Shokri-Kojori E, Wang G, Wiers CE, et al. β-amyloid accumulation in the human brain after one night of sleep deprivation. PNAS. 2018;115(17):4483-4488.
Design and Objective
To determine the effects of 1 night of acute sleep deprivation on β-amyloid clearance in the human brain of healthy individuals using positron emission tomography (PET) and F-florbetaben (FBB) measurements. A night of restful sleep was used as the baseline.
Twenty healthy participants, 10 women and 10 men, ages 22 to 72.
Exclusion criteria included the following:
- Urine positive for psychotropic drugs
- History of alcohol or drug use disorders
- Present or past neurological or psychiatric disorders
- Evidence of cognitive impairment
- Use of psychoactive medications in the past month
- Current use of prescription medications
- Medical conditions that may alter cerebral function
- Cardiovascular and metabolic diseases
- History of head trauma
Study Parameters Assessed
All participants completed 2 PET scan sessions using FBB to measure β-amyloid burden; FBB radiotracers bind to β-amyloid plaques.
The first scan was taken after a full night of restful sleep and the second scan was taken at the same time after a night of sleep deprivation. The Pittsburgh Sleep Quality Index (PSQI) questionnaire was used to assess sleep quality. The PSQI analyzes self-reported sleep hours and other factors associated with sleep quality.
Secondary measurements in mood were also evaluated via mood questionnaires that were gathered before, during, and after the PET scans.
The primary outcome measures were changes in PET-FBB results after a night of restful sleep vs changes in PET-FBB results after a night of sleep deprivation.
The PET-FBB images showed significantly higher uptake of FBB tracer in the right lateralized cluster (hippocampal, parahippocampal, and thalamic regions) area of the brain in 19/20 participants after sleep deprivation.
Just 1 night of acute sleep deprivation increased β-amyloid burden by 5%, specifically in brain regions that are associated with the development of Alzheimer's disease (eg, the hippocampus). The researchers speculate that the interruption of glymphatic clearance during sleep deprivation contributes to the β-amyloid accumulation.
Not surprisingly, a worsening of mood was noted after the night of sleep deprivation. After 1 night of sleep deprivation, measures of alertness, energy, and happiness significantly decreased compared to baseline.
The glymphatic system is a waste clearance pathway that detoxifies soluble proteins and metabolites from the central nervous system.1 It was first proposed as a distinct entity by Dr Maiken Nedergaard and her colleagues in 2012.2 Through a series of rodent experiments, Nedergaard et al showed that solutes in the interstitial space of the brain are cleared by a perivascular system into the cerebral spinal fluid (CSF). They also demonstrated that β-amyloid, a potentially pathogenic protein involved in the amyloid plaques of Alzheimer's disease, is among the many soluble proteins cleared by the glymphatic system. The glymphatic system—a dedicated system that is analogous to the lymphatics of the body—is beginning to revolutionize our understanding of brain health and disease.
Nedergaard and colleagues also showed that there is a massive increase in the exchange of solutes through the glymphatics during deep sleep.3 Sleep disturbance is well known to increase with age.4 In addition, the glymphatic system undergoes functional decline with age.5 Together, this combination may explain the increasing risk of Alzheimer's disease, dementia, and cognitive decline with aging and poor sleep.
In short, sleep deprivation suppresses glymphatic activity, and this leads to poorer clearance of molecules in the interstium of the brain. According to a 2015 review, “…the sleep state is particularly conducive to convective fluid fluxes and thereby to clearance of metabolites. Thus, a major function of sleep appears to be that the glymphatic system is turned on and that the brain clears itself of neurotoxic waste products produced during wakefulness.”6
It was previously thought that blood-brain barrier (BBB) transport was the only mechanism by which the brain cleared interstitial solutes such as β-amyloid and other waste proteins that accumulate in the brain. It now appears that the glymphatic system and the BBB are complementary. The authors of a 2018 review that investigated how the BBB and the glymphatic system interact note that “Disruption of these mechanisms can lead to protein accumulation and may initiate neurodegenerative disorders, for instance amyloid-β accumulation and Alzheimer’s disease.”7
In short, sleep deprivation suppresses glymphatic activity, and this leads to poorer clearance of molecules in the interstium of the brain.
It becomes obvious that sleep is critical to brain detoxification, but we are also finding out it’s not just the quantity of sleep that is important; it’s also the type of sleep. Preliminary research suggests that specifically regarding glymphatic function, slow-wave sleep is critical.8 Slow-wave sleep is the deepest phase of non–rapid eye movement (non-REM) sleep, when dreaming takes place. This type of sleep is also associated with enhanced memory consolidation.
Integrative practitioners have many tools to help sleep-deprived patients. In addition to addressing sleep disturbance, clinicians may want to consider supporting brain function directly as well.
Supporting brain function can be done using a variety of integrative approaches. To date, however, there are no studies on the enhancement of glymphatic activity specifically using natural or prescriptive substances. That said, there are many natural agents with evidence that they improve cognition, memory, and focus. The following is a list of a few natural substances to consider for supporting brain health.
Citicoline increases neurotransmitter levels via its influence on brain phospholipids, such as phosphatidylcholine.9,10 A 2015 randomized placebo-controlled trial demonstrated that citicoline improved attention (P=0.02) and increased psychomotor speed (P=0.03) compared to placebo in male adolescents.11 A 2008 study using magnetic resonance spectroscopy demonstrated that citicoline supplementation produced significant changes in membrane phospholipids, and it increased beta-nucleoside triphosphates largely as adenosine triphosphate (ATP) in the brain (+14%), as well as phosphocreatine (+7%) and the ratio of phosphocreatine to inorganic phosphate (+32%).7 A 2012 double-blind, randomized, placebo-controlled 3-arm study featuring healthy middle-aged women demonstrated that citicoline supplementation improved attention span and focus compared to placebo.12
Curcumin also has potential in improving cognitive function. A 2018 randomized, double-blind, 2-group parallel design trial involving 46 adults age 50 to 90 demonstrated that curcumin supplementation improved long-term memory, visual memory, and attention compared to placebo.13 In addition, FDDNP testing of 30 participants in that study (15 intervention and 15 placebo) showed a significant decreased binding in the amygdala in the intervention group, which is important because increased FDDNP binding is positively associated with dementia. A 2016 randomized, placebo-controlled, double-blind study of curcumin in community-dwelling older adults showed that while the placebo group had declines in cognitive measurements, the curcumin group had no declines.14
Omega-3 fatty acids have also been shown to improve cognitive function. A 2017 double-blind randomized controlled trial showed that omega-3 supplementation improved perceptual speed (P=0.001), space efficiency (P=0.013), working memory (P=0.018), and total Basic Cognitive Aptitude Test scores (P=00.000).15 A 2014 meta-analysis of 12 randomized controlled trials found that omega-3 fatty acids produced a significant reduction in cognitive decline rate (−0.07; 95% confidence interval [CI] −0.01 to −0.02) compared to placebo.16 A 2015 meta-analysis found that docosahexaenoic acid (DHA) in particular, either alone or in combination with eicosapentaenoic acid (EPA), significantly improved episodic memory (P<0.004) compared to placebo.17
There are many other natural substances that have been shown to enhance memory or cognition, such as Ginkgo biloba,18 berries,19 American ginseng,20 vitamin E,21 and vitamin K.22 In addition, vitamin deficiencies, including deficiencies of vitamins B1223 and C,24 are associated with poor brain function, so correcting deficiencies can be clinically important.25
Addressing sleep issues in clinical practice can be challenging. This latest study suggests that it may be prudent to focus on supporting overall brain health to help preserve and enhance cognition, memory, and focus among those who struggle with sleep disturbance.
- Jessen NA, Munk AS, Lundgaard I, Nedergaard M. The glymphatic system—a beginner's guide. Neurochem Res. 2015;40(12):2583-2599.
- Iliff JJ, Wang M, Liao Y, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med. 2012;4(147):147ra11.
- Xie L, Kang H, Xu Q, et al. Sleep drives metabolite clearance from the adult brain. Science. 2013;342(6156):373-377.
- Gulia KK, Kumar VM. Sleep disorders in the elderly: a growing challenge. Psychogeriatrics. 2018;18(3):155-165.
- Kress BT, Iliff JJ, Xia M, et al. Impairment of paravascular clearance pathways in the aging brain. Ann Neurol. 2014;76(6):845-861.
- Jessen NA, Munk A, Lundgaard I, Nedergaard M. The glymphatic system—a beginner’s guide. Neurochem Res. 2015;40(12):2583-2599.
- Verheggen ICM, Van Boxtel MPJ, Verhey FRJ, et al. Interaction between blood-brain barrier and glymphatic clearance. Neurosci Biobehav Rev. 2018;90:26-33.
- Benveniste H, Liu X, Koundal S, et al. The glymphatic system and waste clearance with brain aging: a review. Gerontology. 2019;65(2):106-119.
- Chitu I, Tudosescu R, Leasu-Branet C, et al. Citicoline—a neuroprotector with proven effects on glaucomatous disease. Rom J Ophthalmol. 2017;61(3):152-158.
- Silveri MM, Dikan J, Ross AJ, et al. Citicoline enhances frontal lobe bioenergetics as measured by phosphorus magnetic resonance spectroscopy. NMR Biomed. 2008;21(10):1066-1075.
- McGlade E, Agoston AM, DiMuzio J, et al. The effect of citicoline supplementation on motor speed and attention in adolescent males. J Atten Disord. 2019;23(2):121-134.
- McGlade E, Locatelli A, Hardy J, et al. Improved attentional performance following citicoline administration in healthy adult women. Food and Nutrition Sciences. 2012;3:769-773.
- Small GW, Siddarth P, Li Z, et al. Memory and brain amyloid and tau effects of a bioavailable form of curcumin in non-demented adults: a double-blind, placebo-controlled 18-month trial. Am J Geriatr Psychiatry. 2018;26(3):266-277.
- Rainey-Smith SR, Brown BM, Sohrabi HR, et al. Curcumin and cognition: a randomised, placebo-controlled, double-blind study of community-dwelling older adults. Br J Nutr. 2016;115(12):2106-2113.
- Bo Y, Zhang X, Wang Y, et al. The n-3 polyunsaturated fatty acids supplementation improved the cognitive function in the Chinese elderly with mild cognitive impairment: a double-blind randomized controlled trial. Nutrients. 2017;9(1):54.
- Abubakari A, Naderali M, Naderali EK. Omega-3 fatty acid supplementation and cognitive function: are smaller dosages more beneficial? Int J Gen Med. 2014;7:463-473.
- Yurko-Mauro K, Alexander DD, Van Elswyk ME. Docosahexaenoic acid and adult memory: a systematic review and meta-analysis. PLoS One. 2015;10(3):e0120391.
- Silberstein RB, Pipingas A, Song J, et al. Examining brain-cognition effects of Ginkgo biloba extract: brain activation in the left temporal and left prefrontal cortex in an object working memory task. Evid Based Complement Alternat Med. 2011;2011:164139.
- Nilsson A, Salo I, Plaza M, Björck I. Effects of a mixed berry beverage on cognitive functions and cardiometabolic risk markers; a randomized cross-over study in healthy older adults. PLoS One. 2017;12(11):e0188173.
- Scholey A, Ossoukhova A, Owen L, et al. Effects of American ginseng (Panax quinquefolius) on neurocognitive function: an acute, randomised, double-blind, placebo-controlled, crossover study. Psychopharmacology (Berl). 2010;212(3):345-356.
- Mangialasche F, Xu W, Kivipelto M, et al. Tocopherols and tocotrienols plasma levels are associated with cognitive impairment. Neurobiol Aging. 2012;33(10):2282-2290.
- Chouet J, Ferland G, Feart C, et al. Dietary vitamin K intake is associated with cognition and behavior among geriatric patients: the CLIP study. Nutrients. 2015;7(8):6739-6750.
- Health Quality Ontario. Vitamin B12 and cognitive function. Ont Health Technol Assess Ser. 2013;13(23):1-45.
- Travica N, Ried K, Sali A, et al. Vitamin C status on cognitive function: a systematic review. Nutrients. 2017;9(9):960.
- Harris E, Macpherson H, Vitetta L, Kirk J, Sali A, Pipingas A. Effects of a multivitamin, mineral and herbal supplement on cognition and blood biomarkers in older men: a randomised, placebo-controlled trial. Hum Psychopharmacol. 2012;27(4):370-377.