Non-invasive assessment of retinal alterations in mouse models of infantile and juvenile neuronal ceroid lipofuscinosis by spectral domain optical coherence tomography

Abstract

IntroductionThe neuronal ceroid lipofuscinoses constitute a group of fatal inherited lysosomal storage diseases that manifest in profound neurodegeneration in the CNS. Visual impairment usually is an early symptom and selective degeneration of retinal neurons has been described in patients suffering from distinct disease subtypes. We have previously demonstrated that palmitoyl protein thioesterase 1 deficient (Ppt1-/-) mice, a model of the infantile disease subtype, exhibit progressive axonal degeneration in the optic nerve and loss of retinal ganglion cells, faithfully reflecting disease severity in the CNS. Here we performed spectral domain optical coherence tomography (OCT) in Ppt1-/- and ceroid lipofuscinosis neuronal 3 deficient (Cln3-/-) mice, which are models of infantile and juvenile neuronal ceroid lipofuscinosis, respectively, in order to establish a non-invasive method to assess retinal alterations and monitor disease severity in vivo.ResultsBlue laser autofluorescence imaging revealed increased accumulation of autofluorescent storage material in the inner retinae of 7-month-old Ppt1-/- and of 16-month-old Cln3-/- mice in comparison with age-matched control littermates. Additionally, optical coherence tomography demonstrated reduced thickness of retinae in knockout mice in comparison with age-matched control littermates. High resolution scans and manual measurements allowed for separation of different retinal composite layers and revealed a thinning of layers in the inner retinae of both mouse models at distinct ages. OCT measurements correlated well with subsequent histological analysis of the same retinae.ConclusionsThese results demonstrate the feasibility of OCT to assess neurodegenerative disease severity in mouse models of neuronal ceroid lipofuscinosis and might have important implications for diagnostic evaluation of disease progression and therapeutic efficacy in patients. Moreover, the non-invasive method allows for longitudinal studies in experimental models, reducing the number of animals used for research.

Whole-body positional manipulators for ocular imaging of anaesthetised mice and rats: a do-it-yourself guide

“…[20][21][22] The high resolution of third-generation spectral-domain OCT devices renders in vivo retinal imaging in mice and rats possible, gaining an increasing importance in ophthalmological and neurological preclinical research. [23][24][25][26][27][28][29][30][31][32][33] The obtained results are in good accordance with histological sections of the animals' retinae. 34 The application of OCT technology in rodent models, however, is still challenging, mainly because of the small size of the rodents' eyes.…”

Sialoadhesin promotes neuroinflammation‐related disease progression in two mouse models of CLN disease

“…To test whether similar reactions also occur in other CLN models, we investigated microglia/macrophages in optic nerves of Cln3 −/− mice, a model of CLN3 disease (Batten disease). In these mice, pathological alterations including degeneration of retinal ganglion cells occur at advanced age (Groh et al, ). Correlating with this late disease phenotype, we detected an increase in the number of CD11b+ microglia/macrophages in comparison with Cln3 +/+ mice at 18 months of age (Fig.…”

Targeting microglia attenuates neuroinflammation‐related neural damage in mice carrying human PLP1 mutations

“…Mice were subjected to OCT imaging with a commercially available device (Spectralis OCT; Heidelberg Engineering, Heidelberg, Germany) and additional lenses as previously described (Groh et al, ; Groh, Friedman, et al, ; Groh, Stadler, Buttmann, & Martini, ). Mice were measured at different ages for longitudinal analysis and the thickness of the innermost retinal composite layer comprising nerve fiber layer (NFL), GCL, and inner plexiform layer (IPL) were measured in high‐resolution peripapillary circle scans (at least 10 measurements per scan) by an investigator unaware of the genotype of the mice.…”

“…Mice were subjected to OCT imaging with a commercially available device (Spectralis OCT; Heidelberg Engineering, Heidelberg, Germany) and additional lenses as previously described Groh, Friedman, et al, 2016;Groh, Stadler, Buttmann, & Martini, 2014).…”