Limits...
Comparative Magnetic Resonance Imaging and Histopathological Correlates in Two SOD1 Transgenic Mouse Models of Amyotrophic Lateral Sclerosis.

Caron I, Micotti E, Paladini A, Merlino G, Plebani L, Forloni G, Modo M, Bendotti C - PLoS ONE (2015)

Bottom Line: A longitudinal in vivo analysis of T2 maps, compared to ex vivo histological changes, was performed on cranial motor nuclei.The identification of prognostic markers of the disease nevertheless requires validation in multiple models of ALS to ensure that these are not merely model-specific.Eventually this approach has the potential to lead to the development of robust and validated non-invasive imaging biomarkers in ALS patients, which may help to monitor the efficacy of therapies.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Neurobiology, Neuroscience Department, IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.

ABSTRACT
Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal disease due to motoneuron degeneration. Magnetic resonance imaging (MRI) is becoming a promising non-invasive approach to monitor the disease course but a direct correlation with neuropathology is not feasible in human. Therefore in this study we aimed to examine MRI changes in relation to histopathology in two mouse models of ALS (C57BL6/J and 129S2/SvHsd SOD1G93A mice) with different disease onset and progression. A longitudinal in vivo analysis of T2 maps, compared to ex vivo histological changes, was performed on cranial motor nuclei. An increased T2 value was associated with a significant tissue vacuolization that occurred prior to motoneuron loss in the cranial nuclei of C57 SOD1G93A mice. Conversely, in 129Sv SOD1G93A mice, which exhibit a more severe phenotype, MRI detected a milder increase of T2 value, associated with a milder vacuolization. This suggests that alteration within brainstem nuclei is not predictive of a more severe phenotype in the SOD1G93A mouse model. Using an ex vivo paradigm, Diffusion Tensor Imaging was also applied to study white matter spinal cord degeneration. In contrast to degeneration of cranial nuclei, alterations in white matter and axons loss reflected the different disease phenotype of SOD1G93A mice. The correspondence between MRI and histology further highlights the potential of MRI to monitor progressive motoneuron and axonal degeneration non-invasively in vivo. The identification of prognostic markers of the disease nevertheless requires validation in multiple models of ALS to ensure that these are not merely model-specific. Eventually this approach has the potential to lead to the development of robust and validated non-invasive imaging biomarkers in ALS patients, which may help to monitor the efficacy of therapies.

No MeSH data available.


Related in: MedlinePlus

Disease progression in C57 and 129Sv SOD1G93A mice.Grip strength measurements of C57 SOD1G93A (A) and 129Sv SOD1G93A (B) mice analysed in vivo for T2 relaxation time. Time points of MRI and histological studies are reported as arrows in correspondence to the respective ages of analysis: ON = Onset, SS = symptomatic, AS = advanced stage. (C) Disease onset of C57 SOD1G93A (15.6 ± 0.8) and 129Sv SOD1G93A mice (13.8 ± 0.4) analysed with T2 MRI. Statistical analysis: Student’s t-test. ** = p-value<0.01. Data are expressed as mean ± SD. N = 6 animals for C57 SOD1G93A mice and 5 animals for 129Sv SOD1G93A mice.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4488470&req=5

pone.0132159.g001: Disease progression in C57 and 129Sv SOD1G93A mice.Grip strength measurements of C57 SOD1G93A (A) and 129Sv SOD1G93A (B) mice analysed in vivo for T2 relaxation time. Time points of MRI and histological studies are reported as arrows in correspondence to the respective ages of analysis: ON = Onset, SS = symptomatic, AS = advanced stage. (C) Disease onset of C57 SOD1G93A (15.6 ± 0.8) and 129Sv SOD1G93A mice (13.8 ± 0.4) analysed with T2 MRI. Statistical analysis: Student’s t-test. ** = p-value<0.01. Data are expressed as mean ± SD. N = 6 animals for C57 SOD1G93A mice and 5 animals for 129Sv SOD1G93A mice.

Mentions: Animals assigned to in vivo analysis of T2 relaxation time of brainstem were monitored for disease progression using grip strength test (see below) (Fig 1). In vivo data acquisition started at 7 weeks of age in both strains as a baseline and then followed at different time points during the disease progression. In Fig 1 the differences in the disease progression between the two strains are shown, starting from the disease onset (Fig 1C), which corresponds to the first time point at which the mice are unable to maintain the grip to the grid for at least 90 seconds. The different time points of the MRI analysis are indicated by arrows in the graphs for each of the two SOD1G93A mouse strains. For the in vivo analysis, the C57SOD1G93A mice were examined at 11, 15, 19 and 22 weeks of age corresponding to the pre-symptomatic, onset, symptomatic and advanced stage. The 129Sv SOD1G93A mice were examined only at the 11, 14 and 16 weeks of age, corresponding to pre-symptomatic, onset and advanced stage of the disease. The intermediate stage of 15 weeks was not included in this analysis to avoid subjecting the mice to frequent anaesthesia for in vivo MRI analysis.


Comparative Magnetic Resonance Imaging and Histopathological Correlates in Two SOD1 Transgenic Mouse Models of Amyotrophic Lateral Sclerosis.

Caron I, Micotti E, Paladini A, Merlino G, Plebani L, Forloni G, Modo M, Bendotti C - PLoS ONE (2015)

Disease progression in C57 and 129Sv SOD1G93A mice.Grip strength measurements of C57 SOD1G93A (A) and 129Sv SOD1G93A (B) mice analysed in vivo for T2 relaxation time. Time points of MRI and histological studies are reported as arrows in correspondence to the respective ages of analysis: ON = Onset, SS = symptomatic, AS = advanced stage. (C) Disease onset of C57 SOD1G93A (15.6 ± 0.8) and 129Sv SOD1G93A mice (13.8 ± 0.4) analysed with T2 MRI. Statistical analysis: Student’s t-test. ** = p-value<0.01. Data are expressed as mean ± SD. N = 6 animals for C57 SOD1G93A mice and 5 animals for 129Sv SOD1G93A mice.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4488470&req=5

pone.0132159.g001: Disease progression in C57 and 129Sv SOD1G93A mice.Grip strength measurements of C57 SOD1G93A (A) and 129Sv SOD1G93A (B) mice analysed in vivo for T2 relaxation time. Time points of MRI and histological studies are reported as arrows in correspondence to the respective ages of analysis: ON = Onset, SS = symptomatic, AS = advanced stage. (C) Disease onset of C57 SOD1G93A (15.6 ± 0.8) and 129Sv SOD1G93A mice (13.8 ± 0.4) analysed with T2 MRI. Statistical analysis: Student’s t-test. ** = p-value<0.01. Data are expressed as mean ± SD. N = 6 animals for C57 SOD1G93A mice and 5 animals for 129Sv SOD1G93A mice.
Mentions: Animals assigned to in vivo analysis of T2 relaxation time of brainstem were monitored for disease progression using grip strength test (see below) (Fig 1). In vivo data acquisition started at 7 weeks of age in both strains as a baseline and then followed at different time points during the disease progression. In Fig 1 the differences in the disease progression between the two strains are shown, starting from the disease onset (Fig 1C), which corresponds to the first time point at which the mice are unable to maintain the grip to the grid for at least 90 seconds. The different time points of the MRI analysis are indicated by arrows in the graphs for each of the two SOD1G93A mouse strains. For the in vivo analysis, the C57SOD1G93A mice were examined at 11, 15, 19 and 22 weeks of age corresponding to the pre-symptomatic, onset, symptomatic and advanced stage. The 129Sv SOD1G93A mice were examined only at the 11, 14 and 16 weeks of age, corresponding to pre-symptomatic, onset and advanced stage of the disease. The intermediate stage of 15 weeks was not included in this analysis to avoid subjecting the mice to frequent anaesthesia for in vivo MRI analysis.

Bottom Line: A longitudinal in vivo analysis of T2 maps, compared to ex vivo histological changes, was performed on cranial motor nuclei.The identification of prognostic markers of the disease nevertheless requires validation in multiple models of ALS to ensure that these are not merely model-specific.Eventually this approach has the potential to lead to the development of robust and validated non-invasive imaging biomarkers in ALS patients, which may help to monitor the efficacy of therapies.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Neurobiology, Neuroscience Department, IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.

ABSTRACT
Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal disease due to motoneuron degeneration. Magnetic resonance imaging (MRI) is becoming a promising non-invasive approach to monitor the disease course but a direct correlation with neuropathology is not feasible in human. Therefore in this study we aimed to examine MRI changes in relation to histopathology in two mouse models of ALS (C57BL6/J and 129S2/SvHsd SOD1G93A mice) with different disease onset and progression. A longitudinal in vivo analysis of T2 maps, compared to ex vivo histological changes, was performed on cranial motor nuclei. An increased T2 value was associated with a significant tissue vacuolization that occurred prior to motoneuron loss in the cranial nuclei of C57 SOD1G93A mice. Conversely, in 129Sv SOD1G93A mice, which exhibit a more severe phenotype, MRI detected a milder increase of T2 value, associated with a milder vacuolization. This suggests that alteration within brainstem nuclei is not predictive of a more severe phenotype in the SOD1G93A mouse model. Using an ex vivo paradigm, Diffusion Tensor Imaging was also applied to study white matter spinal cord degeneration. In contrast to degeneration of cranial nuclei, alterations in white matter and axons loss reflected the different disease phenotype of SOD1G93A mice. The correspondence between MRI and histology further highlights the potential of MRI to monitor progressive motoneuron and axonal degeneration non-invasively in vivo. The identification of prognostic markers of the disease nevertheless requires validation in multiple models of ALS to ensure that these are not merely model-specific. Eventually this approach has the potential to lead to the development of robust and validated non-invasive imaging biomarkers in ALS patients, which may help to monitor the efficacy of therapies.

No MeSH data available.


Related in: MedlinePlus