Microdialysis tail (Wegrzynowicz 2019), Nigrosomes (dopaminergic) neurons in SNpc (postmortem 98% loss in nigrosome-1), brain MRI swallow-tail panels, Dopa Imaging — dopamine synthesis capacity (11C-LDOPA / 18F-DOPA / Brooks / Snow / Hunhoff-Detto / Sossi / Morley / Adams / Lee / Oehme / Nagatsu narratives), dopamine transporter Imaging opener

Nigrosomes (dopaminergic) neurons in SNpc

c-shaped and situated along the rostral/caudal axis of the SN in its dorsal part, at caudal and intermediate levels (figure B of Damier et al., figure n. 1 on the Neurology Web see at www.neurology.org). Postmortem (PM) studies have shown dopaminergic neuronal loss in PD to be higher in the nigrosomes than other SN subregions, with maximal loss (98%) in nigrosome 1 (98%).
In healthy population, nigrosome-1 appears as a hyperintense lens or ‘swallow-tail-shaped structure’.

Nigrosome 1	Nigrosome 2	Nigrosome 3	Nigrosome ?

Dopa Imaging — dopamine synthesis capacity

	What does it measure?	In PD
11C-labeled L-DOPA in β-position	(18F-radiolabeled, nonproteinogenic amino acid 3,4-dihydroxy-6-(18F)Fluoro-L-DOPA) 18F-labeling in β position on the aromatic ring	(Calabria, 2016 #2786) 18F is the most extensively used in clinical applications. (P. 2011 #1813)
18F-DOPA is used less frequently than 18F-FP-CIT in the clinical setting because of the need for a cyclotron-based radiopharmacy and the relative complexity of the synthesis, higher cost (Z)
18F	In 18F-Dopa-PET, the accumulation of 18F activity in the basal ganglia can be attributed to AADC-mediated formation of 18F-DA, and the trapping of (18F)DA in synaptic vesicles. 18F-Dopa decarboxylation is rate-limiting. The accumulation of (18F)Fluorodopamine in the synaptic vesicles is responsible for most of the striatal radioactivity for the first 90 to 120 minutes. After F2 administration because (18F)fluorodopamine, like dopamine cannot cross the blood-brain barrier. During this time, FD thus appears as an irreversibly bound tracer. Later times: indicative of the slow loss of radioactivity from the trapping compartment as a result of (18F)Fluorodopamine metabolism by COMT and MAO and diffusion of the metabolites out of the brain: rate constant kt~o~ is a measure of the frequency of turnover of the trapped tracer component
figure sossi 2002.
Influx rate constant (Ki) (KISH, 18B transport, decarboxylation, and vesicular storage Ki = K1k3/(k2 + k3), where K1 and k2 are the clearance rates from plasma into tissue and from tissue into plasma and k3 is the rate constant describing the trapping of brain FD Ki: a marker of dopamine synthesis and storage Ki is generally obtained from the data acquired in the first 90 minutes after tracer injection.
(Morley, 2023 #2810) In patients with PD: Ki of 18F-DOPA is significantly decreased in the caudate and putamen (Brooks et al. 1990; Snow et al. 1993; Hunhoff-Detto et al. 1997)
EDVR: (Morley, 2023 #2810): the ratio of the distribution volumes of 18F-DOPA in the specific and precursor compartments reduced by the factor k2/(k2 + k3) inverse of effective dopamine turnover (Sossi et al. 2002). EDVR ↑ dopamine turnover ↑ AADC activity (dopamine turnover is defined as the ratio between dopamine metabolites and dopamine itself) (Dopamine turnover : the ratio of the dopamine metabolite DOPAC to DA) AADC activity (which converts (18F)F-DOPA to 18F-dopamine.) Dopamine turnover can be evaluated with extended scanning time, and the effective (dopamine) distribution volume ratio (EDVR) of 18F-DOPA. (Sossi et al., 2001) An increase in dopamine turnover was also observed in asymptomatic LRRK2 mutation carriers before any evidence of changes in Ki (Sossi et al., 2010). This has been hypothesized to be a compensatory mechanism in early PD potentially related to upregulation of AADC activity (Lee et al., 2000; Adams et al., 2005). The rat is easily amenable to 18F-DOPA PET imaging and correlation with disturbances of dopamine in the rat brain. Dopamine in the 6-OHDA lesion model has been shown to have decreased dopamine compensation in 6-hydroxydopamine (6-OHDA) lesion rat model of PD has been demonstrated (Cyono et al. 2011). Furthermore, in vivo dopaminergic compensation has been reported in the rat 6-OHDA lesion model of PD (Sossi et al, 2009). The MPTP (1)-methyl-4-phenyl-1,2,3,6-tetrahydropyridine] lesion model in monkeys have also identified a very close correlation with the loss of dopamine in the striatum and multiple measures of parkinsonism, include symptoms on the Kuhler scale, striatal dopamine content, and markers of dopaminergic neurons, such as tyrosine hydroxylase (Bietsa et al., 2012). RT Ki/k(loss) can be interpreted as an effective distribution volume (EDV) of the specific compartment alone with respect to the plasma tracer concentration and is a similarly discriminating measure of the ability of the trapping mechanism to store tracer. (Morley, 2023 #2810). EDVR in SNCA TG rats vs WT Rats)
Lee 2000	(18F)dopa uptake was reduced to a lesser extent than the corresponding (11C) DTBZ or (11C) MP BP in patients with PD
(Sossi, 2002 #2813)	6HC 10 early PD scanning, EDVR was 55% of HC.
(Oehme, 2011 #2814)	EDVR
(Nagatsu, 2007 #2816)	AADC activity was found to be decreased in the nigro-striatum in PD (Lloyd and Hornykiewicz, 1970).
Coalska 2017 #2817) postmortem, 12 PD, 10 hc, striatum only. Control human striatum contained much less AADC activity than rat and NHP striata. A dramatic loss of AADC activity in PD striatum compared to controls was detected. In MPTP-treated NHP, caudate nucleus was almost as greatly affected as putamen, although mean DA turnover was higher in caudate nucleus. Similarly, DA and DA metabolites were dramatically reduced in different regions of PD brains, including caudate nucleus, whereas serotonin was relatively spared. Yet L-DOPA administration in MPTP-treated NHP very poor conversion to DA was detected, suggesting that AADC in NHP nigrostriatal fibers is mainly responsible for L-DOPA to DA conversion

Dopamine transporter Imaging

Distribution of DAT

• on the presynaptic nerve terminal of dopaminergic neurons
• the single most important determinant of extracellular dopamine concentrations.