The ageing central nervous system in multiple sclerosis: the imaging perspective

Abstract

The interaction between ageing and multiple sclerosis is complex and carries significant implications for patient care. Managing multiple sclerosis effectively requires an understanding of how ageing and multiple sclerosis impact brain structure and function. Ageing inherently induces brain changes, including reduced plasticity, diminished grey matter volume, and ischaemic lesion accumulation. When combined with multiple sclerosis pathology, these age-related alterations may worsen clinical disability. Ageing may also influence the response of multiple sclerosis patients to therapies and/or their side effects, highlighting the importance of adjusted treatment considerations. MRI is highly sensitive to age- and multiple sclerosis-related processes. Accordingly, MRI can provide insights into the relationship between ageing and multiple sclerosis, enabling a better understanding of their pathophysiological interplay and informing treatment selection. This review summarizes current knowledge on the immunopathological and MRI aspects of ageing in the CNS in the context of multiple sclerosis. Starting from immunosenescence, ageing-related pathological mechanisms and specific features like enlarged Virchow-Robin spaces, this review then explores clinical aspects, including late-onset multiple sclerosis, the influence of age on diagnostic criteria, and comorbidity effects on imaging features. The role of MRI in understanding neurodegeneration, iron dynamics and myelin changes influenced by ageing and how MRI can contribute to defining treatment effects in ageing multiple sclerosis patients, are also discussed.

Keywords: MRI; ageing; comorbidities; diagnosis; multiple sclerosis; progression.

Figure 1

The ageing perivascular compartment in multiple sclerosis. Perivascular spaces (PVS), which are implicated in brain waste removal, are involved in ageing and multiple sclerosis (MS) at different levels. CSF, produced in the choroid plexus, exchanges with brain interstitial fluid. In addition to the established CSF exit pathways along the spinal subarachnoid space, cranial nerves and arachnoid granulations, a portion of CSF flows into the brain parenchyma via the periarterial space. This flow is part of the glymphatic drainage pathway, illustrated along the arteries and through pial fenestrations. Concurrently, protein degradation products are conveyed within the muscularis of arteries, moving counter to the direction of blood flow, into the subarachnoid arteries. This process is part of the intramural peri-arterial drainage pathway, represented in blue along the artery (A). At the arterial and arteriolar level, cross-sectional views reveal that the perivascular space comprises the astrocytic end-feet processes (including their corresponding basement membrane), the pia mater (which becomes increasingly fenestrated closer to the capillary level), smooth muscle cells and the endothelium (each with their respective basement membranes). Within capillaries, the perivascular space is defined by the shared basement membranes of the astrocytic end-feet processes and the endothelium. The CSF-filled subarachnoid spaces are also evident along veins and venules, where the layers of smooth muscle cells are largely absent (B). Age-related factors, such as atherosclerosis/arteriolosclerosis, elastin dysfunction and periarterial collagen deposition, have been implicated in vascular stiffness, diminished debris transport capacity, and an increased barrier to oxygen delivery. In multiple sclerosis, perivascular changes include collagen deposition and perivenous inflammatory infiltrates that come into contact with CSF (C).

Figure 2

Summary of the typical lesional MRI findings in multiple sclerosis compared to ageing and cerebral small vessel disease. Typical multiple sclerosis (MS) lesions include (A) periventricular lesions, (B) juxtacortical and cortical lesions, (C) white matter (WM) lesions showing the central vein sign (CVS), (E) paramagnetic rim lesion (PRLs), (F) infratentorial lesions mainly located at the periphery, close to the CSF, and (G) spinal cord lesions. Typical lesions occurring with ageing and cerebral small vessel disease (cSVD) include (H) subcortical WM lesions, (I) deep WM lesions, (J) periventricular lesions and ‘capping’, (K) cortical microinfarcts, (L) central pontine lesions and (L) no spinal cord lesions. See text for further details.

Figure 3

Schematic representation of the interplay between the effects of multiple sclerosis-related neurodegeneration and ageing on brain atrophy. Both ageing and multiple sclerosis (MS) are associated with brain atrophy, with partially overlapping patterns (blue arrow). Rather than being simply additive, the effects of ageing and multiple sclerosis on brain atrophy are linked by a complex interaction (red arrow): the relationship between age and brain volume is influenced by multiple sclerosis and encodes disease-related information; ageing shapes multiple sclerosis-related brain atrophy by modifying the disease course and the response to treatment. Created with http://www.biorender.com/.