Brain Health

The healthyher.life team supports a holistic approach to managing women’s hormonal healthcare. Our goal is to help our members be well-informed about their hormonal health, by providing them with evidence-based integrated health information that includes the current standard of medical care advised by qualified physicians, clinical insights from licensed allied health professionals (naturopathic doctors, nurse-practitioners, nutritionists, psychotherapists) and new health innovations that will be soon coming to market. Always consult with your doctor regarding your medical condition, diagnosis, treatment, or to seek personalized medical advice.
How the Brain Clears Waste Metabolites During
Your Sleep
Reviewed by Rina Carlini, PhD
Jan 31, 2025

Your brain doesn’t have a traditional waste removal system like the rest of your body, but it still needs to clear out toxins. Scientists have discovered a special process, called the glymphatic system, which acts like a cleaning service for your brain—and it works best when you are in deep sleep.
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The glymphatic system allows cerebrospinal fluid (CSF) to flow into the brain through spaces around blood vessels, washing away waste.[1] The fluid then drains out, carrying toxins away. This system depends on a water channel called Aquaporin-4 (AQP4), found in brain cells called astrocytes. When AQP4 doesn’t function properly, waste accumulates, increasing the risk of neurodegenerative diseases like Alzheimer’s Disease and Parkinson’s Disease.[1]
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When we age however, the brain’s process to clear waste becomes less effective.[2] The glymphatic system slows down while sleep becomes more disrupted, and the brain accumulates harmful proteins such as amyloid-beta and tau, both linked to Alzheimer’s Disease.[3] This buildup of waste metabolites contributes to a person’s sleep disturbances, memory issues, and increases their risk of brain diseases. Worse, the combination of a weakened brain lymphatic system and chronic inflammation can block waste removal, creating a vicious cycle where poor sleep leads to the accumulation of more toxins, and in turn, more toxins worsen sleep.[2]
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Prioritizing deep non-REM sleep is one of the best things you can do for long-term brain health.
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5 Key Takeaways:
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Your brain has a built-in cleaning system (known as the glymphatic system) that removes waste while you sleep.
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Deep sleep is essential for brain detoxification—without it, harmful proteins like amyloid-beta and tau can build up.
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As you age, your brain’s waste removal slows down, increasing the risk of neurodegenerative diseases like Alzheimer’s Disease and Parkinson’s Disease.
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Chronic inflammation combined with a weakened glymphatic system make waste clearance even harder as you get older.
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Prioritizing quality sleep and deep rest is key to keeping your brain healthy and reducing disease risk.
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References:
[1] Iliff, J. J., Wang, M., Liao, Y., Plogg, B. A., Peng, W., Gundersen, G. A., Benveniste, H., Vates, G. E., Deane, R., Goldman, S. A., Nagelhus, E. A., and Nedergaard, M. (2012). A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Science Translational Medicine; 4(147), 147ra111. https://doi.org/10.1126/scitranslmed.3003748
[2] Jiang-Xie, L. F., Drieu, A., & Kipnis, J. (2025). Waste clearance shapes aging brain health. Neuron; 113(1), 71–81. https://doi.org/10.1016/j.neuron.2024.09.017
[3] Lucey, B. P., McCullough, A., Landsness, E. C., Toedebusch, C. D., McLeland, J. S., Zaza, A. M., Fagan, A. M., McCue, L., Xiong, C., Morris, J. C., Benzinger, T. L. S., & Holtzman, D. M. (2019). Reduced non-rapid eye movement sleep is associated with tau pathology in early Alzheimer's disease. Science Translational Medicine; 11(474), eaau6550. https://doi.org/10.1126/scitranslmed.aau6550
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​Depression & Menopause Coinciding for Midlife Women: Know the Symptoms and Treatment Options
By Susan Johnson
Reviewed by Rina Carlini, PhD
November 19, 2024

Image Source: Shutterstock (ID: 12208279959)
Depression is a significant mental health concern, affecting around 280 million people in the world–most of them women. [1] In most women, the risk of experiencing depression spikes in midlife (ages 45 to 54), with about 20-30% facing first or recurrent episodes of major clinical depression during this time. [2] While concerns about aging, dealing with workplace issues, and challenges in intimate relationships are a few reasons to blame, menopause is another crucial factor.
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The transition to menopause is accompanied by notable psychological changes, such as mood swings and anxiety, in nearly one in three women. Even women with no prior history of depression are two to four times more likely to experience depressive symptoms during perimenopause than their younger or older counterparts. [3]
The Menopausal Transition
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According to the American College of Obstetricians and Gynecologists (ACOG), menopause is the time when a woman’s menstrual periods stop permanently following 12 consecutive months of no periods.[4]
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The period leading up to menopause is called perimenopause, which can span a period of 3-7 years on average. During this time, the hormone levels, particularly estrogen, begin to decline, causing irregular menstrual cycles and symptoms like hot flashes, insomnia, anxiety, mood swings, and depressive feelings.
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Depressive symptoms during the menopause transition can manifest in several ways:
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Fatigue or low-energy
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Irritability, restlessness, or agitation
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Difficulty concentrating or making decisions
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Persistent sadness or feeling of emptiness
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Sleep disorders, such as insomnia or oversleeping
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Loss of interest in activities once enjoyed
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Feelings of worthlessness or guilt
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Changes in appetite or weight
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Suicidal thoughts
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Most women get relief from depressive symptoms in the post-menopause years, but some may continue to experience mood disturbances. This could be due to poor social support, unaddressed mental health concerns, substance abuse, and others.
Are Hormones The Only Thing To Blame?
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In the past, researchers have studied the association between mood changes and hormones like follicle-stimulating hormone (FSH) and estradiol. The results were inconsistent, with some studies linking higher levels of these hormones to increased depressive symptoms while others not confirming this connection.
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During perimenopause, the estrogen and progesterone levels start to fall. Since estrogen acts as a protective agent in the brain, a decline in estrogen levels plays a crucial role in increasing the risk of developing depression, particularly in those who have suffered major depression in the past. Estrogen also impacts serotonin transmission (a neurotransmitter that promotes feelings of happiness) by influencing serotonin receptor expression. When the estrogen levels fall, it disrupts serotonin balance, potentially destabilizing moods and leading to irritability, anxiety, and sadness. [5]
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Changes in the transmission of other neuropeptides, such as dehydroepiandrosterone sulfate (DHEAS) and gamma-aminobutyric acid (GABA), may also happen during perimenopause and can cause depressive symptoms. Lower levels of DHEAS and GABA in older women have been associated with increased symptoms of depression, similar to those seen in major depressive disorders. [6] [7]
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Beyond hormonal changes, studies have also shown two major risk factors–biological and psychological–that shape a woman’s experience during menopause. Biological risk factors include hot flashes, night sweats, sleep disturbances, and unrelated chronic medical conditions. For instance, hot flashes occur as a result of the dysregulation in the brain’s thermoregulatory center due to ovarian failure and estrogen loss. It can lead to poor sleep quality, making women feel low and anxious and, ultimately, depressed. [8] Sleep disturbances and chronic health conditions can also add stress, which increases the likelihood of experiencing mood changes.
A history of depression/ postpartum depression, an adverse perception of menopause, and higher levels of neuroticism—a personality trait associated with negative emotions–are psychological factors that are strongly related to depressive symptoms during the menopause transition. [9]
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Lastly, additional life challenges such as relationship conflicts, caregiver responsibilities, career transitions or job demands, financial stress, retirement planning, or even kids moving out can contribute to feeling depressed and anxious during menopause.
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How Is Menopausal Depression Managed/ Treated?​
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Current guidelines recommend treating menopausal depression with a combination of antidepressants like selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), psychological therapy, and lifestyle changes. [10] However, antidepressants may not work for everyone and can cause side effects like serotonin syndrome, emotional numbness, diarrhea, agitation, nausea, anorexia, excessive sweating, insomnia, headache, decreased libido, etc. [11] For example, some menopausal women with
significant insomnia, irritability, or anxiety may not respond well to common SSRIs like escitalopram, or they might experience an exacerbation of symptoms with fluoxetine. For this reason, the choice of antidepressants should be tailored for each woman.
Newer medications, like desvenlafaxine (an SNRI) and agomelatine, have shown promise for perimenopausal women, with agomelatine proving to help treat insomnia. [12] [13] [14]
When it comes to psychosocial treatment, it is effective in women with perimenopausal depression that stems from work or relationship stresses common in midlife. In addition, exercise, mindfulness techniques, yoga, and dietary adjustments are also helpful in managing symptoms of depression to some extent.
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According to the data so far, menopausal hormone therapy (MHT) has shown promise in treating mild perimenopausal depression linked to hormonal fluctuations, but its effectiveness for postmenopausal depression remains unclear. [15] Recently, newer MHT regimens like low-dose hormones and transdermal estradiol, which can cross the blood-brain barrier, are also being explored. [16]
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However, MHT is not suitable for women with a history of hormone-dependent cancers or venous thromboembolism. The Australasian Menopause Society (AMS) has evidence-based guidelines that healthcare providers should follow when prescribing MHT. [17] [18]​
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How effective are lifestyle changes such as meditation, exercise and choice of diet?
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Hormonal treatments are not generally prescribed for women who smoke, have high blood pressure, have a history of blood clotting, have heart or liver diseases, have conditions like diabetes or epilepsy or are already postmenopausal.
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For these patients, lifestyle adjustments are recommended, such as adopting a balanced diet [19], practicing meditation, exercising regularly, and limiting caffeine and alcohol intake. These strategies can promote mental well-being and significantly ease perimenopausal symptoms. While these adjustments may alleviate symptoms, they cannot fully resolve the major depressive disorder and should be combined with medication and/or psychological therapy for the best outcomes.
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References:
[1] World Health Organization: WHO & World Health Organization: WHO. (n.d.). Depressive disorder (depression). https://www.who.int/news-room/fact-sheets/detail/depression
[2] Colvin A, Richardson GA, Cyranowski JM, Youk A, Bromberger JT. Does family history of depression predict major depression in midlife women? Study of Women's Health Across the Nation Mental Health Study (SWAN MHS). Arch Womens Ment Health. 2014 Aug;17(4):269-78. doi: 10.1007/s00737-014-0433-8. Epub 2014 Jun 21. PMID: 24952069; PMCID: PMC4120816.
[3] Bromberger JT, Kravitz HM, Chang YF, Cyranowski JM, Brown C, Matthews KA. Major depression during and after the menopausal transition: Study of Women's Health Across the Nation (SWAN). Psychol Med. 2011 Sep;41(9):1879-88. doi: 10.1017/S003329171100016X. Epub 2011 Feb 9. Erratum in: Psychol Med.2011 Oct;41(10):2238. PMID: 21306662; PMCID: PMC3584692.
[4] The menopause years. (n.d.). ACOG. https://www.acog.org/womens-health/faqs/the-menopause-years
[5] Freeman EW, Sammel MD, Lin H, Nelson DB. Associations of Hormones and Menopausal Status With Depressed Mood in Women With No History of Depression. Arch Gen Psychiatry. 2006;63(4):375–382. doi:10.1001/archpsyc.63.4.375
[6] Morrison MF, Ten Have T, Freeman EW, Sammel MD, Grisso JA. DHEA-S levels and depressive symptoms in a cohort of African American and Caucasian women in the late reproductive years. Biol Psychiatry. 2001 Nov 1;50(9):705-11. doi: 10.1016/s0006-3223(01)01169-6. PMID: 11704078.
[7] Wang Z, Zhang A, Zhao B, Gan J, Wang G, Gao F, Liu B, Gong T, Liu W, Edden RA. GABA+ levels in postmenopausal women with mild-to-moderate depression: A preliminary study. Medicine (Baltimore). 2016 Sep;95(39):e4918. doi: 10.1097/MD.0000000000004918. PMID: 27684829; PMCID: PMC5265922.
[8] Freeman EW, Sammel MD, Lin H. Temporal associations of hot flashes and depression in the transition to menopause. Menopause. 2009 Jul-Aug;16(4):728-34. doi: 10.1097/gme.0b013e3181967e16. PMID: 19188849; PMCID: PMC2860597.
[9] Ormel J, Jeronimus BF, Kotov R, Riese H, Bos EH, Hankin B, Rosmalen JGM, Oldehinkel AJ. Neuroticism and common mental disorders: meaning and utility of a complex relationship. Clin Psychol Rev. 2013 Jul;33(5):686-697. doi: 10.1016/j.cpr.2013.04.003. Epub 2013 Apr 29. PMID: 23702592; PMCID: PMC4382368.
[10] Managing menopausal symptoms. (n.d.). https://ranzcog.edu.au/wp-content/uploads/Managing-Menopausal-Symptoms.pdf
[11] Ma H, Cai M, Wang H. Emotional Blunting in Patients With Major Depressive Disorder: A Brief Non-systematic Review of Current Research. Front Psychiatry. 2021 Dec 14;12:792960. doi: 10.3389/fpsyt.2021.792960. PMID: 34970173; PMCID: PMC8712545.
[12] Soares CN, Thase ME, Clayton A, Guico-Pabia CJ, Focht K, Jiang Q, Kornstein SG, Ninan PT, Kane CP. Open-label treatment with desvenlafaxine in postmenopausal women with major depressive disorder not responding to acute treatment with desvenlafaxine or escitalopram. CNS Drugs. 2011 Mar;25(3):227-38. doi: 10.2165/11586460-000000000-00000. PMID: 21323394.
[13] Kornstein SG, Jiang Q, Reddy S, Musgnung JJ, Guico-Pabia CJ. Short-term efficacy and safety of desvenlafaxine in a randomized, placebo-controlled study of perimenopausal and
postmenopausal women with major depressive disorder. J Clin Psychiatry. 2010 Aug;71(8):1088-96. doi: 10.4088/JCP.10m06018blu. PMID: 20797382.
[14] S. Krüger, T. Tran, EPA-1061 – Agomelatine in the treatment of perimenopausal depression - a pilot study, European Psychiatry, Volume 29, Supplement 1, 2014, Page 1, ISSN 0924-9338, https://doi.org/10.1016/S0924-9338(14)78345-2. (https://www.sciencedirect.com/science/article/pii/S0924933814783452)
[15] Gnanasegar R, Wolfman W, Galan LH, Cullimore A, Shea AK. Does menopause hormone therapy improve symptoms of depression? Findings from a specialized menopause clinic. Menopause. 2024 Apr 1;31(4):320-325. doi: 10.1097/GME.0000000000002325. Epub 2024 Feb 19. PMID: 38377443.
[16] Goldštajn MŠ, Mikuš M, Ferrari FA, Bosco M, Uccella S, Noventa M, Török P, Terzic S, Laganà AS, Garzon S. Effects of transdermal versus oral hormone replacement therapy in postmenopause: a systematic review. Arch Gynecol Obstet. 2023 Jun;307(6):1727-1745. doi: 10.1007/s00404-022-06647-5. Epub 2022 Jun 17. PMID: 35713694; PMCID: PMC10147786.
[17] Grainger, S. (n.d.). AMS Guide to MHT/HRT Doses Australia only - Australasian Menopause Society. https://www.menopause.org.au/hp/information-sheets/ams-guide-to-mht-hrt-doses
[18] Grainger, S. (n.d.-b). Treatment Options - Australasian Menopause Society. https://www.menopause.org.au/hp/management/treatment-options
[19] Samuthpongtorn C, Nguyen LH, Okereke OI, et al. Consumption of Ultraprocessed Food and Risk of Depression. JAMA Netw Open. 2023;6(9):e2334770. doi:10.1001/jamanetworkopen.2023.34770
Fezolinetant And Elizanetant: What Should You Know About These New Non-Hormonal Therapies For Menopause
By Susan Johnson
Reviewed by Rina Carlini, PhD
October 30, 2024

For decades, hormone replacement therapy (HRT) has been the standard for treating menopausal symptoms, especially vasomotor symptoms (VMS) like hot flashes and night sweats, which affect nearly 80% of women during menopause.[1] However, HRT isn’t suitable for everyone. Women with a history of breast cancer and blood clots are not typically prescribed hormonal therapies since they can increase the risk of recurrence.
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Until recently, there were only a few non-hormonal treatment options available for treating the disruptive symptoms of menopause, and they are mostly naturopathic treatments. However, that is changing with the development of new non-hormonal pharmaceutical drugs like fezolinetant (available under the commercial name VEOZAH™) and elinzanetant–the latest therapies and the first significant advances in more than two generations for managing vasomotor symptoms (VMS) associated with perimenopause and menopause.
What Is Fezolinetant And Elinzanetant?
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Fezolinetant (developed by Astellas Pharma) and elinzanetant (developed by Bayer) are both non-hormonal oral medications that are indicated to specifically treat the VMS associated with menopause. In May 2023, fezolinetant made history as the first of its kind to be approved by the US Food and Drug Administration (FDA) for treating severe VMS.[2] Although Bayer’s elinzanetant hasn’t been commercialized yet, it was recently submitted for FDA approval in August 2024.[3]
How Do These Drugs Work?
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Fezolinetant and elizanetant are not synthetic hormone drugs like conventional HRT drugs. Instead, these are a new class of drugs that act on the neural activity that causes flushing and sweating spells in women who are experiencing the perimenopause transition.
Recently, researchers identified a new pathway in the brain that could potentially be responsible for the VMS experienced by menopausal women. This pathway involves the kisspeptin/neurokinin B/dynorphin (KNDy) neurons, which contain neurokinin 3 (NK3) receptors on their surface. When estrogen binds to the NK3 receptors, it inhibits the KNDy neurons that cause VMS. On the other hand, neurokinin B (NKB) stimulates the receptors and signals the induction of hot flashes.[4]
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Before menopause, a balance exists between estrogen and NKB in the body. This balance helps women regulate their body temperature based on their surroundings. However, during menopause, when estrogen levels drop significantly, the balance gets disrupted. More NKB binds to the NK3 receptors, causing increased KNDy neuronal activity, which in the long term leads to the hypertrophy (or enlargement) of KNDy neurons. This affects the woman’s ability to regulate core body temperature and triggers hot flashes. [4]
Fezolinetant is a selective NK3 receptor antagonist. It binds to NK3 receptors, making them unavailable for NKB to bind to, which in turn blocks neuronal activity and supports thermoregulation, thereby reducing the frequency and severity of menopausal VSM. [5]
Elizanetant works similar to fezolinetant. However, it is a dual receptor antagonist drug that targets two receptors in the brain: NK3, which regulates body temperature, and NK1, which affects mood and sleep. [6]
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"Oftentimes, the focus on a lot of these drugs is hot flashes, hot flashes, hot flashes, but we know hot flashes do not occur in isolation,” said Chrisandra Shufelt, MD, professor and chair of general internal medicine and associate director of the Women's Health Research Center at Mayo Clinic. “Elinzanetant is an interesting compound because it actually works on sleep, and that was critical because sleep disturbance precedes many other menopausal symptoms,” she shared with Medscape Medical News
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Who Should Consider Taking Non-Hormonal Therapies?​
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During the perimenopause transition phase, as a woman’s estrogen and progesterone levels start to drop significantly, menopausal hormone therapy (MHT) is considered one of the fastest and most effective ways to treat the bothersome VSM that can occur since MHT works to replenish the body’s estrogen and progesterone levels.
Some women should not be administered MHT even if they are requesting it to be prescribed by their doctors. Menopausal women with a history of breast or endometrial cancer, especially hormone receptor-positive (HR+) cancers, should not take MHT because these types of cancer cells have receptors for estrogen, progesterone, or both, which can significantly increase the risk that these tumors can grow, metastasize and cause more serious complications. For this reason, women who have had breast or endometrial cancer, any family members who had these cancers, or those women who are considered high risk for developing these cancers should not be prescribed MHT. [7]
In addition, women with a history of venous thromboembolic events or stroke, gallbladder problems, and coronary heart diseases should avoid MHT. However, they can instead consider non-hormonal treatments like fezolinetant or elinzanetant.
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How Effective Are Non-Hormonal Therapies For Treating VMS?​
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SKYLIGHT 1
SKYLIGHT 1, a Phase III randomized controlled clinical study, was performed to assess the effectiveness of fezolinetant in treating moderate-to-severe vasomotor symptoms associated with menopause. The clinical study included over 500 women between 40 and 65 years of age, who were selected from around the world and who had experienced at least seven hot flashes a day. [8]
The study participants were split into three groups, one receiving a placebo intervention and the other two receiving 35 mg and 45 mg of fezolinetant, respectively. After 4 weeks, the women who were administered fezolinetant reported a reduction in the frequency and severity of hot flashes. After 12 weeks, 45% of women taking 30 mg of fezolinetant, 57% of women taking 45 mg of fezolinetant, and 30% of the placebo group reported a reduction in the frequency of hot flashes. [8]
The study's authors also wrote that the participants reported better quality of life and fewer night-time awakenings. [8]
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OASIS 1 and 2
Bayer conducted three Phase III clinical studies–OASIS 1, 2, and 3–to analyze the effectiveness of elinzanetant. OASIS 1 and 2 were specifically conducted to analyze the impact of elinzanetant on moderate to severe VMS, its effects on sleep disturbances, and overall menopause-related quality of life. These trials followed a double-blind, placebo-controlled design to ensure accurate results.
Both OASIS 1 and 2 studies met all primary endpoints. Compared to the placebo, there was a 50% reduction in the frequency and severity of hot flashes in 80% of participants taking elinzanetant by the fourth and twelfth weeks. In addition, the participants also said they slept better while taking elinzanetant. Improvement in these areas was seen as early as week one, indicating a rapid onset of action. The drug’s safety was consistent with prior studies, with no unexpected adverse effects.
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According to Dr Michelle Jacobson, a Canadian OB/GYN physician and certified menopause specialist based in Toronto, Canada, these findings mark a significant milestone for managing menopausal symptoms. She said, “As a menopause specialist, I am truly excited to see the results of the Phase III trials on elinzanetant. For so long, we have been treating those suffering from menopausal symptoms with second-line, non-indicated therapies. Now, we are one step closer to having effective, indicated, and safe treatments for our patients. I look forward to being able to offer women a novel treatment that has such positive outcomes once it is approved by Health Canada. The more options we have, the better we can individualize therapies for our patients to help them live their best and healthiest lives possible."
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Claudio N Soares, MD, PhD, who is a Professor of Psychiatry at Queen’s University in Canada, an experienced clinical researcher in menopause and women’s mental health, and President-elect of The Menopause Society, also expressed similar views.
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“These results are really encouraging. For too long, we have underestimated, sometimes even overlooked, the negative impact that menopausal symptoms–hot flashes, sleep disturbances, mood changes–may have on a woman’s health and quality of life. It is reassuring to see that this is no longer the case and that women may soon have access to novel, non-hormonal options to alleviate these symptoms and improve their quality of life”.
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While the findings of OASIS 3 have not yet been published, the study was performed with a large sample size of participants to confirm the findings of OASIS 1 and 2. [9][10]
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Are There Any Side Effects?
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In the SKYLIGHT 1 study, a significant number of participants had experienced side effects or adverse reactions (listed below), which were 37% of women taking 30 mg and 43% of women taking 45 mg Fezolinetant. Interestingly, 45% of women in the placebo group (who were not taking any drug) also reported similar side effects. So, the difference in side effects between the drug medication group and placebo groups was minimal. [8]
The most commonly reported side effects included:
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Headache
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Abdominal pain
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Diarrhea
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Insomnia
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Back pain
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Elevated hepatic transaminase levels (potential risk of liver damage)
The study also included a warning for potential liver damage or elevated hepatic transaminase levels. Therefore, women considering Fezolinetant are advised to have their baseline bloodwork done to evaluate liver function and injury before starting the medication. While on the drug, follow-up blood tests should be performed every three months for the first nine months of treatment to monitor liver health.
Additionally, patients should watch for symptoms and signs of liver damage, such as nausea, vomiting, or jaundice (yellowing of the skin and eyes), and contact their physician if these signs appear.
With elinzanetant, no participant showed signs of hepatotoxicity or possible drug-induced liver injury. Safety assessments were performed to look for adverse effects in participants and included endometrial biopsies, bone mineral density, weight, and blood tests. It was found that 30.4% of participants taking elinzanetant and 14.6% of participants taking the placebo pill reported adverse effects, which were, most commonly, headache, fatigue, and sleepiness. [9]
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Final Thoughts
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Over 75% of menopausal women experience VMS, with 25% describing their symptoms as severe. In one-third of women, these symptoms can persist for seven years or more.[11] A pooled analysis of individual-level data revealed that women experiencing both persistent and severe hot flashes and night sweats had a significantly higher risk of cardiovascular disease (CVD). [12]
In such cases, having access to medications like fezolinetant and elinzanetant will not only expand treatment options for women but also prove to be an effective alternative for women who should not take HRT.
It should be noted that both fezolinentant and elinzanetant are very new classes of drugs that do not have a long clinical history, and as such, the clinical practice guidelines on how to incorporate them into the treatment regimen are currently unclear. While both these drugs will prove to be exciting options for women, whether they can be used in combination with other treatments for menopausal symptoms still needs further study.
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References:
[1] Gold EB, Colvin A, Avis N, Bromberger J, Greendale GA, Powell L, Sternfeld B, Matthews K. Longitudinal analysis of the association between vasomotor symptoms and race/ethnicity across the menopausal transition: study of women's health across the nation. Am J Public Health. 2006 Jul;96(7):1226-35. doi: 10.2105/AJPH.2005.066936. Epub 2006 May 30. PMID: 16735636; PMCID: PMC1483882.
[3] https://www.bayer.com/en/us/news-stories/new-drug-application-to-us-fda-for-elinzanetant
[4] Prague JK, Roberts RE, Comninos AN, Clarke S, Jayasena CN, Mohideen P, Lin VH, Stern TP, Panay N, Hunter MS, Webber LC, Dhillo WS. Neurokinin 3 receptor antagonism rapidly improves vasomotor symptoms with sustained duration of action. Menopause. 2018 Aug;25(8):862-869. doi: 10.1097/GME.0000000000001090. PMID: 29533369; PMCID: PMC6092106.
[5] Santoro N, Waldbaum A, Lederman S, Kroll R, Fraser GL, Lademacher C, Skillern L, Young J, Ramael S. Effect of the neurokinin 3 receptor antagonist fezolinetant on patient-reported outcomes in postmenopausal women with vasomotor symptoms: results of a randomized, placebo-controlled, double-blind, dose-ranging study (VESTA). Menopause. 2020 Dec;27(12):1350-1356. doi: 10.1097/GME.0000000000001621. PMID: 32769757; PMCID: PMC7709922.
[6] Pawsey S, Mills EG, Ballantyne E, Donaldson K, Kerr M, Trower M, Dhillo WS. Elinzanetant (NT-814), a Neurokinin 1,3 Receptor Antagonist, Reduces Estradiol and Progesterone in Healthy Women. J Clin Endocrinol Metab. 2021 Jul 13;106(8):e3221-e3234. doi: 10.1210/clinem/dgab108. PMID: 33624806; PMCID: PMC8277204.
[7] Clusan L, Ferrière F, Flouriot G, Pakdel F. A Basic Review on Estrogen Receptor Signaling Pathways in Breast Cancer. Int J Mol Sci. 2023 Apr 6;24(7):6834. doi: 10.3390/ijms24076834. PMID: 37047814; PMCID: PMC10095386.
[8] Lederman S, Ottery FD, Cano A, Santoro N, Shapiro M, Stute P, Thurston RC, English M, Franklin C, Lee M, Neal-Perry G. Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomized controlled study. Lancet. 2023 Apr 1;401(10382):1091-1102. doi: 10.1016/S0140-6736(23)00085-5. Epub 2023 Mar 13. PMID: 36924778.
[9] Pinkerton JV, Simon JA, Joffe H, et al. Elinzanetant for the Treatment of Vasomotor Symptoms Associated With Menopause: OASIS 1 and 2 Randomized Clinical Trials. JAMA. 2024;332(16):1343–1354. doi:10.1001/jama.2024.14618
[12] Zhu, Dongshan et al.Vasomotor menopausal symptoms and risk of cardiovascular disease: a pooled analysis of six prospective studies; American Journal of Obstetrics & Gynecology, Volume 223, Issue 6, 898.e1 - 898.e16
Risk factors for dementia — 2024 update from The Lancet
Source: Dementia prevention, intervention, and care: 2024 report of The Lancet standing Commission; Livingston, Gill et al., 2024.
August 6, 2024

A 2024 update to The Lancet Commission on Dementia Prevention, Intervention and Care has added new evidence that untreated vision loss and high LDL cholesterol are risk factors for dementia. Overall, 45% of cases of dementia are potentially preventable by addressing 14 modifiable risk factors at different stages in life. ​
Reference:
Dementia prevention, intervention, and care: 2024 report of The Lancet standing Commission; Livingston, Gill et al., 2024.
Sleep and Hormones
By Henry Xu, PhD. and Joanne Tejeda, PhD.
July 19, 2024

Reproductive hormones play a crucial role in regulating various physiological processes in women, including sleep. The interplay between estrogen and progesterone significantly influences sleep patterns and quality, with noticeable variations across different phases of the menstrual cycle, during pregnancy, and throughout menopause. These hormonal fluctuations can lead to sleep disturbances, such as insomnia, fragmented sleep, and changes in sleep patterns.
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Women have a more than 40% higher risk of sleep disorders compared to men. Over 50% of menopausal women globally suffer from sleep disorders, and up to 65% of young adult women experience poor sleep quality due to factors such as irregular sleep schedules, high rates of anxiety and depression, and excessive screen time [1-3].
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Keep reading to discover how reproductive hormones affect sleep patterns and uncover essential strategies to combat sleep-related issues that many women face throughout their reproductive lives.
How is Sleep affected at each stage of your menstrual cycle?
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During the follicular phase, the first half of the menstrual cycle, rising estrogen levels can promote better sleep by increasing rapid eye movement (REM) sleep and enhancing overall sleep quality [4].
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During the luteal phase, the second half of the menstrual cycle, estrogen levels fluctuate and drop just before menstruation, contributing to sleep disturbances. Progesterone levels increase and have a sedative effect, initially promoting sleepiness. However, as progesterone levels drop just before menstruation, women may experience premenstrual syndrome (PMS) symptoms, including insomnia, disrupted sleep, night sweats [4].

Figure 1. Hormone changes during the average 28-day menstrual cycle without a fertilization event. FSH is Follicle Stimulating Hormone and LH is Luteinizing Hormone. Shaded gray area is the Ovulation phase, which represents when you are most fertile.
Menstruation
During menstruation, women often experience specific changes in their sleep patterns due to a combination of physical discomfort and hormonal shifts. Common issues include increased sleep disturbances, such as frequent awakenings and difficulty falling asleep, primarily caused by menstrual pain, cramps, bloating, headaches and fatigue. Additionally, hormonal fluctuations during this phase can lead to mood changes, such as irritability and anxiety, which further contribute to sleep disruptions. Some women also report experiencing more vivid dreams and nightmares during menstruation. Understanding these patterns can aid in developing better sleep management strategies during this time [5].
How is sleep affected during pregnancy?
During pregnancy, sleep patterns shift significantly across each trimester [6, 7]:
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First Trimester: increased levels of progesterone can cause excessive daytime sleepiness and frequent awakenings at night due to nausea and increased urination.
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Second Trimester: sleep generally improves as hormone levels stabilize, although some women may still experience disruptions.
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Third Trimester: sleep disturbances often increase again due to physical discomfort, frequent urination, and hormonal changes.
Sleep Changes During Menopause
Sleep changes during the menopause transition (e.g., perimenopause, menopause, and post-menopause) are significant due to hormonal fluctuations. During perimenopause, declining estrogen and progesterone levels can cause hot flashes, night sweats, and mood swings, leading to insomnia and fragmented sleep. Menopause intensifies these symptoms, further disrupting sleep and increasing the risk of sleep disorders such as sleep apnea and restless legs syndrome.
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In menopausal women, Hormone Replacement Therapy (HRT) can help alleviate sleep disturbances by stabilizing hormone levels. However, HRT is not suitable for everyone and should be considered carefully with medical guidance.
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In post-menopause, while some symptoms may stabilize, many women continue to experience sleep disturbances due to persistent hot flashes, increased anxiety, and other health changes [6, 7].
How Women’s Sleep and Hormones Impact Memory
Sleep plays a crucial role in cognitive functions, including memory consolidation, which is the process of transforming short-term memories into long-term ones. For women, hormonal changes throughout their reproductive lives can significantly impact sleep quality and, consequently, memory [6].
Estrogen
Estrogen has been shown to have neuroprotective effects, which can enhance cognitive functions, including memory. It promotes the growth and survival of neurons, enhances synaptic plasticity, and increases neurotransmitter levels.
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As estrogen levels decline during menopause, many women report difficulties with memory and other cognitive functions. HRT has been found to mitigate some of these cognitive declines, although its use must be carefully considered due to other health risks.
Progesterone
Progesterone's impact on memory is more complex and can vary. Some studies suggest it may impair certain types of memory, particularly verbal and spatial memory, while others indicate it might support memory consolidation during sleep. High levels of progesterone during the luteal phase can sometimes lead to difficulties in memory and concentration, often referred to as "brain fog."
Research Insights on Estrogen and Progesterone Effects on Memory
Recent research highlights that estradiol (a form of estrogen) strengthens brain cell mechanisms crucial for memory formation and retrieval. Estradiol can induce rapid changes in brain cells within minutes to hours, essential for enhancing memory consolidation. This demonstrates estradiol's powerful and swift impact on the brain. Estrogen's memory-enhancing ability suggests potential for treating cognitive decline associated with aging and neurodegenerative diseases [8]. In addition, new findings reveal progesterone's rapid inhibitory role on memory during navigational tasks [9].
Strategies for Improving the Sleep Quality
Improving sleep quality is important for overall health and well-being. Here are some practices that women can adopt to get better sleep [6, 7]:
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Establish a consistent sleep schedule – going to bed and waking up at the same time every day, even on weekends, helps regulate your body’s internal clock.
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Create a relaxing bedtime routine by engaging in calming activities like reading. Avoid screens (phones, tablets, computers, TV) at least an hour before bedtime as the blue light can interfere with melatonin production.
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Avoid heavy meals before bed as they a can cause discomfort and interfere with sleep
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Limit caffeine and alcohol intake.
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Manage your stress by practicing relaxation techniques such as medication, breathing exercises to help calm the mind.
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Regular physical activity can promote better sleep. Aim for at least 30 minutes of moderate exercise most days of the week but avoid vigorous exercise close to bedtime.
For women suffering from chronic insomnia, Cognitive Behavioral Therapy for Insomnia (CBT-I) may be beneficial. CBT-I includes components such as sleep hygiene education, stimulus control, sleep restriction, and cognitive restructuring. Unlike sleeping pills, CBT-I has long-lasting effects without the risk of side effects. If medication is necessary, options like benzodiazepines and melatonin receptor agonists are available but should be used short-term to avoid potential dependency [10]. In addition, medications such as dopamine agonists and anti-seizure drugs can be used to treat specific disorders like Restless Legs Syndrome.
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If sleep problems persist, it may be helpful to consult a healthcare provider or a sleep specialist to rule out sleep disorders and to find the best treatment solution for you.
References
[1] Salari, Nader et al. “Global prevalence of sleep disorders during menopause: a meta-analysis.” Sleep & breathing = Schlaf & Atmung vol. 27,5 (2023): 1883-1897. doi:10.1007/s11325-023-02793-5
[2] Fatima, Yaqoot et al. “Exploring Gender Difference in Sleep Quality of Young Adults: Findings from a Large Population Study.” Clinical medicine & research vol. 14,3-4 (2016): 138-144. doi:10.3121/cmr.2016.1338
[3] Phillips, Barbara A et al. “Sleep disorders and medical conditions in women. Proceedings of the Women & Sleep Workshop, National Sleep Foundation, Washington, DC, March 5-6, 2007.” Journal of women's health (2002) vol. 17,7 (2008): 1191-9. doi:10.1089/jwh.2007.0561
[4] Alana M C Brown, Nicole J Gervais, “Role of Ovarian Hormones in the Modulation of Sleep in Females Across the Adult Lifespan”, Endocrinology, Volume 161, Issue 9, September 2020, doi: 10.1210/endocr/bqaa128
[5] Baker, Fiona C, and Kathryn Aldrich Lee. “Menstrual Cycle Effects on Sleep.” Sleep medicine clinics vol. 13,3 (2018): 283-294. doi:10.1016/j.jsmc.2018.04.002
[6] Nicole J. Gervais, Jessica A. Mong, Agnès Lacreuse, “Ovarian hormones, sleep and cognition across the adult female lifespan: An integrated perspective”,Frontiers in Neuroendocrinology, Volume 47, 2017, Pages 134-153, doi: 10.1016/j.yfrne.2017.08.002
[7] Harrington YA, Parisi JM, Duan D, Rojo-Wissar DM, Holingue C, Spira AP. “Sex Hormones, Sleep, and Memory: Interrelationships Across the Adult Female Lifespan”, Frontier in Aging Neuroscience, 2022 Jul 14, Volume 14 - 2022, doi: 10.3389/fnagi.2022.800278
[8] Luine, Victoria N., and Maya Frankfurt, “Estrogenic Regulation of Recognition Memory and Spinogenesis.” Karyn M. Frick (ed.), Estrogens and Memory: Basic Research and Clinical Implications (2020): 159–169. doi:10.1093/oso/9780190645908.003.0011
[9] Lacasse, Jesse M et al. “Progesterone rapidly alters the use of place and response memory during spatial navigation in female rats.” Hormones and behavior vol. 140 (2022): 105137. doi:10.1016/j.yhbeh.2022.105137
[10] Abad, Vivien C, and Christian Guilleminault. “Diagnosis and treatment of sleep disorders: a brief review for clinicians.” Dialogues in clinical neuroscience vol. 5,4 (2003): 371-88. doi:10.31887/DCNS.2003.5.4/vabad
Association of serum cortisol in women with brain biomarkers of Alzheimer’s risk
Reviewed by Rina Carlini, PhD
April 22, 2024

Image licensed from Shutterstock #2188096049
New research insights about menopausal women’s brain health was reported in March 2024 in a neuroscience research study led by Dr. Lisa Mosconi and co-workers of the Weill Cornell Medicine in New York City [1]. The research investigated the sex-specific relationship between serum cortisol levels and brain biomarkers associated with Alzheimer's disease risk.
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Alzheimer's disease is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss, with increasing evidence suggesting a link between stress-related hormones such as cortisol and the development of Alzheimer's Disease (AD). However, existing research has largely overlooked potential sex differences in these associations.
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To address this gap, Dr. Mosconi and colleagues conducted a study involving 277 participants, to examine the relationship between serum cortisol levels and brain biomarkers of Alzheimer's risk, while considering sex-specific differences. The study included both male and female participants aged 35–65 years who have risk factors for late-onset AD such as a family history and/or the APOE4 genotype, and who were assessed prior to the study of having normal cognitive function. The research methods used advanced neuroimaging techniques to assess various brain biomarkers associated with Alzheimer's disease, such as amyloid-beta deposits and neurodegeneration.
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The study revealed sex-specific associations between serum cortisol levels and brain biomarkers of Alzheimer's risk. Specifically, higher levels of serum cortisol were associated with increased amyloid-beta deposits in women but not in men. Amyloid-beta deposition is a hallmark pathological feature of Alzheimer's disease and is believed to contribute to the development and progression of the condition. The research findings suggests that elevated cortisol levels may exacerbate amyloid-beta deposition in women, thereby increasing their risk of developing Alzheimer's disease.
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Furthermore, the study found no significant association between serum cortisol levels and neurodegeneration biomarkers in either men or women. Neurodegeneration is another critical aspect of Alzheimer's pathology, and is characterized by the progressive loss of neurons and brain tissue. The lack of association suggests that cortisol may have a more specific effect on amyloid-beta deposition rather than overall neurodegeneration, in the context of Alzheimer's disease risk.
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The researchers did not observe reduced cognitive performance in women compared to men, nor did their study confirm the findings of a previous research study in 2018 that reported a stronger association of cortisol with memory in women compared to age-controlled men [2]. It was recommended that to advance this research, a broad range of cognitive tests might be needed to capture the subtle cognitive changes in men and women that are associated with cortisol levels.
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In summary, Dr. Mosconi's study sheds light on the sex-specific associations of serum cortisol with brain biomarkers of Alzheimer's risk. The findings underscore the importance of considering sex differences in Alzheimer's research and highlight the potential role of stress-related hormones in the development and progression of the disease. Further research in this area may contribute to the development of personalized strategies and therapeutic interventions for Alzheimer's prevention and treatment.
References
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Mosconi, L., Williams, S., Carlton, C. et al. Sex-specific associations of serum cortisol with brain biomarkers of Alzheimer’s risk. Scientific Reports, volume 14, 5519 (2024). https://doi.org/10.1038/s41598-024-56071-9
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Echouffo-Tcheugui, J. B. et al. Circulating cortisol and cognitive and structural brain measures: The Framingham Heart Study. Neurology 91, e1961–e1970 (2018). https://doi.org/10.1212/WNL.0000000000006549