels of neurotrophic factors and in some cases, larger hippocampal volume because of exercise. Older adults at risk for AD who engage in physical activity also show less hippocampal atrophy, which could slow down the onset of dementia and memory-related symptoms.

1. Diet and nutrition are also important for maintaining brain health and protecting against cognitive decline. Sources of unsaturated fats like olive oil and nuts are important for helping neurons maintain the integrity of their synapses (i.e., gaps between neurons). Antioxidants like folic acid from fruits and vegetables, as well as vitamins like vitamin D confer some protection against neurodegeneration by regulating neurotrophic factors to maintain neuronal health and by clearing amyloid protein in the brain. In fact, individuals with a vitamin D receptor gene mutation tend to be more at risk for developing AD. Thus, a well-balanced and nutritious diet - such as the Mediterranean diet, which is rich in antioxidants - can reduce the risk of developing AD in older age.

1. Psychosocial factors also have a protective effect against dementia, including social enrichment, educational attainment, leisure activities, and psychological well-being. Older adults with an active social life are more likely to be intellectually and socially stimulated, which is linked to increased neurogenesis and lower levels of stress. Similarly, having a strong social support system increases our sense of belonging, reduces feelings of loneliness, and improves our mental well-being. Higher educational attainment early in life and stimulating leisure activities - like learning a new language or playing an instrument - also help prevent the onset of dementia. The idea is that engaging in these social and intellectual domains ensures that the neural circuits in the brain remain active and are less likely (or at the very least slower) to deteriorate during aging.

1. Sleep disturbances are linked to a higher risk of cognitive decline and AD. For example, amyloid and tau accumulation and clearance are modified by sleep patterns. Getting enough good quality sleep is important because that is when toxins like amyloid and tau are cleared through the glymphatic (fluid flow) system in the brain. Interestingly, the relationship between sleep and AD appears to be bidirectional: healthy individuals with amyloid and tau pathology (precursors to AD) and individuals with AD tend to have poor sleep quality and more sleep disturbances. As a result, it is unclear whether sleep quality contributes to the onset of AD, whether it is one of the outcomes of AD pathology, or some mix of the two.

 
Overall, there are many modifiable lifestyle variables that can help prevent cognitive decline and protect against the onset of neurodegenerative disorders like AD. Emerging research indicates that a personalized, multidomain, lifestyle-based interventional approach will have the most beneficial effects on slowing down pathological processes in aging, especially in older adults who might be genetically at risk for developing dementia.

References +

Li et al. (2014, BioMed Research International). Behavioral and psychological symptoms in Alzheimer’s disease. Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123596/

Silva et al. (2019, Journal of Biomedical Science). Alzheimer’s disease: Risk factors and potentially protective measures. Link: https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-019-0524-y

Wang et al. (2021, Alzheimer’s & Dementia). Shared risk and protective factors between Alzheimer’s disease and ischemic stroke: A population-based longitudinal study. Link: https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/alz.12203

Iso-Markku et al. (2021, British Journal of Sports Medicine). Physical activity as a protective factor for dementia and Alzheimer’s disease: Systematic review, meta-analysis, and quality assessment of cohort and case-control studies. Link: https://bjsm.bmj.com/content/bjsports/56/12/701.full.pdf

Rosenberg et al. (2020, The Journal of Prevention of Alzheimer’s Disease). Multidomain interventions to prevent cognitive impairment, Alzheimer’s disease, and dementia: From FINGER to World-Wide FINGERS. Link: https://link.springer.com/content/pdf/10.14283/jpad.2019.41.pdf

Walsh & Brayne (2021, Alzheimer’s & Dementia). Does playing a musical instrument prevent dementia? Link: https://alz-journals.onlinelibrary.wiley.com/doi/abs/10.1002/alz.049684

Liu et al. (2013, Nature Reviews Neurology). Apolipoprotein E and Alzheimer’s disease: Risk, mechanisms, and therapy. Link: 10.1038/nrneurol.2012.263

Qiu et al. (2009, Dialogues in Clinical Neuroscience). Epidemiology of Alzheimer’s disease: Occurrence, determinants, and strategies toward intervention. Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181909/

Kuiper et al. (2015, Ageing Research Reviews). Social relationships and risk of dementia: A systematic review and meta-analysis of longitudinal cohort studies. Link: https://individuallytics.com/wp-content/uploads/2020/02/Social-Relationships-and-Risk-of-Dementia-Kuiper-et-al-2015.pdf

Wang et al. (2017, PLoS Medicine). Association of lifelong exposure to cognitive reserve-enhancing factors with dementia risk: A community-based cohort study. Link: https://journals.plos.org/plosmedicine/article/file?id=10.1371/journal.pmed.1002251

Lucey, B. P. (2020, Neurobiology of Disease). It’s complicated: The relationship between sleep and Alzheimer’s disease in humans. Link: https://www.sciencedirect.com/science/article/pii/S0969996120303065

Wang & Holtzman (2020, Neuropsychopharmacology). Bidirectional relationship between sleep and Alzheimer’s disease: Role of amyloid, tau, and other factors. Link: https://www.nature.com/articles/s41386-019-0478-5

Zhang et al. (2022, Translational Psychiatry). Sleep in Alzheimer’s disease: A systematic review and meta-analysis of polysomnographic findings. Link: https://www.nature.com/articles/s41398-022-01897-y

Irwin & Vitiello (2019, The Lancet Neurology). Implications of sleep disturbance and inflammation for Alzheimer’s disease dementia. Link: https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(18)30450-2