Introduction
Multiple sclerosis (MS) is a chronic immune-mediated inflammatory disease of the central nervous system, characterized by the involvement of white matter (WM) and gray matter (GM) since the early stages [
1]. The hippocampus, a complex structure in the medial temporal lobe responsible for learning and episodic memory, has consistently shown abnormalities in MS [
2]. Memory impairment is common in MS and can be observed early and across disease phenotypes [
3,
4]. MS patients often experience difficulties in episodic memory, visual-spatial ability, and short-term working memory, while semantic memory, implicit memory, and linguistic ability are typically preserved [
5]. Memory impairment tends to be both more prevalent and more severe among patients with progressive forms of MS compared to those with relapsing–remitting MS (RRMS). This discrepancy persists even after a decade of the disease's progression [
4]. These deficits can be attributed, at least in part, to specific damage in the hippocampus, such as demyelinating lesions and/or diffuse atrophy [
6]. Furthermore, memory issues can be influenced by a range of broader psychosocial factors. These factors may include but are not limited to psychological stress, social support networks, lifestyle choices, and coping strategies adopted by individuals facing the challenges of MS. Thus, the impact of memory impairment in MS is multifaceted, encompassing not only the progression of the disease itself but also the complex interplay of psychosocial dynamics [
7].
Neuropathology has consistently revealed extensive demyelination, neuronal damage, and synaptic abnormalities in the hippocampus of patients with MS [
8]. Similarly, MRI studies have confirmed these abnormalities in-vivo. Hippocampal lesions are frequently seen in individuals with MS, and hippocampal atrophy is a consistent finding at all disease stages. Moreover, it has been found that hippocampal atrophy correlates with deficits in verbal and visuospatial memory performance, even in the early phases of MS [
6]. Assessing hippocampal atrophy through imaging is a promising approach to gain insights into the mechanisms and neuroanatomical basis of MS-related memory impairment, particularly when performed at the onset of the disease.
It is important to note here that the hippocampus is not a uniform brain structure and consists of various subfields with distinct structures and functions. Previous cross-sectional studies have suggested different patterns of hippocampal damage throughout the course of MS, initially affecting the cornu ammonis (CA) region [
9]. In a study with 23 RRMS patients, 11 SPMS patients, and 18 healthy controls, early CA1 hippocampal volume loss was seen in RRMS, worsening in SPMS, correlating with declining verbal learning, especially in word-list tasks. The subiculum, linked to CA1, also correlated with word-list learning [
9]. Another study of 53 pediatric MS patients showed more CA1 and subiculum atrophy, impacting cognition more than overall atrophy [
10]. Longitudinal studies in 56 clinically isolated syndrome (CIS) patients found hippocampal atrophy starting from the dentate gyrus and progressing to CA1, correlating with verbal memory deficits at one year. Despite a small sample, the dentate gyrus remained a significant predictor of CA1 and overall hippocampal volumes after one year [
11]. However, most of these studies were conducted at a single center and included a small number of patients, potentially limiting the generalizability of their findings.
Against this background, our work focused on a relatively large cohort of early RRMS patients with the overall aim to gain insights into the relationship between hippocampal atrophy and memory function by (i) assessing whether there is global and regional hippocampal atrophy observable at this early stage of the disease, and (ii) investigating the correlation between hippocampal atrophy and memory performance in patients with varying degrees of impairment.
Discussion
In this multicenter study, we found that hippocampal atrophy is a distinctive feature of the early stages of MS and might represent a reliable marker of memory dysfunction, particularly in patients with mild impairment. When we performed an analysis of hippocampal subfields to explore the different vulnerability of the hippocampal structures to MS-related pathogenic mechanisms, we found a relevant role of the CA adding to previous studies on the specific susceptibility of this region to damage and its subsequent impact on memory function.
We observed significant hippocampal atrophy in both the right and left hippocampi of MS patients when compared to HC, indicating widespread tissue damage in the hippocampus during the early stages of the disease. These findings align with recent MRI studies that have also reported a decrease in hippocampal volume not only at the initial demyelinating event but also over time, suggesting ongoing structural changes in the hippocampus throughout the course of the disease [
11,
27]. Importantly, our study extends previous research by demonstrating that, despite the presence of similar hippocampal atrophy in patients with MMI-MS and SMI-MS during the early stages of the disease, only the MMI-MS subgroup exhibited a correlation between hippocampal volumes and memory performance. This might be due to other mechanisms that contribute to memory impairment from the earliest stages of the disease, which cannot be solely explained by reduced hippocampal volume. In line with this hypothesis, a recent study has identified different cognitive phenotypes in MS and found a selective and clinically meaningful hippocampal atrophy in the mildly impaired group, while a widespread brain atrophy and high lesion load was detected in severely impaired patients [
17].
An additional interpretation of our findings may lie in the different expression of compensatory mechanisms between the two groups, potentially attributed to variations in brain plasticity and widespread neuronal activation. This differential expression of compensatory mechanisms may account for the favorable clinical outcome observed in patients with MMI-MS. This hypothesis is supported by previous studies that have demonstrated compensatory mechanisms, such as increased structural and functional connectivity, in cognitively preserved MS patients during the early stages of the disease, particularly in those with mild structural abnormalities [
27,
28]. These compensatory mechanisms appear to be most effective within the first two years of MS with an efficacy that diminishes as the disease progresses and finally reaches a plateau [
29]. Thus, it can be speculated that in patients with MMI-MS, even during these early stages, a compensatory functional reorganization of damaged hippocampal tissue may occur, mitigating the loss of hippocampal volume and temporarily preventing the onset of more severe memory impairment. Future studies assessing the relationship between structural and functional connectivity in MMI-MS and SMI-MS patients would further improve our understanding in this area and provide valuable insights into the compensatory processes occurring in the hippocampus. In addition, the reduced hippocampal volume loss in MMI-MS patients might also be associated with those with mild impairments effectively utilizing cognitive compensatory strategies, or potentially having received some form of intervention.
Consistent with previous studies examining pathology and imaging, our research revealed different vulnerabilities of hippocampal subfields during the earliest stages of MS, which may impact memory performance. While atrophic voxels were detected in all subfields, the CA region appeared to be the most severely affected, whereas the hippocampal tail showed a relatively preserved structure. The CA region is commonly identified as the most vulnerable area in various neurological disorders, and its heightened vulnerability to damage in MS is well-documented [
9,
11]. This susceptibility can be attributed to factors such as increased exposure to hypoxic damage and glutamate-mediated excitotoxicity [
30,
31]. Additionally, recent studies have demonstrated an increased permeability of the blood–brain barrier (BBB) during the normal aging process, with initial changes occurring in the hippocampus, particularly in the CA region [
30,
31]. This breakdown of the BBB has also been observed in patients with mild cognitive impairment but not in young and cognitively preserved MS patients, potentially due to limited sample sizes [
30]. On the other hand, the hippocampal tail is known for its robust connectivity and high neuronal plasticity, playing a crucial role in long-term potentiation. A recent study investigating hippocampal subfields reported larger volumes in the tail region in MS patients carrying the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism, which is associated with a protective effect in MS. This finding further emphasizes the potential for functional compensation within this specific subfield of the hippocampus [
32]. When examining the correlations between hippocampal volumes and memory performances, these correlations remained numerous and significant in the MMI-MS subgroup. In contrast, only weaker correlations were observed in the SMI-MS subgroup. This highlights the distinct vulnerability of hippocampal structures to MS-related pathogenic mechanisms at different stages of MS.
From a clinical perspective, understanding the varying vulnerability of different parts of the hippocampus in the early stages of MS could have practical implications for evaluating the effectiveness of treatment approaches, especially when certain psychotherapy methods are available to enhance cognition [
33]. Apart from being prone to damage, the hippocampus also shows heightened synaptic plasticity and potential for neurogenesis [
34], which are thought to respond to exercise training effects [
35]. Recent research suggests using changes in hippocampal volume as an outcome measure in clinical trials. For example, in a recent trial involving MS patients with learning and memory issues, treadmill walking exercise was linked to preserved hippocampal volume, whereas the control group exhibited atrophy [
36]. Identifying a specific hippocampal subfield that is vulnerable to damage early on could aid in both selecting patients for early intervention and assessing the early effects of treatment. Therefore, the involvement of the CA region in early MS patients implies that targeting this specific area could be promising for cognitive rehabilitation interventions aimed at enhancing memory.
From a technical standpoint, the MRI analysis procedure used here has shown to be feasible and the reported results indicate that hippocampal volume can serve as a reliable imaging biomarker for assessing memory impairment, even in a multicenter setting such as a clinical trial. One of the challenges encountered when evaluating hippocampal atrophy in MS is the lack of standardized methods and tools for analysis. To address this issue, we utilized a semiautomated method following the protocol recommended by EACD-ADNI [
23], which strikes a balance between accuracy and reliability/reproducibility. Additionally, we incorporated a lesion-filling procedure to address potential biases and challenges associated with hippocampal assessment in the MS group. This approach allowed us to mitigate subtle changes at the hippocampus interface with other structures, which could have introduced bias during the manual refinement process. By implementing these methods, we were able to enhance the accuracy and robustness of our analysis [
37,
38].
This study is not without limitations. First, the cross-sectional design of the study did not allow for an investigation of volume changes over time (i.e., from the disease onset to the evaluation). Conducting further longitudinal analyses would be valuable in identifying patterns of atrophy at different stages of the disease. Additionally, it is important to recognize that the impact of other MS symptoms, such as depression, as well as other measures of neuroinflammation, which have been demonstrated to potentially influence hippocampal damage in MS, were not specifically examined in this study [
39,
40]. Another limitation of this study is the lack of available information regarding whether any of the recruited MS patients received cognitive rehabilitation or psychotherapy before the study, which could potentially influence the interpretation of results due to the neuroplastic changes induced by such interventions. Lastly, the analysis conducted on hippocampal subfields might be subject to a reduction in statistical power. Consequently, any interpretations or speculations derived from these subgroup analyses should be approached with caution.
In conclusion, our study provides valuable insights into the involvement of the hippocampus in patients with early RRMS. The relationship between atrophy in specific hippocampal regions, particularly the CA, and impairment of verbal and spatial processing performance points out the relevance of memory-related processes from the early phases of the disease. Moreover, the association between hippocampal atrophy and memory deterioration in the MMI-MS group only, argues for the presence of efficient but saturable compensatory mechanisms even during the early stages of disease. Future studies are needed to elucidate the pathogenetic mechanisms underlying early hippocampal atrophy in RRMS, enhance our understanding of neuronal loss in this brain region, explore its association with inflammation, and evaluate the potential impact of current treatments on this process.
Declarations
Competing interests
R. Cortese was awarded a MAGNIMS-ECTRIMS fellowship in 2019; she received speaker honoraria from Roche, Merck Serono and Sanofi and travel support for conferences by Novartis. A. Gallo received speaker and consulting fees from Biogen, Genzyme, Merck Serono, Mylan, Novartis, Roche, and Teva, and receives research sup- port from Fondazione Italiana Sclerosi Multipla. E. Pagani received honorarium from Biogen. P. Valsasina received honorarium from Biogen. P. Preziosa received research support from Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla; honoraria from Roche, Biogen, Novartis, Merck Serono, Bristol Myers Squibb, and Genzyme. M.A. Rocca received consulting fees from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen, Roche; and speaker honoraria from AstraZaneca, Biogen, Bristol Myers Squibb, Bromatech, Celgene, Genzyme, Horizon Therapeutics Italy, Merck Serono SpA, Novartis, Roche, Sanofi and Teva. She receives research support from the MS Society of Canada, the Italian Ministry of Health, and Fondazione Italiana Sclerosi Multipla. She is Associate Editor for Multiple Sclerosis and Related Disorders. M. Filippi is Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Associate Editor of Radiology, and Associate Editor of Neurological Sciences; received compensation for consulting services from Alexion, Almirall, Biogen, Merck, Novartis, Roche, Sanofi; speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA; participation in Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, Takeda; scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol-Myers Squibb, Lilly, Novartis, Sanofi-Genzyme; he receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). N. De Stefano has received honoraria from Biogen-Idec, Bristol Myers Squibb, Celgene, Genzyme, Immunic, Merck Serono, Novartis, Roche and Teva for consulting services, speaking, and travel support. He serves on advisory boards for Merck, Novartis, Biogen-Idec, Roche, and Genzyme, Immunic and he has received research grant support from the Italian MS Society. M. Battaglini, M.L. Stromillo, L. Luchetti, M. Leoncini, G. Gentile, D. Gasparini, D. Plantone, M. Altieri, A. d’Ambrosio, C. Gianni’, C. Piervincenzi, N. Tedone have nothing to disclose.