In vivo MRI reveals the dynamics of pathological changes in the brains of cathepsin D-deficient mice and correlates changes in manganese-enhanced MRI with microglial activation.
Cathepsin D (CTSD; EC 3.4.23.5) is essential for normal development and/or maintenance of neurons in the central nervous system: its deficiency causes a devastating neurological disorder with severely shortened life span in man, sheep and mouse. Neuropathologically, the CTSD deficiencies are characterized by selective neuronal degeneration, gliosis and accumulation of autofluorescent proteinaceous storage material in neurons. Our aim was to study the dynamics behind the pathological alterations occurring in the brains of CTSD-deficient (CTSD-/-) mice by using in vivo magnetic resonance imaging (MRI) and histology. In order to do this, we measured T(2) signal intensity (SI), apparent diffusion coefficient, area and volume of multiple brain structures from MR images acquired using T(2)-, T(1)- and diffusion-weighted sequences at three time points during disease progression. MRI revealed no differences in the brains between CTSD-/- and control mice at postnatal day 15+/-1 (P15+/-1), representing an initial stage of the disease. In the intermediate stage of the disease, P19(+/-1), SI alterations in the thalami of the affected mice became evident in both T(1)- and T(2)-weighted images. The terminal stage of the disease, P25, was characterized by marked alterations in the T(2) SI, apparent diffusion coefficient and volume of multiple brain structures in CTSD-/- mice. In addition, manganese enhanced high-resolution T(1)-weighted 3D sequences (MEMRI) and histological stainings revealed that the hyperintense signal areas in MEMRI matched perfectly with areas of microglial activation in the brains of CTSD-/- mice at the terminal disease stage. In conclusion, the SI alterations in the thalami of CTSD-/- mice preceded other changes, and the degenerative process was greatly enhanced at the age P19(+/-1), leading to severely reduced brain volume in just 6 days.
Haapanen
Aleksi
A
Institute of Biomedicine/Biochemistry and Neuroscience Research Program, University of Helsinki, P.O. Box 63, FIN-00014 Helsinki, Finland.
Ramadan
Usama Abo
UA
Autti
Taina
T
Joensuu
Raimo
R
Tyynelä
Jaana
J
D000818:Animals; D001921:Brain / Q000473:pathology*; D002403:Cathepsins / Q000172:deficiency*; D007091:Image Processing, Computer-Assisted; D007124:Immunoenzyme Techniques; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008345:Manganese; D051379:Mice; D017628:Microglia / Q000473:pathology*
D008345:Manganese; D002403:Cathepsins