The Role of the Immune System in Neurodegeneration

Post by Andrew Vo

The takeaway

The immune system plays a potential role in neurodegenerative diseases, such as Lewy body dementia. The mechanism by which an inflammatory response is trafficked to the brains of these patients might be a potential therapeutic target.

What's the science?

Lewy body dementia (LBD) is distinguished by the abnormal accumulation of α-synuclein protein in the brain, leading to changes in the memory and behavior of these patients. Animal studies have suggested a role of the immune system in LBD, although the mechanism by which T cells (specialized cells in our bodies that identify and attack substances with foreign “antigens” or markers) migrate and function in the brain remains unknown. This week in Science, Gate et al. examine biological samples collected from living and postmortem patients to investigate the relationship between immunity-related T cells and LBD pathology. 

How did they do it?

The authors first compared cognitive function and cerebrospinal fluid (CSF) levels of neurofilament light chain (a protein marker of neurodegeneration) in LBD patients and healthy controls. To directly test if the immune system interacted with LDB pathology, they then examined postmortem brains of LBD patients for T cell localization with α-synuclein accumulation. Next, they used sequencing analyses to measure T cell binding molecules, namely CXCR4 and CXCL12, in the CSF and meninges (protective membranes inside the skull and surrounding the brain) of LBD patients. Finally, they measured T cell immune activation in CSF samples from LBD patients through stimulation with a pool of peptide proteins derived from α-synuclein.

What did they find?

DLB patients were found to have reduced cognitive function and increased neurofilament light chain levels in their CSF. Examining postmortem brains, T cells were observed to be localized next to α-synuclein deposits and were mostly concentrated near the substantia nigra (a brain region containing dopamine neurons that degenerate in Parkinson’s disease) in LBD patients. This demonstrated a link between the immune system and brain pathology in LBD.

Sequencing of T cells in the CSF revealed greater expression of CXCR4 and CXCL12 markers in LBD patients compared to controls. A similar pattern was found in the meninges of LBD patients and specifically localized to the brain’s vasculature (or blood supply). Increased CXCL12 levels measured in CSF were related to lower cognitive function and higher neurofilament light chain levels. Together, these results show that increased CXCR4-CXCL12 signaling is associated with neurodegeneration in LBD.

Before stimulation with a peptide pool containing proteins derived from α-synuclein, T cells in the CSF showed greater baseline activation in LBD patients versus controls. This immune activation was further enhanced following peptide stimulation. Sequencing of these stimulated cells showed increased expression of interleukin 17A, which is related to inflammatory responses mediated by TH17 cells. Examining postmortem brains, they found T cells localized near TH17 cells in the substantia nigra of LBD patients. These findings suggest the involvement of TH17 cells and immunoreactivity in LBD neurodegeneration. 

What's the impact?

In summary, this study demonstrated a link between the immune system, specifically CXCR4-CXCL12 signaling that recruits T cells to the brain, and neurodegeneration in LBD. The authors highlight a pathological mechanism in human patients that was previously only established in animal models of neurodegeneration. This signaling mechanism may be a potential therapeutic target for the treatment of LBD.

Access the original scientific publication here.

Morning Larks and Night Owls: The Impact of Chronotype

Post by Anastasia Sares

The takeaway

Chronotype, or day/night preference, is a genetically influenced trait that affects how active and alert we are at various points in the day. In the past few years, studies have linked chronotype to both mental and physical health, and people can suffer adverse effects when their daily schedule doesn’t align with their chronotype—a phenomenon called “social jet lag.”

How do we measure chronotype?

The simplest way to measure a person’s chronotype is by asking about their sleeping habits. It’s important to do this for workdays and for free days, as someone might change their habits between the two, and may try to make up for missed sleep on their free days by oversleeping. There are more objective ways to measure chronotype, but they take longer. Actimetry measures the amount of movement a person makes throughout the day by some kind of wearable device. Another popular measure is dim light melatonin onset, or DLMO, which measures how fast people produce the sleep-related hormone melatonin in response to dim light. All of these measures agree with each other pretty well, even an ultra-short version recently developed for use in clinics or as a part of other studies that don’t have much extra time.

Chronotype also varies hugely over the lifespan, with adolescents having very late chronotypes and older adults having earlier chronotypes. People in urban environments have more varied later chronotypes than those in rural environments, and even people’s location within a time zone (eastern vs. western edge) can affect their chronotype due to small differences in sunlight hours.

How is chronotype related to health outcomes?

Late chronotypes (night owls) are prone to more adverse health outcomes like hypertension and depression. However, it is not clear that being a night owl causes these effects. The less our daily schedule is synchronized with our natural sleeping rhythm, the more stress we experience, and this stress is what can lead to health problems. This is called “social jet lag,” and it is more likely to affect night-owls because societal structures tend to follow earlier schedules (the writer of this article, being a moderately late chronotype, still remembers getting up at 6:15 am during high school with much chagrin). Social jet lag is at its most extreme in shift-workers, like hospital staff who have work during the night.

Chronotype isn’t just a matter of psychology; every cell in the body has a circadian rhythm and is affected by these day-night cycles. Under social jet lag, the body’s cellular clocks adjust at different rates and cannot keep up with the switch between workdays and free days. It is these unsynchronized cellular clocks that may be responsible for the health risks of social jet lag. Worldwide, workers’ sleep habits when working from home during the COVID-19 pandemic shifted later, indicating that society as a whole had been under social jet lag.

How can we lessen the impact of social jet lag?

Chronotype can be manipulated to some degree. Being outside during the day can help to naturally regulate your sleep cycle. On the other hand, exposure to light before bed can disturb natural sleep-wake cycles, and so it is helpful to limit your evening screen time if you want to shift your schedule earlier (put away your phone!). A regular sleep schedule will also lower your risk for adverse health effects, especially if your work hours are very early or very late compared to your natural rhythm. However, don’t sacrifice your free-day sleep in order to keep a normal wake-up time. Rather, try to go to sleep at the same time each night.

On a societal level, we can take chronotype into account in school start times and in assigning shifts to workers, something that is already starting to be done. Some researchers are also calling for governments to abolish daylight savings time, which can cause a host of sleep-related problems.

What's the impact?

In our industrialized society, many people live predominantly indoors and are more detached from natural day-night cycles, making their chronotypes later and more varied. It is important to provide daily structures that accommodate differences in chronotype—this will have a significant impact on human health and well-being, as well as increasing work productivity and quality.

References +

1. Roenneberg, T., Pilz, L. K., Zerbini, G., & Winnebeck, E. C. (2019). Chronotype and social jetlag: A (self-) critical review. Biology, 8(3), 1–19. https://doi.org/10.3390/biology8030054
2. Shahid, A., Wilkinson, K., Marcu, S., & Shapiro, C. M. (2011). Munich Chronotype Questionnaire (MCTQ). STOP, THAT and One Hundred Other Sleep Scales, 245–247. https://doi.org/10.1007/978-1-4419-9893-4_58
3. Ghotbi, N., Pilz, L. K., Winnebeck, E. C., Vetter, C., Zerbini, G., Lenssen, D., … Roenneberg, T. (2020). The µMCTQ: An Ultra-Short Version of the Munich ChronoType Questionnaire. Journal of Biological Rhythms, 35(1), 98–110. https://doi.org/10.1177/0748730419886986
4. Kalmbach, D. A., Schneider, L. D., Cheung, J., Bertrand, S. J., Kariharan, T., Pack, A. I., & Gehrman, P. R. (2017). Genetic Basis of Chronotype in Humans: Insights From Three Landmark GWAS. Sleep, 40(2). https://doi.org/10.1093/sleep/zsw048
5. Wittmann, M., Dinich, J., Merrow, M., & Roenneberg, T. (2006). Social jetlag: Misalignment of biological and social time. Chronobiology International, 23(1–2), 497–509. https://doi.org/10.1080/07420520500545979
6. Hulsegge, G., Loef, B., van Kerkhof, L. W., Roenneberg, T., van der Beek, A. J., & Proper, K. I. (2019). Shift work, sleep disturbances and social jetlag in healthcare workers. Journal of Sleep Research, 28(4). https://doi.org/10.1111/jsr.12802
7. Korman, M., Tkachev, V., Reis, C., Komada, Y., Kitamura, S., Gubin, D., … Roenneberg, T. (2020). COVID-19-mandated social restrictions unveil the impact of social time pressure on sleep and body clock. Scientific Reports, 10(1), 1–10. https://doi.org/10.1038/s41598-020-79299-7
8. Roenneberg, T., Wirz-Justice, A., Skene, D. J., Ancoli-Israel, S., Wright, K. P., Dijk, D. J., … Klerman, E. B. (2019). Why Should We Abolish Daylight Saving Time? Journal of Biological Rhythms, 34(3), 227–230. https://doi.org/10.1177/0748730419854197

Perceived Social Support is Related to Depressive Symptoms in Those with Physical Disability

Post by Elisa Guma

The takeaway

Increased perceived social support can buffer against depressive symptoms in individuals with long-term physical disability, while decreased support can worsen symptoms.

What's the science?

Perceived social support is an important factor for maintaining good mental health in vulnerable groups, such as those with long-term physical disability, or in an aging population. Cross-sectional studies have identified a strong association between lack of social support and depression in these groups. However, no longitudinal studies — with comprehensive measures of social support — have been conducted to investigate the association between perceived social support and mental health outcomes. In Disability and Health Journal, de la Vega and colleagues assess the relationship between perceived social support and depressive symptoms in individuals with long-term physical disability including multiple sclerosis, spinal cord injury, and muscular dystrophy.

How did they do it?

Participants with one of three different chronic physical disabilities (spinal cord injury, multiple sclerosis, and muscular dystrophy) were asked to complete surveys every 12-15 months over the course of a 6 year period. The sample used for this study (n=475) included survey responses two time points, spaced 6 years apart. In addition to basic demographic information (age, sex, ethnicity, diagnosis, household income, marital status, education), the severity of depressive symptoms was recorded (using the Patient-Reported Outcomes Measurement Information System), as was the perceived social support (using the Multi-dimensional Scale of Perceived Social Support). 

With these data, the authors intended to ask whether a change in perceived social support over the two timepoints was associated with a change in depressive symptomatology. However, for a large majority of the sample, little change in perceived social support over the 6-year period as observed. Therefore, the authors identified a subgroup of individuals for which social support did change in order to investigate this relationship.

What did they find?

The majority of individuals enrolled in the study reported no differences in social support over the 6 year follow up period, with no differences in social support between the three diagnosis groups, or between men and women. Interestingly, the subset of individuals who did report changes in perceived social support also reported changes in depressive symptoms. Those that experience increased social support reported decreased depressive symptoms, while those that reported decreased social support reported increases in depressive symptoms.

What's the impact?

This study provides support for the association between social support and mental health outcomes, particularly in vulnerable individuals suffering from chronic physical disability. These findings suggest that providing social support to individuals struggling with chronic disability may be an important buffer against negative mental health outcomes. Investigating the provision of social support as a possible treatment intervention for individuals struggling with disability, as well as an aging population, or isolated groups will be an important avenue for future research.

Access the original scientific publication here.