October 2022, Amydis Inc, a privately held company, announced that patient enrollment for the phase 1/2a Prospective Randomized Open, Blinded Endpoint (PROBE) trial was under way. The trial is designed to evaluate a "retinal tracer" — a fluorescent, nonradioactive retinal imaging agent (AMDXP-2011P) that targets protein biomarkers in patients who have PD or ALS. The PROBE study is examining the safety, tolerability, pharmacokinetics, and activity of a single intravenous bolus of AMDXP-2011P in patients with PD and ALS. Designed for use with currently available ocular imaging devices, the imaging agent is capable not only of detecting but also of quantifying deposits of αSyn and TDP-43 (Figure 1).
(Sung, 2019 #232)
Inner retinal thining
(Veys, 2019 #1093)
Review
(Elena, 2019 #1094)
OCT in PD patients
retinal nerve fibre layer thinning in PD patients as compared to controls [12, 24, 70, 75, 84].
thinning of the inner retinal layers: the ganglion cell layer, inner plexiform layer, and inner nuclear layer [1, 22, 71, 128, 133].
ERG
decreases in theamplitude of the photopic b-wave and scotopic oscillatorypotentials were observed [27, 48, 57, 95], which are diagnosticindicators of the functioning of retinal interneurons,which comprise, amongst many other cells, dopaminergicamacrine cells [10].
one paper reveals post-mortemevidence for a reduction in dopamine levels to support andbetter understand these findings [30, 39, 51].
p-aSyn in all nine patients strong positive correlation between Lewy - type synopathy density in the retina and brain.Furthermore, retina Lewy - type synopathy density score correlated with the Unified Parkinson's disease pathology stage.
Beach TG, Carew J, Serrano G, Adler CH, Shill HA, Sue LI et al(2014) Phosphorylated alpha-syn-immunoreactive retinalneuronal elements in Parkinson's disease subjects. Neurosci Lett571:34-38. https://doi.org/10.1016/j.neulet.2014.04.027
Postmortem
aSyn accumutation in retina and/or visual system , p-aSyn in seven out of nine PD patients
(Bodis-Wollner, 2014 #1096)
Postmortem
(3 PD subjects, 8 HC) The presence of misfolded aSyn in retinal neurons within the inner retina
(Ho, 2014 #1598)
Postmortem
matched sample: eye and brain from the same PD patients
6 cases of PD or PD with dementia, and 6 age-matched controls
when assayed using the same protocols as in the brain.
Eyes lacked definite Lewy bodies or Lewy neurites in either PD or AD cases. Patchy cytoplasmic α-syn positivity was seen in the retina of AD, PD and control cases, but did not correlate with the presence or extent of Lewy body pathology in the brain.
Only in toxin-induced models, retinal PD manifestationswere studied in the retina [56, 93, 141],
Animal model
scarce
viral vector- and αSYN fibril-based studies, this is notthe case yet [26, 96, 102, 142].
Animal model
In transgenic rodent models,only two papers report on retinal αSYN accumulation intwo different transgenic mice: one expressing human A53TαSYN under the control of the Prnp promoter (TgM83) [78],the other expressing fused αSYN::GFP under the PDGFβpromoter [113].
Animal model
Sx
Jove: Using Retinal Imaging to Study Dementia (OCT보는법)
the timing of aSyn occurrence in the retina relative to the brain
Presence of p-aSyn in the retina in MSA
How to visualize retinal aSyn in living subjects
Retina: a window of brain
α-synuclein (+) ganglion cell morphology in PD retina = “degenerating neuron in the brain”
Retina is a small brain
Cell organization and environment,
Immunological response
Direct connection to the CNS
(Bodis-Wollner, 2014)
(Ortuño-Lizarán, et al., 2018)
Immunostainings of αSYN on retinal sections in human (Veys, 2019)
MDS Virtual Congress 2020 — SEPTEMBER 12-SEPTEMBER 16
Rob Rubens
ob Rubens
D strategy TAU
Prodromal PD?
MIBG for prodromal PD diagnostic accuracy
BA
priority
GBA activator
GBA GT
ho will do GBA activator?
itochondria
Parkin GT
c GAS
omarkers
Disease-related BMs
aSyn
pSyn, oligomeric (RT quic)
aSyn imaging, spreading, NHP
?
DA system integrity
D, DLB, MSA
OS / Mechanism
The main sites of ROS production in mammalian cells are mitochondria [69], in turn,
and its generation is initiated by the electron leak primarily at complex I through partial reduction of molecular oxygen (O2) to superoxide radical (O2*-) by a single electron uptake
it leads to either hydroxyl radical (OH*) generation through iron catalyzed Fenton reaction or to peroxynitrite (ONOO-) (Fig. 3).
Superoxide radical (O2*-) is also converted to hydrogen peroxide (H2O2) by superoxide dismutase 2
H2O2 is subsequently broken down to H2O and O2 by catalase to maintain its homeostasis [70].
↑ ROS
Dopamine in PD brain is oxidized to form dopamine quinones and free radicals either by self-oxidation or by mitochondrial outer membrane bound monoamine oxidases (MAO) such as MAO-A (in neurons) and MAO-B (in glia). → Oxidation products of dopamine may cyclize to form aminochromes, and are reactive enough to produce superoxide radicals [72].
Evidence in PD (mainly 2019 Raza)
csf
Blood
n, 2018 #582)
, 2018 #581)
Looks better than Khan 2018
Nothing is significant
Measurement of OS
Redox state
Oxidized DNA
Oxysterol
example
example
Example
Uncertain Spans
location
text/status
reason
Rob Rubens table left column
leftmost cell labels (ob Rubens, D strategy TAU, BA, ho will do GBA activator?, itochondria, omarkers, D, DLB, MSA)
The left edge of this table is clipped by the photo crop; visible label fragments are transcribed as-is.
Ortuño-Lizarán scatter plot
exact p / ρ values
The scatter plot in the Retina: a window of brain slide shows P<0.05, p=0.6661, p=0.7861; values are tiny but legible from the body_r03_c02 crop.
Evidence in PD left column
citation labels (n, 2018 #582), , 2018 #581))
Left edge of these citation cells is clipped by the photo crop.
OS Mechanism table column count
exact column boundaries
Column rules between ROS chemistry cells are faint; transcribed as 7 visible cells based on text break and ruling supported by the body_r05 crops.