Outcome measure (continued), Sample size in nGD, Oculomotor measurements, Saccade & PLR, Retina in nGD
Outcome measure (continued)
| Tool | Reference | Description | Used in |
|---|---|---|---|
| Unified Myoclonus Rating Scale (UMRS); 24 | (Frucht, 2002 #784) | UMRS is a statistically validated, quantitative clinical rating instrument designed to evaluate the response of patients undergoing antimyoclonic therapies. Changes in the myoclonus scores with action, functional tests, and stimulus sensitivity were evaluated in patients who could follow the instructions. | (Narita, 2016 #560) |
| Gross Motor Function Measure (GMFM); 25 | (Michaelis, 2015 #785) (Beckers, 2015 #786) | (Narita, 2016 #560) | |
| Functional Independence Measure (FIM); 26 | (Keith, 1987 #787) | (Narita, 2016 #560) | |
| scale for the assessment and rating of ataxia (SARA) | Schmitz-Hubsch T, du Montcel ST, Baliko L, Berciano J, Boesch S, Depondt C, et al. Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology. 2006;66:1717-20 |
Sample size estimation in nGD
| Reference | text | |
|---|---|---|
| Miglustat p2 | (Schiffmann, 2008 #866) | A sample size of 30 patients was selected on pragmatic grounds because limited longitudinal data for VSEM were available for GD3 patients at the time of study design. The sample was expected to provide 86% power to detect a difference of 0.0012 msec/degree between treatment groups on the primary efficacy end point, VSEM-a, at the two-sided 5% level of statistical significance. This calculation was based on VSEM data obtained from six GD3 patients evaluated before study initiation. |
Oculomotor measurements
Measurement is Easy and reliable
Resources
- The book ‘Translational medicine in CNS drug development’ page 73.
NHP
- Js: no need to kill?
- Good homology exist
- neurophysiological and neurochemical basis involved in oculomotor control in nonhuman primate brain is well characterized from single unit recordings. The homology of involved brain regions between human and nonhuman primate species is supported by objective functional imaging studies. Behavioral pharmacology
PK/PD
- Relevant to GBA activator?
Examples
- Benzodiazepine
- decrease in peak velocity associated with benzodiazepines is generally thought to be related to the sedative properties; thus the oculomotor responses have predictive validity for sedative properties of drugs
Photoreceptors (in retina겠지)
| photoreceptor | Wavelength that stimulate each photoreceptors | note |
|---|---|---|
| M/L cones | beyond 620 nm (red light, λmax = 543, 566 nm) | |
| Rods | blue light (λmax = 507 nm) at low luminance levels (normal threshold at -3 to -5 log cd/m²) | |
| ipRGC | blue light (λmax = 482 nm) at higher luminance levels (100 cd/m²). | Ip RGC may be resistant to neurodegeneration |
saccade correlate with clinical but failed to respond in ambroxol (AMC), & Venglustat p2 (LEAP), So not useful
PLR: rationale (retinal atrophy, gaucher cell in retina), responded in narita.
Saccade and PLR
| Normal mechanism | Pathologic mechanism | method | Frequency | Correlation with behavioral phenotype | Tx response | mice | NHP | ||
|---|---|---|---|---|---|---|---|---|---|
| Horizontal saccadic latency (=saccade initiation failure = oculomotor apraxia=horizontal supranuclear gaze palsy.) | definition |
The superior colliculus and frontal eye fields are thought to initiate saccades Pathway: frontal eye field → superior colliculus → PPRF (paramedian pontine reticular formation) → abducens nucleus → MLF (medial longitudinal fasciculus) → oculomotor nucleus voluntary saccades are triggered by the frontal eye fields, visually guided saccades, visual information from the retina passes through the optic nerves, chiasm, and tracts to the lateral geniculate nucleus of the thalamus, where it is brought to the primary visual cortex by the optic radiations[9]. At the primary visual cortex, the visual stimulus is registered within 100-120 ms after its presentation[9]. Information is then sent from the primary visual cortex to the extrastriate cortical regions, which are involved in mapping relevant stimuli in visual space[9]. The visual cortex also sends inputs to the superior colliculus, which in turn can initiate a saccade by activating the horizontal and vertical brainstem gaze centers[13]. | (Blume, 2017 #892) Reduced velocity of horizontal saccades is caused by affection of the premotor burst neurons in the ipsilateral paramedian pontine reticular formation |
DC-electrooculogram (EOG) technique (methods see Data S1). (Narita, 2016 #560) Biopac system MP150WS, and EOG 100C (Biopac Systems, Santa Barbara, CA, USA). Each patient sat with the head immobilized and faced a screen. A visual dot stimulus of LEDs horizontally jumped approximately every 3 sec in a visual range of +/- 15 degrees. Saccades were recorded for 30 sec, and acquired eye movements were then low-pass filtered at 100 Hz and sampled at 500 Hz. For each variable, we used the average of all measurements for both the eyes. | (Blume, 2017 #892) slowing of vertical saccades indicates a subsequent involvement of the rostral interstitial medial longitudinal fascicle (14) | (2011 Benko) Change over time is not clear: only two cases of 15 (aged 8-28, 15명) showed deterioration over 4 years, (Bremova-Ertl, 2018 #565) 11명, Mean age 18 y) Quite variable and Horizontal and vertical saccade impairment were not evident over 1 year follow up (except vertical upward and downward smooth pursuit gains at 0.1 Hz) | No change in venglu p2, AMC, what about in narita 2016? | (Sakatani, 2007 #832) | (neuronal loss/gliosis)가져야 하는데, 그러려면 오랜 시간 걸릴테니 CBE로 어렵지 않나? |
| vertical saccade | definition |
(Bremova-Ertl, 2018 #565)에 잘 설명, vertical gaze center or rostral interstitial nucleus, is located in the rostral part of the midbrain reticular formation, (Schiffmann, 2008 #866) VSEM velocity was used as the primary efficacy measure in this study rather than the HSEM because it appears later and is virtually always milder; | (Blume, 2017 #892) slowing of vertical saccades indicates a subsequent involvement of the rostral interstitial medial longitudinal fascicle (14) | VSEM abnormality appears later and milder than HSEM | (Bremova-Ertl, 2018 #565) with mSST, SARA |
(Hopf, 2019 #831) (important)
- saccadometry using EyeSeeCam, saccades was more frequent horizontally (15/16) than vertically (12/16). Saccadometry revealed slowed peak velocity compared to 100 controls (most evident horizontally and downwards). Saccades were delayed and hypometric.
- Best correlating with SARA (scale for the assessment and rating of ataxia), disease duration, mSST (modified Severity Scoring Tool) and reduced IQ was peak velocity (both up- and downwards Correlation analysis between saccade parameters and other neurologic parameters
Clinical scores correlated with subjective and objective saccadic peak velocity and with saccade hypometria. Phenotype severity showed mild correlation with longer latency. High mSST (adjusted for saccades), high SARA, long duration of disease and low IQ correlate with slow and hypometric saccades. The correlation was found to be greater in vertical than in horizontal saccades. Phenotype severity correlated with longer latency, while its correlation with other saccade parameters was not universal. The underlying analyses data are provided in the Additional file 3, and the neurologic items are listed in the Additional file 4 [see Additional files 3 and 4].
Retina in nGD
- (Hopf, 2019 #831) Js, (retinal, OCT) 2 of 16 n GD patients, showed following, drusen-like deposits possibly Gaucher cell collections) in the peripapillary region, retinal atrophy, loss of photoreceptors and retinal pigment epithelium
- (McNeill, 2013 #843) thinning of the RGC layer) (by optical coherence tomography (OCT)) in (adult) GD patients (type 1 but had neurological signs (and without eye movement disorder), n=4) compared with normal control and GD patients without neurological signs
- (Coussa, 2013 #860) (case report) OCT, Normal acuity and ERG findings, white globular lesions IN retina
- Winter, 2019 #830) The majority of reports suggest that Gaucher cells are indeed present at the site of disease. These sites include the bulbar conjunctiva (pinguecula-like lesions), vitreous, the ciliary body, inner surface of the retina, inner retinal layer, choroid and sclera. Macular atrophy has been reported and the retinal vasculature may be abnormally permeable. Corneal opacities have been seen in some patient
- retinal detatchment
- (Matos, 2017 #861) 1st: OCT, preretinal white matter deposit (probable accumulation of glucosylceramide), thinning of the nerve fiber layer of the retina
- (Abu-Asab, 2017 #862) (autopsy, two pts, Transmission electron micrograph) Gaucher body inclusions (GBIs) were present in the ciliary body, RGC, choroid, and sclera
Plan : pathology is glycolipid accumulation in RGC and RGC atrophy (thinning, loss). Neuroptics 에는 꼭 contact
- Anatomical change in RGC (layer) by OCT, (mouse feasible (Jagodzinska, 2017 #864, jove)
- Functional neurophysiologic recovery of RGC by PLR, (A-2000)
ERG is often normal despite structural lesion in Ngd (including Sawicka-Gutaj 2016)
아래 셋은 꼭 retina는 아닌 듯
- Cogan DG, Chu FC, Gittinger J, Tychsen L. Fundal abnormalities of Gaucher’s disease. Arch Ophthalmol 1980;98;2202-3.
- Sheck LHN, Wilson CJ, Vincent AL. Analysis of the pre-retinal opacities in Gaucher disease using spectral domain optical coherent tomography. Ophthalmic Genet 2012;33:253-6.
- Hsing YE, Foster A. Preretinal and posterior vitreous deposits in Gaucher disease. JAMA Ophthalmol 2014;132:992.
[Questions]
Can OCT differentially visualize n fiber layer, RGC layer, photoreceptor layer (ONL), RPE layer in human and mice? → yes in human
Retina & LSD
(Collin, 2020 #867) LSDs terminate in a similar pathology of reduced clearance of metabolic aggregates.
Retinal degeneration (RD) is an early consequence of LSD, especially in neuronal ceroid lipofuscinoses (NCL) [251], also called Batten disease, an early-onset neurodegenerative disease with other systemic features such as dementia and epilepsy [252]. NCL shows accumulation of ceroid. Similar to the early retinal phenotype reported for most human NCLs, most mouse models for NCL disease show an early onset of PR degeneration, beginning at 1 month of age and showing greater than 60% degeneration by 6-9 months [253-256].
Mouse models for other lysosomal disorders, namely, mucopolysaccharidosis and mucolipidosis due to mutations in lysosomal proteins required for the breakdown of glycosaminoglycans and enzymes required for phosphorylation of glycoproteins, respectively, also develop PR degeneration. For example, mouse models for mucopolysaccharidosis with a mutation in Naglu present with a slowly progressive rod-cone degeneration [258], and for mucolipidosis with a mutation in Gnptab develop a severe PR degeneration with complete PR loss by 10 months [259].
chromatic pupillometry (Narita, 2016 …
| pathway | retina → afferent → Nucleus (pretectal nucleus at the level of superior colliculus) in midbrain → efferent, 2014 Narita에 잘설명 |
|---|---|
| ↑ GlcCer/GlcCer (in RGC cell일걸) → | |
| citations | (Narita, 2014 #564) red light- ; (Narita, 2014 #564) the ; (Narita, 2016 #560) ; (Kircher, 2019 #806) age-related ; Human PLR is similar |
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
| Photoreceptors / Rods row | -3 to -5 log cd/m² | reads as written; OCR alternated with _3 to _5. |