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. 2013 Aug 22;8(8):e72841.
doi: 10.1371/journal.pone.0072841. eCollection 2013.

Enlargement of Cerebral Ventricles as an Early Indicator of Encephalomyelitis

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Free PMC article

Enlargement of Cerebral Ventricles as an Early Indicator of Encephalomyelitis

Stefano Lepore et al. PLoS One. .
Free PMC article

Abstract

Inflammatory disorders of the central nervous system such as multiple sclerosis and acute disseminated encephalomyelitis involve an invasion of immune cells that ultimately leads to white matter demyelination, neurodegeneration and development of neurological symptoms. A clinical diagnosis is often made when neurodegenerative processes are already ongoing. In an attempt to seek early indicators of disease, we studied the temporal and spatial distribution of brain modifications in experimental autoimmune encephalomyelitis (EAE). In a thorough magnetic resonance imaging study performed with EAE mice, we observed significant enlargement of the ventricles prior to disease clinical manifestation and an increase in free water content within the cerebrospinal fluid as demonstrated by changes in T2 relaxation times. The increase in ventricle size was seen in the lateral, third and fourth ventricles. In some EAE mice the ventricle size started returning to normal values during disease remission. In parallel to this macroscopic phenomenon, we studied the temporal evolution of microscopic lesions commonly observed in the cerebellum also starting prior to disease onset. Our data suggest that changes in ventricle size during the early stages of brain inflammation could be an early indicator of the events preceding neurological disease and warrant further exploration in preclinical and clinical studies.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Pre-symptomatic changes in ventricle size in an EAE mouse model.
(A) T2-weighted horizontal views of the mouse brain show the evolution of changes in ventricle size of a representative mouse from baseline (pre EAE induction) 15 days prior (d-15) to disease manifestation up till 4 days after disease manifestation (d +4). (B) Shown are 20 mice (1–20) exhibiting increase in ventricle volume prior to or concurrent to disease onset. For each animal, gray bars represent the first occurrence of ventricle enlargement and ensuing time points following EAE induction and black vertical lines indicate the symptom onset post immunization. The animals were sorted according to the time difference between first changes in ventricle size (light gray bars) and onset of clinical symptoms post immunization (black vertical lines). Mouse 1 exhibited ventricle enlargement 5 days prior to clinical symptoms, Mouse 17 – Mouse 19 exhibited ventricle enlargement on the same day as clinical symptoms and Mouse 20 showed no ventricle enlargement.
Figure 2
Figure 2. Pre-symptomatic development of cerebellar lesion in an EAE mouse model.
(A) T2-weighted horizontal views of the mouse cerebellum, which show the temporal progression of lesions in the arbor vitae of the cerebellum of a representative mouse starting from pre EAE induction 15 days before clinical symptoms (baseline d-15) up till 2 days after disease manifestation (d +2); stars highlights hyperintense lesion appearance, arrowheads points to the hypointense lesions. (B) Graph showing the first day when cerebellar modifications were observed (gray bars) and the symptom onset (black vertical lines) for all animals in the study. The x-axis indicates the time points after EAE induction (0). The animals were sorted according to the time difference between first occurrence in cerebellar lesions and the onset of clinical symptoms post immunization. Mouse 1 exhibited cerebellar lesions 5 days prior to clinical symptoms, Mouse 19 and Mouse 20 showed no cerebellar lesions.
Figure 3
Figure 3. Time-line for weight, score and ventricle volume during EAE development.
All the animals were weighed and scored before EAE induction and daily starting from the day of immunization onwards. At baseline and then starting from day 5 after EAE induction micro MRI measurements were performed and the ventricle volumes measured. Graph shows the temporal changes in weight (A), score (B) and ventricle volume (C) for control mice (n=6) and EAE mice (n=20) synchronized to the first day of clinical symptoms. (D) Weight, (E) score and (F) ventricle volume changes of EAE animals that showed remission in ventricle enlargement (n=3) against control animals (n=6).
Figure 4
Figure 4. Changes in volume for the single ventricular compartments.
Shown is a graphical representation of the temporal changes in volume for both lateral (A), left lateral (B), right lateral (C), third (D) and fourth (E) ventricles for all EAE (n=20) and control (n=6) mice. All points represent a ratio of the daily ventricle volume to the ventricle volume prior to immunization (baseline d-15) and are synchronized to the day of clinical disease onset.
Figure 5
Figure 5. Pre- and post- symptomatic changes in ventricle size and cerebrospinal fluid T2 relaxation time.
(A) Maps depicting the absolute T2 relaxation time (ms) prior to and after disease manifestation. (B) Values for the ventricle volume were grouped into two groups for all EAE animals (3 days before and 3 days after first symptom) and compared with control animals. Shown are the differences in ventricle volume between the control (CTRL) and EAE groups prior to (Pre (3d), p = 0.0180) and after (Post (3d), p = 0.0003) disease onset. (C) Values for the CSF T2 relaxation time were also grouped as above and compared with control animals. Shown are the differences in T2 relaxation times between the control (CTRL) and EAE groups prior to (Pre (3d), p = 0.0386) and after (Post (3d), p = 0.0002) disease manifestation.

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Grant support

This work was supported by a university grant from the Experimental and Clinical Research Center (ECRC2010-2013), a research grant from Novartis and research grants from the German Research Foundation (DFG Exc 257 to FP, WA 2804/1-1 to SW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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