Neuroinflammation may play independent role from amyloid in Alzheimer disease

A recent neuroimaging study published in Communications Biology, a journal within the Nature portfolio, reports a possible link in individuals with Alzheimer disease between neuroinflammation in the brain and task-related activities, independent of amyloid aggregation.1 These early findings may indicate that abnormal brain activity may possibly be restored by targeting neuroinflammation; however, additional studies and clinical trials are still needed to corroborate and build upon these findings. 

This study by Canário and colleagues examined the link between brain activity, neuroinflammation caused by microglia, and amyloid aggregation (A𝛃) by using duel positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). Two different PET radiotracers were used to simultaneously determine neuroinflammation and A𝛃 accumulation. 

PET allows for the in vivo imaging of biomarkers associated with Alzheimer disease (AD). Radiotracers, such as 11C‐labeled Pittsburgh compound B ([11C]PiB), target the amyloid protein associated with AD,2 and have even been used in studies associating amyloid protein to impaired memory.2,3 Similarly, 11C-PK11195 is a PET radiotracer that binds to the translocator protein expressed in activated microglia associated with neuroinflammation.4 

Microglia are involved in the CNS immune response, yielding different effects depending on the signals received from the neurons. Typically, homeostatic signals, such as CD200, would elicit an anti-inflammatory response from microglia, but A𝛃 and pathogen-associated molecules cause an inflammatory response.5 

Researchers saw a statistically significant (P = 0.013) positive correlation in the posterior cingulate cortex (PCC) between the 11C-PK11195 radiotracer measuring neuroinflammation (microglial activation) and the beta values derived from the fMRI in the AD group whereas no relationship was evident with the control group (P = 0.185). They also did not see a correlation between A𝛃 and fMRI beta values. Higher beta values indicate higher neuronal activation required for the task.1 

These results imply that future studies may focus on reducing neuroinflammation to restore abnormal brain activity since neuroinflammation may have an independent role from A𝛃 in cognition in symptomatic AD patients.1


  1. Canário N, Jorge L, Martins R, Santana I, Castelo-Branco M. Dual PET-fMRI reveals a link between neuroinflammation, amyloid binding and compensatory task-related brain activity in Alzheimer’s disease. Commun Biol. 2022;5(1):1-7. doi:10.1038/s42003-022-03761-7
  2. Chandra A, Valkimadi P, Pagano G, Cousins O, Dervenoulas G, Politis M. Applications of amyloid, tau, and neuroinflammation PET imaging to Alzheimer’s disease and mild cognitive impairment. Hum Brain Mapp. 2019;40(18):5424-5442. doi:10.1002/hbm.24782
  3. Frings L, Spehl TS, Weber WA, Hüll M, Meyer PT. Amyloid-β load predicts medial temporal lobe dysfunction in Alzheimer dementia. J Nucl Med Off Publ Soc Nucl Med. 2013;54(11):1909-1914. doi:10.2967/jnumed.113.120378
  4. Rissanen E, Tuisku J, Rokka J, et al. In Vivo Detection of Diffuse Inflammation in Secondary Progressive Multiple Sclerosis Using PET Imaging and the Radioligand 11C-PK11195. J Nucl Med Off Publ Soc Nucl Med. 2014;55(6):939-944. doi:10.2967/jnumed.113.131698
  5. Augusto-Oliveira M, Arrifano GP, Lopes-Araújo A, et al. What do microglia really do in healthy adult brain? Cells. 2019;8(10):1293. doi:10.3390/cells8101293

Gender, history of depression associated with lack of sleep after a “heart attack”

A recent PLOS One study of acute coronary syndrome (ACS) (1) reports on factors that impact sleep disturbance. Even though it may seem obvious that people who have a heart attack may suffer from a lack of sleep later, this study finds that some factors may have a greater impact than others, and some of these may even be actionable. By taking a few steps, could it be possible to help decrease the lack of sleep after a heart attack? While it may not revolutionize cardiac (or sleep) medicine, this study does gives us a baseline to start a discussion.

Man is holding his chest in pain (unstable angina)
Holding chest in pain, free public domain CC0 photo

Acute Coronary Syndrome (ACS)


According to the CDC and Mayo Clinic, acute coronary syndrome is a generic term describing conditions causing a sudden reduction in blood flow to the heart. This can include myocardial infarction (“heart attack”) and unstable angina (chest pain that occurs even at rest without an apparent reason)(refs 2,3).


This was a longitudinal study, meaning that the researchers followed the participants over a given length of time. The study started with 180 patients, and the researchers assessed sleep disturbance (using the 4-item Jenkins Sleep Scale, or JSS-4) at the time of hospital admission (time zero), 3 months, and 12 months. 101 patients completed the entire 12-month study. Also, the investigators did an extensive search of other factors or variables (covariates) that may have an effect. The covariates included within the study were:

  • Demographic factors, such as
    • Age
    • Employment status (full-time, part-time, retired, or unemployed)
    • Living arrangement (living alone or with at least one other person)
    • Level of education
  • Clinical variables
    • Cardiac clinical variables, of course, such as the index event (STEMI vs. non-STEMI), severity of acute coronary syndrome
    • Pain
    • Fear of dying
    • Feeling of helplessness
    • Depression
    • Sleep apnea
    • Use of sleeping pills and antidepressants
    • Other comorbidities (meaning other diseases or conditions also present within a single patient)
  • Health behaviors
    • Body-mass index (BMI)
    • Smoking status (Never smoked, previous smokers, or current smokers)
    • Alcohol consumption
    • Weekly physical activity

What were the results?

Interestingly, the study did not find a statistically relevant general connection between sleep disturbance after having an ACS, such as a heart attack, and socioeconomic factors or most clinical factors. So, did they find any factors that may be tied to an in increase in sleep disturbances after cardiac events? Yes. The researchers note a statistically significant increase in sleep disturbance for three general categories:

Figure depicting concept of female with unstable angina or myocardial infarction (heart attack)
Photo by Marco Verch (CC 2.0)
  1. Females
  2. Individuals with a history of depression
  3. Patients who experienced “distress during ACS”

The authors define “distress during ACS” as patients who reported a greater fear of dying or a sense of helplessness during the actual cardiac event.

Why does sleep (and this study) matter?

Anecdotally, we have been told that a good nights’ sleep is ‘good for you’. Studies have shown that many people who have had a heart attack or other sudden cardiac event (ACS) experience sleep disturbance of some degree afterward (4-6). Some studies have indicated that impaired sleep after cardiac events are associated with a worse prognosis (7-9). This current study helps define what factors may be associated with increased sleep impairment. Some of these factors are not preventable or cannot be modified, such as gender. However, other factors are “potentially modifiable” (as the authors state it) and easier to assess at time of admission during the heart attack. For example, trying to remain as calm as possible and decrease anxiety (decrease fear of dying and feelings of helplessness) may have have a greater, long-term impact on decreasing sleep disturbance in the patient’s future.

References
  1. von Känel R, Meister-Langraf RE, Zuccarella-Hackl C, et al. Sleep disturbance after acute coronary syndrome: A longitudinal study over 12 months. Pizzi C, ed. PLoS ONE. 2022;17(6):e0269545. doi:10.1371/journal.pone.0269545
  2. CDC. Other conditions related to heart disease | CDC. Gov. Centers for Disease Control and Prevention. Published January 20, 2022. Accessed July 14, 2022. https://www.cdc.gov/heartdisease/other_conditions.htm
  3. Acute coronary syndrome – Symptoms and causes. Mayo Clinic. Accessed July 14, 2022. https://www.mayoclinic.org/diseases-conditions/acute-coronary-syndrome/symptoms-causes/syc-20352136
  4. Madsen MT, Huang C, Zangger G, Zwisler ADO, Gögenur I. Sleep disturbances in patients with coronary heart disease: a systematic review. J Clin Sleep Med. 2019;15(3):489-504. doi:10.5664/jcsm.7684
  5. Shaffer JA, Kronish IM, Burg M, Clemow L, Edmondson D. Association of acute coronary syndrome-induced posttraumatic stress disorder symptoms with self-reported sleep. Ann Behav Med. 2013;46(3):349-357. doi:10.1007/s12160-013-9512-8
  6. Coryell VT, Ziegelstein RC, Hirt K, Quain A, Marine JE, Smith MT. Clinical correlates of insomnia in patients with acute coronary syndrome. Int Heart J. 2013;54(5):258-265. doi:10.1536/ihj.54.258
  7. Clark A, Lange T, Hallqvist J, Jennum P, Rod NH. Sleep impairment and prognosis of acute myocardial infarction: a prospective cohort study. Sleep. 2014;37(5):851-858. doi:10.5665/sleep.3646
  8. Zhu CY, Hu HL, Tang GM, et al. Sleep quality, sleep duration, and the risk of adverse clinical outcomes in patients with myocardial infarction with non-obstructive coronary arteries. Front Cardiovasc Med. 2022;9:834169. doi:10.3389/fcvm.2022.834169
  9. Kim JW, Stewart R, Lee HJ, et al. Sleep problems associated with long-term mortality in acute coronary syndrome: Effects of depression comorbidity and treatment. Gen Hosp Psychiatry. 2020;66:125-132. doi:10.1016/j.genhosppsych.2020.08.004

Why a career change to medical writing?

Desktop of an active freelance medical writer's desk with texts, eyeglasses, computer mouse, keyboard, and notebook

In 2018, after many years in academia, I decided to make a career switch to a full-time medical writer. Previously, I had been doing freelance medical writing and copyediting odd jobs here and there ever since I realized that I enjoyed writing and researching in graduate school. When I first told others of my plan to switch careers, almost without fail they would ask why.  I cannot claim that what works for me or is ‘right’ for me will necessarily be true for others…but I can give you my “why”.

Reasons why I switched careers to medical writing…

Before just delving in and listing reasons 1, 2, 3,… I should give a little context. I am driven. No doubt. I make goals for myself, and I work hard to achieve them. After graduate school, I sped through my post-docs with the goal in mind to get a job in academia. I loved teaching, researching, and writing, and I knew that a small, private university position would be perfect for me. I found such a position, and I worked very hard within the institution to be promoted to full professor and department chair. For the most part, I loved it. I would not trade the experience of meeting all the students I taught through the years. I also learned so much from that time.

After more than 10 years at the same university, the stress was taking its toll on me. I had married. My wife and I had been told that it would be unlikely that we could have a family due to health issues…and then we were blessed (and wonderfully surprised) to discover we were expecting. I had a health crisis and needed to reprioritize life. It was not easy to leave a rolling-contract full professor position, but I knew I had to leave for health, my sanity, and my growing family.

So, rather than scale down my duties or find a similar job, why did I change careers? I had been doing freelance medical writing work (primarily copyediting) occasionally, and I loved to learn, research, and write. Why make the career change specifically to medical writing…?

1. Flexibility

Free work from home image, public domain scrabble CC0 photo.

For me, flexibility is the main reason. I set out looking for opportunities with flexibility in scheduling because the top priority for me was being ‘there’ or ‘around’ for my growing family. I wanted to be involved in their lives, and my previous career was unbelievably time-consuming. It was a given during the academic year that I would put in a minimum of 60+ hours each week with occasional weeks of 80 or more hours spent working. Yes, I did get a reprieve during the summer, but by that time I was spent and broken.

I entered my career switch with the goal being I needed more time with my family, and I requested flex-time in scheduling. A medical writer who is 100% full-time freelancing will have more power in scheduling; however, for those switching careers and seeking medical writing positions within industry, it is doable to find remote medical writing positions with flex-time.

For freelance medical writers, there is also flexibility in the projects (or jobs) that they accept. I typically did not get veto power in the courses I had to teach at the university. Even as department chair, I usually worked beyond contract and had to pick up classes that were required to teach (but lacking professors).

2. Less stress

man near carton boxes with many different words about stress
Photo by SHVETS production on Pexels.com

For me, I felt so much relief just announcing I was leaving academia and pursuing medical writing full-time. I did not have any jobs or contracts lined up or ready. I just made the metaphorical leap. Every interview I went to did ask me ‘why’, and most interviewers would specifically ask why I wouldn’t change my mind to go back to academia. I answered honestly about needing more family time/flex-time, and I would tell them I wanted, and needed, less stress.

Medical writing projects are usually less stressful for me because I broach them using project management skills. [Don’t worry this will not devolve into a diatribe on the agile method!] I personally find it gratifying to accomplish goals–even small deliverables or milestones–so I live by checklists. My previous career did not allow for that on the macro level. I was to the point professionally where it felt more like I was working in HR while juggling countless hours between the business office, academic affairs, and the lab. Now, my life is not stress-free, but it is orders of magnitude less stressful. I actually get to enjoy my cup of coffee in the morning! I plan projects as they come along, and I get to see them accomplished. Yes, curve balls can still get lobbed at me occasionally, but I’m ready at the bat.

3. Boredom

Man at desk bored rubbing his eyes
Photo by Thirdman on Pexels.com

I loved teaching and interacting with the students; however, the aspects of my previous career I had enjoyed had grown stale and monotonous. Less time was spent with teaching and curricula development while more time was spent on all other aspects of the job. Even after I had stepped down as department chair that last year, this situation did not improve. I was being asked to teach the same materials semester after semester. Some people find comfort in the monotony; I find restlessness. I love learning new things. One of my favorite responsibilities I had (at times) was curricula development, especially writing new courses where I could learn more about new topics.

Medical writing is such a vast field. I am constantly learning. Some medical writers may choose to really focus in one particular subject-matter area while others may prefer to primarily specialize in deliverable or service (such as CME/CE development or copyediting). Before I started to actively pursue this career, I did not realize how broad medical writing was or really everything it could encompass.

Do I have my regrets?

The Day-Storms sons sitting on a bridge on a Florida Spring afternoon
The Day-Storms Boys
(Photo by J. & D. Day-Storms)

Honestly, not at all! I have not considered returning to a career in academia. Just as I suspect with any career, I have learned more about myself, and I have encountered both ups and downs; however, I do not regret making my mid-life career change to full-time medical writing. Now, our family has grown to include two sons, so flexibility, less stress, and wise time management are all even more important. Life in our house is never boring.

For more information on medical writing, check out the American Medical Writing Association (AMWA) website. The AMWA provides many resources on medical writing, including a job directory for members. The AMWA also collaborates with the Medical Writing Certification Commission (MWCC) to develop the Medical Writer Certified (MWC®) credential, which some employers may refer to in their job postings. [Full disclosure: I am currently an office holder of the Florida chapter of the AMWA and also have my MWC certification. If you are a medical writer in Florida, we would love to have you join us.]

Spasers (and Star Trek) Revisited

In 2014, as part of an initiative to encourage my biochemistry students to actively read and discuss scientific journals and publications, I read a brief IEEE Spectrum article on the proposed use of graphene-based plasmon lasers (spasers) as a possible cancer therapeutic (1). The class blog entry was a popular topic for some time (2). Since that initial post, I made the decision to become a full-time medical writer, I had a family, and years had passed. When reviewing old course materials, I came across the post, and I decided that it would be interesting to do a follow-up review of this topic…sort of a “Spasers: Where are they now?

YouTube Video Explaining Surface Plasmon Resonance Technology (3)

Site-directed chemotherapy is highly desirable since healthy cells are also often affected by the treatment of malignant cells in systemic chemotherapeutics, resulting in general tissue destruction. The original article proposal was to develop a site-directed tumor therapy using a combination of lasers, nanotubes, antibodies, and surface plasmon technology. [For a brief tutorial on how surface plasmon resonance is used in small molecule interactions, please see the video by BiosensingUSA (3).] Spasers are similar to lasers except that surface plasmons are used in lieu of light. The original article hypothesizes that spasers could be used in the treatment of cancer. Carbon nanotubes conjugated to tumor-specific antibodies would be directed to the surface of the cancer cell where the surface plasmons are located. Then, a laser is used to excite the carbon nanotubes that then excite the surface plasmon. By exciting the surface plasmon, heat is generated. This heat then kills only the localized cancerous tissue in theory. The wavelength of light used in the laser is such that it can penetrate the skin and various layers to reach the cancerous tissues (1).

In a 2017 study by Galanzha and colleagues published in Nature Communications, the authors report developing a biocompatible spaser capable of generating stimulated emission inside either cells or animal tissues. The authors report detecting emission through approximately 1-mm-thick blood layer. This depth is more than 10-times greater than the depth typically observed using a conventional quantum dot method (4).

Principle of photoswitchable spasers: the gold spaser core is encapsulated with polymer shell containing the photoswitchable fluorescent protein
Figure from Harrington, 2019 (Ref. 7) depicting principle of photoswitchable spasers.
Note: This figure is originally published and licensed under a Creative Commons Attribution 4.0 International License which permits use, sharing, adaptation, distribution and reproduction as long as appropriate credit is given to original author(s). To view a copy of the Creative Commons license, visit http://creativecommons.org/licenses/by/4.0/.

One limitation to the use of spasers in vivo is the weak fluorescence signal due to the background noise (autofluorescence background found within tissues)(5-7). Harrington et al., 2019 (7) published results of a proof-of-concept experiment to create a ‘multimodal photoswitchable spaser’ utilizing a spherical plasmonic gold core with a non-absorbing polymer shell containing photoswitchable fluorescent proteins (PFPs). The researchers successfully synthesized stable spaser nanoparticles capable of photoswitching between wavelengths. The importance of these findings is the possible extension in spaser applications due to multicolor capacity while retaining photothermal applications. The authors conclude that “these results suggest that multimodal photoswitchable spasers could extend the traditional applications of spasers and PFPs in laser spectroscopy, multicolor cytometry, and theranostics with the potential to track, identify, and kill abnormal cells in circulation (7).”

References

  1. Tiny Cancer-Killing Death Rays: Spaser Therapy Proposed. IEEE Spectrum. Published November 4, 2014. Accessed July 1, 2022. https://spectrum.ieee.org/spaserpowered-cancer-therapy
  2. Star trek meets cancer therapy. MaestroSci. Accessed July 1, 2022. https://maestrosci.blogspot.com/2014/11/star-trek-meets-cancer-therapy.html
  3. Surface Plasmon Resonance Explained. Accessed July 1, 2022. https://www.youtube.com/watch?v=sM-VI3alvAI
  4. Galanzha EI, Weingold R, Nedosekin DA, et al. Spaser as a biological probe. Nat Commun. 2017;8:15528. doi:10.1038/ncomms15528
  5. Bindels DS, Goedhart J, Hink MA, van Weeren L, Joosen L, Gadella TWJ. Optimization of fluorescent proteins. Methods Mol Biol. 2014;1076:371-417. doi:10.1007/978-1-62703-649-8_16
  6. Yashchenok AM, Jose J, Trochet P, Sukhorukov GB, Gorin DA. Multifunctional polyelectrolyte microcapsules as a contrast agent for photoacoustic imaging in blood. J Biophotonics. 2016;9(8):792-799. doi:10.1002/jbio.201500293
  7. Harrington WN, Novoselova MV, Bratashov DN, et al. Photoswitchable spasers with a plasmonic core and photoswitchable fluorescent proteins. Sci Rep. 2019;9(1):12439. doi:10.1038/s41598-019-48335-6