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Enlargement of cerebral ventricles as an early indicator of encephalomyelitis.

Lepore S, Waiczies H, Hentschel J, Ji Y, Skodowski J, Pohlmann A, Millward JM, Paul F, Wuerfel J, Niendorf T, Waiczies S - PLoS ONE (2013)

Bottom Line: The increase in ventricle size was seen in the lateral, third and fourth ventricles.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.

View Article: PubMed Central - PubMed

Affiliation: Berlin Ultrahigh Field Facility (B.U.F.F.), Max Delbrueck Center for Molecular Medicine, Berlin, Germany.

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.

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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.
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pone-0072841-g002: 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.

Mentions: Both hyperintense and hypointense lesions could be detected in multiple brain areas prior to disease manifestation in EAE, however, most commonly hyperintense lesions in the cerebellum [19]. We here investigated the temporal changes of these lesions by T2-weighted micro MRI, keeping our main focus on the cerebellum (Figure 2). Figure 2A shows a representative EAE mouse (mouse 7 in Figure 2B), in which lesions were identified in the white matter of the cerebellum as hyper-intense regions (Figure 2A, asterisks) on T2-weighted images; these lesions were detected already 3 days before clinical disease onset (d -3). The shape and spatial distribution of these lesions changed over time, also involving other areas of the arbor vitae (d -2 and d -1). Some lesions, especially those surrounding small vessels, turned hypo-intense (Figure 2A, white arrows) and appeared to partially resolve two days after the first neurological symptoms (d +2). Figure 2B recapitulates the temporal differences between the time of first appearance of cerebellar lesions and the time of first symptom manifestation in all EAE mice. Out of 20 animals that developed EAE, 18 showed pre-symptomatic cerebellar lesions on average 2.5 (±1.09 S.D.) days before the first manifestation of clinical signs. Lesion appearance could be observed up to 5 days before disease onset (mouse 1). With the exception of two animals, that did not develop micro MRI visible pathology within the cerebellum, EAE mice commonly manifested early lesions at least one day before appearance of clinical symptoms. Of note, the only mouse that developed clinical disease but no evident changes on MRI (mouse 20) was not only devoid of cerebellar lesions but also exhibited no ventricle enlargement.


Enlargement of cerebral ventricles as an early indicator of encephalomyelitis.

Lepore S, Waiczies H, Hentschel J, Ji Y, Skodowski J, Pohlmann A, Millward JM, Paul F, Wuerfel J, Niendorf T, Waiczies S - PLoS ONE (2013)

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.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3750011&req=5

pone-0072841-g002: 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.
Mentions: Both hyperintense and hypointense lesions could be detected in multiple brain areas prior to disease manifestation in EAE, however, most commonly hyperintense lesions in the cerebellum [19]. We here investigated the temporal changes of these lesions by T2-weighted micro MRI, keeping our main focus on the cerebellum (Figure 2). Figure 2A shows a representative EAE mouse (mouse 7 in Figure 2B), in which lesions were identified in the white matter of the cerebellum as hyper-intense regions (Figure 2A, asterisks) on T2-weighted images; these lesions were detected already 3 days before clinical disease onset (d -3). The shape and spatial distribution of these lesions changed over time, also involving other areas of the arbor vitae (d -2 and d -1). Some lesions, especially those surrounding small vessels, turned hypo-intense (Figure 2A, white arrows) and appeared to partially resolve two days after the first neurological symptoms (d +2). Figure 2B recapitulates the temporal differences between the time of first appearance of cerebellar lesions and the time of first symptom manifestation in all EAE mice. Out of 20 animals that developed EAE, 18 showed pre-symptomatic cerebellar lesions on average 2.5 (±1.09 S.D.) days before the first manifestation of clinical signs. Lesion appearance could be observed up to 5 days before disease onset (mouse 1). With the exception of two animals, that did not develop micro MRI visible pathology within the cerebellum, EAE mice commonly manifested early lesions at least one day before appearance of clinical symptoms. Of note, the only mouse that developed clinical disease but no evident changes on MRI (mouse 20) was not only devoid of cerebellar lesions but also exhibited no ventricle enlargement.

Bottom Line: The increase in ventricle size was seen in the lateral, third and fourth ventricles.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.

View Article: PubMed Central - PubMed

Affiliation: Berlin Ultrahigh Field Facility (B.U.F.F.), Max Delbrueck Center for Molecular Medicine, Berlin, Germany.

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.

Show MeSH
Related in: MedlinePlus