RESUMEN
BACKGROUND AND OBJECTIVES: We aimed to assess the presence of retinal neurodegeneration independent of optic neuritis (ON) in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and to investigate the development of trans-synaptic anterograde degeneration in these patients after ON. METHODS: Cross-sectional, retrospective study of 34 adult patients with MOGAD and 23 healthy controls (HC). Clinical, optical coherence tomography (OCT), and MRI data were collected. Peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell inner plexiform layer (GCIPL) were obtained using Heidelberg Spectralis. FreeSurfer7 was used to obtain the lateral geniculate nucleus (LGN), occipital volume fractions (to total estimated intracranial volume), and occipital cortical thickness. For the anterior visual pathway, the analysis was conducted using eyes, classified based on the history of ON (Eye-ON and Eye-NON) and compared with Eye-HC. The analysis of OCT and brain volumetric measures was conducted comparing MOGAD-ON, MOGAD-NON, and HC groups. The analysis of covariance with a Bonferroni-adjusted post hoc test was used to test differences between groups and linear regression analysis to evaluate OCT/MRI associations; age and sex were considered as covariates. RESULTS: 24 (70.5%) patients had a prior ON. Median pRNFL and GCIPL thickness (um) was significantly reduced in Eye-ON vs EyeNON and HC (pRNFL: 69.4 (17.3), 89.6 (13.7), 98.2 (11.7), p < 0.001; GCIPL: 55.8 (8.7), 67.39 (8.7), 72.6 (4.5), p < 0.001). pRNFL and GCIPL thickness had a negative correlation with the number of ON episodes (p = 0.025 and p = 0.031, respectively). LGN volume fraction was significantly lower in patients with MOGAD-ON than in HC (0.33 (0.05) vs 0.39 (0.04), p = 0.002). The occipital cortical thickness was lower in MOGAD-ON compared with MOGAD-NON and HC (p = 0.010). In patients with MOGAD-ON, pRNFL correlated with LGN volume (p = 0.006), occipital thickness (p = 0.002), and the medial occipital cortex (p = 0.002), but not the lateral occipital lobe. DISCUSSION: Compared with HC, MOGAD-ON exhibits reduced retinal thickness, primarily influenced by the presence and the number of prior ON episodes. Moreover, MOGAD-ON demonstrates significant atrophy in the retinal, subcortical, and cortical regions of the visual pathway, distinguishing them from MOGAD-NON and HC. These findings suggest that in patients with MOGAD neurodegeneration is tightly correlated with damage to the involved pathway.
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Neuritis Óptica , Vías Visuales , Adulto , Humanos , Glicoproteína Mielina-Oligodendrócito , Vías Visuales/diagnóstico por imagen , Estudios Transversales , Degeneración Retrógrada , Estudios Retrospectivos , Neuritis Óptica/diagnóstico por imagen , RetinaRESUMEN
Traumatic brain injury (TBI) elicits neuronal loss at the site of injury and progressive neuronal loss in the penumbra. However, the consequences of TBI on afferent neurons projecting to the injured tissue from distal locations is unknown. Basal forebrain cholinergic neurons (BFCNs) extend long projections to multiple brain regions including the cortex, regulate many cognitive functions, and are compromised in numerous neurodegenerative disorders. To determine the consequence of cortical injury on these afferent neurons, we used the fluid percussion injury model of traumatic brain injury and assessed the effects on BFCN survival and axon integrity in male and female mice. Survival or death of BF neurons can be regulated by neurotrophins or proneurotrophins, respectively. The injury elicited an induction of proNGF and proBDNF in the cortex and a loss of BFCNs ipsilateral to the injury compared with sham uninjured mice. The p75NTR knock-out mice did not show loss of BFCN neurons, indicating a retrograde degenerative effect of the cortical injury on the afferent BFCNs mediated through p75NTR. In contrast, locus ceruleus neurons, which also project throughout the cortex, were unaffected by the injury, suggesting specificity in retrograde degeneration after cortical TBI. Proneurotrophins (proNTs) provided directly to basal forebrain axons in microfluidic cultures triggered retrograde axonal degeneration and cell death, which did not occur in the absence of p75NTR. This study shows that after traumatic brain injury, proNTs induced in the injured cortex promote BFCN axonal degeneration and retrograde neuron loss through p75NTR.
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Prosencéfalo Basal , Lesiones Traumáticas del Encéfalo , Receptores de Factor de Crecimiento Nervioso , Animales , Femenino , Masculino , Ratones , Lesiones Traumáticas del Encéfalo/metabolismo , Neuronas Colinérgicas/metabolismo , Neuronas Aferentes , Degeneración Retrógrada/metabolismo , Receptores de Factor de Crecimiento Nervioso/metabolismoRESUMEN
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.
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Esclerosis Amiotrófica Lateral , Degeneración Retrógrada , Animales , Ratones , Esclerosis Amiotrófica Lateral/patología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Neuronas Motoras/metabolismo , Degeneración Retrógrada/metabolismo , Degeneración Retrógrada/patología , Médula Espinal/patologíaRESUMEN
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.
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Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Neuritis Óptica , Humanos , Esclerosis Múltiple Recurrente-Remitente/complicaciones , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/patología , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/patología , Degeneración Retrógrada/patología , Cuerpos Geniculados/diagnóstico por imagen , Cuerpos Geniculados/patología , Retina/diagnóstico por imagen , Retina/patología , Neuritis Óptica/diagnóstico por imagen , Neuritis Óptica/patología , Tomografía de Coherencia ÓpticaRESUMEN
BACKGROUND: The multi-order visual system represents an excellent testing site regarding the process of trans-synaptic degeneration. The presence and extent of global versus trans-synaptic neurodegeneration in people with multiple sclerosis (pwMS) is not clear. OBJECTIVE: To explore cross-sectional and longitudinal relationships between retinal, thalamic and cortical changes in pwMS with and without MS-related optic neuritis (pwMSON and pwoMSON) using MRI and optical coherence tomography (OCT). METHODS: 162 pwMS and 47 healthy controls (HCs) underwent OCT and brain MRI at baseline and 5.5-years follow-up. Peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell inner plexiform layer (mGCIPL) thicknesses were determined. Global volume measures of brain parenchymal volume (BPV)/percent brain volume change (PBVC), thalamic volume and T2-lesion volume (LV) were derived using standard analysis protocols. Regional cortical thickness was determined using FreeSurfer. Cross-sectional and longitudinal relationship between the retinal measures, thalamic volume and cortical thickness were assessed using age, BPV/PBVC and T2-LV adjusted correlations and regressions. RESULTS: After age, BPV and T2-LV adjustment, the thalamic volume explained additional variance in the thickness of pericalcarine (R2 increase of 0.066, standardized ß = 0.299, p = 0.039) and lateral occipital (R2 increase of 0.024, standardized ß = 0.299, p = 0.039) gyrii in pwMSON. In pwoMSON, the thalamic volume was a significant predictor only of control (frontal) regions of pars opercularis. There was no relationship between thalamic atrophy and cortical thinning over the follow-up in both pwMS with and without MSON. While numerically lower in the pwMSON group, the inter-eye difference was not able to predict the presence of MSON. CONCLUSIONS: MSON can induce a measurable amount of trans-synaptic pathology on second-order cortical regions.
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Adelgazamiento de la Corteza Cerebral , Esclerosis Múltiple , Neuritis Óptica , Degeneración Retrógrada , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Transversales , Estudios Longitudinales , Imagen por Resonancia Magnética , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/patología , Neuritis Óptica/complicaciones , Neuritis Óptica/diagnóstico por imagen , Neuritis Óptica/patología , Retina/diagnóstico por imagen , Retina/patología , Células Ganglionares de la Retina , Tomografía de Coherencia Óptica , Adelgazamiento de la Corteza Cerebral/patologíaRESUMEN
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.
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Degeneración Retrógrada , Traumatismos de la Médula Espinal , Humanos , Estudios Longitudinales , Degeneración Retrógrada/complicaciones , Degeneración Retrógrada/patología , Traumatismos de la Médula Espinal/patología , Médula Espinal/patología , Tractos Piramidales/patología , Atrofia/patologíaRESUMEN
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.
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Degeneración Retrógrada , Accidente Cerebrovascular , Humanos , Adulto , Degeneración Retrógrada/complicaciones , Degeneración Retrógrada/patología , Fibras Nerviosas/patología , Vías Visuales/patología , Pruebas del Campo Visual , Trastornos de la Visión , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/diagnóstico , Infarto Cerebral/complicaciones , Lóbulo Occipital/diagnóstico por imagen , Lóbulo Occipital/patología , Tomografía de Coherencia Óptica/métodosRESUMEN
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.
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Esclerosis Múltiple , Neuritis Óptica , Humanos , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/patología , Degeneración Retrógrada/patología , Neuritis Óptica/diagnóstico por imagen , Neuritis Óptica/etiología , Retina/diagnóstico por imagen , Retina/patología , Imagen por Resonancia Magnética , Tomografía de Coherencia Óptica , Atrofia/patologíaRESUMEN
Introducción: El síndrome de Guillain-Barré (SGB) es un trastorno agudo e inmuno-mediado del sistema nervioso periférico. Sus dos subtipos básicos son el desmielinizante (AIDP) y el axonal (AMAN). El objetivo de este trabajo es abordar los mecanismos de daño axonal en la fase precoz del síndrome (≤ 10 días del inicio sintomático). Desarrollo: Se han revisado aspectos histológicos, neurofisiológicos y de imagen descritos tanto en la AIDP como en la AMAN. Los hallazgos en la patología humana han sido contrastados con lo reportado en la neuritis alérgica experimental inducida por el componente P2 de la mielina. El edema inflamatorio de las raíces raquídeas y de los nervios espinales constituye la lesión inicial en el SGB. En los nervios espinales de casos fatales de AIDP se ha demostrado la presencia de lesiones isquémicas endoneurales, lo cual sugiere que la inflamación puede condicionar un incremento de su presión con reducción del flujo sanguíneo transperineural, que puede desencadenar fallo de la conducción y eventualmente degeneración axonal secundaria. En la AMAN con anticuerpos antigangliósido el bloqueo de la conducción por disfunción de los canales del sodio nodales puede afectar a troncos nerviosos proximales, intermedios y distales. Además de los mecanismos que operan en la AIDP, la degeneración axonal activa en la AMAN puede ir ligada a la disrupción del axolema nodal inducida por los anticuerpos anti-gangliósido. Conclusión: En la fase precoz del SGB hay edema inflamatorio de los troncos nerviosos proximales, que puede condicionar fallo de la conducción nerviosa y degeneración axonal activa. (AU)
Introduction: Guillain-Barré syndrome (GBS) is an acute-onset, immune-mediated disease of the peripheral nervous system. It may be classified into 2 main subtypes: demyelinating (AIDP) and axonal (AMAN). This study aims to analyse the mechanisms of axonal damage in the early stages of GBS (within 10 days of onset). Development: We analysed histological, electrophysiological, and imaging findings from patients with AIDP and AMAN, and compared them to those of an animal model of myelin P2 protein-induced experimental allergic neuritis. Inflammatory oedema of the spinal nerve roots and spinal nerves is the initial lesion in GBS. The spinal nerves of patients with fatal AIDP may show ischaemic lesions in the endoneurium, which suggests that endoneurial inflammation may increase endoneurial fluid pressure, reducing transperineurial blood flow, potentially leading to conduction failure and eventually to axonal degeneration. In patients with AMAN associated with anti-ganglioside antibodies, nerve conduction block secondary to nodal sodium channel dysfunction may affect the proximal, intermediate, and distal nerve trunks. In addition to the mechanisms involved in AIDP, active axonal degeneration in AMAN may be associated with nodal axolemma disruption caused by anti-ganglioside antibodies. Conclusion: Inflammatory oedema of the proximal nerve trunks can be observed in early stages of GBS, and it may cause nerve conduction failure and active axonal degeneration. (AU)
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Humanos , Animales , Ratas , Axones/patología , Síndrome de Guillain-Barré , Conducción Nerviosa/fisiología , Nervios Periféricos/patología , Degeneración Retrógrada , Neuritis Autoinmune ExperimentalRESUMEN
Objetivo: La degeneración neuronal distal (DND) define el proceso de desintegración de una neurona o un circuito neuronal como consecuencia de una noxa localizada a distancia. Es un hallazgo frecuente debido al creciente número de realización de pruebas de imagen y a que refleja un desenlace común a múltiples etiologías. El objetivo de este artículo es definir los distintos tipos de daño neuronal a distancia, revisar la anatomía y función de los tractos más frecuentemente afectados e ilustrar la DND con esquemas y casos representativos de la práctica habitual. Conclusión: El conocimiento de la respuesta a distancia esperable según la topografía de una lesión neuronal es crucial para evitar errores diagnósticos. La degeneración axonal y transináptica puede ser tanto anterógrada como retrógrada. Los estudios de metabolismo cerebral, las secuencias de perfusión y de difusión muestran cambios cada vez más precoces del mismo proceso con los que debemos estar familiarizados.(AU
Objective: Distal nerve degeneration refers to the process of disintegration of a neuron or neuronal circuit as a consequence of distal damage. The end result of multiple etiologies, this finding is becoming common due to the increasing number of imaging tests done. This paper aims to define the different types of distal nerve damage, review the anatomy and function of the most commonly affected tracts, and illustrate distal nerve damage through diagrams and representative cases from routine practice. Conclusion: Knowing the distant response that can be expected according to the topography of a neuronal lesion is crucial to avoid diagnostic errors. Axonal degeneration and transsynaptic degeneration can be both antegrade and retrograde. Studies of cerebral metabolism, perfusion sequences, and diffusion sequences are showing increasingly earlier changes related to the same process; radiologists need to be aware of these changes.(AU)
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Humanos , Masculino , Femenino , Degeneración Nerviosa , Neuronas/patología , Degeneración Nerviosa/diagnóstico por imagen , Degeneración Nerviosa/patología , Degeneración Retrógrada , Enfermedades del Sistema Nervioso Periférico , Radiología , AnisotropíaRESUMEN
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.
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Enfermedades Neurodegenerativas , Degeneración Retrógrada , Humanos , Enfermedades Neurodegenerativas/complicaciones , Enfermedades Neurodegenerativas/patología , Células Ganglionares de la Retina/patología , Degeneración Retrógrada/patología , Sinapsis/patología , Vías Visuales/patologíaRESUMEN
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.
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Degeneración Retrógrada , Vías Visuales , Humanos , Lóbulo Occipital/patología , Células Ganglionares de la Retina/patología , Degeneración Retrógrada/patología , Tomografía de Coherencia Óptica , Vías Visuales/diagnóstico por imagen , Vías Visuales/patologíaRESUMEN
OBJECTIVE: The dopaminergic nigrostriatal neurons (DA cells) in healthy people present a slow degeneration with aging, which produces cellular debris throughout life. About 2%-5% of people present rapid cell degeneration of more than 50% of DA cells, which produces Parkinson's disease (PD). Neuroinflammation accelerates the cell degeneration and may be critical for the transition between the slow physiological and the rapid pathological degeneration of DA cells, particularly when it activates microglial cells of the medial forebrain bundle near dopaminergic axons. As synaptic debris produced by DA cell degeneration may trigger the parkinsonian neuroinflammation, this study investigated the removal of axonal debris produced by retrograde degeneration of DA cells, paying particular attention to the relative roles of astrocytes and microglia. METHODS: Rats and mice were injected in the lateral ventricles with 6-hydroxydopamine, inducing a degeneration of dopaminergic synapses in the striatum which was not accompanied by non-selective tissue damage, microgliosis or neuroinflammation. The possible retrograde degeneration of dopaminergic axons, and the production and metabolization of DA-cell debris were studied with immunohistochemical methods and analyzed in confocal and electron microscopy images. RESULTS: The selective degeneration of dopaminergic synapses in the striatum was followed by a retrograde degeneration of dopaminergic axons whose debris was found within spheroids of the medial forebrain bundle. These spheroids retained mitochondria and most (e.g., tyrosine hydroxylase, the dopamine transporter protein, and amyloid precursor protein) but not all (e.g., α-synuclein) proteins of the degenerating dopaminergic axons. Spheroids showed initial (autophagosomes) but not late (lysosomes) components of autophagy (incomplete autophagy). These spheroids were penetrated by astrocytic processes of the medial forebrain bundle, which provided the lysosomes needed to continue the degradation of dopaminergic debris. Finally, dopaminergic proteins were observed in the cell somata of astrocytes. No microgliosis or microglial phagocytosis of debris was observed in the medial forebrain bundle during the retrograde degeneration of dopaminergic axons. CONCLUSIONS: The present data suggest a physiological role of astrocytic phagocytosis of axonal debris for the medial forebrain bundle astrocytes, which may prevent the activation of microglia and the spread of retrograde axonal degeneration in PD.
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Neuronas Dopaminérgicas , Enfermedad de Parkinson , Animales , Astrocitos/metabolismo , Axones/patología , Neuronas Dopaminérgicas/patología , Humanos , Ratones , Enfermedad de Parkinson/metabolismo , Ratas , Ratas Sprague-Dawley , Degeneración Retrógrada/metabolismo , Degeneración Retrógrada/patologíaRESUMEN
Following lesions of the primary visual cortex (V1), the lateral geniculate nucleus (LGN) undergoes substantial cell loss due to retrograde degeneration. However, visually responsive neurons remain in the degenerated sector of LGN, and these have been implicated in mediation of residual visual capacities that remain within the affected sectors of the visual field. Using immunohistochemistry, we compared the neurochemical characteristics of LGN neurons in V1-lesioned marmoset monkeys (Callithrix jacchus) with those of non-lesioned control animals. We found that GABAergic neurons form approximately 6.5% of the neuronal population in the normal LGN, where most of these cells express the calcium-binding protein parvalbumin. Following long-term V1 lesions in adult monkeys, we observed a marked increase (~ sevenfold) in the proportion of GABA-expressing neurons in the degenerated sector of the LGN, indicating that GABAergic cells are less affected by retrograde degeneration in comparison with magno- and parvocellular projection neurons. In addition, following early postnatal V1 lesions and survival into adulthood, we found widespread expression of GABA in putative projection neurons, even outside the degenerated sectors (lesion projection zones). Our findings show that changes in the ratio of GABAergic neurons in LGN need to be taken into account in the interpretation of the mechanisms of visual abilities that survive V1 lesions in primates.
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Cuerpos Geniculados , Degeneración Retrógrada , Corteza Visual , Animales , Callithrix , Cuerpos Geniculados/patología , Degeneración Retrógrada/patología , Corteza Visual/patología , Vías Visuales/patología , Ácido gamma-AminobutíricoRESUMEN
Pain is a common non-motor symptom of Parkinson's disease (PD), with current limited knowledge of its pathophysiology. Here, we show that peripheral inoculation of mouse alpha-synuclein (α-Syn) pre-formed fibrils, in a transgenic mouse model of PD, elicited retrograde trans-synaptic spreading of α-Syn pathology (pSer129) across sensory neurons and dorsal nerve roots, reaching central pain processing regions, including the spinal dorsal horn and the projections of the anterolateral system in the central nervous system (CNS). Pathological peripheral to CNS propagation of α-Syn aggregates along interconnected neuronal populations within sensory afferents, was concomitant with impaired nociceptive response, reflected by mechanical allodynia, reduced nerve conduction velocities (sensory and motor) and degeneration of small- and medium-sized myelinated fibers. Our findings show a link between the transneuronal propagation of α-Syn pathology with sensory neuron dysfunction and neuropathic impairment, suggesting promising avenues of investigation into the mechanisms underlying pain in PD.
Asunto(s)
Neuralgia/etiología , Neuralgia/fisiopatología , Degeneración Retrógrada/patología , Degeneración Retrógrada/fisiopatología , Células Receptoras Sensoriales/patología , Sinucleinopatías/patología , Sinucleinopatías/fisiopatología , Animales , Modelos Animales de Enfermedad , Femenino , Ratones , Ratones Transgénicos , Microscopía Electrónica de Transmisión , Enfermedad de Parkinson/fisiopatología , Células Receptoras Sensoriales/metabolismo , Células Receptoras Sensoriales/ultraestructura , Transmisión Sináptica , alfa-Sinucleína/metabolismoRESUMEN
BACKGROUND: Transection-induced axonal retrograde degeneration, in contrast to Wallerian degeneration, has not been widely recognized in clinical practice. AIMS OF THE STUDY: To assess a potential of corticospinal tractography for detecting axonal retrograde degeneration. METHODS: We assessed the corticospinal tractography of a 74-year-old woman with monoplegia of the lower limb due to a unilateral thoracic spinal cord tumor. RESULTS: The tractography revealed integrity reduction of the corticospinal tract in the cerebra contralateral to the spinal cord tumor. CONCLUSIONS: The present report supports that magnetic resonance tractography has the potential for detecting this under-recognized phenomenon.
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Traumatismos de la Médula Espinal , Neoplasias de la Médula Espinal , Anciano , Femenino , Humanos , Espectroscopía de Resonancia Magnética , Tractos Piramidales/diagnóstico por imagen , Tractos Piramidales/patología , Degeneración Retrógrada/patología , Médula Espinal/patología , Neoplasias de la Médula Espinal/diagnóstico por imagen , Neoplasias de la Médula Espinal/patologíaRESUMEN
PURPOSE: To investigate optic nerve head (ONH) microvascular changes secondary to transsynaptic retrograde degeneration (TRD), comperatively with direct retrograde degeneration and healthy controls. METHODS: Patients with hemianopia due to intracranial lesion included in the study. Intracranial lesion was categorized by location: postgeniculate (causing TRD), chiasmal (causing direct retrograde degeneration). For the postgeniculate lesions, the eye on the same side of the lesion was defined as the ipsilateral eye and the eye on the opposite side as the contralateral eye. Optic disc microvasculature was evaluated with the help of optic coherence tomography angiography. RESULTS: Sixteen eyes of 16 patients with chiasmal lesion, 28 eyes of 14 patients with postgeniculate lesion, and 30 eyes of 30 healthy subjects were included in the study. Ipsilateral eyes of the patients with postgeniculate lesion had decreased vessel density at the temporal sectors compatible with the affected nasal side of the visual field. Contralateral eyes showed no reduction of the vessel density at the affected nasal sectors. The eyes with chiasmal lesions had decreased vessel density at the peripapillary region and nasal half of the ONH compatible with temporal hemianopia. Vascular changes in the chiasmal lesion were more prominent than those of the postgeniculate lesion. Retinal nerve fiber layer and ganglion cell complex thickness were reduced. CONCLUSION: Vessel density of ONH was reduced in patients with homonymous hemianopia, providing evidence for TRD secondary to acquired postgeniculate lesion. Direct retrograde degeneration was more prominent in affected sectors when compared to TRD.
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Disco Óptico , Hemianopsia/diagnóstico , Hemianopsia/etiología , Hemianopsia/patología , Humanos , Fibras Nerviosas/patología , Células Ganglionares de la Retina/patología , Degeneración Retrógrada/patología , Tomografía de Coherencia ÓpticaAsunto(s)
Lesiones Traumáticas del Encéfalo/patología , Núcleos Cerebelosos/patología , Lesión Axonal Difusa/patología , Núcleo Olivar/patología , Núcleo Rojo/patología , Degeneración Retrógrada/patología , Temblor/patología , Adulto , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/diagnóstico por imagen , Lesiones Traumáticas del Encéfalo/fisiopatología , Núcleos Cerebelosos/diagnóstico por imagen , Lesión Axonal Difusa/complicaciones , Lesión Axonal Difusa/diagnóstico por imagen , Lesión Axonal Difusa/fisiopatología , Imagen de Difusión Tensora , Femenino , Humanos , Núcleo Olivar/diagnóstico por imagen , Núcleo Rojo/diagnóstico por imagen , Degeneración Retrógrada/diagnóstico por imagen , Temblor/etiología , Temblor/fisiopatología , Adulto JovenRESUMEN
OBJECTIVE: To measure exosomal and plasma levels of candidate blood biomarkers in veterans with history of mild traumatic brain injury (mTBI) and test their relationship with chronic symptoms. METHODS: Exosomal and plasma levels of neurofilament light (NfL) chain, tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, and vascular endothelial growth factor (VEGF) were measured using an ultrasensitive assay in a cohort of 195 veterans, enrolled in the Chronic Effects of Neurotrauma Consortium Longitudinal Study. We examined relationships between candidate biomarkers and symptoms of postconcussive syndrome (PCS), posttraumatic stress disorder (PTSD), and depression. Biomarker levels were compared among those with no traumatic brain injury (TBI) (controls), 1-2 mTBIs, and repetitive (3 or more) mTBIs. RESULTS: Elevated exosomal and plasma levels of NfL were associated with repetitive mTBIs and with chronic PCS, PTSD, and depression symptoms. Plasma TNF-α levels correlated with PCS and PTSD symptoms. The total number of mTBIs correlated with exosomal and plasma NfL levels and plasma IL-6. Increased number of years since the most recent TBI correlated with higher exosomal NfL and lower plasma IL-6 levels, while increased number of years since first TBI correlated with higher levels of exosomal and plasma NfL, as well as plasma TNF-α and VEGF. CONCLUSION: Repetitive mTBIs are associated with elevated exosomal and plasma levels of NfL, even years following these injuries, with the greatest elevations in those with chronic PCS, PTSD, and depression symptoms. Our results suggest a possible neuroinflammatory and axonal disruptive basis for symptoms that persist years after mTBI, especially repetitive.