Abstract
Duchenne muscular dystrophy (DMD) is an X-linked recessive muscle wasting disease caused by mutations in the DMD gene, which encodes the large cytoskeletal protein dystrophin. Approximately one-third of DMD patient's exhibit cognitive problems yet it is unknown if cognitive impairments worsen with age. The mdx mouse model is deficient in dystrophin demonstrates cognitive abnormalities, but no studies have investigated this longitudinally. We assessed the consequences of dystrophin deficiency on brain morphology and cognition in male mdx mice. We utilised non-invasive methods to monitor CNS pathology with an aim to identify changes longitudinally (between 4 and 18 months old) which could be used as outcome measures. MRI identified a total brain volume (TBV) increase in control mice with ageing (p < 0.05); but the mdx mice TBV increased significantly more (p < 0.01). Voxel-based morphometry (VBM) identified decreases in grey matter volume, particularly in the hippocampus of the mdx brain, most noticeable from 12 months onwards, as were enlarged lateral ventricles in mdx mice. The caudate putamen of older mdx mice showed increases in T2- relaxometry which may be considered as evidence of increased water content. Hippocampal spatial learning and memory was decreased in mdx mice, particularly long-term memory, which progressively worsened with age. The novel object recognition (NOR) task highlighted elevated anxiety-related behaviour in older mdx mice. Our studies suggest that dystrophin deficiency causes a progressive cognitive impairment in mice (compared to ageing control mice), becoming evident at late disease stages, and may explain why progressive CNS symptoms are not obvious in DMD patients.
Highlights
Duchenne muscular dystrophy (DMD) is an X-linked recessive disease, occurring at an incidence of 1 in 3600– 10,000 live male births [1,2]
We included the entire cerebellum in our cerebellar volume measurements, but found no difference in the cerebellar volume or any gross structural abnormalities between control and mdx mice at any time point investigated, which is in accordance with studies in DMD patients [55,56]. These findings suggest that dystrophin loss does not cause any gross abnormalities in the cerebellum but may have a further impact at a cellular level, as previously reported in the mdx mouse [57]
We have identified noninvasive measures to detect several longitudinal changes in cognitive function and brain morphology in the mdx mouse, including: enlarged cerebral ventricles; larger total brain volume; and increased primary latency on the Barnes maze test
Summary
Duchenne muscular dystrophy (DMD) is an X-linked recessive disease, occurring at an incidence of 1 in 3600– 10,000 live male births [1,2]. DMD is characterised by a severe pathology of the skeletal musculature causing progressive loss of muscle, with premature death frequently occurring in the third decade of life as a result of cardiac and respiratory complications [3]. This fatal disease arises from mutations in the DMD gene; the largest gene in the human genome, with 79 exons spanning 2.4 Mb [4], and coding for a 427 kDa intracellular protein named dystrophin [5]. Within the CNS full-length-dystrophin is highly expressed in pyramidal neurons of the hippocampus, which has important roles in memory formation and consolidation [6]
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