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. 2024 Mar;11(2):e200205.
doi: 10.1212/NXI.0000000000200205. Epub 2024 Feb 13.

Chronic Active Lesions and Larger Choroid Plexus Explain Cognition and Fatigue in Multiple Sclerosis

Paolo Preziosa  1 , Elisabetta Pagani  1 , Alessandro Meani  1 , Loredana Storelli  1 , Monica Margoni  1 , Yury Yudin  1 , Nicolò Tedone  1 , Diana Biondi  1 , Martina Rubin  1 , Maria A Rocca  1 , Massimo Filippi  1
Affiliations

Chronic Active Lesions and Larger Choroid Plexus Explain Cognition and Fatigue in Multiple Sclerosis

Paolo Preziosa et al. Neurol Neuroimmunol Neuroinflamm. 2024 Mar.

Abstract

Background and objectives: Chronic inflammation may contribute to cognitive dysfunction and fatigue in patients with multiple sclerosis (MS). Paramagnetic rim lesions (PRLs) and choroid plexus (CP) enlargement have been proposed as markers of chronic inflammation in MS being associated with a more severe disease course. However, their relation with cognitive impairment and fatigue has not been fully explored yet. Here, we investigated the contribution of PRL number and volume and CP enlargement to cognitive impairment and fatigue in patients with MS.

Methods: Brain 3T MRI, neurologic evaluation, and neuropsychological assessment, including the Brief Repeatable Battery of Neuropsychological Tests and Modified Fatigue Impact Scale, were obtained from 129 patients with MS and 73 age-matched and sex-matched healthy controls (HC). PRLs were identified on phase images of susceptibility-weighted imaging, whereas CP volume was quantified using a fully automatic method on brain three-dimensional T1-weighted and fluid-attenuated inversion recovery MRI sequences. Predictors of cognitive impairment and fatigue were identified using random forest.

Results: Thirty-six (27.9%) patients with MS were cognitively impaired, and 31/113 (27.4%) patients had fatigue. Fifty-nine (45.7%) patients with MS had ≥1 PRLs (median = 0, interquartile range = 0;2). Compared with HC, patients with MS showed significantly higher T2-hyperintense white matter lesion (WM) volume; lower normalized brain, thalamic, hippocampal, caudate, cortical, and WM volumes; and higher normalized CP volume (p from <0.001 to 0.040). The predictors of cognitive impairment (relative importance) (out-of-bag area under the curve [OOB-AUC] = 0.707) were normalized brain volume (100%), normalized caudate volume (89.1%), normalized CP volume (80.3%), normalized cortical volume (70.3%), number (67.3%) and volume (66.7%) of PRLs, and T2-hyperintense WM lesion volume (64.0%). Normalized CP volume was the only predictor of the presence of fatigue (OOB-AUC = 0.563).

Discussion: Chronic inflammation, with higher number and volume of PRLs and enlarged CP, may contribute to cognitive impairment in MS in addition to gray matter atrophy. The contribution of enlarged CP in explaining fatigue supports the relevance of immune-related processes in determining this manifestation independently of disease severity. PRLs and CP enlargement may contribute to the pathophysiology of cognitive impairment and fatigue in MS, and they may represent clinically relevant therapeutic targets to limit the impact of these clinical manifestations in MS.

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Conflict of interest statement

The authors declare that they have no competing interests in relation to this work. Potential conflicts of interest outside the submitted work are as follows: P. Preziosa received speaker honoraria from Roche, Biogen, Novartis, Merck Serono, Bristol-Myers Squibb, Genzyme, Horizon and Sanofi, he has received research support from Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla; E. Pagani has nothing to disclose; A. Meani has nothing to disclose; L. Storelli has nothing to disclose; M. Margoni reports grants and personal fees from Sanofi Genzyme, Merck Serono, Novartis and Almiral; Y. Yudin has nothing to disclose; N. Tedone has nothing to disclose; D. Biondi has nothing to disclose; M. Rubin has nothing to disclose; 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, the Italian Ministry of University and Research, 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, Neurological Sciences, and Radiology, 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, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla. Go to Neurology.org/NN for full disclosures.

Figures

Figure 1
Figure 1. Examples of Paramagnetic Rim Lesions Identification and Choroid Plexus Segmentation
(A) On 3D axial fluid-attenuated inversion recovery (FLAIR) sequence, multiple T2-hyperintense white matter lesions are visible in a in a 51-year-old man with relapsing-remitting MS (disease duration = 14 years, Expanded Disability Status Scale [EDSS] score = 4.0). (B) On unwrapped phase image, several paramagnetic rim lesions (light blue arrowheads, also magnified) were found. Example of automatic choroid plexus segmentation (red-coded) on (C) axial and (D) coronal planes of a 3D FLAIR sequence obtained from a 39-year-old woman, with relapsing-remitting MS (disease duration = 9 years, EDSS score = 2.0). See text for further details.
Figure 2
Figure 2. Number and Volume of PRLs and CP Volume in Patients With Multiple Sclerosis According to the Presence of Cognitive Impairment and Fatigue
Violin plots show PRL number (A) and volume (B) as well as normalized CP plexus volume distribution in patients with MS according to the presence of cognitive impairment (Co-P and Co-I) or fatigue (nF and F). In (C), normalized CP plexus volume distribution in patients with MS compared with HC is also shown. p values of between-group comparisons are also reported (significant comparisons are shown in bold). See text for further details. Co-I= cognitively impaired; Co-P = cognitively preserved; CP = choroid plexus; F = fatigued; mL = milliliter; nF = nonfatigued; pFDR = False Discovery Rate p value; PRLs value; PRLs = paramagnetic rim lesions.
Figure 3
Figure 3. Random Forest Informative Predictors of Cognitive Impairment and Fatigue in Patients With Multiple Sclerosis
Distribution of variable importance, achieved across iterations of Boruta algorithm, of demographic, clinical, and MRI features to explain (A) cognitive impairment and (B) fatigue. Boruta compares the importance of the original variables with the highest feature importance of the shadow features, obtained using feature-permuted copies. Poorly performing variables are progressively discarded. Selected features are shown in green, discarded features in red. Maximum, mean, and minimum importance achieved by shadows attributes are shown in blue. LV = lesion volume; NBV = normalized brain volume; OOB-AUC = out-of-bag area under the curve; PRL = paramagnetic rim lesion; WM = white matter.
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