Glymphatic failure as a final common pathway to dementia

In the paper

“The quality of sleep decreases as we age and disruption of the regular sleep architecture is a frequent antecedent to the onset of dementia in neurodegenerative diseases.”

• Also stated in: § Sleep, aging, neurodegeneration and the glymphatic system · plain

  “Most NREM sleep in people over 60 years is light, consisting of the more superficial stages 1–2 (79)”

What the sources say

• Not checked yetcites [79] Landolt HP, Borbely AA, Age-dependent changes in sleep EEG topography. Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 112, 369– 377 (2001). 11165543 source
• Not checked yetcites [80] Malhotra RK, Neurodegenerative Disorders and Sleep. Sleep medicine clinics 13, 63– 70 (2018). 29412984 source

In the paper

“The glymphatic system is a highly organized cerebrospinal fluid transport system that shares several key functions with the lymphatic vessels of peripheral tissues, including the export of excess interstitial fluid and proteins”

What the sources say

• Not checked yetcites [24] Iliff JJ, A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Science translational medicine 4, 147ra 111 (2012). PMC3551275 22896675 source

In the paper

“Yet brain tissue itself lacks histologically-distinct lymphatic vessels. Rather, fluid clearance from the brain proceeds via the glymphatics, a structurally distinct system of fluid transport that utilizes the perivascular spaces created by the vascular endfeet of astrocytes (26).”

What the sources say

• Not checked yetcites [26] Simard M, Arcuino G, Takano T, Liu QS, Nedergaard M, Signaling at the gliovascular interface. The Journal of neuroscience: the official journal of the Society for Neuroscience 23, 9254– 9262 (2003). 14534260 PMC6740832 source

In the paper

“The glymphatic system, which clears the brain of protein waste products, is mostly active during sleep.”

• Also stated in: § The glymphatic and lymphatic systems · plain

  “fluid transport is enabled by sleep and suppressed during wakefulness”

What the sources say

• Not checked yetcites [35] Xie L, Sleep drives metabolite clearance from the adult brain. Science 342, 373– 377 (2013). 24136970 PMC3880190 source
• Not checked yetcites [36] Hablitz LM, Increased glymphatic influx is correlated with high EEG delta power and low heart rate in mice under anesthesia. Sci Adv 5, eaav5447 (2019). 30820460 PMC6392807 source

In the paper

“the antecedent sleep loss can be identified post hoc by an increase in EEG slow wave activity during recovery sleep (8)”

What the sources say

• Not checked yetcites [8] Rodriguez AV, Why Does Sleep Slow-Wave Activity Increase After Extended Wake? Assessing the Effects of Increased Cortical Firing During Wake and Sleep. The Journal of neuroscience: the official journal of the Society for Neuroscience 36, 12436– 12447 (2016). 27927960 PMC5148229 source

In the paper

“glymphatic clearance is temporally regulated and cyclically so, in that fluid transport is enabled by sleep and suppressed during wakefulness.”

What the sources say

• Not checked yetcites [35] Xie L, Sleep drives metabolite clearance from the adult brain. Science 342, 373– 377 (2013). 24136970 PMC3880190 source
• Not checked yetcites [36] Hablitz LM, Increased glymphatic influx is correlated with high EEG delta power and low heart rate in mice under anesthesia. Sci Adv 5, eaav5447 (2019). 30820460 PMC6392807 source

In the paper

“As such, waste removal is likely most efficient in the early hours of sleep, and especially during recovery sleep after prolonged wakefulness (37).”

What the sources say

• Not checked yetcites [37] Hauglund L, Pavan C, Nedergaard M, Cleaning the sleeping brain – the potential restorative function of the glymphatic system. Current Opinion in Physiology 15 1– 6 (2020). source

In the paper

“This rhythm is supported by the temporally-regulated localization of AQP4 via the dystrophin associated complex, providing a dynamic link to the molecular circadian clock (38),”

What the sources say

• Not checked yetcites [38] Hablitz L, Circadian control of brain glymphatic/lymphatic fluid flow. Nature communications (in press), (2020). PMC7468152 32879313 source

In the paper

“The astrocytic endfeet are connected by gap junctions, and almost 50% of their plasma membrane facing the vessel wall is occupied by square arrays composed of the water channel AQP4 (29).”

What the sources say

• Not checked yetcites [29] Nagelhus EA, Ottersen OP, Physiological roles of aquaporin-4 in brain. Physiological reviews 93, 1543– 1562 (2013). 24137016 PMC3858210 source

In the paper

“Deletion of AQP4 channels reduces both the influx of CSF tracers and the efflux of solutes from the neuropil (24, 30, 31).”

What the sources say

• Not checked yetcites [24] Iliff JJ, A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Science translational medicine 4, 147ra 111 (2012). PMC3551275 22896675 source
• Not checked yetcites [30] Mestre H, Aquaporin-4-dependent glymphatic solute transport in the rodent brain. eLife 7, (2018). PMC6307855 30561329 source
• Not checked yetcites [31] Mestre H, Cerebrospinal fluid influx drives acute ischemic tissue swelling. Science 367, (2020). PMC7375109 32001524 source

In the paper

“fluid transport through the glymphatic system is directionally polarized, with influx along penetrating arteries, fluid entry into the neuropil supported by AQP4, and efflux along the peri-venous spaces, as well as along the cranial and spinal nerves (24, 32–34).”

What the sources say

• Not checked yetcites [24] Iliff JJ, A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Science translational medicine 4, 147ra 111 (2012). PMC3551275 22896675 source
• Not checked yetcites [32] Braun M, Iliff JJ, The impact of neurovascular, blood-brain barrier, and glymphatic dysfunction in neurodegenerative and metabolic diseases. International review of neurobiology 154, 413– 436 (2020). 32739013 source
• Not checked yetcites [33] Wang X, An ocular glymphatic clearance system removes beta-amyloid from the rodent eye. Science translational medicine 12, (2020). PMC7356596 32213628 source
• Not checked yetcites [34] Mestre H, Mori Y, Nedergaard M, The Brain’s Glymphatic System: Current Controversies. Trends in neurosciences, (2020). PMC7331945 32423764 source

In the paper

“Brain fluid transport initiates and proceeds during NREM sleep, and CSF tracer influx correlates with the prevalence of EEG slow wave activity (35, 36).”

What the sources say

• Not checked yetcites [35] Xie L, Sleep drives metabolite clearance from the adult brain. Science 342, 373– 377 (2013). 24136970 PMC3880190 source
• Not checked yetcites [36] Hablitz LM, Increased glymphatic influx is correlated with high EEG delta power and low heart rate in mice under anesthesia. Sci Adv 5, eaav5447 (2019). 30820460 PMC6392807 source

In the paper

“A recent analysis showed that glymphatic flow is also regulated by circadian rhythmicity, such that fluid transport peaks during the sleep phase of diurnal activity, and falls during the active phase, independent of the light cycle.”

What the sources say

• Not checked yetcites [38] Hablitz L, Circadian control of brain glymphatic/lymphatic fluid flow. Nature communications (in press), (2020). PMC7468152 32879313 source

In the paper

“Conversely, both UV photoablation of meningeal lymphatic vessels and mechanical ligation of cervical lymphatics aggravated amyloid plaque formation in the same mouse models of Alzheimer disease (50, 51).”

What the sources say

• Not checked yetcites [50] Da Mesquita S, Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature 560, 185– 191 (2018). 30046111 PMC6085146 source
• Not checked yetcites [51] Wang L, Deep cervical lymph node ligation aggravates AD-like pathology of APP/PS1 mice. Brain pathology 29, 176– 192 (2019). 30192999 PMC8028636 source

In the paper

“VEGFC-overexpression induced spouting of the meningeal lymphatic vessels and slowed the cognitive decline in a mouse model of Alzheimer disease (50).”

What the sources say

• Not checked yetcites [50] Da Mesquita S, Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature 560, 185– 191 (2018). 30046111 PMC6085146 source

In the paper

“Yet the glymphatic and meningeal lymphatic systems are clearly connected: CSF tracers can exit the CNS via the meningeal lymphatic vessels, particularly by way of the lymph vessels draining the ventral aspect of the brain draining to the cervical lymph nodes (39, 40, 42).”

What the sources say

• Not checked yetcites [39] Louveau A, Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337– 341 (2015). 26030524 PMC4506234 source
• Not checked yetcites [40] Aspelund A, A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. The Journal of experimental medicine 212, 991– 999 (2015). 26077718 PMC4493418 source
• Not checked yetcites [42] Ahn JH, Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid. Nature 572, 62– 66 (2019). 31341278 source

In the paper

“in a murine model of Alzheimer disease, amyloid-b was present in high concentrations in the cervical and axillary lymph nodes, at levels analogous to those in the brain, and yet was either undetectable or barely so in the spleen and other peripheral tissues (47).”

What the sources say

• Not checked yetcites [47] Pappolla M, Evidence for lymphatic Abeta clearance in Alzheimer’s transgenic mice. Neurobiology of disease 71, 215– 219 (2014). 25102344 PMC5589075 source

In the paper

“CSF exit from the CNS by way of the meningeal lymph vessels, as well as via both cranial and spinal nerve roots, is rapid; contrast agents can be detected in the deep cervical lymph nodes within minutes after CSF delivery (42–45).”

What the sources say

• Not checked yetcites [42] Ahn JH, Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid. Nature 572, 62– 66 (2019). 31341278 source
• Not checked yetcites [43] Ma Q, Rapid lymphatic efflux limits cerebrospinal fluid flow to the brain. Acta neuropathologica 137, 151– 165 (2019). 30306266 PMC6338719 source
• Not checked yetcites [44] Ma Q, Decker Y, Muller A, Ineichen BV, Proulx ST, Clearance of cerebrospinal fluid from the sacral spine through lymphatic vessels. The Journal of experimental medicine 216, 2492– 2502 (2019). 31455602 PMC6829589 source
• Not checked yetcites [45] Jacob L, Anatomy and function of the vertebral column lymphatic network in mice. Nature communications 10, 4594 (2019). PMC6785564 31597914 source

In the paper

“glymphatic CSF influx and CSF clearance are each reduced in early stages of amyloid deposition in the APP/PS1 model of Alzheimer disease, compared with littermate controls; CSF clearance continues to decline as the amyloid burden increases (Fig. 1b).”

What the sources say

• Not checked yetcites [50] Da Mesquita S, Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature 560, 185– 191 (2018). 30046111 PMC6085146 source
• Not checked yetcites [55] Peng W, Suppression of glymphatic fluid transport in a mouse model of Alzheimer’s disease. Neurobiology of disease 93, 215– 225 (2016). 27234656 PMC4980916 source

In the paper

“The suppressive effects of both age and amyloid-ß overexpression on glymphatic flow can be extended to other experimental rodent models of neurodegeneration; both traumatic brain injury and Parkinson’s disease are similarly linked to a sustained reduction of glymphatic fluid transport (56–58).”

What the sources say

• Not checked yetcites [56] Iliff JJ, Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. The Journal of neuroscience: the official journal of the Society for Neuroscience 34, 16180– 16193 (2014). 25471560 PMC4252540 source
• Not checked yetcites [57] Zou W, Blocking meningeal lymphatic drainage aggravates Parkinson’s disease-like pathology in mice overexpressing mutated alpha-synuclein. Translational neurodegeneration 8, 7 (2019). 30867902 PMC6396507 source
• Not checked yetcites [58] Sundaram S, Establishing a framework for neuropathological correlates and glymphatic system functioning in Parkinson’s disease. Neuroscience and biobehavioral reviews 103, 305– 315(2019). 31132378 PMC6692229 source

In the paper

“The decrease in glymphatic flow in old mice is in part mediated by mislocation of AQP4 water channels away from the vascular wall (52) and possible by atrophy of meningeal lymphatic vessel (42).”

What the sources say

• Not checked yetcites [52] Kress BT, Impairment of paravascular clearance pathways in the aging brain. Annals of neurology 76, 845– 861 (2014). 25204284 PMC4245362 source
• Not checked yetcites [42] Ahn JH, Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid. Nature 572, 62– 66 (2019). 31341278 source

In the paper

“The hallmark feature of these proteinopathies are the fibrillary aggregates of misfolded or hyperphosphorylated proteins (59).”

What the sources say

• Not checked yetcites [59] Soto C, Unfolding the role of protein misfolding in neurodegenerative diseases. Nature reviews. Neuroscience 4, 49– 60 (2003). 12511861 source

In the paper

“The arguments for synaptic spread are somewhat weakened by the fact that aggregate spread happens in both antero- and retrograde directions across regions that are anatomical neighbors (68).”

What the sources say

• Not checked yetcites [68] Henderson MX, Spread of alpha-synuclein pathology through the brain connectome is modulated by selective vulnerability and predicted by network analysis. Nature neuroscience 22, 1248– 1257 (2019). 31346295 PMC6662627 source

In the paper

“The recent discovery that specific misfolded and aggregated proteins can propagate and spread in a prion-like fashion has sparked considerable interest (67).”

What the sources say

• Not checked yetcites [67] Jucker M, Walker LC, Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 501, 45– 51 (2013). 24005412 PMC3963807 source

In the paper

“An alternative hypothesis is that aggregates simply spread via the extracellular spaces, and that the age-dependent reduction in glymphatic flow, with its attendant fluid stagnation, raises the local protein concentration to a level that favors aggregation.”

In the paper

“These aggregation-prone proteins include amyloid-ß in Alzheimer Disease; phosphorylated tau in frontotemporal dementia (FTD) and chronic traumatic encephalopathy, as well as in Alzheimer’s; α-synuclein in Parkinson’s, Lewy body disease, and the multisystem atrophies; mutant huntingtin in Huntington’s disease, and TDP-43 in ALS and FTD (60).”

What the sources say

• Not checked yetcites [60] Soto C, Pritzkow S, Protein misfolding, aggregation, and conformational strains in neurodegenerative diseases. Nature neuroscience 21, 1332– 1340 (2018). 30250260 PMC6432913 source

In the paper

“Although the specific protein species differ in the different neurodegenerative disorders, in most cases their protein aggregates are formed in part by the interactions of intermolecular β-sheet-rich strands.”

What the sources say

• Not checked yetcites [60] Soto C, Pritzkow S, Protein misfolding, aggregation, and conformational strains in neurodegenerative diseases. Nature neuroscience 21, 1332– 1340 (2018). 30250260 PMC6432913 source

In the paper

“A lack of fluid flow, i.e. stagnation, or its opposite, shear stress, can also promote aggregation (64, 65), which can occur at a distance from the protein source - for example, along the cerebral vasculature (Fig. 1) (66).”

What the sources say

• Not checked yetcites [64] Trumbore CN, Shear-Induced Amyloid Formation in the Brain: I. Potential Vascular and Parenchymal Processes. Journal of Alzheimer’s disease: JAD 54, 457– 470 (2016). 27567812 PMC5026135 source
• Not checked yetcites [65] Roeters SJ, Evidence for Intramolecular Antiparallel Beta-Sheet Structure in Alpha-Synuclein Fibrils from a Combination of Two-Dimensional Infrared Spectroscopy and Atomic Force Microscopy. Scientific reports 7, 41051 (2017). 28112214 PMC5253669 source
• Not checked yetcites [66] Weller RO, Pathology of cerebrospinal fluid and interstitial fluid of the CNS: significance for Alzheimer disease, prion disorders and multiple sclerosis. Journal of neuropathology and experimental neurology 57, 885– 894 (1998). 9786239 source

In the paper

“Neuroimaging studies from the Eide group have shown that intrathecally-delivered contrast agents first are propelled into the brain along the large cerebral arteries entering the mediobasal frontal lobe and cingulate cortex along the anterior cerebral artery, insula via the middle cerebral artery and the limbic structures, including the hippocampus and entorhinal cortex via the posterior cir”

What the sources say

• Not checked yetcites [74] Ringstad G, Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. JCI insight 3, (2018). PMC6124518 29997300 source
• Not checked yetcites [75] Ringstad G, Vatnehol SAS, Eide PK, Glymphatic MRI in idiopathic normal pressure hydrocephalus. Brain: a journal of neurology 140, 2691– 2705 (2017). 28969373 PMC5841149 source

In the paper

“In Alzheimer disease, amyloid-ß deposition typically first deposit in the basal portions of the frontal, temporal, and occipital lobes. Later the plaques spread to include the hippocampus and posterior parietal cortex, initially sparing both the motor and sensory cortex. These latter regions are first recruited in the final stages of the disease, along with subcortical gray matter regions.”

What the sources say

• Not checked yetcites [71] Hong S, Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712– 716 (2016). 27033548 PMC5094372 source
• Not checked yetcites [72] Terada T, In vivo direct relation of tau pathology with neuroinflammation in early Alzheimer’s disease. Journal of neurology 266, 2186– 2196 (2019). 31139959 source

In the paper

“These proteins all lack N-terminal signal sequences, so that unconventional mechanisms must be responsible for their release (76).”

What the sources say

• Not checked yetcites [76] Davis AA, Leyns CEG, Holtzman DM, Intercellular Spread of Protein Aggregates in Neurodegenerative Disease. Annual review of cell and developmental biology 34, 545– 568 (2018). PMC6350082 30044648 source

In the paper

“Thus, the aged brain spends less time in NREM sleep, potentially causing a catastrophic decline in clearance of brain waste, as the efficacy of glymphatic fluid transport correlates directly with the prevalence of slow wave activity (36).”

What the sources say

• Not checked yetcites [36] Hablitz LM, Increased glymphatic influx is correlated with high EEG delta power and low heart rate in mice under anesthesia. Sci Adv 5, eaav5447 (2019). 30820460 PMC6392807 source
• Not checked yetcites [79] Landolt HP, Borbely AA, Age-dependent changes in sleep EEG topography. Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 112, 369– 377 (2001). 11165543 source

In the paper

“several studies have highlighted the critical role of oligomers as both directly toxic, and as niduses for macromolecular aggregation.”

What the sources say

• Not checked yetcites [60] Soto C, Pritzkow S, Protein misfolding, aggregation, and conformational strains in neurodegenerative diseases. Nature neuroscience 21, 1332– 1340 (2018). 30250260 PMC6432913 source

In the paper

“while proteins involved in neurodegenerative diseases may normally be either intracellular or extracellular in nature, all are present in the extracellular space.”

What the sources say

• Not checked yetcites [76] Davis AA, Leyns CEG, Holtzman DM, Intercellular Spread of Protein Aggregates in Neurodegenerative Disease. Annual review of cell and developmental biology 34, 545– 568 (2018). PMC6350082 30044648 source

In the paper

“Perhaps more critically, older individuals rarely enter deep NREM, stage 3 sleep. Most NREM sleep in people over 60 years is light, consisting of the more superficial stages 1–2 (79)”

What the sources say

• Not checked yetcites [79] Landolt HP, Borbely AA, Age-dependent changes in sleep EEG topography. Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 112, 369– 377 (2001). 11165543 source

In the paper

“sleep quality decreases as a function of normal aging. Insomnia is more frequent with age, and total sleep duration becomes shorter and more interrupted.”

What the sources say

• Not checked yetcites [79] Landolt HP, Borbely AA, Age-dependent changes in sleep EEG topography. Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 112, 369– 377 (2001). 11165543 source

In the paper

“The failure of these clinical trials may reflect the relatively late initiation of treatment or that the antibody load was not enough to clear sufficient amyloid-ß to yield clinical benefit.”

What the sources say

• Not checked yetcites [77] Knopman DS, Sifting through a failed Alzheimer trial: What biomarkers tell us about what happened. Neurology 90, 447– 448 (2018). 29429973 source

In the paper

“while cardiovascular fitness positively correlates with cognition in young adults (89) and preserves cognitive performance with aging (90).”

What the sources say

• Not checked yetcites [89] Aberg MAI, Cardiovascular fitness is associated with cognition in young adulthood. Proceedings of the National Academy of Sciences of the United States of America 106, 20906– 20911 (2009). 19948959 PMC2785721 source
• Not checked yetcites [90] Wendell CR, Cardiorespiratory fitness and accelerated cognitive decline with aging. J Gerontol A Biol Sci Med Sci 69, 455– 462 (2014). 24192540 PMC3968827 source

In the paper

“Structurally, the integrity of perivascular AQP4 localization was found to degrade with AD, while it was preserved by subjects older than 85 years, who remained cognitively intact (84).”

What the sources say

• Not checked yetcites [84] Zeppenfeld DM, Association of Perivascular Localization of Aquaporin-4 With Cognition and Alzheimer Disease in Aging Brains. JAMA neurology 74, 91– 99 (2017). 27893874 source

In the paper

“Patients with two specific AQP4 SNPs exhibited slower cognitive decline after AD diagnosis, while conversely, cognitive decline progressed more rapidly in subjects with two other AQP4 SNPs (85).”

What the sources say

• Not checked yetcites [85] Burfeind KG, The effects of noncoding aquaporin-4 single-nucleotide polymorphisms on cognition and functional progression of Alzheimer’s disease. Alzheimer’s & dementia 3, 348– 359 (2017). PMC5651426 29067342 source

In the paper

“In man, genetic variation in AQP4 has been shown to impact both sleep and amyloid-β burden (82).”

What the sources say

• Not checked yetcites [82] Rainey-Smith SR, Genetic variation in Aquaporin-4 moderates the relationship between sleep and brain Aβ-amyloid burden. Translational psychiatry 8, 47 (2018). 29479071 PMC5865132 source

In the paper

“Targeting the brain’s waste removal system may thus an attractive approach for alleviating the waste burden of the proteinopathies, because aggregation-prone proteins are removed by bulk flow, without the requirement for specific transporters.”

In the paper

“Thus, although AQP4 is expressed only in astrocytes, and not in amyloid-producing neurons, considerable evidence indicates that AQP4 modulates both sleep architecture, the tolerance to sleep deprivation, amyloid-ß accumulation, and the progression of Alzheimer disease.”

In the paper

“SVD is common in hypertensive patients, many of whom are concurrently diabetic or smokers, and it progresses silently for years before dementia is clinically evident (99).”

What the sources say

• Not checked yetcites [99] Wardlaw JM, Smith C, Dichgans M, Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. The Lancet. Neurology 12, 483– 497 (2013). 23602162 PMC3836247 source

In the paper

“Indeed, the cognitive decline frequently noted in patients with low cardiac ejection fraction, so often attributed to low cerebral perfusion, may also reflect poor glymphatic flow and incomplete waste clearance, as well as a consequent predisposition to aggregate formation and still-slower glymphatic flow as a result (95).”

What the sources say

• Not checked yetcites [95] Vogels RL, Profile of cognitive impairment in chronic heart failure. Journal of the American Geriatrics Society 55, 1764– 1770 (2007). 17727641 source

In the paper

“It is also well-establish that the quality of sleep is compromised in cardiovascular diseases (93) perhaps providing a link to impaired glymphatic clearance and subsequent protein aggregation and dementia (94).”

What the sources say

• Not checked yetcites [93] Gonzaga C, Bertolami A, Bertolami M, Amodeo C, Calhoun D, Obstructive sleep apnea, hypertension and cardiovascular diseases. Journal of human hypertension 29, 705– 712 (2015). 25761667 source
• Not checked yetcites [94] Mestre H, Kostrikov S, Mehta RI, Nedergaard M, Perivascular spaces, glymphatic dysfunction, and small vessel disease. Clinical science 131, 2257– 2274 (2017). 28798076 PMC5567781 source

In the paper

“Small vessel disease (SVD) is a vascular disorder that targets the small cerebral vessels, in which penetrating arterioles undergo progressive thickening of their walls (96).”

What the sources say

• Not checked yetcites [96] Wardlaw JM, Smith C, Dichgans M, Small vessel disease: mechanisms and clinical implications. The Lancet. Neurology 18, 684– 696 (2019). 31097385 source

In the paper

“Deterioration of the vascular bed may occur alone or in combination with other pathologies (97), leading to progressive demyelination and loss of white matter (98).”

What the sources say

• Not checked yetcites [97] Iadecola C, The pathobiology of vascular dementia. Neuron 80, 844– 866 (2013). 24267647 PMC3842016 source
• Not checked yetcites [98] Zlokovic BV, Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nature reviews. Neuroscience 12, 723– 738 (2011). 22048062 PMC4036520 source

In the paper

“Hypertension in particular induces hypertrophy of vascular smooth muscle cells, with a stiffening of the arterial wall that dampens arterial wall pulsatility and compliance, thus reducing convective perivascular flow (94, 100).”

What the sources say

• Not checked yetcites [94] Mestre H, Kostrikov S, Mehta RI, Nedergaard M, Perivascular spaces, glymphatic dysfunction, and small vessel disease. Clinical science 131, 2257– 2274 (2017). 28798076 PMC5567781 source
• Not checked yetcites [100] Wardlaw JM, Perivascular spaces in the brain: anatomy, physiology and pathology. Nature reviews. Neurology 16, 137– 153 (2020). 32094487 source

In the paper

“These various processes are linked in their regulation by the brain’s glymphatic system, whose directed regulation in turn may present bold new therapeutic opportunities for the disease-modifying treatment of patients with these disorders (75).”

What the sources say

• Not checked yetcites [75] Ringstad G, Vatnehol SAS, Eide PK, Glymphatic MRI in idiopathic normal pressure hydrocephalus. Brain: a journal of neurology 140, 2691– 2705 (2017). 28969373 PMC5841149 source

In the paper

“We need sleep to clear proteins from the brain extracellular space, less they aggregate, impede flow, and in a vicious positive feedback cycle, potentiate further fibril polymerization, which together with inflammation then suppresses glymphatic flow in the most affected regions.”

In the paper

“Yet the most fundamental incentive for the brain to sleep lies in its own self-preservation: Only the sleeping brain is capable of efficiently cleaning up the waste products generated during active wakefulness.”

In the paper

“Indeed, the high incidence of interstitial lung disease that is emerging in patients with resolved COVID19 may predict a higher risk of aggregation disorders for these individuals going forward, as their greater risk of long-term heart failure may predict their impaired lymphatic and hence glymphatic flow.”

In the paper

“These systems are intimately connected, so that modulation of glymphatic flow and hence protein clearance from the brain will ultimately require a deeper understanding of the dependence of both glymphatic and lymphatic flow on intracardiac pressures.”

In the paper

“In that regard, recent advances in neuroimaging have provided multiple approaches to map the human glymphatic system, and hence to assess its functional competence in the context of disease, as well as of the effects thereof on sleep-dependent glymphatic cyclicity (72, 73, 108).”

What the sources say

• Not checked yetcites [72] Terada T, In vivo direct relation of tau pathology with neuroinflammation in early Alzheimer’s disease. Journal of neurology 266, 2186– 2196 (2019). 31139959 source
• Not checked yetcites [73] Brundin P, Melki R, Kopito R, Prion-like transmission of protein aggregates in neurodegenerative diseases. Nature reviews. Molecular cell biology 11, 301– 307 (2010). 20308987 PMC2892479 source
• Not checked yetcites [108] Holth JK, The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Science 363, 880– 884 (2019). 30679382 PMC6410369 source

In the paper

“The diagnostic neuroimaging of glymphatic function via such “glymphograms” may indeed provide both a means to predict the risk of developing proteinopathies, and an approach by which to evaluate the efficacy of glymphatic flow-directed treatments as they are developed.”

In the paper

“amyloid-ß, tau and α-synuclein are all present at higher levels in the brain extracellular fluid and CSF during wakefulness than during sleep, and sleep deprivation increases their levels further (106–108).”

What the sources say

• Not checked yetcites [106] Bateman RJ, Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nature medicine 12, 856– 861 (2006). PMC2983090 16799555 source
• Not checked yetcites [107] Kang JE, Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science 326, 1005– 1007 (2009). 19779148 PMC2789838 source
• Not checked yetcites [108] Holth JK, The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Science 363, 880– 884 (2019). 30679382 PMC6410369 source