Cholinergic system and PET

ACh

Cholinergic system uses acetylcholine (ACh) as the neurotransmitter. Cholinergic system includes the muscarinic and nicotinic acetylcholine receptors (mAChRs and nAChRs), vesicular acetylcholine transporter (VAChT), acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and choline acetyltransferase (ChAT).

ChAT synthesizes ACh from choline and acetyl-coenzyme A (acetyl-CoA) in the presynaptic cholinergic neurons, and it is considered as a marker of cholinergic neurons. VAChT transports cytosolic ACh into the presynaptic vesicles. From the synaptic cleft, ACh is cleared by AChE, BuChE, and resulting choline is taken back into presynaptic nerve terminals by choline transporter (Tiepolt et al., 2022).

Parasympathetic nervous system is almost exclusively cholinergic. Pre- and postganglionic neurons of the sympathetic nervous system are also cholinergic. Sympathetic ganglion neuron bodies are located in the bilateral chain of sympathetic ganglia, while the terminal ganglia of the parasympathetic nervous system are close or within the innervated organ.

In the CNS the major cholinergic projection systems are (Roy et al., 2016):

  1. the nucleus basalis of Meynert, supplying cholinergic projections throughout the cerebral cortex and hippocampus
  2. pedunculopontine nucleus pars compacta, projecting to the forebrain and subcortical structures such as thalamus
  3. striatal cholinergic neurons.

Dementia is associated with loss of cholinergic neurotransmission.

Acetylcholine receptors

PET can be used to estimate regional acetylcholine concentration variation in human brain, utilizing mAChR or nAChR radioligands (Smart et al., 2021).

mAChRs

Muscarinic acetylcholine receptors (mAChRs) are highly expressed in caudate nucleus and nucleus accumbens, less in somatosensory, primary motor, and temporal cortices, and very little in the cerebellar cortex (Roy et al., 2016). Subtypes M1, M3, and M5 are mostly postsynaptic and excitatory, whereas M2 and M4 are presynaptic and suppressive. Scopolamine is a muscarinic antagonist.

PET radioligands for mAChRs include [11C]NMPB which is not selective for the receptor subtypes, M1 subtype specific [11C]LSN3172176 (Naganawa et al., 2021; Smart et al., 2021), M2 subtype specific [18F]FP-TZTP (Cannon et al., 2006; Ichise et al., 2008), and M4 subtype specific [11C]MK-6884 (Tong et al., 2020; Li et al., 2022).

Decreased uptake of mAChR radioligand binding has been seen in AD and PD.

nAChRs

Nicotinic acetylcholine receptors (nAChRs) are highly expressed in the entorhinal, temporal, and primary motor cortices, and in the hippocampus and thalamus (Roy et al., 2016). The nAChRs can be composed of various subunit combinations, leading to large differences in their affinity to ACh and other ligands (including nicotine), and Ca2+ permeability.

Nicotine increases the release of many neurotransmitters, including ACh. It has neuroprotective actions, possibly via α7-nAChRs. Continuous exposure to nicotine causes upregulation of nAChRs in smokers, and nAChRs are thought to have essential role in nicotine addiction.

The nAChRs have been targeted with [11C]nicotine, α4β2-nAChRs specifically with 2-[18F]fluoro-A85380, 6-[18F]fluoro-A85380, [18F]nifene, [18F]AZAN, and (+)- and (-)-[18F]flubatine, and α7-nAChRs with [11C]CHIBA1001, [18F]ASEM, and its paraisomer [18F]DBT10.

Decreased uptake of α4β2-nAChR radioligands has been seen for example in AD, PD, and DLB. The decrease of α7-nAChRs has been associated with schizophrenia, TBI, and AD, while increased expression of α7-nAChR is seen in bipolar disorder. Since α7-nAChR is expressed across the CNS, there is no suitable reference region to be used in analysis.

Acetyl- and butyrylcholinesterases

AChE

In the CNS, the distributions of AChE and ChAT overlap, and AChE activity is also considered as a marker of cholinergic system.

Since dementia is associated with loss of cholinergic neurotransmission, acetylcholinesterase (AChE) inhibitors (donepezil, rivastigmine) have been used as treatment for the dementia symptoms in AD and PD. The effect of AChE inhibitors can be studied using FDG.

AChE inhibitors have been labelled with positron emitting isotopes to be used in PET imaging of dementia as markers of the integrity of the cortical cholinergic system; these tracers include [11C]MP4A and [11C]PMP.

Cholinergic perturbation is also apparent in traumatic brain injury (TBI), which can be seen as decreased AChE activity using [11C]MP4A PET (Östberg et al., 2011); in TBI patients with treatment response to rivastigmine the baseline AChE activity is lower than in non-responders (Östberg et al., 2018).

[11C]Donepezil is a reversible antagonist radioligand of AChE (inhibitor, not a substrate), and has been used for imaging cholinergic mechanisms also in peripheral organs (Gjerløff et al., 2014). However, donepezil also binds to σ1 receptors with comparable affinity to that of AChE (Kato et al., 1999; Horsager et al., 2019).

BuChE

Butyrylcholinesterase (BuChE) is associated with amyloid β in AD. BuChE activity can be assessed using [11C]MP4B. [123I]PIP has been used to detect BuChE activity in brain autoradiography (Thorner et al., 2021).

VAChT

Vesicular acetylcholine transporter (VAChT) is located only in the cholinergic nerve terminals of the central and peripheral nervous system. It may be a better indicator of presynaptic cholinergic terminal density than other targets (Bohnen et al., 2018), and it is not directly affected by cholinesterase inhibitor drugs.

[123I]IBVM SPECT is well-established in human use. PET radiopharmaceuticals for CNS VAChT imaging have been introduced, including [18F]FEOBV and [18F]VAT. Cerebellar grey matter is suitable reference region in [18F]FEOBV and [18F]VAT studies (Petrou et al., 2014; Jin et al., 2018). Also white matter is used as the reference region since it does not contain cholinergic nerve terminals (Aghourian et al., 2017; Nejad-Davarani et al., 2019).

[18F]FEOBV may be suitable for assessing VAChT density also in peripheral organs, even from a late static PET scan (Horsager et al., 2022).

Inflammation

Components of cholinergic system are upregulated in active inflammatory cells, which use ACh as a paracrine signalling molecule (Kawashima et al., 2012; Fujii et al., 2017) and therefore the tracers of the cholinergic system may be useful in research and diagnosis of infection and inflammation and cancer (Stokholm et al., 2016; Jørgensen et al., 2017; Boswijk et al., 2017). In white matter lesions of MS patients, BuChE activity correlates with microglial activation and is absent within demyelinated lesions (Thorner et al., 2021).

In COPD patients the blood AChE and BuChE activities are increased, especially in smokers (Ben Anes et al., 2018).


See also:



Literature

Eisenmenger LB, Huo EJ, Hoffman JM, Minoshima S, Matesan MC, Lewis DH, Lopresti BJ, Mathis CA, Okonkwo DO, Mountz JM. Advances in PET imaging of degenerative, cerebrovascular, and traumatic causes of dementia. Semin Nucl Med. 2016; 46(1): 57-87. doi: 10.1053/j.semnuclmed.2015.09.003.

Gjerløff T, Jakobsen S, Nahimi A, Munk OL, Bender D, Alstrup AKO, Vase KH, Hansen SB, Brooks DJ, Borghammer P. In vivo imaging of human acetylcholinesterase density in peripheral organs using 11C-donepezil: dosimetry, biodistribution, and kinetic analyses. J Nucl Med. 2014; 55: 1818-1824. doi: 10.2967/jnumed.114.143859.

Maziere M. Cholinergic neurotransmission studied in vivo using positron emission tomography or single photon emission computerized tomography. Pharmac Ther. 1995; 66: 83-101. doi: 10.1016/0163-7258(95)00003-Y.

Roy R, Niccolini F, Pagano G, Politis M. Cholinergic imaging in dementia spectrum disorders. Eur J Nucl Med Mol Imaging 2016; 43: 1376-1386. doi: 10.1007/s00259-016-3349-x.

Tiepolt S, Meyer PM, Patt M, Deuther-Conrad W, Hesse S, Barthel H, Sabri O. PET imaging of cholinergic neurotransmission in neurodegenerative disorders. J Nucl Med. 2022; 63(Suppl 1): 33S-44S. doi: 10.2967/jnumed.121.263198.



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Updated at: 2023-02-01
Created at: 2016-05-28
Written by: Vesa Oikonen