PMC:7523471 / 49133-54500 JSONTXT

{"project":"TEST0","denotations":[{"id":"33041751-219-227-816574","span":{"begin":263,"end":267},"obj":"[\"2819446\"]"},{"id":"33041751-235-243-816576","span":{"begin":292,"end":296},"obj":"[\"17460292\"]"},{"id":"33041751-234-242-816577","span":{"begin":309,"end":313},"obj":"[\"20609426\"]"},{"id":"33041751-228-236-816578","span":{"begin":327,"end":331},"obj":"[\"25886372\"]"},{"id":"33041751-234-242-816579","span":{"begin":351,"end":355},"obj":"[\"26505992\"]"},{"id":"33041751-233-241-816581","span":{"begin":396,"end":400},"obj":"[\"31551688\"]"},{"id":"33041751-113-121-816582","span":{"begin":516,"end":520},"obj":"[\"28522986\"]"},{"id":"33041751-139-147-816583","span":{"begin":662,"end":666},"obj":"[\"16518161\"]"},{"id":"33041751-233-241-816584","span":{"begin":978,"end":982},"obj":"[\"28522986\"]"},{"id":"33041751-138-146-816585","span":{"begin":1123,"end":1127},"obj":"[\"26505992\"]"},{"id":"33041751-217-225-816586","span":{"begin":1492,"end":1496},"obj":"[\"28814675\"]"},{"id":"33041751-121-129-816589","span":{"begin":2393,"end":2397},"obj":"[\"12699953\"]"},{"id":"33041751-140-148-816590","span":{"begin":2412,"end":2416},"obj":"[\"24688166\"]"},{"id":"33041751-234-242-816591","span":{"begin":2608,"end":2612},"obj":"[\"24398104\"]"},{"id":"33041751-47-55-816593","span":{"begin":3574,"end":3578},"obj":"[\"28814675\"]"},{"id":"33041751-37-45-816594","span":{"begin":3673,"end":3677},"obj":"[\"27645291\"]"},{"id":"33041751-81-89-816595","span":{"begin":3881,"end":3885},"obj":"[\"12466113\"]"},{"id":"33041751-100-108-816596","span":{"begin":3900,"end":3904},"obj":"[\"23750207\"]"},{"id":"33041751-119-127-816597","span":{"begin":3919,"end":3923},"obj":"[\"24709310\"]"},{"id":"33041751-138-146-816598","span":{"begin":3938,"end":3942},"obj":"[\"24398104\"]"},{"id":"33041751-168-176-816599","span":{"begin":4113,"end":4117},"obj":"[\"12466113\"]"},{"id":"33041751-185-193-816600","span":{"begin":4305,"end":4309},"obj":"[\"24709310\"]"},{"id":"33041751-93-101-816601","span":{"begin":4405,"end":4409},"obj":"[\"24398104\"]"},{"id":"33041751-92-100-816602","span":{"begin":4504,"end":4508},"obj":"[\"25912193\"]"},{"id":"33041751-112-120-816603","span":{"begin":4524,"end":4528},"obj":"[\"27133194\"]"},{"id":"33041751-169-177-816604","span":{"begin":4581,"end":4585},"obj":"[\"25912193\"]"},{"id":"33041751-150-158-816605","span":{"begin":4738,"end":4742},"obj":"[\"29880901\"]"},{"id":"33041751-164-172-816606","span":{"begin":4909,"end":4913},"obj":"[\"28774322\"]"}],"text":"Retinal Degeneration in Alzheimer’s Disease\nIn agreement with the observed distribution of retinal Aβ deposits in AD patients, reports have indicated NFL thinning and RGC degeneration in the GCL chiefly within the superior quadrants of the retina (Blanks et al., 1989, 1996b; Berisha et al., 2007; Lu et al., 2010; Liu et al., 2015; La Morgia et al., 2016; Asanad et al., 2019b; Grimaldi et al., 2019). In vivo OCT imaging of these patient retinas revealed degeneration in multiple retinal layers (La Morgia et al., 2017). Reduced macular thickness and volume, measured by OCT, was also found to correlate with cognitive impairment in AD patients (Iseri et al., 2006). The first study that evaluated melanopsin-containing retinal ganglion cells (mRGCs), photoreceptors known to drive circadian photoentrainment, in the postmortem retina of AD patients described a significant mRGC degeneration reflected in reduction of both dendritic density and cell number (La Morgia et al., 2017). Notably, dendrite loss and cell death were closely linked to Aβ pathology and were colocalized at sites of Aβ deposits (La Morgia et al., 2016).\nThese findings were corroborated in another study, which indicated a substantial loss of retinal cells at sites of Aβ deposition (Figures 5A–D). When compared with age-matched cognitively normal controls, 22-29% retinal neuronal degeneration was detected by Nissl staining (n = 17 subjects) in the GCL, INL, and ONL of AD patients (Figures 5B,C; Koronyo et al., 2017). More recently, Asanad and colleagues analyzed retinal atrophy morphometrically in the superior quadrants of postmortem retinas from 8 AD and 11 age-matched controls (Asanad et al., 2019b). Measurements were acquired along a distance of 4mm from the optic nerve on the supero-temporal (reaching the macular region) and supero-nasal sides. Significant retinal thinning was revealed in the NFL (∼40%), GCL (35%), IPL (∼20%), and both nuclear layers (25%) in AD patients. In the supero-temporal region, NFL thinning was more pronounced closer to the optic nerve, whereas the other retinal layers showed prominent thinning closer to the macula. However, all analyzed retinal layers showed consistent thinning throughout the supero-nasal retinal quadrant (Asanad et al., 2019b). Beyond these changes, several studies have demonstrated accumulation of Aβ in the lens of AD patients (Goldstein et al., 2003; Tian et al., 2014) as well as reductions in the choroid coat – the vascular layer of the eye – and offered insights into the retinal choroid as an oculovascular biomarker for Alzheimer’s disease (Tsai et al., 2014; Asanad et al., 2019a).\nFIGURE 5 Increased Aβ42-associated neuronal loss in post-mortem retinas of AD patients. (A) Representative images of post-mortem retinal cross-sections from CN and AD cases, immunostained with anti-Aβ42 mAb (12F4) and labeled with peroxidase-based DAB (brown) and hematoxylin counterstain (violet). Intracellular Aβ42-inclusions are observed in GCL, INL and ONL of AD retina. Scale bars: 20 μm. (B) Nissl staining of retinal cross-sections from a control subject and AD patient, revealing cellular and retinal layer alterations in AD. (C) Quantitation of neuronal Nissl-positive total area in retinas of AD patients (n = 9) compared to age-/sex-matched CN control subjects (n = 8). Data shown as group mean ± SEM. **P \u003c 0.01, unpaired 2-tailed Student’s t-test (D) Qualitative geometric map of increased retinal Aβ deposits (red shapes) and neuronal loss (green triangles) in AD patients. Panels a-c are reproduced from Koronyo et al. (2017) with permission of ASCI via Copyright Clearance Center. Panel d is adapted from Hart et al. (2016) under terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/). These findings are further supported by animal models of AD (Frederikse and Ren, 2002; Yang et al., 2013; Park et al., 2014; Tsai et al., 2014). In the hTgAPPtg/tg mouse lens, markers of degeneration included nuclear disorganization, organelle loss, cellular swelling, and shape irregularity (Frederikse and Ren, 2002). In the 5xFAD mouse, Aβ deposits in the retinal pigment epithelium, hypopigmentation, large vacuoles, and Bruch membrane thickening with Drusen-like deposits were observed (Park et al., 2014). Hypertrophy along with choroid changes were also detected in the TgF344-AD rat (Tsai et al., 2014). Further, in the APPSWE/PS1ΔE9 mouse, RGC density was lower than in WT controls (Gao et al., 2015; Gupta et al., 2016) and amacrine cell apoptosis was noted (Gao et al., 2015).\nA recent finding in 3xTg mice indicated colocalization of both retinal tau tangles and Aβ plaques with neurodegeneration in the GCL (Grimaldi et al., 2018). In the same mouse model, tau accumulation was associated with retinal neural dysfunction, as measured by deficits in anterograde axonal transport (Chiasseu et al., 2017).\nAltogether, observations of retinal atrophy in layers recognized as sites of proteinaceous deposition in both AD patients and animal models of the disease illustrate the vulnerability of retinal cell types to pathological processes traditionally associated with the cerebral disease. In addition, these findings further support the suitability of retinal thinning, in combination with more specific markers, as a diagnostic and monitoring tool for AD."}

{"project":"2_test","denotations":[{"id":"33041751-2819446-38666360","span":{"begin":263,"end":267},"obj":"2819446"},{"id":"33041751-17460292-38666362","span":{"begin":292,"end":296},"obj":"17460292"},{"id":"33041751-20609426-38666363","span":{"begin":309,"end":313},"obj":"20609426"},{"id":"33041751-25886372-38666364","span":{"begin":327,"end":331},"obj":"25886372"},{"id":"33041751-26505992-38666365","span":{"begin":351,"end":355},"obj":"26505992"},{"id":"33041751-31551688-38666367","span":{"begin":396,"end":400},"obj":"31551688"},{"id":"33041751-28522986-38666368","span":{"begin":516,"end":520},"obj":"28522986"},{"id":"33041751-16518161-38666369","span":{"begin":662,"end":666},"obj":"16518161"},{"id":"33041751-28522986-38666370","span":{"begin":978,"end":982},"obj":"28522986"},{"id":"33041751-26505992-38666371","span":{"begin":1123,"end":1127},"obj":"26505992"},{"id":"33041751-28814675-38666372","span":{"begin":1492,"end":1496},"obj":"28814675"},{"id":"33041751-12699953-38666375","span":{"begin":2393,"end":2397},"obj":"12699953"},{"id":"33041751-24688166-38666376","span":{"begin":2412,"end":2416},"obj":"24688166"},{"id":"33041751-24398104-38666377","span":{"begin":2608,"end":2612},"obj":"24398104"},{"id":"33041751-28814675-38666379","span":{"begin":3574,"end":3578},"obj":"28814675"},{"id":"33041751-27645291-38666380","span":{"begin":3673,"end":3677},"obj":"27645291"},{"id":"33041751-12466113-38666381","span":{"begin":3881,"end":3885},"obj":"12466113"},{"id":"33041751-23750207-38666382","span":{"begin":3900,"end":3904},"obj":"23750207"},{"id":"33041751-24709310-38666383","span":{"begin":3919,"end":3923},"obj":"24709310"},{"id":"33041751-24398104-38666384","span":{"begin":3938,"end":3942},"obj":"24398104"},{"id":"33041751-12466113-38666385","span":{"begin":4113,"end":4117},"obj":"12466113"},{"id":"33041751-24709310-38666386","span":{"begin":4305,"end":4309},"obj":"24709310"},{"id":"33041751-24398104-38666387","span":{"begin":4405,"end":4409},"obj":"24398104"},{"id":"33041751-25912193-38666388","span":{"begin":4504,"end":4508},"obj":"25912193"},{"id":"33041751-27133194-38666389","span":{"begin":4524,"end":4528},"obj":"27133194"},{"id":"33041751-25912193-38666390","span":{"begin":4581,"end":4585},"obj":"25912193"},{"id":"33041751-29880901-38666391","span":{"begin":4738,"end":4742},"obj":"29880901"},{"id":"33041751-28774322-38666392","span":{"begin":4909,"end":4913},"obj":"28774322"}],"text":"Retinal Degeneration in Alzheimer’s Disease\nIn agreement with the observed distribution of retinal Aβ deposits in AD patients, reports have indicated NFL thinning and RGC degeneration in the GCL chiefly within the superior quadrants of the retina (Blanks et al., 1989, 1996b; Berisha et al., 2007; Lu et al., 2010; Liu et al., 2015; La Morgia et al., 2016; Asanad et al., 2019b; Grimaldi et al., 2019). In vivo OCT imaging of these patient retinas revealed degeneration in multiple retinal layers (La Morgia et al., 2017). Reduced macular thickness and volume, measured by OCT, was also found to correlate with cognitive impairment in AD patients (Iseri et al., 2006). The first study that evaluated melanopsin-containing retinal ganglion cells (mRGCs), photoreceptors known to drive circadian photoentrainment, in the postmortem retina of AD patients described a significant mRGC degeneration reflected in reduction of both dendritic density and cell number (La Morgia et al., 2017). Notably, dendrite loss and cell death were closely linked to Aβ pathology and were colocalized at sites of Aβ deposits (La Morgia et al., 2016).\nThese findings were corroborated in another study, which indicated a substantial loss of retinal cells at sites of Aβ deposition (Figures 5A–D). When compared with age-matched cognitively normal controls, 22-29% retinal neuronal degeneration was detected by Nissl staining (n = 17 subjects) in the GCL, INL, and ONL of AD patients (Figures 5B,C; Koronyo et al., 2017). More recently, Asanad and colleagues analyzed retinal atrophy morphometrically in the superior quadrants of postmortem retinas from 8 AD and 11 age-matched controls (Asanad et al., 2019b). Measurements were acquired along a distance of 4mm from the optic nerve on the supero-temporal (reaching the macular region) and supero-nasal sides. Significant retinal thinning was revealed in the NFL (∼40%), GCL (35%), IPL (∼20%), and both nuclear layers (25%) in AD patients. In the supero-temporal region, NFL thinning was more pronounced closer to the optic nerve, whereas the other retinal layers showed prominent thinning closer to the macula. However, all analyzed retinal layers showed consistent thinning throughout the supero-nasal retinal quadrant (Asanad et al., 2019b). Beyond these changes, several studies have demonstrated accumulation of Aβ in the lens of AD patients (Goldstein et al., 2003; Tian et al., 2014) as well as reductions in the choroid coat – the vascular layer of the eye – and offered insights into the retinal choroid as an oculovascular biomarker for Alzheimer’s disease (Tsai et al., 2014; Asanad et al., 2019a).\nFIGURE 5 Increased Aβ42-associated neuronal loss in post-mortem retinas of AD patients. (A) Representative images of post-mortem retinal cross-sections from CN and AD cases, immunostained with anti-Aβ42 mAb (12F4) and labeled with peroxidase-based DAB (brown) and hematoxylin counterstain (violet). Intracellular Aβ42-inclusions are observed in GCL, INL and ONL of AD retina. Scale bars: 20 μm. (B) Nissl staining of retinal cross-sections from a control subject and AD patient, revealing cellular and retinal layer alterations in AD. (C) Quantitation of neuronal Nissl-positive total area in retinas of AD patients (n = 9) compared to age-/sex-matched CN control subjects (n = 8). Data shown as group mean ± SEM. **P \u003c 0.01, unpaired 2-tailed Student’s t-test (D) Qualitative geometric map of increased retinal Aβ deposits (red shapes) and neuronal loss (green triangles) in AD patients. Panels a-c are reproduced from Koronyo et al. (2017) with permission of ASCI via Copyright Clearance Center. Panel d is adapted from Hart et al. (2016) under terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/). These findings are further supported by animal models of AD (Frederikse and Ren, 2002; Yang et al., 2013; Park et al., 2014; Tsai et al., 2014). In the hTgAPPtg/tg mouse lens, markers of degeneration included nuclear disorganization, organelle loss, cellular swelling, and shape irregularity (Frederikse and Ren, 2002). In the 5xFAD mouse, Aβ deposits in the retinal pigment epithelium, hypopigmentation, large vacuoles, and Bruch membrane thickening with Drusen-like deposits were observed (Park et al., 2014). Hypertrophy along with choroid changes were also detected in the TgF344-AD rat (Tsai et al., 2014). Further, in the APPSWE/PS1ΔE9 mouse, RGC density was lower than in WT controls (Gao et al., 2015; Gupta et al., 2016) and amacrine cell apoptosis was noted (Gao et al., 2015).\nA recent finding in 3xTg mice indicated colocalization of both retinal tau tangles and Aβ plaques with neurodegeneration in the GCL (Grimaldi et al., 2018). In the same mouse model, tau accumulation was associated with retinal neural dysfunction, as measured by deficits in anterograde axonal transport (Chiasseu et al., 2017).\nAltogether, observations of retinal atrophy in layers recognized as sites of proteinaceous deposition in both AD patients and animal models of the disease illustrate the vulnerability of retinal cell types to pathological processes traditionally associated with the cerebral disease. In addition, these findings further support the suitability of retinal thinning, in combination with more specific markers, as a diagnostic and monitoring tool for AD."}

{"project":"0_colil","denotations":[{"id":"33041751-2819446-816574","span":{"begin":263,"end":267},"obj":"2819446"},{"id":"33041751-17460292-816576","span":{"begin":292,"end":296},"obj":"17460292"},{"id":"33041751-20609426-816577","span":{"begin":309,"end":313},"obj":"20609426"},{"id":"33041751-25886372-816578","span":{"begin":327,"end":331},"obj":"25886372"},{"id":"33041751-26505992-816579","span":{"begin":351,"end":355},"obj":"26505992"},{"id":"33041751-31551688-816581","span":{"begin":396,"end":400},"obj":"31551688"},{"id":"33041751-28522986-816582","span":{"begin":516,"end":520},"obj":"28522986"},{"id":"33041751-16518161-816583","span":{"begin":662,"end":666},"obj":"16518161"},{"id":"33041751-28522986-816584","span":{"begin":978,"end":982},"obj":"28522986"},{"id":"33041751-26505992-816585","span":{"begin":1123,"end":1127},"obj":"26505992"},{"id":"33041751-28814675-816586","span":{"begin":1492,"end":1496},"obj":"28814675"},{"id":"33041751-12699953-816589","span":{"begin":2393,"end":2397},"obj":"12699953"},{"id":"33041751-24688166-816590","span":{"begin":2412,"end":2416},"obj":"24688166"},{"id":"33041751-24398104-816591","span":{"begin":2608,"end":2612},"obj":"24398104"},{"id":"33041751-28814675-816593","span":{"begin":3574,"end":3578},"obj":"28814675"},{"id":"33041751-27645291-816594","span":{"begin":3673,"end":3677},"obj":"27645291"},{"id":"33041751-12466113-816595","span":{"begin":3881,"end":3885},"obj":"12466113"},{"id":"33041751-23750207-816596","span":{"begin":3900,"end":3904},"obj":"23750207"},{"id":"33041751-24709310-816597","span":{"begin":3919,"end":3923},"obj":"24709310"},{"id":"33041751-24398104-816598","span":{"begin":3938,"end":3942},"obj":"24398104"},{"id":"33041751-12466113-816599","span":{"begin":4113,"end":4117},"obj":"12466113"},{"id":"33041751-24709310-816600","span":{"begin":4305,"end":4309},"obj":"24709310"},{"id":"33041751-24398104-816601","span":{"begin":4405,"end":4409},"obj":"24398104"},{"id":"33041751-25912193-816602","span":{"begin":4504,"end":4508},"obj":"25912193"},{"id":"33041751-27133194-816603","span":{"begin":4524,"end":4528},"obj":"27133194"},{"id":"33041751-25912193-816604","span":{"begin":4581,"end":4585},"obj":"25912193"},{"id":"33041751-29880901-816605","span":{"begin":4738,"end":4742},"obj":"29880901"},{"id":"33041751-28774322-816606","span":{"begin":4909,"end":4913},"obj":"28774322"}],"text":"Retinal Degeneration in Alzheimer’s Disease\nIn agreement with the observed distribution of retinal Aβ deposits in AD patients, reports have indicated NFL thinning and RGC degeneration in the GCL chiefly within the superior quadrants of the retina (Blanks et al., 1989, 1996b; Berisha et al., 2007; Lu et al., 2010; Liu et al., 2015; La Morgia et al., 2016; Asanad et al., 2019b; Grimaldi et al., 2019). In vivo OCT imaging of these patient retinas revealed degeneration in multiple retinal layers (La Morgia et al., 2017). Reduced macular thickness and volume, measured by OCT, was also found to correlate with cognitive impairment in AD patients (Iseri et al., 2006). The first study that evaluated melanopsin-containing retinal ganglion cells (mRGCs), photoreceptors known to drive circadian photoentrainment, in the postmortem retina of AD patients described a significant mRGC degeneration reflected in reduction of both dendritic density and cell number (La Morgia et al., 2017). Notably, dendrite loss and cell death were closely linked to Aβ pathology and were colocalized at sites of Aβ deposits (La Morgia et al., 2016).\nThese findings were corroborated in another study, which indicated a substantial loss of retinal cells at sites of Aβ deposition (Figures 5A–D). When compared with age-matched cognitively normal controls, 22-29% retinal neuronal degeneration was detected by Nissl staining (n = 17 subjects) in the GCL, INL, and ONL of AD patients (Figures 5B,C; Koronyo et al., 2017). More recently, Asanad and colleagues analyzed retinal atrophy morphometrically in the superior quadrants of postmortem retinas from 8 AD and 11 age-matched controls (Asanad et al., 2019b). Measurements were acquired along a distance of 4mm from the optic nerve on the supero-temporal (reaching the macular region) and supero-nasal sides. Significant retinal thinning was revealed in the NFL (∼40%), GCL (35%), IPL (∼20%), and both nuclear layers (25%) in AD patients. In the supero-temporal region, NFL thinning was more pronounced closer to the optic nerve, whereas the other retinal layers showed prominent thinning closer to the macula. However, all analyzed retinal layers showed consistent thinning throughout the supero-nasal retinal quadrant (Asanad et al., 2019b). Beyond these changes, several studies have demonstrated accumulation of Aβ in the lens of AD patients (Goldstein et al., 2003; Tian et al., 2014) as well as reductions in the choroid coat – the vascular layer of the eye – and offered insights into the retinal choroid as an oculovascular biomarker for Alzheimer’s disease (Tsai et al., 2014; Asanad et al., 2019a).\nFIGURE 5 Increased Aβ42-associated neuronal loss in post-mortem retinas of AD patients. (A) Representative images of post-mortem retinal cross-sections from CN and AD cases, immunostained with anti-Aβ42 mAb (12F4) and labeled with peroxidase-based DAB (brown) and hematoxylin counterstain (violet). Intracellular Aβ42-inclusions are observed in GCL, INL and ONL of AD retina. Scale bars: 20 μm. (B) Nissl staining of retinal cross-sections from a control subject and AD patient, revealing cellular and retinal layer alterations in AD. (C) Quantitation of neuronal Nissl-positive total area in retinas of AD patients (n = 9) compared to age-/sex-matched CN control subjects (n = 8). Data shown as group mean ± SEM. **P \u003c 0.01, unpaired 2-tailed Student’s t-test (D) Qualitative geometric map of increased retinal Aβ deposits (red shapes) and neuronal loss (green triangles) in AD patients. Panels a-c are reproduced from Koronyo et al. (2017) with permission of ASCI via Copyright Clearance Center. Panel d is adapted from Hart et al. (2016) under terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/). These findings are further supported by animal models of AD (Frederikse and Ren, 2002; Yang et al., 2013; Park et al., 2014; Tsai et al., 2014). In the hTgAPPtg/tg mouse lens, markers of degeneration included nuclear disorganization, organelle loss, cellular swelling, and shape irregularity (Frederikse and Ren, 2002). In the 5xFAD mouse, Aβ deposits in the retinal pigment epithelium, hypopigmentation, large vacuoles, and Bruch membrane thickening with Drusen-like deposits were observed (Park et al., 2014). Hypertrophy along with choroid changes were also detected in the TgF344-AD rat (Tsai et al., 2014). Further, in the APPSWE/PS1ΔE9 mouse, RGC density was lower than in WT controls (Gao et al., 2015; Gupta et al., 2016) and amacrine cell apoptosis was noted (Gao et al., 2015).\nA recent finding in 3xTg mice indicated colocalization of both retinal tau tangles and Aβ plaques with neurodegeneration in the GCL (Grimaldi et al., 2018). In the same mouse model, tau accumulation was associated with retinal neural dysfunction, as measured by deficits in anterograde axonal transport (Chiasseu et al., 2017).\nAltogether, observations of retinal atrophy in layers recognized as sites of proteinaceous deposition in both AD patients and animal models of the disease illustrate the vulnerability of retinal cell types to pathological processes traditionally associated with the cerebral disease. In addition, these findings further support the suitability of retinal thinning, in combination with more specific markers, as a diagnostic and monitoring tool for AD."}