GABA (continued)
Further readings
- Lang AE, Lozano AM. Parkinson’s disease. First of two parts. N Engl J Med 1998;339:1044-53.
- Lang AE, Lozano AM. Parkinson’s disease. Second of two parts. N Engl J Med 1998;339:1130-43.
GABA imaging
| Flumaz {Kim, 2017 #1820} |
[18F]flumazenil A novel tracer for PET imaging of human benzodiazepine receptors [18F]-flumazenil (FMZ) has been synthesized by various strategies involving complex purification by on-line high-performance liquid chromatography (HPLC) and also by solid-phase cartridges. [18F]-FMZ has been used for the assessment of the gamma-aminobutyric acid (GABA) receptors by positron emission tomography (PET). |
| {Huang, 2019 #1821} |
In MPTP monkey: ↑ GABA by HPLC, =GABA by MRS No )[18F]flumazenil PET in PD patients? |
Gait
- review {Magrinelli, 2016 #1063}
| early | Late | |
|---|---|---|
| Mechanism | early PD, hypokinetic gait, which is characterized by reduced gait speed and amplitude with nearly normal cadence, is an expression of the bradykinesia |
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| Tx response | with this concept, hypokinetic gait may be ameliorated by dopaminergic treatment and external visual cues [91] | According to this view, some reports showed improvement of PD gait disturbances to inhibitors of cholinesterase [21, 43]. |
- pedunculopontine nucleus (PPN):
- in the upper pons in the brainstem.
- It has two divisions of subnuclei; the pars compacta containing mainly cholinergic neurons, and the pars dissipata containing mainly glutamatergic neurons and some non-cholinergic neurons.21
- The pedunculopontine nucleus is one of the main components of the reticular activating system.34
8 types of pathologic gaits: (nice review) https://stanfordmedicine25.stanford.edu/the25/gait.html
Assessment of Gait
| DigiGait | Mouse Specific Inc | (2019 Wegrzymoicz) Stride length, stance duration, propulsion duration | NZP437 (NEW Zealand pharmaceutical) |
| Noldus CatWalk XT system | {Patterson, 2019 #1376, Sortwell} A Noldus CatWalk XT system was used to assess 40 gait related variables (Table S1), → Of these parameters, we found stand time (duration of contact between paw and floor), terminal dual stance time (duration where both fore or hindlimbs are in contact with the floor at the end of a step cycle), body speed (speed of fore and hindlimbs over the run), average body speed (speed of the entire body over a run), and cadence (steps per second) were affected in either the fore or hindlimb (Fig. 9). In forelimb stand time, the PBS group had an average of 0.3599 ± 0.0189 s, whereas the PFF group had a decreased stand time of 0.3066 ± 0.0126 s (two-tailed t test, p=0.0226). In hindlimb stand time, the PBS group had an average of 0.3786 ± 0.0240 s, whereas the PFF group had a decreased stand time of 0.2735 ± 0.0109 s (two-tailed t test, p=0.0002). In forelimb terminal dual stance time, the PBS group had an average of 0.1022 ± 0.0078 s, whereas the PFF group had a decreased stand time of 0.0815 ± 0.0054 s (two-tailed t test, p=0.0342). Similarly, initial dual stance time for forelimb showed a strong trend towards a decrease in the PFF treatment group (p=0.0509). In the hindlimb terminal dual stance, the PBS group had an average of 0.0745 ± 0.0148 s, whereas the PFF group had a decreased stand time of 0.0593 ± 0.0062 s (two-tailed t test, p=0.3333). In forelimb body speed, the PBS group had an average of 0.3599 ± 0.0189 cm/s, whereas the PFF group displayed an increased rate of 0.3066 ± 0.0126 cm/s (two-tailed t test, p=0.0226). In hindlimb body speed, the PBS group had an average of 23.00 ± 1.09 s, whereas the PFF group had an increased rate of 26.64 ± 1.16 cm/s (two-tailed t test, p=0.0299). As for average speed, the PBS group had an average of 19.03 ± 1.50 cm/s, whereas the PFF group had an increased rate of 25.84 ± 1.76 cm/s (two-tailed t test, p=0.0113). The overall step cadence for the PBS group had an average of 7.1260 ± 0.476 steps/s, whereas the PFF group had an increased rate of 8.507 ± 0.356 steps/s (two-tailed t test, p=0.0305). Other results related to these metrics are graphed in Fig. S9, while all results and statistics are found in the supplementary dataset. Collectively, CatWalk system suggest ↓ standing time, ↑ speed and ↑ cadence in rats receiving bilateral PFF injection at 6 m (fig 9, supple fig 9, {Patterson, 20 #1376} suppl table , CatWalk included.xls) |
Galectin-3
- Gene name: LGALS3
- Function
- (Marianthi) This is a marker of pyroptosis and should be detected at least in plasma/PBMCs and of course it is related to NLRP3 inflammasome pathway. A couple of recent studies showed a precise correlation between Gal-3 serum levels and disease progression based on Hoehn and Yahr scores, suggesting a potential role for Gal-3 as a biomarker of PD progression.
- (Janaky) a typical marker for endolysosomal rupture, and is expected to be seen with mechanisms related to Alpha-Syn seeding/aggregation mechanisms
GCS inhibitor
below is GCSi , so pathway and degree of correlation may be different from GBA activator,
Obtained preclinical PoC for Gaucher’s disease (GD)
- but differentiation by their efficacy is a challenge…
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- :p < 0.025, ** :p < 0.005 Williams. Mean ± SE
Main isoform in brain among 16:0 GlcCer, 18:0 GlcCer and 24:1 GlcCer
Takeda Pharmaceutical Company Limited (Confidential)
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
Assessment of Gait / DigiGait / NZP437 | the right-most cell reads NZP437 (NEW Zealand pharmaceutical); reads as written. | low confidence on NEW Zealand vs New Zealand. |
Galectin-3 / Marianthi note | the body literally reads inflammasom_e pathway. A couple of recent studies showed a precise c_orrelation between Gal-3 serum levels and disease progression based on Hoehn and Ya_hr scores, suggesting a potential role for Gal-3 as a bioma_rker of PD progression. | line breaks within the source paragraph are preserved. |
GCS inhibitor / Animal: Gba D409V KI (22W) | the (22W) weeks-of-age annotation is partially clipped on the figure footer; reads as 22W. | low confidence on the W glyph. |