Hopf saccadometry tail, Retina in nGD / Retina & LSD, PLR / chromatic pupillometry, ERG, CRO / KOL, Lipofuscin

Hopf saccadometry (continued)

(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].

(narrow upper cell): vertical upward and downward smooth pursuit gains at 0.1 Hz)

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), in vitreous, in 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)	1*: 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)

(side column) 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].

PLR / chromatic pupillometry

chromatic pupillometry (#560; Narita, 2014 #564)	dilated pupils and reacted sluggishly to a broad-spectrum (white) light
pathway	retina → afferent → Nucleus (pretectal nucleus at the level of superior colliculus) in midbrain → efferent, 2014 Narita에 잘설명
storage	↑ GlcCer/GlcCer (in RGC cell일걸) →
pathway detail	Photoreceptor → RGC → Optic n → pretectal nucleus of the upper midbrain → From the pretectal nucleus, axons connect to neurons in the Edinger-Westphal nucleus → Oculomotor nerve axons synapse on ciliary ganglion neurons. → short ciliary n innervates the constrictor muscle of the iris
link	https://www.wikidoc.org/index.php/Pupillary_light_reflex
(Narita 2014 author conclusion)	we assume that the primary deficit (storage of substrate) caused secondary functional changes to the inner retina, and the synaptic rod/cone inputs to both RGCs via bipolar cells may be blocked, resulting eventually in the progression of R-CR (derived from cone/rod activation via conventional RGCs and ipRGCs) to loss. On the other hand, B-CR may be relatively spared because of their intrinsic response of ipRGCs.
(side interpretation)	functional changes to inner retina → synaptic rod/cone inputs to both RGCs (conventional RGC & ipRGC) via bipolar cells are blocked → Loss of R-CR (derived from cone/rod activation via conventional RGCs and ipRGCs)
(Narita, 2014 #564)	red light-induced Constriction Rates (R-CRs) were markedly attenuated or absent in ALL neuronopathic GD patients (N=9)
(Narita, 2014 #564)	the qualitative trend for reduced R-CRs was associated with the severity of (ADL)
(Narita, 2016 #560)	ambroxol, n=5, done with A2000 → R-CR
(Kircher, 2019 #806)	age-related characterization done with A2000,
(side note)	Js: can we differentiate between retina (ie ↑ GlcCer/GlcSph) vs dorsal brainstem (ie neuronal loss/gliosis)? 후자라야 의미 크겠지만 오래 소요될텐데, 전자는 CSF GlcSph보니까 필요가 적고. 또한 oculomotor n도 생각할 필요 없음 (cell body 없이 axon만 있나?)
mouse	Mouse eyes constrict to light without direct link to the brain (Wang, 2017 #859),
human	Human PLR is similar to macaque monkeys (Pong, 2000 #799) & rhesus monkey (Clarke, 2003 #801),

PLR figure caption:

Figure 1. Example of a normal pupillary light reflex PLD profile. PLR parameters. D1 = initial pupil diameter (mm), D2 = minimum pupil diameter (mm) after a pupillary reaction to light, CR = constriction rate (%) = (D1-D2)/D1 × 100. Actual recordings for both pupils.

위 그림 보면 (narita 2014), 속도는 안 따지고 pupil diameter 차이만 따지네. (R-CR은 이상인데) B-CR은 정상이네 - (Conventional RGC 말고) IpRGC는 intact하구나 photoreceptor (rod & cone cell)은 functional 하구나! pathologic site는 inner retina (라면 과장이고 PLR pathway상 N fiber layer & RGC layer겠지) 구나!

decreased ERG OPs were found in our patients and decreased ERG b-wave amplitudes have been reported in a visually asymptomatic GD patient.20

nGD involve the midline of the dorsal brainstem, EWN, and oculomotor nucleus

(figure attribution) JE Kum 저술 - 2016

Rationale: much of what is learned from eye research could be applicable to the brain and spinal cord, and vice versa.

• 원래 part of the CNS
• Development: the retina and optic nerve extend from the diencephalon, and are thus considered part of the CNS.
• Neurons,
• Similar regeneration milieu and conditions
• Connected: the axons of RGCs extend to thalamus (lateral geniculate nucleus, Approximately 80% of the axons of each optic tract synapse (‘synapse’ 분명히 기술됨, https://www.ncbi.nlm.nih.gov/books/NBK549340/?report=printable & midbrain (superior colliculus), just one synaptic connection (optic n의 경우, 이는 brain내와 마찬가지)
• The retina is part of the CNS. The retinal neurons are connected to the brain via the optic nerve and its synaptic connection onto the thalamus and midbrain.
• Having lysosome
• RGCs display the typical properties of CNS neurons,
• BRB (blood retinal barrier) strongly resembles BBB.
• It is possible that TPP1 administered via the CSF will reach RGC via the optic nerve, which is in contact with the CSF,
• Connection between retina and LSD (peripheral이라 좀 약할 듯)
  • RD is an early consequence
• Connection between retina and GD3
  • Pathology: both in brain and retina (↓ saccade is rare in type I)

Localization / GD3

• GD Sx: associated
• 병소?
• How can we localize/distinguish brain lesion? ERG도 RETINA만 보는 것 같은데?
• PLR in conjunction with the ERG can be particularly useful in characterizing diseases such as CLN2 in which pathological changes occur in both the retina and other areas of the CNS involved in mediating the PLR and in assessing the pharmacological activity of therapeutic interventions ?
• Tx
• Does a small molecule enter retina through blood-retina-barrier? Ie. Drug concentration between brain tissue vs retina?

Narita 2014 ERG Normal

All patients exhibited normal a-wave amplitudes with flash ERG, which reflects cone activity. (2nd) On the other hand, decreased ERG OPs were found in our patients and decreased ERG b-wave amplitudes have been reported in a visually asymptomatic GD patient.20 Lowering OPs and b-wave amplitudes are typically attributed to changes in the inner nuclear layer (amacrine cells and Mueller cells) of the retina.

ERG figure labels: ERG Normal, b-wave (inner retina), a-wave (photoreceptors), 100 μV, 25 msec.

ERG explanatory text:

If a dim flash ERG is performed on a dark-adapted eye, the response is primarily from the rod system. Flash ERGs performed on a light adapted eye will reflect the activity of the cone system. Sufficiently bright flashes will elicit ERGs containing an a-wave (initial negative deflection) followed by a b-wave (positive deflection). The leading edge of the a-wave is produced by the photoreceptors, while the remainder of the wave is produced by a mixture of cells including photoreceptors, bipolar, amacrine, and Muller cells or Muller glia.[1] The pattern ERG (PERG), evoked by an alternating checkerboard stimulus, primarily reflects activity of retinal ganglion cells

CRO / Vendors / KOL

CRO	Neuroptics	https://neuroptics.com/a-2000-animal-pupillometer/ Device: ‘A-2000 small animal pupillometer’ (PC-based Desktop Pupillometer), Pupil variables: Latency, diameter at onset and peak of constriction, constriction and dilation velocity, 75% recovery time), ! ophthalmologist who has experience in pupillometry in mice! Is needed.
	Phoenix	MICRON(TM) Image-Guided OCT (Simply ‘Phoenix MICRON OCT’ https://phoenixtech.com/phoenix-micron/image-guided-oct/ OCT optimized for mice & rat
	JAX	Eye Mutant Resource (EMR) and the Translational Vision Research Models (TVRM) centers in Jackson Laboratory in Bar Harbor, Maine and Mahidol University in Bangkok, Thailand: to screen for or generate mouse models with ocular diseases
KOL	Sylvan Crippa	https://www.unil.ch/line/en/home/menuinst/research-topics/vision—seeing.html, Sylvain V. Crippa Orthoptist, Jules Gonin University Eye Hospital (Kircher, 2019 #806)

Whiting / NCL PLR

(Whiting, 2013 #858)	Canine model of neuronal ceroid lipofuscinosis, (miniature Dachshunds), to dim light, PLR deficits: latency, constriction velocity, constriction amplitude, and redilation velocity
(Whiting, 2014 #856)	CSF-delivered ERT prevented (probably fig 4, 10 m old) and restored (probably fig 6, 12 m old) PLR deficits in this animals, (15m old때는 무효과인듯)

Lipofuscin (age pigment)

definition

• is a brown-yellow, electron-dense, autofluorescent material that accumulates progressively over time in lysosomes of postmitotic cells, such as neurons and cardiac myocytes. The exact mechanisms behind this accumulation are still unclear.

components

• Aside from a large lipid content (oxidation of unsaturated fatty acids), lipofuscin is known to contain sugars and metals, including mercury, aluminium, iron, copper and zinc.[4] Lipofuscin is also accepted as consisting of oxidized proteins (30-70%) as well as lipids (20-50%).[5]

location

• It is a type of lipochrome[6] and is specifically arranged around the nucleus.