title: Secondary post-geniculate involvement in Leber's hereditary optic neuropathy.
abstract: Leber's hereditary optic neuropathy (LHON) is characterized by retinal ganglion cell (RGC) degeneration with the preferential involvement of those forming the papillomacular bundle. The optic nerve is considered the main pathological target for LHON. Our aim was to investigate the possible involvement of the post-geniculate visual pathway in LHON patients. We used diffusion-weighted imaging for in vivo evaluation. Mean diffusivity maps from 22 LHON visually impaired, 11 unaffected LHON mutation carriers and 22 healthy subjects were generated and compared at level of optic radiation (OR). Prefrontal and cerebellar white matter were also analyzed as internal controls. Furthermore, we studied the optic nerve and the lateral geniculate nucleus (LGN) in post-mortem specimens obtained from a severe case of LHON compared to an age-matched control. Mean diffusivity values of affected patients were higher than unaffected mutation carriers (P<0.05) and healthy subjects (P<0.01) in OR and not in the other brain regions. Increased OR diffusivity was associated with both disease duration (B = 0.002; P<0.05) and lack of recovery of visual acuity (B = 0.060; P<0.01). Post-mortem investigation detected atrophy (41.9% decrease of neuron soma size in the magnocellular layers and 44.7% decrease in the parvocellular layers) and, to a lesser extent, degeneration (28.5% decrease of neuron density in the magnocellular layers and 28.7% decrease in the parvocellular layers) in the LHON LGN associated with extremely severe axonal loss (99%) in the optic nerve. The post-geniculate involvement in LHON patients is a downstream post-synaptic secondary phenomenon, reflecting de-afferentation rather than a primary neurodegeneration due to mitochondrial dysfunction of LGN neurons.
authors.affiliation: Department of Biomedical and NeuroMotor Sciences (DiBiNeM), University of Bologna, Bologna, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Rizzo
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Tozer
authors.forename: Caterina
authors.initials: C
authors.lastname: Tonon
authors.forename: David
authors.initials: D
authors.lastname: Manners
authors.forename: Claudia
authors.initials: C
authors.lastname: Testa
authors.forename: Emil
authors.initials: E
authors.lastname: Malucelli
authors.forename: Maria Lucia
authors.initials: ML
authors.lastname: Valentino
authors.forename: Chiara
authors.initials: C
authors.lastname: La Morgia
authors.forename: Piero
authors.initials: P
authors.lastname: Barboni
authors.forename: Ruvdeep S
authors.initials: RS
authors.lastname: Randhawa
authors.forename: Fred N
authors.initials: FN
authors.lastname: Ross-Cisneros
authors.forename: Alfredo A
authors.initials: AA
authors.lastname: Sadun
authors.forename: Valerio
authors.initials: V
authors.lastname: Carelli
authors.forename: Raffaele
authors.initials: R
authors.lastname: Lodi
mesh_terms: D000328:Adult; D000368:Aged; D001284:Atrophy / Q000473:pathology; D001931:Brain Mapping / Q000379:methods; D016022:Case-Control Studies; D004272:DNA, Mitochondrial / Q000378:metabolism; D004058:Diffusion; D038524:Diffusion Magnetic Resonance Imaging / Q000379:methods; D005260:Female; D006579:Heterozygote; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009412:Nerve Fibers / Q000473:pathology; D009474:Neurons / Q000473:pathology; D029242:Optic Atrophy, Hereditary, Leber / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D009900:Optic Nerve / Q000502:physiology; D010655:Phenylenediamines / Q000494:pharmacology; D014785:Vision, Ocular
chemical_list: D004272:DNA, Mitochondrial; D010655:Phenylenediamines; C029728:4-phenylenediamine