The brain and spinal cord make up the central nervous system (CNS). The brain consists of the cerebrum, brainstem, and cerebellum. The cerebrum, cerebellum, and spinal cord are connected via the brainstem. Brainstem consists of the midbrain, pons, and medulla.
CNS is covered by three membranes (meninges): pia mater, arachnoid mater, and the outer tough membrane dura mater. The basement membrane of pia mater is attached to glia limitans, the outermost membrane of the cerebral cortex. The cortex (grey matter) of cerebrum and cerebellum contains the neuronal synapses, and the subcortical regions (white matter) contains myelinated axons of the neurons. The cerebral cortex is about 2-4 mm thick, while cortex of cerebellum is thinner; due to the relatively poor spatial resolution in PET images, this causes considerable partial volume effect.
Subclavian arteries branch into internal carotid and vertebral arteries, which provide 70 and 30% of the total cerebral blood flow (CBF), respectively. Vertebral arteries supply mainly the brainstem, cerebellum, and occipital cortex. Internal carotid leads to the circle of Willis, from which arteries branch into highly vascularized tissue within pia mater. Pia mater protrudes into the cortex with the arterioles, until arterioles are fully surrounded by astrocytes in the parenchyma. Blood vessels in the brain form a chaotic mesh of capillaries with indeterminate direction; therefore the simplified capillary models assuming long and parallel capillaries are not applicable to the brain (Wang & Bassingthwaighte, 2001), if that is even the case in the skeletal muscle (Honig et al., 1971).
Cerebrospinal fluid (CSF) circulates in the CNS in the subarachnoid space between arachnoid mater and pia mater, in the ventricular system (interconnected cavities in the brain) and in the central canal of the spinal cord. Ventricles and the central canal of spinal cord are lined with specialized epithelium, ependyma with relatively loose junctions. Specialized sections of ventricular walls (choroid plexus) produce the CSF, and have rich vasculature, with tight capillary wall junctions like the rest of the brain, (blood brain barrier). Bulk flow of CSF into the periarterial spaces (glymphatic influx) is driven by arterial pulsation, and it is important for the delivery of glucose and lipids. Glymphatic system of perivascular tunnels, formed by astroglial cells, allow CSF to exchange with interstitial fluid (ISF) in the brain (Jessen et al., 2015; Kiviniemi et al., 2016). CSF is eliminated also via the arachnoid granulations (villi) in the arachnoid mater into the venous blood via cervical (from brain) and lumbar (from spine) lymph nodes. ISF drains from the CNS along basement membranes within the walls of vasculature to cervical lymph nodes. In humans, nasal turbinate is part of the CSF clearance system, and it is impaired in AD patients as measured by ventricular clearance of [18F]THK-5117 using PET (de Leon et al., 2017). Gd-DTPA MRI has been used to map glymphatic system (Iliff et al., 2013; Davoodi-Bojd et al., 2019).
The brain weights about 1.2 - 1.4 kg, about 2% of the body weight, but it receives about 15% of the cardiac output and uses about 20% of oxygen used by the body. The brain has an intrinsic ability to maintain an adequate perfusion in the presence of blood pressure changes (cerebral autoregulation), mainly via myogenic responses in arterioles. Cerebral autoregulation is impaired in diabetes, dementia, stroke, and traumatic brain injuries. Temporal and regional neural activity and blood flow are closely linked (neurovascular coupling). Cerebral arteries are extensively innervated by both sympathetic and parasympathetic neurons. Parenchymal arterioles are regulated by astrocytes. Cerebral perfusion is very sensitive to changes in the arterial partial pressure of CO2. In baseline, red blood cell (RBC) flux in cerebral cortical capillaries is very heterogeneous; under hypercapnia, RBC flux is increased in low baseline-flux capillaries, resulting in RBC flux homogenization. Prolonged changes in the local neuronal activity and demand for oxygen leads to vascular remodelling and more permanent change in the capillary network (“angioplasticity”). PET tracers [15O]H2O and [15O]O2 can be used to measure perfusion and oxygen consumption, respectively. fMRI methods for absolute quantification of cerebral oxygen consumption are being developed (Germuska & Wise, 2019), and ASL MRI method for assessing CBF is reaching maturity (Zhang et al., 2017; Ho, 2018).
Brain normally uses glucose as source of energy (which can be measured using [18F]FDG), but can also use ketone bodies, such as β-hydroxybutyrate and acetoacetate, and lactate, and acetate. GLUT3 is the dominant glucose transporter in neurons, and GLUT1 in astrocytes. Astroglial metabolism can be specifically assessed using acetate, and it has been shown to be sensitive to changes in MS. Aerobic glycolysis decreases by age in healthy brain (Goyal et al., 2017).
Lipids constitute about half of the dry weights of brain tissue. Fatty acids are not an important source of energy for the brain, but still about 50-60% of [11C]palmitate is oxidized and the rest enters rapidly the stable brain lipid pool. Brain preferentially incorporates fatty acids into phosphoglyserides instead of neutral lipids. [18F]FTHA can also be used to measure the uptake of fatty acids in the brain. Docosahexaenoic acid (DHA) is a polyunsaturated fatty acid (PUFA) that is an important constituent of gray matter lipids, especially in the synapses. The rate of DHA incorporation in the brain can be measured using [11C]DHA (Umhau et al., 2009; Yassine et al., 2017). The incorporation rate of arachidonic acid (AA), another PUFA, can be measured using [1-11C]AA, and used as an index of dopamine D2R signal transduction (Thambisetty et al., 2012).
Microglial cells make up the innate immune system of the CNS. Astrocytes (astroglia) are the most abundant cell type in the brain, supporting the neurons and blood brain barrier (BBB). Glial cells response to traumatic brain injury (TBI) or infection by releasing cytokines and chemokines, promoting inflammation and recruiting more microglia. Sustained neuroinflammation may compromise the BBB, and attract also peripheral immune cells to the site of injury, contributing to neurodegeneration.
Neuroinflammation can be detected with PET based on several biomarkers, including Translocator protein (TSPO) (Knezevic and Mizrahi, 2018) and P2X7 receptor. While inflammation is mainly studied is neurodegenerative diseases, it has also been studied in psychological disorders, for instance in development of depression (Kopschina Feltes et al., 2019). Astrocyte activation could be assessed using MAO-B tracers, such as [11C]L-deprenyl-D2 (Matthews et al., 2015). Adenosine 2A receptors are upregulated in neuroinflammatory and neurodegenerative diseases, and could be targeted in PET imaging studies (Vuorimaa et al., 2017).
The morphology and size of neurons (nerve cells) is very diverse. The perikaryon (cell body, soma) is often large in comparison to other cells in nervous system, and packed with mitochondria, ER, Golgi complex, lysosomes and peroxisomes, etc. Yet, the dendritic and axonal processes may represent up to 99% of the total nerve cell volume. Both dendrites and axons can be extensively branched, receiving input from and sending output to large tissue volumes.
The axon starts as a thin thread that often does not branch until near its target. Axons (but not cell bodies or dendrites) are often myelinated to increase the signal conductance speed and energy efficiency, both in central and peripheral nervous system. The diameter of myelinated axons is more than 1-20 µm, and unmyelinated axons are 0.1-2 µm in diameter; in the CNS most axons with diameter <0.2 µm are myelinated. Myelinated axons are white, hence the “white matter” of the brain. ∼50% of the dry mass of the white matter is myelin.
Microtubules are a prominent feature of axons, and the primary cytoskeletal elements in thin unmyelinated axons. Microtubules have a uniform polarity, important for the fast axonal transport of vesicles and mitochondria. In large myelinated axons the neurofilaments occupy most of the axon space. Axonal cytoskeleton is modulated via signals from the glial cells and neurons close by. Disrupted cytoskeleton is common in many neurodegenerative disorders, including Alzheimer’s disease.
Dendrites have microtubules and microfilaments and local protein synthesis machinery.
Glial cells surrounding neurons have an important role in the growth and support of axons and dendrites. Amyloid precursor protein (APP) is needed in axon and dendrite outgrowth, synaptogenesis, and intracellular protein trafficking.
Synapse is a structure that permits a neuron to pass a chemical or electrical signal to another neuron. In a chemical synapse, electrical activity in the presynaptic neuron is converted, via the activation of voltage-gated Ca2+-channels, into the release of a neurotransmitter from synaptic vesicles into the narrow synaptic cleft. Neurotransmitter binds to receptors located in the plasma membrane of the postsynaptic cell. The neurotransmitter may initiate either an electrical response, or a secondary messenger pathway that may either excite or inhibit the postsynaptic neuron. In an electrical synapse, the presynaptic and postsynaptic cell membranes are connected by intercellular channels, clustered into gap junctions, that can quickly pass on the voltage change from the presynaptic cell to the postsynaptic cell (Miller & Pereda, 2017).
Neurotransmitter release at the presynaptic terminal requires that the synaptic vesicles (SVs), containing the transmitter, are clustered within the terminal, docked at release sites (active zones), and fused with the synaptic cell membrane (Rizo & Xu, 2015). Membrane fusion is mediated by SNARE complex, involving a wide array of specialized proteins, including synapsins, synaptobrevin, and SV2 and SVOP. Vesicular proteins stranded on the cell surface are retrieved for reformation of the synaptic vesicles, possibly via clathrin-dependent and -independent pathways (Kaempf & Maritzen, 2017). Also the released neurotransmitter are partially collected back into the presynaptic neurons and synaptic vesicles, via specific transporters such as DAT and VMAT2 for dopamine and VGLUT for glutamate.
PET can be used to assess synaptic density for example in neurodegenerative diseases.
Cerebral small vessel disease (SVD) can be found in patients suffering from neurodegenerative diseases and dementia, especially in AD, and are common in elderly subjects. SVD may be linked to impaired glymphatic function. The neuropathological processes in SVD affect small perforating arteries, arterioles, capillaries, and venules. SVD can be diagnosed using MRI already during the subclinical phase (Mestre et al., 2017). Typically in SVD the perivascular spaces are enlarged and cerebral microbleeds and abluminal protein deposits are found. White matter lesions and lacunas can be seen with MRI, but damage in deep grey matter is also common.
Narrowing of arteries that supply the brain, type 1 SVD or cerebrovascular disease (CVD), is usually caused by atherosclerosis, which often causes vascular diseases in other tissues, too. Type 2 SVD consists of sporadic or hereditary cerebral amyloid angiopathy (CAA), which can be studied using Amyloid β tracers. These and other SVD types are described by Pantoni (2010), Wardlaw et al. (2013a and 2013b), Charidimou et al. (2016), and Haffner et al. (2016). Cerebral perfusion can be quantified with [15O]H2O PET. Reduced cerebral perfusion is compensated by increased oxygen extraction fraction (OEF), which can be assessed using [15O]O2 PET.
- Spinal cord
- Adenosine receptors
- Dopaminergic system
- Adrenergic system
- Endocannabinoid system
- Cholinergic system
- Glutamatergic system
- Histaminergic system
- Opioid system
- P2 purinoceptors
- Serotonin system
- Somatostatin receptors
- Synaptic density
- [15O]H2O in the brain
- [15O]O2 in the brain
- Inflammation and infection
- Instructions by tracer
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Updated at: 2019-05-12
Created at: 2016-05-14
Written by: Vesa Oikonen