Trans-Synaptic Degeneration Following Acute Optic Neuritis in Multiple Sclerosis.

OBJECTIVE: To explore longitudinal changes in brain volumetric measures and retinal layer thicknesses following acute optic neuritis (AON) in people with multiple sclerosis (PwMS), to investigate the process of trans-synaptic degeneration, and determine its clinical relevance. METHODS: PwMS were recruited within 40 days of AON onset (n = 49), and underwent baseline retinal optical coherence tomography and brain magnetic resonance imaging followed by longitudinal tracking for up to 5 years. A comparator cohort of PwMS without a recent episode of AON were similarly tracked (n = 73). Mixed-effects linear regression models were used. RESULTS: Accelerated atrophy of the occipital gray matter (GM), calcarine GM, and thalamus was seen in the AON cohort, as compared with the non-AON cohort (-0.76% vs -0.22% per year [p = 0.01] for occipital GM, -1.83% vs -0.32% per year [p = 0.008] for calcarine GM, -1.17% vs -0.67% per year [p = 0.02] for thalamus), whereas rates of whole-brain, cortical GM, non-occipital cortical GM atrophy, and T2 lesion accumulation did not differ significantly between the cohorts. In the AON cohort, greater AON-induced reduction in ganglion cell+inner plexiform layer thickness over the first year was associated with faster rates of whole-brain (r = 0.32, p = 0.04), white matter (r = 0.32, p = 0.04), and thalamic (r = 0.36, p = 0.02) atrophy over the study period. Significant relationships were identified between faster atrophy of the subcortical GM and thalamus, with worse visual function outcomes after AON. INTERPRETATION: These results provide in-vivo evidence for anterograde trans-synaptic degeneration following AON in PwMS, and suggest that trans-synaptic degeneration may be related to clinically-relevant visual outcomes. ANN NEUROL 2023;93:76-87.

TDP-43 differentially propagates to induce antero- and retrograde degeneration in the corticospinal circuits in mouse focal ALS models.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by TDP-43 inclusions in the cortical and spinal motor neurons. It remains unknown whether and how pathogenic TDP-43 spreads across neural connections to progress degenerative processes in the cortico-spinal motor circuitry. Here we established novel mouse ALS models that initially induced mutant TDP-43 inclusions in specific neuronal or cell types in the motor circuits, and investigated whether TDP-43 and relevant pathological processes spread across neuronal or cellular connections. We first developed ALS models that primarily induced TDP-43 inclusions in the corticospinal neurons, spinal motor neurons, or forelimb skeletal muscle, by using adeno-associated virus (AAV) expressing mutant TDP-43. We found that TDP-43 induced in the corticospinal neurons was transported along the axons anterogradely and transferred to the oligodendrocytes along the corticospinal tract (CST), coinciding with mild axon degeneration. In contrast, TDP-43 introduced in the spinal motor neurons did not spread retrogradely to the cortical or spinal neurons; however, it induced an extreme loss of spinal motor neurons and subsequent degeneration of neighboring spinal neurons, suggesting a degenerative propagation in a retrograde manner in the spinal cord. The intraspinal degeneration further led to severe muscle atrophy. Finally, TDP-43 induced in the skeletal muscle did not propagate pathological events to spinal neurons retrogradely. Our data revealed that mutant TDP-43 spread across neuro-glial connections anterogradely in the corticospinal pathway, whereas it exhibited different retrograde degenerative properties in the spinal circuits. This suggests that pathogenic TDP-43 may induce distinct antero- and retrograde mechanisms of degeneration in the motor system in ALS.

Transsynaptic Ganglion Cell Degeneration in Adult Patients After Occipital Lobe Stroke.

BACKGROUND: Loss of retinal ganglion cells after occipital lobe damage is known to occur through transsynaptic retrograde degeneration in congenital lesions; however, studies of this phenomenon in acquired pathology, such as strokes affecting postgenicular visual pathway, are scant. We studied a cohort of adult patients with known onset of occipital lobe stroke to look for the presence, rate, and timing of macular ganglion cell loss on optical coherence tomography. METHODS: Retrospective review of patients seen in tertiary neuro-ophthalmology practice with homonymous hemianopia secondary to occipital lobe stroke of known onset. Optical coherence tomography of the macular ganglion cell complex (GCC) was performed, and hemifields corresponding to the side of the visual field (VF) defect were compared with the control retinal hemifield. RESULTS: Fifteen patients with homonymous VF defects were included in the study, and 8 of these (53.3%) demonstrated GCC hemifield thickness of less than 90% on the side corresponding to VF loss including 2/9 (22%) patients who had a stroke less than 2.5 years ago and 6/6 (100%) patients who had a stroke longer than 2.5 years ago. The amount of hemifield atrophy correlated to the logarithm of time since stroke onset ( P =0.030) but not age ( P = 0.95) or mean deviation on VF ( P = 0.19). Three patients with longitudinal data showed GCC thinning rates of 1.99, 5.13, and 5.68 µm per year. CONCLUSION: Transsynaptic retrograde degeneration occurs after occipital lobe stroke as early as 5.5 months after injury and was observed in all patients 2.5 years after stroke.

[Retrograde degeneration of visual pathway]. / Retrogradnaya degeneratsiya zritel'nogo puti.

BACKGROUND: Optical coherence tomography (OCT) gives the opportunity to examine retrograde degeneration of visual pathway damaged at various levels. OBJECTIVE: To estimate OCT data on retrograde degeneration of visual pathway damaged at various levels. MATERIAL AND METHODS: Ganglion cell layer (GCL) thickness was measured by OCT in 79 patients with visual pathway damaged at various levels and known duration of visual disturbances. Twenty-One patients were diagnosed with traumatic lesions of the optic nerves and/or chiasma. Fifty-eight patients had retro-genicular visual pathway damage. Thirty-three patients were examined for postoperative homonymous hemianopia after surgery for drug-resistant temporal lobe epilepsy. Twenty-five patients were diagnosed with occipital lobe damage following stroke (12 patients), surgery for arteriovenous malformation (11 patients) and traumatic brain injury (2 patients). All patients underwent assessment of visual acuity, automatic static perimetry, MRI/CT of the brain. Retinal ganglion cell complex was analyzed during OCT. RESULTS: GCL thinning following anterior visual pathway damage was detected in 20 out of 21 patients after ≥22 days. In case of post-genicular visual pathway damage, GCL thinning was found in 25 out of 58 patients (9 out of 33 ones after surgery for temporal lobe epilepsy and 16 out of 25 patients with occipital lobe lesion). After surgery for temporal lobe epilepsy, minimum period until GCL thinning detection after previous visual pathway damage was 3 months, in case of occipital lobe lesion - 5 months. CONCLUSION: Retrograde visual pathway degeneration is followed by GCL thinning and depends on the level of visual pathway lesion.

Trans-synaptic Retrograde Degeneration in the Human Visual System: Slow, Silent, and Real.

Degeneration of neuron and axons following injury to cells with which they synapse is termed trans-synaptic degeneration. This phenomenon may be seen in postsynaptic neurons (anterograde) or in presynaptic neurons (retrograde). Retrograde trans-synaptic degeneration (RTSD) of the retinal ganglion cells and retinal nerve fiber layer following injury to the occipital lobe has been well documented histologically in animal studies, but its occurrence in the human retina was, for many years, felt to be limited to cases of neonatal injury during a critical period of neuronal development. Over the last decade, imaging techniques such as MRI and optical coherence tomography have allowed us to visualize and quantify RTSD and analyze its time course and relationship to degree of vision loss and age of cortical injury. A deeper understanding of RTSD in the human visual system may allow us to interfere with its occurrence, potentially allowing for greater recovery following visual cortex injury.

Trans-synaptic degeneration of motoneurons distal to chronic cervical spinal cord compression in cervical spondylotic myelopathy.

OBJECTIVE: To assess the effect of chronic cervical spinal cord compression upon remote motor unit function in patients with cervical spondylotic myelopathy (CSM). METHODS: Fifty-three CSM patients and 47 healthy subjects were included. Bilateral motor unit number estimations (MUNEs) were recorded from both abductor digiti minimi and abductor pollicis brevis, and bilateral flexor carpi radialis (FCR) H-reflexes were examined in all subjects along with the nine-hole peg test (NHPT). The main outcome measures included the number of motor units, the average single motor unit potential (SMUP) area, the FCR Hmax/Mmax ratios and the NHPT time. RESULTS: Statistically significant results compared to healthy controls included increased average SMUP area, increased FCR Hmax/Mmax ratio and increased NHPT time (p < 0.05). Abnormal SMUP was observed in 10/53 (18.9%) CSM patients along with reduced motor units in 3 of these 10 patients, while the FCR Hmax/Mmax ratios in the CSM patients with abnormal MUNE were higher than those in others (p < 0.05). There was a positive correlation between the NHPT time and the average SMUP area, and a negative correlation was noted between the NHPT time and the number of motor units (p < 0.05). CONCLUSION: In CSM patients, the motor units below the level of compression may exhibit dysfunction, which is likely a result of trans-synaptic degeneration. Both cervical spinal cord compressive injury and this trans-synaptic degeneration contribute to the impairment of fine motor ability in CSM patients. Therefore, treatment and rehabilitation efforts should account for these two dysfunctions.

[Structural retinal and optic nerve changes in patients with post-geniculate visual pathway damage]. / Strukturnye izmeneniia setchatki i zritel'nogo nerva pri porazhenii tsentral'nogo nevrona zritel'nogo puti.

AIM: To establish the possibility of retrograde trans-synaptic neural degeneration following acquired post-geniculate visual pathway damage. MATERIAL AND METHODS: Twenty-two patients with homonymous hemianopia caused by acquired post-geniculate visual pathway damage were examined. Peripapillary retinal nerve fiber layer (RNFL) thickness and ganglion cell complex (GCC) measurements were assessed with RTVue-100 Fourier-domain optical coherence tomography (OCT). RESULTS: In 12 out of 22 patients we detected binocular GCC thinning that was ipsilateral to post-geniculate involvement. Nine patients showed a decrease in the RNFL thickness. However, topographic correspondence between the post-geniculate lesion and RNFL thickness was established for 2 of them only. GCC thinning was more common in patients with hemianopsia acquired more than 6 months ago (p<0.0009). CONCLUSION: Having assessed the ganglion cell complex and retinal nerve fiber layer with OCT, we have proved possible that trans-synaptic retrograde degeneration develops in patients with post-geniculate visual pathway damage.

Transsynaptic Retrograde Degeneration: Clinical Evidence with Homonymous RGCL Loss on OCT.

BACKGROUND: Retinal thinning after a retrogeniculate lesion (transsynaptic retrograde degeneration) was first described 50 years ago, but has long been a controversial issue. It is now possible to use OCT for the in vivo measurement of retinal thickness. MATERIAL AND METHODS: This was a retrospective study of patients with homonymous visual field loss, with SD-OCT assessment (RNFL and RGCL measurements) in isolated retrogeniculate lesions, subsequently confirmed by a neuroradiologist. RESULTS: Nine patients with vascular, inflammatory or tumour brain lesions were included in the study. Homonymous RGCL thinning was found in all patients, and correlated with the visual field defect. No correlation was found with RNFL. CONCLUSIONS: The homonymous defect of RGCL in patients with retrogeniculate lesions demonstrates the presence of transsynaptic retrograde degeneration. RGCL is a better predictor of visual field defects than RNFL measurement.

Quantifying the pattern of optic tract degeneration in human hemianopia.

BACKGROUND: The existence of transsynaptic retrograde degeneration (TRD) in the human visual system has been established, however the dependence of TRD on different factors such as lesion location, size and manner of lesion acquisition has yet to be quantified. METHODS: We obtained T1-weighted structural and diffusion-weighted images for 26 patients with adult-acquired or congenital hemianopia and 12 age-matched controls. The optic tract (OT) was defined and measured in the structural and diffusion-weighted images, and degeneration assessed by comparing the integrity of tracts in the lesioned and in the undamaged hemisphere. RESULTS: OT degeneration was found in all patients with established lesions, regardless of lesion location. In patients with acquired lesions, the larger the initial lesion, the greater is the resulting TRD. However, this was not the case for congenital patients, who generally showed greater degeneration than would be predicted by lesion size. A better predictor of TRD was the size of the visual field deficit, which was correlated with degeneration across all patients. Interestingly, although diffusion-weighted imaging (DWI) is more frequently used to examine white matter tracts, in this study the T1-weighted scans gave a better indication of the extent of tract degeneration. CONCLUSIONS: We conclude that TRD of the OT occurs in acquired and congenital hemianopia, is correlated with visual field loss, and is most severe in congenital cases. Understanding the pattern of TRD may help to predict effects of any visual rehabilitation training.

Immunohistochemical study of pseudohypertrophy of the inferior olivary nucleus.

OBJECTIVE: Pathogenesis of pseudohypertrophy of the inferior olivary nucleus (PH-IO) was analyzed based on immunohistochemical study. METHODS: Immunostained medullas with PH-IO were observed with confocal laser microscopy. RESULTS: αB-crystallin (αBC) was frequently expressed in the neurons and co-localized with microtubule-associated protein 2 (MAP2). The neurons were occasionally positive for SMI-31. αBC and SMI-31 were co-localized in some neurons. Synaptophysin (SYP)-immunoreactive dots were present around MAP2-positive hypertrophic neurons and hypertrophic thick neurites. Periphery-stained Lys-Asp-Glu-Leu (KDEL)-positive neurons were shown. Central chromatolytic neurons were found with Klüver-Barrera staining, which indicated that the rough endoplasmic reticulum (ER) was distributed to the periphery of the cytoplasm. CONCLUSIONS: αBC prevents microtubule disassembly and phosphorylation of the neurofilaments under stressful conditions. Our results indicated that αBC protected microtubules and neurofilaments in PH-IO. The retrograde transport of KDEL receptors from the Golgi complex to the ER is increased under stressful conditions. We considered that KDEL receptors were retro-transported to ER, and then the ER containing KDEL receptors was distributed to the periphery of the cytoplasm. PH-IO showed various immunohistochemical changes due to trans-synaptic degeneration.

Retrograde and Wallerian axonal degeneration occur synchronously after retinal ganglion cell axotomy.

Axonal injury and degeneration are pivotal pathological events in diseases of the nervous system. In the past decade, it has been recognized that the process of axonal degeneration is distinct from somal degeneration and that axoprotective strategies may be distinct from those that protect the soma. Preserving the cell body via neuroprotection cannot improve function if the axon is damaged, because the soma is still disconnected from its target. Therefore, understanding the mechanisms of axonal degeneration is critical for developing new therapeutic interventions for axonal disease treatment. We combined in vivo imaging with a multilaser confocal scanning laser ophthalmoscope and in vivo axotomy with a diode-pumped solid-state laser to assess the time course of Wallerian and retrograde degeneration of unmyelinated retinal ganglion cell axons in living rats for 4 weeks after intraretinal axotomy. Laser injury resulted in reproducible axon loss both distal and proximal to the site of injury. Longitudinal polarization-sensitive imaging of axons demonstrated that Wallerian and retrograde degeneration occurred synchronously. Neurofilament immunostaining of retinal whole-mounts confirmed axonal loss and demonstrated sparing of adjacent axons to the axotomy site. In vivo fluorescent imaging of axonal transport and photobleaching of labeled axons demonstrated that the laser axotomy model did not affect adjacent axon function. These results are consistent with a shared mechanism for Wallerian and retrograde degeneration.

Transneuronal retrograde degeneration of the retinal ganglion cells in patients with cerebral infarction.

PURPOSE: The objective of this study was to determine whether transneuronal retrograde degeneration (TRD) of the retinal ganglion cells (RGCs) could be detected by optical coherence tomography (OCT) in humans with lesions other than of the occipital lobe or visual cortex. In addition, whether laterality and severity of retinal nerve fiber layer (RNFL) damage correlated with 3 other variables was determined: laterality of hemispheric damage, arterial territory of infarct, and age of infarct. DESIGN: Cross-sectional, case-control design. PARTICIPANTS: Forty-six patients with cerebral ischemic infarction diagnosed based on brain magnetic resonance imaging and 46 normal controls were enrolled. METHODS: All subjects underwent a complete ophthalmic examination including OCT. Cerebral infarction was categorized by arterial territory: anterior cerebral artery (ACA), middle cerebral artery (MCA), and posterior cerebral artery (PCA). Eyes on the same side of the infarction were referred to as ipsilateral eyes, and eyes on the opposite side of the infarction were referred as contralateral eyes. MAIN OUTCOME MEASURES: Retinal nerve fiber layer thickness. RESULTS: Average, superior, temporal, inferior, and nasal RNFL thicknesses were different significantly between patients with cerebral infarction and normal controls. The RNFL thicknesses were reduced significantly at the superior, inferior, and nasal quadrants in the contralateral eyes and at the superior, inferior, and temporal quadrants in the ipsilateral eyes. The RNFL thickness reduction was greater in patients with PCA infarction, followed by MCA and ACA infarction, respectively. Factors related to the average RNFL thickness were time after stroke onset and infarction territory based on both univariate (P = 0.027 and P = 0.046, respectively) and multivariate (P = 0.036 and P = 0.047, respectively) analysis. CONCLUSIONS: Retinal nerve fiber layer thickness was reduced in patients with cerebral infarction, providing evidence for TRD of the RGCs. Transneuronal retrograde degeneration was more pronounced in the nasal nerve fiber layer of the contralateral side and in the temporal nerve fiber layer of the ipsilateral side of cerebral damage. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Wallerian and trans-synaptic degeneration contribute to optic radiation damage in multiple sclerosis: a diffusion tensor MRI study.

BACKGROUND: Optic radiation (OR) damage occurs in multiple sclerosis (MS). OBJECTIVES: The purpose of this study was to explore the contribution of local and distant mechanisms associated with OR damage in MS. METHODS: Diffusion tensor (DT) magnetic resonance imaging (MRI) tractography probability maps of the ORs were derived from 102 MS patients and 11 controls. Between-group differences of OR normal-appearing white matter (NAWM) damage and topographical distribution of OR damage were assessed using quantitative and voxel-wise analyses, considering the influence of previous optic neuritis (ON+) and T2 OR lesions (T2 OR+). RESULTS: OR NAWM diffusivity abnormalities were more severe in ON+ patients vs patients without previous optic neuritis (ON-) and T2 OR+ vs T2 OR- patients. Damage to the anterior portions of the ORs was more severe in ON+ vs ON- patients. Compared to controls and T2 OR- patients, T2 OR+ patients experienced a more distributed pattern of DT MRI abnormalities along the ORs, with an increased axial diffusivity limited to the anterior portions of the ORs. In T2 OR+ group, ON+ vs ON- patients showed DT MRI abnormalities in the middle portion of the ORs, in correspondence with focal lesions. OR damage correlated with OR T2 lesion volume, visual dysfunction and optic nerve atrophy. CONCLUSIONS: Both trans-synaptic degeneration secondary to optic nerve damage and Wallerian degeneration due to local T2 lesions contribute to OR damage in MS.

Dynamics of progressive degeneration of major spinal pathways following spinal cord injury: A longitudinal study.

BACKGROUND: Following spinal cord injury (SCI), disease processes spread gradually along the spinal cord forming a spatial gradient with most pronounced changes located at the lesion site. However, the dynamics of this gradient in SCI patients is not established. OBJECTIVE: This study tracks the spatiotemporal dynamics of remote anterograde and retrograde spinal tract degeneration in the upper cervical cord following SCI over two years utilizing quantitative MRI. METHODS: Twenty-three acute SCI patients (11 paraplegics, 12 tetraplegics) and 21 healthy controls were scanned with a T1-weighted sequence for volumetry and a FLASH sequence for myelin-sensitive magnetization transfer saturation (MTsat) of the upper cervical cord. We estimated myelin content from MTsat maps within the corticospinal tracts (CST) and dorsal columns (DC) and measured spinal cord atrophy by means of left-right width (LRW) and anterior-posterior width (APW) on the T1-weighted images across cervical levels C1-C3. MTsat in the CST and LRW were considered proxies for retrograde degeneration, while MTsat in the DC and APW provided evidence for anterograde degeneration, respectively. Using regression models, we compared the temporal and spatial trajectories of these MRI readouts between tetraplegics, paraplegics, and controls over a 2-year period and assessed their associations with clinical improvement. RESULTS: Linear rates and absolute differences in myelin-sensitive MTsat indicated retrograde and anterograde neurodegeneration in the CST and DC, respectively. Changes in MTsat within the CST and in LRW progressively developed over time forming a gradient towards lower cervical levels by 2 years after injury, especially in tetraplegics (change per cervical level in MTsat: -0.247 p.u./level, p = 0.034; in LRW: -0.323 mm/level, p = 0.024). MTsat within the DC was already decreased at cervical levels C1-C3 at baseline (1.5 months after injury) in both tetra- and paraplegics, while linear decreases in APW over time were similar across C1-C3, preserving the spatial gradient. The relative improvement in light touch score was associated with MTsat within the DC at baseline (rs = 0.575, p = 0.014). CONCLUSION: Rostral and remote to the injury, the CST and DC show ongoing structural changes, indicative of myelin reductions and atrophy within 2 years after SCI. While anterograde degeneration in the DC was already detectable uniformly at C1-C3 early following SCI, retrograde degeneration in the CST developed over time revealing specific spatial and temporal neurodegenerative gradients. Disentangling and quantifying such dynamic pathological processes may provide biomarkers for regenerative and remyelinating therapies along entire spinal pathways.

Trans-synaptic degeneration in the optic pathway: Exploring the role of lateral geniculate nucleus in early stages of relapsing-remitting multiple sclerosis.

BACKGROUND: Optic pathway is considered an ideal model to study the interaction between inflammation and neurodegeneration in multiple sclerosis (MS). METHODS: Optical Coherence Tomography (OCT) and 3.0 T magnetic resonance imaging (MRI) were acquired in 92 relapsing remitting (RR) MS at clinical onset. Peripapillary RNFL (pRNFL) and macular layers were measured. White matter (WM) and gray matter (GM) lesion volumes (LV), lateral geniculate nucleus (LGN) volume, optic radiations (OR) WM LV, thickness of pericalcarine cortex were evaluated. OCT and MRI control groups (healthy controls [HC]-OCT and HC-MRI) were included. RESULTS: A significant thinning of temporal pRNFL and papillo-macular bundle (PMB) was observed (p<0.001) in 16 (17%) patients presented with monocular optic neuritis (MSON+), compared to 76 MSON- and 30 HC (-15 µm). In MSON-, PMB was reduced (-3 µm) compared to HC OCT (p<0.05). INL total volume was increased both in MSON+ (p<0.001) and MSON- (p = 0.033). Inner retinal layers volumes (macular RNFL, GCL and IPL) were significantly decreased in MSON+ compared to HC (p<0.001) and MSON- (p<0.001). Reduced GCL volume in the parafoveal ring was observed in MSON- compared to HCOCT (p < 0.05). LGN volume was significantly reduced only in MSON+ patients compared to HC-MRI (p<0.001) and MSON- (p<0.007). GCL, IPL and GCIP volumes associated with ipsilateral LGN volume in MSON+ and MSON-. Finally, LGN volume associated with visual cortex thickness with no significant difference between MSON+ and MSON-. CONCLUSIONS: Anterograde trans-synaptic degeneration is early detectable in RRMS presenting with optic neuritis but does not involve LGN.

Akt suppresses retrograde degeneration of dopaminergic axons by inhibition of macroautophagy.

Axon degeneration is a hallmark of neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Such degeneration is not a passive event but rather an active process mediated by mechanisms that are distinct from the canonical pathways of programmed cell death that mediate destruction of the cell soma. Little is known of the diverse mechanisms involved, particularly those of retrograde axon degeneration. We have previously observed in living animal models of degeneration in the nigrostriatal projection that a constitutively active form of the kinase, myristoylated Akt (Myr-Akt), demonstrates an ability to suppress programmed cell death and preserve the soma of dopamine neurons. Here, we show in both neurotoxin and physical injury (axotomy) models that Myr-Akt is also able to preserve dopaminergic axons due to suppression of acute retrograde axon degeneration. This cellular phenotype is associated with increased mammalian target of rapamycin (mTor) activity and can be recapitulated by a constitutively active form of the small GTPase Rheb, an upstream activator of mTor. Axon degeneration in these models is accompanied by the occurrence of macroautophagy, which is suppressed by Myr-Akt. Conditional deletion of the essential autophagy mediator Atg7 in adult mice also achieves striking axon protection in these acute models of retrograde degeneration. The protection afforded by both Myr-Akt and Atg7 deletion is robust and lasting, because it is still observed as protection of both axons and dopaminergic striatal innervation weeks after injury. We conclude that acute retrograde axon degeneration is regulated by Akt/Rheb/mTor signaling pathways.

Transneuronal retrograde degeneration of retinal ganglion cells and optic tract in hemianopic monkeys and humans.

Transneuronal retrograde degeneration of retinal ganglion cells after removal of primary visual cortex (area V1) is well established by quantitative neurohistological analysis of the ganglion cell layer in monkeys, but remains controversial in human patients. Therefore, we first histologically examined retinal degeneration in sectioned archived retinae of 26 macaque monkeys with unilateral V1 ablation and post-surgical survival times ranging from 3 months to 14.3 years. In addition, the cross-sectional area of the optic tract was measured in archived coronal histological sections of the brain of every hemianopic monkey and in sections from 10 control monkeys with non-visual bilateral cortical lesions. The ratios of nasal and temporal retinal ganglion cell counts in the contralesional eye and ipsi/contralateral optic tract areas were calculated and compared. They show that the decline was initially more pronounced for the optic tract, slackened after 3 years post-lesion and was steeper for the ganglion cells thereafter. Nevertheless, both measures were highly correlated. Second, we calculated ratios from structural magnetic resonance images to see whether the optic tracts of four human hemianopes would show similar evidence of transneuronal degeneration of their ipsilesional optic tract. The results were consistent with extensive and time-dependent degeneration of the retinal ganglion cell layer. The measures of the optic tracts provide evidence for comparable transneuronal retinal ganglion cell degeneration in both primate species and show that structural magnetic resonance image can both reveal and assess it.

Primary retinal pathology in multiple sclerosis as detected by optical coherence tomography.

Optical coherence tomography studies in multiple sclerosis have primarily focused on evaluation of the retinal nerve fibre layer. The aetiology of retinal changes in multiple sclerosis is thought to be secondary to optic nerve demyelination. The objective of this study was to use optical coherence tomography to determine if a subset of patients with multiple sclerosis exhibit primary retinal neuronopathy, in the absence of retrograde degeneration of the retinal nerve fibre layer and to ascertain if such patients may have any distinguishing clinical characteristics. We identified 50 patients with multiple sclerosis with predominantly macular thinning (normal retinal nerve fibre-layer thickness with average macular thickness < 5th percentile), a previously undescribed optical coherence tomography defined phenotype in multiple sclerosis, and compared them with 48 patients with multiple sclerosis with normal optical coherence tomography findings, 48 patients with multiple sclerosis with abnormal optical coherence tomography findings (typical for multiple sclerosis) and 86 healthy controls. Utilizing a novel retinal segmentation protocol, we found that those with predominant macular thinning had significant thinning of both the inner and outer nuclear layers, when compared with other patients with multiple sclerosis (P < 0.001 for both), with relative sparing of the ganglion cell layer. Inner and outer nuclear layer thicknesses in patients with non-macular thinning predominant multiple sclerosis were not different from healthy controls. Segmentation analyses thereby demonstrated extensive deeper disruption of retinal architecture in this subtype than may be expected due to retrograde degeneration from either typical clinical or sub-clinical optic neuropathy. Functional corroboration of retinal dysfunction was provided through multi-focal electroretinography in a subset of such patients. These findings support the possibility of primary retinal pathology in a subset of patients with multiple sclerosis. Multiple sclerosis-severity scores were also significantly increased in patients with the macular thinning predominant phenotype, compared with those without this phenotype (n = 96, P=0.006). We have identified a unique subset of patients with multiple sclerosis in whom there appears to be disproportionate thinning of the inner and outer nuclear layers, which may be occurring as a primary process independent of optic nerve pathology. In vivo analyses of retinal layers in multiple sclerosis have not been previously performed, and structural demonstration of pathology in the deeper retinal layers, such as the outer nuclear layer, has not been previously described in multiple sclerosis. Patients with inner and outer nuclear layer pathology have more rapid disability progression and thus retinal neuronal pathology may be a harbinger of a more aggressive form of multiple sclerosis.

Trans-synaptic degeneration in the visual pathway: Neural connectivity, pathophysiology, and clinical implications in neurodegenerative disorders.

There is a strong interrelationship between eye and brain diseases. It has been shown that neurodegenerative changes can spread bidirectionally in the visual pathway along neuronal projections. For example, damage to retinal ganglion cells in the retina leads to degeneration of the visual cortex (anterograde degeneration) and vice versa (retrograde degeneration). The underlying mechanisms of this process, known as trans-synaptic degeneration (TSD), are unknown, but TSD contributes to the progression of numerous neurodegenerative disorders, leading to clinical and functional deterioration. The hierarchical structure of the visual system comprises of a strong topographic connectivity between the retina and the visual cortex and therefore serves as an ideal model to study the cellular effect, clinical manifestations, and deterioration extent of TSD. With this review we provide comprehensive information about the neural connectivity, synapse function, molecular changes, and pathophysiology of TSD in visual pathways. We then discuss its bidirectional nature and clinical implications in neurodegenerative diseases. A thorough understanding of TSD in the visual pathway can provide insights into progression of neurodegenerative disorders and its potential as a therapeutic target.