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Beyond axonal transection: Hippocampal damage in multiple sclerosis

The classic perception of multiple sclerosis (MS) as a purely demyelinating disease of the central nervous system (CNS) has recently faced several challenges. Starting with the thrilling rediscovery of axons as immediate victims of inflammatory CNS infiltration, the timing and the precise molecular mechanisms responsible for such irreversible neuronal alterations have been intensively investigated. Succeeding studies demonstrated neuronal cell death and synaptic damage in the neocortex and linked these changes to cortical demyelination, which had previously been neglected when applying standard histochemistry methods. In parallel, extended neuropsychological examinations have indicated that subtle signs of cognitive impairment, such as impaired attention, information processing speed, and decreased working memory, may occur even at early stages of disease and independently of motor deficits. These neuropsychological deficits, which have an obvious impact on the everyday activities of MS patients and hence their quality of life, shifted attention to the possible involvement of the hippocampus as one of the central checkpoints for information handling within the CNS. Following this line of inquiry, Dutta and colleagues present in this issue a comprehensive investigation of neurobiological alterations in the hippocampus of MS patients and provide a structural basis for such cognitive sequelae. Starting with myelin loss as the classic histopathological hallmark of MS, which is known to occur in the hippocampus, Dutta et al performed a side-by-side comparison of demyelinated and myelinated MS hippocampi. Interestingly, demyelinated hippocampi featured pronounced astrocytosis and modest microglia activation; there was a relative preservation of neurons and axons. However, analysis of neuronal gene expression profiles using array technologies revealed profound differences with respect to neuronal homeostasis, indicating that genes related to transport processes, synaptic transmission, and learning and memory were affected. Combining thorough molecular biology (microarray technology with confirmation by polymerase chain reaction and Western blot) and immunohistochemistry colocalization studies, Dutta and colleagues were able to confirm and extend these observations. In the hippocampus, demyelinated axons that appeared otherwise unaffected at first glance displayed profound disturbances in the molecular structures relevant for synapse function and glutamatergic transmission. Of note, few of the neuronal genes altered in demyelinated hippocampus were changed in demyelinated motor cortex and vice versa. This suggests distinct responses of individual neurons in different tracts and areas of the CNS to the demyelinating process in MS. Confocal laser scanning microscopy for multicolor antigen detection indicated synaptic pruning associated with demyelination, as suggested by a reduced density of synaptophysin-positive presynaptic terminals in the CA1 and dentate gyrus region. These findings also suggest compromised long-term potentiation relevant for cognitionrelated processes of the hippocampus. The obvious limitations of the current descriptive study should be considered, such as the heterogeneity of the patient population with respect to disease course, duration of MS, and previous treatment. However, there is growing evidence in the recent literature to support the findings of Dutta et al. With the use of specialized magnetic resonance imaging (MRI) techniques for enhanced gray matter imaging, such as double-inversion recovery, hippocampal lesions can be detected in the majority of patients, including those with a relapsing–remitting course. Hippocampal atrophy was reported in independent series of MS patients with relapsing–remitting and primary–progressive courses and was linked to altered resting-state connectivity, depression, and decreased memory function. Regarding the temporal association between structural changes and the resulting clinical phenotype, clinical presentations beyond chronic cognitive impairment should be considered as well. In a recent case report, an MS patient otherwise unaffected by typical neurological deficits such as sensory or motor symptoms showed acute disease onset with selective memory impairment due to hippocampal and cortical lesions. Indeed, cognitive dysfunction in MS may also fluctuate and be linked to the presence of gadolinium (Gd)-enhancing lesions as transient signs of blood–brain barrier (BBB) leakage. Conversely, relapse therapy with high doses of corticosteroids, known to stabilize the BBB and to reduce the presence of Gdþ lesions, may in fact induce reversible memory function as well. Moreover, chronic memory impairment can also arise from