----To Control Dementia !!!!
Batteries of Brain
Like any other machine in the world, our brain also has many On-&-Off switches which are called as "Neurons". Just like as mitochondria is the powerhouse of the cell, neurons are the engines (like batteries) behind proper functioning of the brain. When fully charged, our brain will execute all functions properly such as memory, thought process, speech etc. However, sometimes, due to genetic or environmental factors, these batteries start dying leading to dementia which, if not controlled, channelizes the overall neurodegeneration or in other words "Neuroapoptosis" (Death of neurons) (Figure-1). This condition leads to the "Cerebral Atrophy" (loss of neurons) which is marked by shrinkage in brain size, cortical and hippocampus atrophy in brain, and enlarged ventricles. When this happens, cognitive decline worsens and develops into neurodegeneration diseases such as Alzheimer's.
Figure-1: Neuronal Apoptosis
Can Sleep Control ?
In simple words, yes, proper sleep can control early onset of dementia. In fact, sleep < 6 hours increases the risk of dementia and stroke 4.5 times more (1). The reason behind is the activation of the "Janitor System" of our brain, also called as "Glymphatic System".
Figure-2: Effects of Sleep on waste clearance in brain
In human body, the balance of electrolytic ions (potassium (K+), calcium (Ca2+) and magnesium (Mg2+)) is crucial for proper cell functioning and significant for vital biochemical signaling pathways. To regulate this ionic homeostasis, the sleep-and-wake cycle (Circadian rhythm) plays the pivotal role. During sleep, the level of corticoid hormone i.e. Aldosterone increases (modulator of homeostatic balance of sodium (Na+) and potassium (K+) ions in plasma) which, in turn, reduces potassium levels significantly and increases the influx of calcium ions (Ca2+) (2-5). In addition, the interstitial volume increases by 60%, resulting in better CSF (Cerebrospinal fluid) flow. However, during wakefulness, the breakdown of ATP (energy-rich compound) elevates the intracellular adenosine level, resulting in the increased level of extracellular potassium ions because of disturbance in ATP-dependent transmembrane potassium channels (2-5). Also, due to sleep deprivation, the cellular stress causes a rapid rise in the levels of ER-stress markers (Endoplasmic reticulum), which alter the conductance of transmembrane calcium ions (2-5).
In simple words, this janitor system of the brain is highly active during sleep, when CSF, without any obstruction, can easily wash away all waste products due to: 1) Increased interstitial volume, 2) reduced adenosine levels, and 3) no cellular stress.
Type of Amyloid Plaques (Waste Products of Brain)
The death of neurons occurs due to the obstruction in neurotransmission (Synaptic transmission) which is the signaling process carried by neurotransmitters across synapsis. When certain waste products start accumulating in the form of clumps in synapses (spaces between neurons), the transmission process is blocked and neurotransmitter released by one neuron (Presynaptic neuron) fails to bind on the receptor on dendrites (Antennas of neurons) of adjacent neurons (Postsynaptic neuron).
Like all other organs in the body, brain also produces waste, usually, in the form of soluble amyloids which are continuously washed away by lymphatic system of the brain, via perivascular tunnels, shaped by the astrocytes (Glial bodies). This movement of the solutes (metabolites, waste material) is mediated by aquaporin-4 channels (APQ-4), present at the astroglial endfeet (Figure-5).
These amyloid-monomers are regularly produced due to the cleavage of neuronal- membrane protein i.e. Amyloid precursor protein (APP) by enzymes such as α- and Υ-secretase. These amyloid monomers are soluble and are regularly washed away from brain if proper sleep is taken. However, in case of less sleep, these monomers form clumps of oligomers outside of neurons in synapses and hinder neurotransmission (Figure-3).
Figure-3: Formation of amyloid plaques
Another type of plaques are formed when APP is cleaved by β- and Υ-secretase, resulting in insoluble monomers which cannot be washed away by CSF and as a result, these monomers form sticky clumps outside of neurons in synapses, ultimately, resulting in the death of neurons. These plaques are called as "Amyloid-β (beta)" plaques and besides tau-tangles, these plaques are considered one of the major contributor towards Alzheimer's (Figure-3).
Why PET ?
The extracellular space of brain (ECS) is a hub of ions, nutrients and metabolites and it is known that cerebrospinal fluid (CSF; 50% of ECS fluid) contains variable concentration of amyloid-beta plaques during the different phases of sleep-wake cycles in humans. Thus, it becomes critical to develop practical diagnostic tools using potential biomarkers capable of accurately measuring ECS and fluid transfer rates, i.e., identifying glymphatic activity in human ageing and neurodegeneration. Though, there are there are certain in vivo methodologies (6-9) available for ECS quantification, yet each modality meets some drawbacks (Figure-4).
Figure-4: Comparison of PET with other modalities
Which Biomarkers for PET ?
Biomarkers such as sucrose, mannitol (182 kD), dextran (10 kD), albumin (6 kD) and inulin (~ 5kD) (dH= 2-10 nm) (10), which mainly distribute extracellularly, can be the potential tools for quantification of ECS (11-14). Each of these compounds may be able to cross the blood-brain barrier (BBB) because of no significant difference in BBB permeability of large molecular-weight molecules between glial-conditional Aqp4-/- and control mice (15). For blood-brain and CSF-blood barriers, the transport of these biomarkers may be driven by bidirectional passive permeability and transporters mediated active efflux and uptake (16) (Figure-5).
The exchange of solutes in brain (waste products) occurs when CSF inflows periarterial space from ventricles and subarachnoid space and the water component of CSF enters via APQ-4 channels into the brain parenchyma, where CSF exchanges solutes with interstitial fluid (ISF), thus, clearing the waste out of brain parenchyma to the perivenous space.
The rapid flow from CSF (50% of ECS fluid) into interstitial fluid (ISF) in brain parenchyma of central nervous system (CNS) allows these markers to be distributed efficiently between CSF compartments (17-19). Additionally, these ECS makers are supposed to neither enter neurons nor glia (13, 20). This drainage is routed via paravascular CSF influx through perivascular astrocytic end-feet sieves (access via ~ 20 nm clefts) (10). Thus, the size dependent passage of paravascular solutes into brain interstitium blocks the entry of large molecular weight markers such as with dH ˃ 32 nm (10) (Figure-5). For future, these biomarkers can be radiofluorinated for CSF quantification by PET.
Figure-5: Possible CSF markers for PET imaging
In a recent PET study for CSF quantification, the superior nasal turbinate in humans was reported to be another possible CSF egress site which may be used as a reference region for PET diagnostics (21). This study also suggested that PET-measured CSF clearance can be of potential interest to evaluate the clearance of amyloid-β plaques and other abnormal metabolites (proteins) (Figure-6).
Figure-6: (Above): PET/MRI image of all subjects (NL: Healthy, AD: Alzheimer's). Red Voxels showing CSF-positive superior turbinate ROIs (Images Courtesy (JNM) (For non-commercial and web-use only): de Leon et al., J Nucl Med. 2017; 58 (9): 1471–1476. (21)). (Below): Superior nasal turbinate (CSF egress Site)
References
Nedergaard M. Neuroscience. Garbage truck of the brain. Sci., 2013; 340 (6140): 1529-30. [CrossRef]
Landolt H-P, Holst SC. Ionic control of sleep and wakefulness. Sci., 2016; 352 (6285): 517-518. [CrossRef]
Chikahisa S, Séi H. The role of ATP in sleep regulation. Front Neurol., 2011; 2:87. [CrossRef]
Tsuji T, Morita S, Saito T, et al. Serum potassium level as a biomarker for acute caffeine poisoning. Acute Med Surg., 2020; 7 (1): e568. [CrossRef]
Mir FA, Jha SK, Jha VM. The Role of Sleep in Homeostatic Regulation of Ionic Balances and Its Implication in Cognitive Functions. In: Jha S., Jha V. (eds) Sleep, Memory and Synaptic Plasticity; 2019, Springer, Singapore. [CrossRef]
Madelin G, Regatte RR. Biomedical applications of sodium MRI in vivo. J Magn Reson Imag., 2013; 38 (3): 511-29. [CrossRef]
Madelin G, Kline R, Walvick R, et al. A method for estimating intracellular sodium concentration and extracellular volume fraction in brain in vivo using sodium magnetic resonance imaging. Sci Rep, 2014; 4: 4763. [CrossRef]
Thulborn KR. Quantitative sodium MR imaging: A review of its evolving role in medicine. Neuroimag., 2016; pii: S1053-8119(16)30674-7. [CrossRef]
Chatterjee K, Carman-Esparza CM, Munson JM. Methods to measure, model and manipulate fluid flow in brain. J Neurosci Methods., 2020; 333: 108541. [CrossRef]
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): 147ra111. [CrossRef]
Ferguson RK, Woodbury DM. Penetration of 14C-inulin and 14C-sucrose into brain, cerebrospinal fluid, and skeletal muscle of developing rats. Exp Brain Res., 1969; 7 (3): 181-94. [CrossRef]
Smith QR, Pershing LK, Johanson CE. A comparative analysis of extracellular fluid volume of several tissues as determined by six different markers. Life Sci., 1981; 29 (5): 449-56. [CrossRef]
Ghersi-Egea JF, Finnegan W, Chen JL, et al. Rapid distribution of intraventricularly administered sucrose into cerebrospinal fluid cisterns via subarachnoid velae in rat. Neurosci., 1996; 75 (4): 1271-88. [CrossRef]
Herscovitch P, Raichle ME, Kilbourn MR, et al. Positron emission tomographic measurement of cerebral blood flow and permeability-surface area product of water using [15O]water and [11C]butanol. J Cereb Blood Flow Metab., 1987; 7 (5): 527-42. [CrossRef]
Haj-Yasein NN, Vindedal GF, Eilert-Olsen M, Gundersen GA, et al. Glial-conditional deletion of aquaporin-4 (Aqp4) reduces blood–brain water uptake and confers barrier function on perivascular astrocyte endfeet. Proc Natl Acad Sci. USA, 2011; 108 (43): 17815–17820. [CrossRef]
Li J, Wu J, Bao X, Honea N, et al. Quantitative and mechanistic understanding of AZD1775 penetration across human blood-brain barrier in glioblastoma patients using an IVIVE-PBPK modeling approach. Clin Cancer Res., 2017; 23 (24): 7454-7466. [CrossRef]
Fenstermacher J, Kaye T. Drug “diffusion” within the brain. Ann N Y Acad Sci., 1988; 531: 29-39. [CrossRef]
Cserr HF, Cooper DN, Suri PK, Patlak CS. Efflux of radiolabeled polyethylene glycols and albumin from rat brain. Am J Physiol., 1981; 240 (4): F319-28. [CrossRef]
Vladić A, Klarica M, Bulat M. Dynamics of distribution of 3H-inulin between the cerebrospinal fluid compartments. Brain Res., 2009; 1248: 127-35. [CrossRef]
Syková E, Nicholson C. Diffusion in brain extracellular space. Physiol Rev., 2008; 88 (4): 1277-340. [CrossRef]
de Leon MJ, Li Y, Okamura N, et al. Cerebrospinal Fluid Clearance in Alzheimer Disease Measured with Dynamic PET. J Nucl Med., 2017; 58 (9): 1471-1476. [CrossRef]
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