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Diffusion MRI quantifies early axonal loss in the presence of nerve swelling

View Article: PubMed Central - PubMed

ABSTRACT

Background: Magnetic resonance imaging markers have been widely used to detect and quantify white matter pathologies in multiple sclerosis. We have recently developed a diffusion basis spectrum imaging (DBSI) to distinguish and quantify co-existing axonal injury, demyelination, and inflammation in multiple sclerosis patients and animal models. It could serve as a longitudinal marker for axonal loss, a primary cause of permanent neurological impairments and disease progression.

Methods: Eight 10-week-old female C57BL/6 mice underwent optic nerve DBSI, followed by a week-long recuperation prior to active immunization for experimental autoimmune encephalomyelitis (EAE). Visual acuity of all mice was assessed daily. Longitudinal DBSI was performed in mouse optic nerves at baseline (naïve, before immunization), before, during, and after the onset of optic neuritis. Tissues were perfusion fixed after final in vivo scans. The correlation between DBSI detected pathologies and corresponding immunohistochemistry markers was quantitatively assessed.

Results: In this cohort of EAE mice, monocular vision impairment occurred in all animals. In vivo DBSI detected, differentiated, and quantified optic nerve inflammation, demyelination, and axonal injury/loss, correlating nerve pathologies with visual acuity at different time points of acute optic neuritis. DBSI quantified, in the presence of optic nerve swelling, ~15% axonal loss at the onset of optic neuritis in EAE mice.

Conclusions: Our findings support the notion that axonal loss could occur early in EAE mice. DBSI detected pathologies in the posterior visual pathway unreachable by optical coherence tomography and without confounding inflammation induced optic nerve swelling. DBSI could thus decipher the interrelationship among various pathological components and the role each plays in disease progression. Quantification of the rate of axonal loss could potentially serve as the biomarker to predict treatment outcome and to determine when progressive disease starts.

No MeSH data available.


Related in: MedlinePlus

Regression of SMI-31, MBP, SMI-312, DAPI counts, and DBSI-derived λǁ (a), λ⊥ (b), fiber fraction (c), and restricted fraction (d) suggested DBSI measurements were able to reflect specific pathologies in the optic nerves of EAE mice, respectively. The regression of DBSI-derived axon volume correlated with SMI-312 area (e, in mm2). In contrast to SMI-312 area estimated as ratio of positive area over the total nerve cross-sectional area (%, c), SMI-312 area in square millimeter reflects the extent of total axons without the dilution effect of inflammation. SE standard error
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Fig6: Regression of SMI-31, MBP, SMI-312, DAPI counts, and DBSI-derived λǁ (a), λ⊥ (b), fiber fraction (c), and restricted fraction (d) suggested DBSI measurements were able to reflect specific pathologies in the optic nerves of EAE mice, respectively. The regression of DBSI-derived axon volume correlated with SMI-312 area (e, in mm2). In contrast to SMI-312 area estimated as ratio of positive area over the total nerve cross-sectional area (%, c), SMI-312 area in square millimeter reflects the extent of total axons without the dilution effect of inflammation. SE standard error

Mentions: Post-MRI immunohistochemistry staining of optic nerves (Fig. 5) was used to assess axon (SMI-312, SMI-31) and myelin (MBP) integrity, and extent of cellularity (DAPI). The EAE optic nerves showed significant axonal swelling (yellow arrows, Fig. 5a), inflammation, and axonal injury (red and white circles, Fig. 5b, c). Both eyes from each EAE mouse was selected for the regression analyses. The regression of SMI-31, MBP, and SMI-312 area fraction and DBSI λ∥, DBSI λ⊥, DBSI fiber fraction, and DBSI restricted fraction (Fig. 6a–d) supported that DBSI indexes were able to reflect the optic-nerve pathologies. Similarly, DBSI-derived axon volume was able to reflect SMI-312 area (Fig. 6e).Fig. 5


Diffusion MRI quantifies early axonal loss in the presence of nerve swelling
Regression of SMI-31, MBP, SMI-312, DAPI counts, and DBSI-derived λǁ (a), λ⊥ (b), fiber fraction (c), and restricted fraction (d) suggested DBSI measurements were able to reflect specific pathologies in the optic nerves of EAE mice, respectively. The regression of DBSI-derived axon volume correlated with SMI-312 area (e, in mm2). In contrast to SMI-312 area estimated as ratio of positive area over the total nerve cross-sectional area (%, c), SMI-312 area in square millimeter reflects the extent of total axons without the dilution effect of inflammation. SE standard error
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5384143&req=5

Fig6: Regression of SMI-31, MBP, SMI-312, DAPI counts, and DBSI-derived λǁ (a), λ⊥ (b), fiber fraction (c), and restricted fraction (d) suggested DBSI measurements were able to reflect specific pathologies in the optic nerves of EAE mice, respectively. The regression of DBSI-derived axon volume correlated with SMI-312 area (e, in mm2). In contrast to SMI-312 area estimated as ratio of positive area over the total nerve cross-sectional area (%, c), SMI-312 area in square millimeter reflects the extent of total axons without the dilution effect of inflammation. SE standard error
Mentions: Post-MRI immunohistochemistry staining of optic nerves (Fig. 5) was used to assess axon (SMI-312, SMI-31) and myelin (MBP) integrity, and extent of cellularity (DAPI). The EAE optic nerves showed significant axonal swelling (yellow arrows, Fig. 5a), inflammation, and axonal injury (red and white circles, Fig. 5b, c). Both eyes from each EAE mouse was selected for the regression analyses. The regression of SMI-31, MBP, and SMI-312 area fraction and DBSI λ∥, DBSI λ⊥, DBSI fiber fraction, and DBSI restricted fraction (Fig. 6a–d) supported that DBSI indexes were able to reflect the optic-nerve pathologies. Similarly, DBSI-derived axon volume was able to reflect SMI-312 area (Fig. 6e).Fig. 5

View Article: PubMed Central - PubMed

ABSTRACT

Background: Magnetic resonance imaging markers have been widely used to detect and quantify white matter pathologies in multiple sclerosis. We have recently developed a diffusion basis spectrum imaging (DBSI) to distinguish and quantify co-existing axonal injury, demyelination, and inflammation in multiple sclerosis patients and animal models. It could serve as a longitudinal marker for axonal loss, a primary cause of permanent neurological impairments and disease progression.

Methods: Eight 10-week-old female C57BL/6 mice underwent optic nerve DBSI, followed by a week-long recuperation prior to active immunization for experimental autoimmune encephalomyelitis (EAE). Visual acuity of all mice was assessed daily. Longitudinal DBSI was performed in mouse optic nerves at baseline (naïve, before immunization), before, during, and after the onset of optic neuritis. Tissues were perfusion fixed after final in vivo scans. The correlation between DBSI detected pathologies and corresponding immunohistochemistry markers was quantitatively assessed.

Results: In this cohort of EAE mice, monocular vision impairment occurred in all animals. In vivo DBSI detected, differentiated, and quantified optic nerve inflammation, demyelination, and axonal injury/loss, correlating nerve pathologies with visual acuity at different time points of acute optic neuritis. DBSI quantified, in the presence of optic nerve swelling, ~15% axonal loss at the onset of optic neuritis in EAE mice.

Conclusions: Our findings support the notion that axonal loss could occur early in EAE mice. DBSI detected pathologies in the posterior visual pathway unreachable by optical coherence tomography and without confounding inflammation induced optic nerve swelling. DBSI could thus decipher the interrelationship among various pathological components and the role each plays in disease progression. Quantification of the rate of axonal loss could potentially serve as the biomarker to predict treatment outcome and to determine when progressive disease starts.

No MeSH data available.


Related in: MedlinePlus