Behavioural NeurologyResolving the cognitive clinico-radiological paradox – Microstructural degeneration of fronto-striatal-thalamic loops in early active multiple sclerosis
Introduction
Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the human central nervous system involving both physical disability and cognitive impairment (CI). CI is one of the most disabling symptoms of the disease, with potentially debilitating effects on young patients' quality of life, employment status, instrumental activities of daily living, social and recreational activities, treatment adherence as well as physical disease progression (Benedict et al., 2017, Chiaravalloti and DeLuca, 2008, Hämäläinen and Rosti-Otajärvi, 2016, Pitteri et al., 2017, Rao et al., 1991, Sumowski et al., 2018). CI is a frequent symptom, affecting up to 70% of patients across early and late disease stages and involving all clinical phenotypes (Johnen et al., 2017, Potagas et al., 2008, Ruano et al., 2017). Convincing evidence further suggests that CI is already detectable in approximately one third of patients with early relapsing-remitting MS (RRMS) and clinically isolated syndrome (CIS) and its progression can be independent of the physical disease burden (Amato et al., 2010, Feuillet et al., 2007, Glanz et al., 2007, Johnen et al., 2018, Patti et al., 2009, Reuter et al., 2011, Uher et al., 2014). However, the overall degree and profile of CI in these early clinical stages are distinct from observations for late disease stages and for patients with progressive phenotypes of MS: Patients with early RRMS typically present with less overt CI, often confined to cognitive tasks that assess processing speed and speed-dependent executive functions, whereas e.g., verbal memory functions are relatively preserved (Bergendal et al., 2007, Eijlers et al., 2018, Johnen et al., 2017, Johnen et al., 2018, Schulz et al., 2006).
Numerous cross-sectional and longitudinal studies provide evidence for associations between structural magnetic resonance imaging (MRI) metrics and CI in patients with RRMS (Eijlers et al., 2018, Filippi et al., 2010; Rocca et al., 2015). More specifically, previous evidence suggests that both white-matter (WM) lesion count and anatomical location of these lesions contribute to the degree and quality of CI in MS (Amato et al., 2010, Patti et al., 2009, Summers et al., 2008). With the development of more advanced imaging techniques and the availability of automated MR-based segmentation techniques, global brain volume measures have been shown to add to the prediction and understanding of CI in patients with RRMS, stressing the neurodegenerative aspect of the disease (Eijlers et al., 2018, Filippi et al., 2010, Riccitelli et al., 2017; Rocca et al., 2015; Rocca et al., 2012). Likewise, regional atrophy of subcortical deep GM structures including the hippocampus, the thalamus and nuclei of the basal-ganglia has been identified as highly relevant for the degree of CI in RRMS and independently contributes to its prediction and understanding (Cruz-Gómez et al., 2018, Damjanovic et al., 2017, Debernard et al., 2015, Deppe et al., 2016, Lansley et al., 2013, Minagar et al., 2013, Rojas et al., 2018, Schoonheim et al., 2015).
In contrast, a number of cross-sectional and longitudinal studies have failed to find consistent associations between CI and MRI parameters for both lesion metrics and brain volume measures – particularly in samples including patients in early disease stages (Hynčicová et al., 2017, Mollison et al., 2017, Nourbakhsh et al., 2016, Uher et al., 2014, Uher et al., 2018). This dilemma has been coined “cognitive clinico-radiological paradox” (Altermatt et al., 2018, Mollison et al., 2017, Uher et al., 2018). A meta-analysis performed on those studies investigating the relationship between global brain volume and cognitive processing speed, the most frequently affected cognitive domain in early RRMS, has identified a substantial reporting bias towards positive results (Rao et al., 2014). Moreover, the authors pointed out several methodological issues in many existing studies, including heterogeneous samples with regard to disease burden and factors such as patients' age and disease duration that may have had mediating effects on the results. In line with these caveats, a large cross-sectional study involving >1000 patients with RRMS and CIS recently showed that the relationship between WM lesion (WML) burden, structural GM volumes and cognitive performance was highly dependent on factors like physical disease burden and patients' age (Uher et al., 2018). More specifically, for younger patients with shorter disease duration and lower physical disability the relationship between MRI metrics and cognitive performance was considerably weaker than for older patients with longer disease duration and advanced physical disability (Uher et al., 2018). Taken together, particularly for early disease stages, knowledge on the structural neural underpinnings of the characteristic and more subtle cognitive performance deficits of patients with RRMS remains fragmentary.
More recently, WM networks connecting cortical and subcortical GM structures crucially involved in cognitive functions have come into stronger scientific focus for this patient group (Deppe et al., 2016, Genova et al., 2013, Kern et al., 2015, Schoonheim et al., 2015, Welton et al., 2014). Microstructural alterations, and thus disruption of WM networks functionally relevant for specific cognitive (sub)-processes, may be more sensitive to the detection of the subtle and domain-specific cognitive changes seen in patients with early RRMS and CIS (Dineen et al., 2009, Welton et al., 2014). Summarizing previous studies that employed tract-based methodology on diffusion tensor imaging (DTI) data, a meta-analysis has revealed particularly strong associations between CI and reduced fractional anisotropy (FA) within thalamic and frontal (anterior callosal) WM tracts (Welton et al., 2014). Moreover, there is ample neuroanatomical evidence that specific parts of the thalamus, specific nuclei of the basal ganglia and specific areas in the prefrontal cortex are densely interconnected by segregated WM fiber tracts, forming so-called “fronto-striatal loops” crucial for a range of motor and cognitive processes (Alexander, DeLong, & Strick, 1986). The differential roles of these closed, parallel and segregated loops have been extensively characterized in numerous experimental paradigms in healthy subjects (Hanganu et al., 2015, Hanlon et al., 2013, Van Schouwenburg et al., 2014) and have also been tested and confirmed in neurological conditions including Parkinson's disease (Jahanshahi et al., 2002) temporal-lobe epilepsy (Riley, Moore, Cramer, & Lin, 2011) and frontotemporal dementia (Bertoux, O'Callaghan, Flanagan, Hodges, & Hornberger, 2015). In an influential and integrative neuropsychological model (Stuss, 2011), three of the five original fronto-striatal loops have been linked to specific cognitive processes, particularly relevant for higher executive functions and speed-related complex attention – which are the two domains most often reported to be impaired in early RRMS. Despite that, fronto-striatal loops have not been systematically investigated in RRMS with regard to CI to our knowledge.
Given the typically found profile of CI in speed-related tasks of attention and executive functions, we hypothesized that reduced FA in specific fronto-striatal-thalamic WM loops may serve as a better marker for these cognitive performance alterations in patients with early RRMS than measures of brain volume. To this end, we compared the relationship of both global and regional (deep GM) brain volumes as well as FA within anatomically predefined fronto-striatal-thalamic loops with the performance in neuropsychological tests within a clinically well-characterized sample of patients with early active RRMS.
Section snippets
Participants
We report how we determined our sample size, all data exclusions (if any), all inclusion/exclusion criteria, whether inclusion/exclusion criteria were established prior to data analysis, all manipulations, and all measures in the study. We recruited 27 consecutive patients with early active RRMS, diagnosed according to the revised McDonald criteria (Polman et al., 2011), from the Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Germany. The sample
Demographic data and clinical characteristics
Descriptive demographic and clinical data of the patients is given in Table 2. All patients [16 female, 11 male; mean age at NPA = 32.3 years (y), standard deviation (SD) = 9.7] were examined early in the course of the disease (mean disease duration 22.6 months, SD = 10.2). Patients were only mildly physically impaired (mean EDSS at NPA 1.6, SD = 1.1, range .0–3.5). Seven patients (26%) suffered one or two relapses in the year prior to NPA, the majority of the patients undergoing their current
Discussion
Despite the clinical relevance of CI, associations between conventional MRI metrics, representing the degree of brain pathology, and performance in standard cognitive tests can be weak in patients with early RRMS (Mollison et al., 2017, Uher et al., 2014, Uher et al., 2018).
In our study, we explored the correlations between cognitive performance and microstructural WM integrity within three parallel, partly segregated fronto-striatal-thalamic loops in a cohort of 27 adult patients with early
Conclusion
For patients diagnosed with early active RRMS we revealed an association between microstructural degeneration within a right-lateralized fronto-striatal WM network and poorer performance in neuropsychological tests for speed-dependent complex attention and executive functions. Our findings emphasize the importance of microstructural integrity within WM networks and establish them as relevant neural substrate for cognitive processes, whereas a disconnection of these WM tracts leads to early
Disclosures
This research was funded by SFB-TR 128, B05 to SGM and by Novartis, Germany. Novartis had no role in the development of the study design, the recruitment of participants, the data acquisition and analysis, the decision to publish, or the preparation of the manuscript. Moreover, this work was supported by the medical Faculty of the University of Münster (18-002 fellowship to JK). AJ received honoraria and reimbursement for travel expenses for acting as a speaker for Actelion Pharmaceuticals.
CRediT authorship contribution statement
Andreas Johnen: Conceptualization, Methodology, Validation, Investigation, Formal analysis, Project administration, Writing - original draft, Writing - review & editing. Patrick Schiffler: Software, Data curation, Formal analysis, Visualization, Writing - review & editing. Nils C. Landmeyer: Software, Formal analysis, Visualization, Data curation. Jan-Gerd Tenberge: Investigation, Data curation. Ester Riepl: Investigation, Data curation. Heinz Wiendl: Resources, Supervision. Julia Krämer:
Acknowledgments
We thank all patients for participating in this study. We thank Dr. Zoë Hunter for proofreading of the manuscript.
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2022, Multiple Sclerosis and Related DisordersCitation Excerpt :Magnetization Transfer Ratio (MTR) and Diffusion Tensor Imaging (DTI) are advanced MRI methods frequently applied to assess tissue microstructure and cell membrane integrity, which can be used as indirect methods to quantify myelin in research settings (Filippi et al., 2019; McKeithan et al., 2019). DTI and MTR metrics were previously associated with cognitive impairment in MS in periventricular regions, particularly white matter and normal-appearing white matter (Johnen et al., 2019; McKeithan et al., 2019). However, the specificity of these sequences as myelin markers is still a matter of debate, since the axonal density, inflammatory cells, and edema interfere with the myelin-specific signal detection (Tu et al., 2016).
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2021, Clinical Neurology and NeurosurgeryCitation Excerpt :Moreover, the hippocampus is the key region known for cognitive functional impairments and according to a study by Kohler et al., the left hippocampus volume is a strong predictor for verbal memory impairment in MS [66]. Microstructural degeneration of the fronto-striatal-thalamic loops as well as multiple WM tract abnormalities have been postulated to be the underlying cause for cognitive impairments in MS [67]. In our MS cohort, only 20 % of patients reported cognitive impairment.
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Contributed equally.