Factors Driving Atrophy

The factors that drive destructive brain pathology, manifest as atrophy, are largely undefined. It has been assumed

Study

Atrophy Measure

Subjects

Duration

Study Design

Atrophy Results

Rudick 1999 IFNß-1a

Ge 2000a GA Rovaris 2001b GA

Zivadinov 2001 IVMP Wolinsky 2000 Linomide Molyneux 2000 IFNß-1b

140 RR-MS

Whole brain volume 27 RR-MS 7-slice volume 227 RR-MS

Whole brain volume CSF volume 4-slice volume

Paolillo 1999 Campath 1H

Filippi 2000 Cladribine

4-slice volume

Whole brain volume

88 RR-MS

718 RRMS

SP-MS 95 SP-MS

29 SP-MS

159 SP PP

24 months

24 months 18 months

60 months <12 months 36 months

18 months

12 months

Double-blind, placebo-controlled

Double-blind, placebo-controlled 9m blind, placebo-controlled, + 9 m open label Single-blind controlled

Double-blind, placebo-

controlled Double-blind, placebo-controlled

Crossover

Double-blind, placebo-controlled

Treatment effect on atrophy in second year (P = 0.03) Treatment effect on atrophy No treatment effect on atrophy

Treatment effect on atrophy (P = 0.003) Study stopped because of toxicity No treatment effect on atrophy overall. In subgroup without gad lesions at baseline, there was significantly more atrophy in placebo (P = 0.003) No treatment effect on atrophy Atrophy strongly correlated to gad lesions pretreatment No treatment effect on atrophy

IFNß-1a, interferon ß-1a; BPF, brain parenchymal fraction; RR-MS, relapsing-remitting multiple sclerosis; SP-MS, secondary progressive multiple sclerosis.

Years from First Symptom of MS 15

Figure 3 Course of MS over 30 years. The diagram shows new MRI lesions (Gad+ lesions) occur frequently during the preclinical and early clinical phase of MS, declining in frequency as the disease progresses. T2 lesion burden gradually increases as a consequence of the occurrence of new lesions. Clinical symptoms consist primarily of relapses followed by remissions in the early disease phase, followed by gradually worsening disability in the later stages. The diagram shows the current view of MS pathogenesis: Inflammation dominates early in the disease, while neurodegeneration ensues and progressively dominates the pathogenesis during later stages. Neurodegeneration may become disconnected from the inflammatory process as the disease progresses. This could explain why anti-inflammatory therapy is more effective in RR-MS than SP-MS.

Figure 3 Course of MS over 30 years. The diagram shows new MRI lesions (Gad+ lesions) occur frequently during the preclinical and early clinical phase of MS, declining in frequency as the disease progresses. T2 lesion burden gradually increases as a consequence of the occurrence of new lesions. Clinical symptoms consist primarily of relapses followed by remissions in the early disease phase, followed by gradually worsening disability in the later stages. The diagram shows the current view of MS pathogenesis: Inflammation dominates early in the disease, while neurodegeneration ensues and progressively dominates the pathogenesis during later stages. Neurodegeneration may become disconnected from the inflammatory process as the disease progresses. This could explain why anti-inflammatory therapy is more effective in RR-MS than SP-MS.

that inflammation initiates the pathological process that plays out as tissue loss. This is a logical interpretation from studies documenting irreversible axonal injury localized to sites of inflammation in MS brain, even in young patients with very short disease durations. However, correlational studies have shown only weak correlations between MRI markers of inflammation (e.g., new T2 lesions or gadolinium-enhancing lesions) and brain atrophy. There are two interpretations of this: (1) our measures of brain inflammation are very insensitive; if we had more sensitive markers of brain inflammation, perhaps the correlation between MRI-defined inflammation and subsequent atrophy would be stronger; and (2) atrophy is driven to a limited degree by inflammation, but there are factors, currently not defined, that are not inflammation-dependent. It also remains possible that inflammation drives atrophy predominantly at the earlier stages of the disease. Clinical trial data are consistent with this possibility.

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