Abstract
IntroductionThe neuronal ceroid lipofuscinoses (NCLs; Batten disease) are a group of fatal neurodegenerative lysosomal storage diseases of children caused by various mutations in a range of genes. Forms associated with mutations in two of these, CLN5 and CLN6, are being investigated in well‐established sheep models. Brain atrophy leading to psychomotor degeneration is among the defining features, as is regional progressive ossification of the inner cranium. Ongoing viral‐mediated gene therapy trials in these sheep are yielding encouraging results. In vivo assessment of brain atrophy is integral to the longitudinal monitoring of individual animals and provides robust data for translation to treatments for humans.MethodsComputed tomography (CT)‐based three‐dimensional reconstruction of the intracranial volume (ICV) over time reflects the progression of cortical brain atrophy, verifying the use of ICV measurements as a surrogate measure for brain size in ovine NCL.ResultsICVs of NCL‐affected sheep increase for the first few months, but then decline progressively between 5 and 13 months in CLN5−/− sheep and 11–15 months in CLN6−/−sheep. Cerebral ventricular volumes are also increased in affected animals. To facilitate ICV measures, the radiodensities of ovine brain tissue and cerebrospinal fluid were identified. Ovine brain tissue exhibited a Hounsfield unit (HU) range of (24; 56) and cerebrospinal fluid a HU range of (−12; 23).ConclusionsComputed tomography scanning and reconstruction verify that brain atrophy ovine CLN5 NCL originates in the occipital lobes with subsequent propagation throughout the whole cortex and these regional differences are reflected in the ICV loss.
Highlights
The neuronal ceroid lipofuscinoses (NCLs; Batten disease) are a group of fatal neurodegenerative lysosomal storage diseases of children caused by various mutations in a range of genes
This study sets out to investigate the im‐ provements that could be achieved through automated methods of image analysis to establish the relationship between the reduction in intracranial volume (ICV) and brain atrophy, and describe the patterns of ICV change in CLN5‐affected Borderdale, CLN6‐affected South Hampshire, and unaffected control sheep
Measurements of radio‐densities of brain tissue and cerebrospinal fluid (CSF) spaces in NCL‐affected sheep and unaffected controls led to improved image analysis
Summary
The neuronal ceroid lipofuscinoses (NCLs; Batten disease) are a group of fatal neurodegenerative lysosomal storage diseases of children caused by various mutations in a range of genes. 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, 2002, 1989 ; Woods et al, 1993) Neuroimaging techniques, such as magnetic resonance imaging (MRI) and computed tomog‐ raphy (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). In vivo assessment of brain atro‐ phy is integral to the longitudinal monitoring of individual animals and provides robust data for translation to human clinical trials
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