Dopamine metabolites in PD — CSF / blood / urine correlation rows (LeWitt 1992 / Stefani 2017 / Wichi 2021), Anderson 2017 DA-HVA L-DOPA narrative, Dormant dopaminergic neurons (Heo 2020 astrocytic GABA / optogenetic SNpc rescue), Summary of dopamine system table opener (Hurley 2010 #1270 J. Boy 2000 Lee 18F-DOPA AADC PET / 11C-DTBZ / 11C-MP / Seeman-Niznik 1990 / Hisahara-Shimohama 2011)
Dopamine metabolites in PD (continued)
| compartment | study | cohort | narrative |
|---|---|---|---|
| CSF | (LeWitt, 1992 #1781) (no df) | mildly affected unmediated subjects with Parkinson disease, no control | (HVA), the most abundant product of DA turnover, was 164.97 ± 95.02 nM. As sequential aliquots of CSF were collected from the first to 23rd ml. CSF HVA concentration almost doubled. After HVA, 3-O-methyldopa (3-O-MD) was the next most abundant compound. The summed concentrations of 3-O-MD, 3,4-dihydroxyphenylacetic acid, 3-methoxytyramine, DA, dl-3-sulfate, norabolic, and levodopa (LD) amounted to 12.6% of HVA. Concentrations of the DA metabolites did not correlate to a variety of indices of PD severity |
| CSF | (Stefani, 2017 #1786) | Medicated early PD patients (N=15; UPDRS III=29.13/H&Y=2.5), NO CONTROL | CSF DA: no difference between untreated and moderately advanced non-dyskinetic PD patients (NS) / CSF HVA concentration (uM/L) correlated with UPDRS-III scale rated before LP (R=0.67), p=0.001), swansy increased dopamine turnover following levodopa carryover, basis. UPDRS III scores did not correlate with DOPAC (R = 0.65) or DA (R = 0.31). CSF HVA levels correlated with DOPAC, CSF levels (R= 0.5&p ≤ 0.01), but not with DA CSF concentration. Also DOPAC, CSF levels did not correlated with DA CSF concentrations. |
| BLOOD | (Wichi, 2021 #1787) | 40 PD (H&Y 2.7), 40 control | Anderson et al. (2017) reporting increased DA and HVA levels in the cerebrospinal fluid of PD patients treated with L-DOPA, and a decrease in untreated PD patients. DA: ALSO no correlation between DA and severity (early/advanced) |
| urine | (Wichi, 2021 #1787) | 40 PD (H&Y 2.7), 40 control | ↑ HVA |
Dormant dopaminergic neurons
| (Heo 2020) | Astrocytes become reactive | GABA synthesis (through MAO-B) in astrocytes | GABA secretion (through Best1 channel) in astrocytes | ↓ DA neuronal firing | ↓ TH expression | ↓ dopamine | ↓ motor Sx | |
|---|---|---|---|---|---|---|---|---|
| In PD | [Heo 2020] | Astrocytes become reactive | ↑ GABA synthesis (through MAO-B) in astrocytes | ↑ GABA secretion (through Best1 channel) in astrocytes | ↓ DA neuronal firing | ↓ TH expression | ↓ dopamine | ↓ motor Sx |
| Tx strategy | Optogenetic activation of SNpc neurons Blocking the astrocytic GABA synthesis | TH/DDC+ neurons (in dormant dopaminergic neurons, DDC+ neurons ↑ ~50% / 1 ((Heo2020 FIG 2h)) | ↑ TH+ cell count ((Heo2020 FIG 2K)) | ↑ dopamine | ↑ motor Sx | |||
| MAO-B inhibitors such as selegiline and rasagiline | ||||||||
Summary of dopamine system
| study | IHC | PET | Human Remaining % | Lee's interpretation | Animal | |
|---|---|---|---|---|---|---|
| DA | (Hurley, 2010 #1270) J. Boy 2000 Lee | (18F)dopa in dopaminergic nerve terminals, fluorodeoxyphenylalanine 18F-DOPA is decarboxylated by AADC to fluorodopamine (FDA), F-18 and stored in presynaptic vesicles in the brain | (54.7%) (-60.3%) (of HC) HV: 50%/2011 (Wills, 1999 ish/sse) | JS: these values congratulate us compensation? i): (18F)dopa uptake was reduced to a lesser extent than the corresponding (11C)DTBZ or (11C)methylphenidate (11C)MP BP in patients with PD | ||
| 2000 Lee | 43.3% / 32.7% | js: 가 어 가 가? compensation? / Js (3-1 가 가 가)? / compensated mechanism | ||||
| VMAT2 | 2000 Lee | (11C)dihydrotetrabenazine (11C)DTBZ | 36.7% / 28.4% 50% (SPECT 1, 1999 ish'sse) | Downregulated to compensate (보상) | ||
| (Wells, 2010 #1270) Hurley 2006 | Postmortem and imaging (PET, SPECT) are combined |
- presynaptic dopamine D2 receptors are lost. - an increase of dopamine D2 receptor density in the striatum (particularly the putamen) of people with untreated PD (and no change in dopamine D1 receptor expression) - i) following antiparkinsonian drug treatment, there is a down-regulation of the elevated dopamine D2 receptors to normal levels in the putamen and often decreased levels in the caudate nucleus | ||||
| (Seeman and Niznik 1990, PMID 2197146; Hisahara and Shimohama, 2011) | Position emission tomography (PET) data and in vivo data generally concur | a rise in the D1 and D2 receptor densities. This is found in the brain putamen and caudate tissues from unmedicated patients, and may account for the good early clinical response to L-dopa treatment, where L-dopa supplement reverts the receptor densities toward normal levels. | ||||
| Microdialysis 도 측정 (Wegrzynowicz et al. 2019, PMID) Putamen 30-50% | ||||||