Rapid and Progressive Regional Brain Atrophy in CLN6 Batten Disease Affected Sheep Measured with Longitudinal Magnetic Resonance Imaging

Abstract

Variant late-infantile Batten disease is a neuronal ceroid lipofuscinosis caused by mutations in CLN6. It is a recessive genetic lysosomal storage disease characterised by progressive neurodegeneration. It starts insidiously and leads to blindness, epilepsy and dementia in affected children. Sheep that are homozygous for a natural mutation in CLN6 have an ovine form of Batten disease Here, we used in vivo magnetic resonance imaging to track brain changes in 4 unaffected carriers and 6 affected Batten disease sheep. We scanned each sheep 4 times, between 17 and 22 months of age. Cortical atrophy in all sheep was pronounced at the baseline scan in all affected Batten disease sheep. Significant atrophy was also present in other brain regions (caudate, putamen and amygdala). Atrophy continued measurably in all of these regions during the study. Longitudinal MRI in sheep was sensitive enough to measure significant volume changes over the relatively short study period, even in the cortex, where nearly 40% of volume was already lost at the start of the study. Thus longitudinal MRI could be used to study the dynamics of progression of neurodegenerative changes in sheep models of Batten disease, as well as to assess therapeutic efficacy.

CRISPR/Cas9 mediated generation of an ovine model for infantile neuronal ceroid lipofuscinosis (CLN1 disease)

“…3D). Features in this model recapitulate the gross anatomical findings in a naturally occurring ovine model caused by mutation of the CLN6 gene 21 .…”

“…This time point was selected to provide the most animals in a specific 2 week period. In addition, this time point was similar to that used in another ovine study of naturally occurring CLN6 model (16 month) 21 .…”

Computed tomography provides enhanced techniques for longitudinal monitoring of progressive intracranial volume loss associated with regional neurodegeneration in ovine neuronal ceroid lipofuscinoses

“…Other common features of the ovine and human NCLs include progressive cerebral atrophy and enlargement of the cerebral ventricles (Frugier et al, 2008;Jolly et al, 2002Jolly et al, , 1989Woods et al, 1993). Neuroimaging techniques, such as magnetic resonance imaging (MRI) and computed tomography (CT), have been used to monitor changes of brain size and intracerebroventricular volumes in both human and ovine NCLs (Dyke et al, 2016;Jadav et al, 2014;Lobel et al, 2013;Sawiak et al, 2015;Valavanis, Friede, Schubinger, & Hayek, 1980;Woods et al, 1993). Viral-mediated gene therapy trials are being conducted in affected sheep (Palmer, 2015).…”

Alzheimer's disease markers in the aged sheep (Ovis aries)

“…Importantly, studies have shown AD-associated neurofibrillary accumulation (tau pathology) in normal aged sheep (Braak et al, 1994, Nelson andSaper 1995); a feature which is absent in wild type rodents and has made AD modelling challenging in rats and mice (Hardy and Selkoe 2002). While the rate of naturally occurring dementia in sheep is unknown (as most farmed sheep are culled before reaching old age), sheep with cognitive deficits are studied due to natural mutations in genes causing Battens Disease in humans (Cook et al, 2002, Jolly et al, 1980, Weber and Pearce 2013 Sheep are readily trainable for use in tests of cognitive function (Morton and Avanzo 2011) and sheep suffering from a progressive neurological disease can be quantified longitudinally using modern methods, such as EEG (Perentos et al, 2015) and MRI (Sawiak et al, 2015).…”