Hippocampal and Deep Gray Matter Nuclei Atrophy Is Relevant for Explaining Cognitive Impairment in MS: A Multicenter Study

Damjanovic, Dusan; Valsasina, Paola; Rocca, Maria A.; Stromillo, Maria Laura; Gallo, Antonio; Enzinger, Christian; Hulst, Hanneke E.; Rovira, Àlex; Muhlert, Nils; Stefano, Nicola De; Bisecco, Alvino; Fazekas, Franz; Arévalo, M. J.; Yousry, Tarek; Filippi, Massimo

doi:10.3174/ajnr.a4952

Cited by 86 publications

(86 citation statements)

References 37 publications

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“…Our results are in line with prior studies that assessed cognition in MS patients and observed stronger decline in males (Lin et al, 2016;Schoonheim et al, 2012), which moreover was related to EDSS scores (Savettieri et al, 2004). In our cohort, better performance in the TMT-B was further associated to higher deep gray matter volume in our regions of interest, again in accordance with previous research (Damjanovic et al, 2017;Modica et al, 2016;Schoonheim et al, 2012). The less complex TMT-A is potentially too insensitive to reflect initial variations in gray matter integrity or network configurations but might be more suitable to distinguish patients of different disease stages.…”

Section: Structural Integrity and Cognitive Performancesupporting

confidence: 93%

“…However, since males are less frequently, but more severely affected by the disease (Greer & McCombe, 2011), an adverse effect of gender on both physical disability and cognitive scores was not unexpected. In our cohort, better performance in the TMT-B was further associated to higher deep gray matter volume in our regions of interest, again in accordance with previous research (Damjanovic et al, 2017;Modica et al, 2016;Schoonheim et al, 2012). Our results are in line with prior studies that assessed cognition in MS patients and observed stronger decline in males (Lin et al, 2016;Schoonheim et al, 2012), which moreover was related to EDSS scores (Savettieri et al, 2004).…”

Section: Structural Integrity and Cognitive Performancesupporting

confidence: 92%

“…By means of magnetic resonance imaging (MRI), a decrease of cortical thickness has been observed in the posterior cortices, temporal lobe, and precentral gyrus with progressing MS (Eshaghi et al, 2018;Steenwijk et al, 2016). Subcortical volume mainly decreased in deep gray matter structures including thalamus, caudate, and brain stem, as well as cerebellar regions (Deppe et al, 2016;Eshaghi et al, 2018) in early stages of MS. Atrophy of deep gray matter nuclei is strongly related to cognitive impairment in MS (Damjanovic et al, 2017). In particular, thalamic atrophy is predictive of cognitive decline (Papathanasiou et al, 2015;Štecková et al, 2014) and correlates with physical disability (Deppe et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Gray matter integrity predicts white matter network reorganization in multiple sclerosis

Radetz

Koirala

Krämer

et al. 2019

Human Brain Mapping

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Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease leadingto gray matter atrophy and brain network reconfiguration as a response to increasing tissue damage. We evaluated whether white matter network reconfiguration appears subsequently to gray matter damage, or whether the gray matter degenerates following alterations in white matter networks. MRI data from 83 patients with clinically isolated syndrome and early relapsing-remitting MS were acquired at two time points with a follow-up after 1 year. White matter network integrity was assessed based on probabilistic tractography performed on diffusion-weighted data using graph theoretical analyses.We evaluated gray matter integrity by computing cortical thickness and deep gray matter volume in 94 regions at both time points. The thickness of middle temporal cortex and the volume of deep gray matter regions including thalamus, caudate, putamen, and brain stem showed significant atrophy between baseline and follow-up. White matter network dynamics, as defined by modularity and distance measure changes over time, were predicted by deep gray matter volume of the atrophying anatomical structures. Initial white matter network properties, on the other hand, did not predict atrophy. Furthermore, gray matter integrity at baseline significantly predicted physical disability at 1-year follow-up. In a sub-analysis, deep gray matter volume was significantly related to cognitive performance at baseline. Hence, we postulate that atrophy of deep gray matter structures drives the adaptation of white matter networks. Moreover, deep gray matter volumes are highly predictive for disability progression and cognitive performance.

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Section: Structural Integrity and Cognitive Performancesupporting

confidence: 93%

Section: Structural Integrity and Cognitive Performancesupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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Gray matter integrity predicts white matter network reorganization in multiple sclerosis

Radetz

Koirala

Krämer

et al. 2019

Human Brain Mapping

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“…MS-related cognitive impairment has been associated with both cortical (Benedict, 2002; Benedict et al, 2005; Morgen et al, 2006) and subcortical (Houtchens et al, 2007; Sicotte et al, 2008; Batista et al, 2012; Damjanovic et al, 2016; Preziosa et al, 2016; Rocca et al, 2016) gray matter atrophy and cortical lesions (Calabrese et al, 2009) explaining between 20 and 60% of the variance of a variety of cognitive tests assessing the most commonly affected cognitive domains using multilinear models.…”

Section: Neuro-anatomymentioning

confidence: 99%

Targeting Cognitive Impairment in Multiple Sclerosis—The Road toward an Imaging-based Biomarker

Schependom

Nagels

2017

Front. Neurosci.

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Multiple Sclerosis (MS) is a neuro-degenerative and -inflammatory disease leading to physical and cognitive impairment, pathological fatigue and depression, and affecting patients' quality of life and employment status. The combination of inflammation, demyelination, and neurodegeneration leads to the emergence of MS lesions, reduced white and gray matter brain volumes, a reduced conduction velocity and microstructural changes in the so-called Normal Appearing White Matter (NAWM). Currently, there are very limited options to treat cognitive impairment and its origin is only poorly understood. Therefore, several studies have attempted to relate clinical scores with features calculated either using T1- and/or FLAIR weighted MR images or using neurophysiology. The aim of those studies is not only to provide an improved understanding of the processes that underlie the different symptoms, but also to develop a biomarker—sensitive to therapy induced change—that could be used to speed up therapeutic developments (e.g., cognitive training/drug discovery/…). Here, we provide an overview of studies that have established relationships between either neuro-anatomical or neurophysiological measures and cognitive outcome scores. We discuss different avenues that may help to improve the prediction of cognitive impairment, and how well we can expect them to predict cognitive scores.

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“…Indeed, it is increasingly recognized that pathology in the gray matter including the cortex is central to the progression of MS (Calabrese et al, 2015;Mahad et al, 2015;Ontaneda et al, 2017). Gray matter pathology correlates with accruing disability, predicts conversion to progressive MS 10 and explains the increasing cognitive deficits that MS patients with advanced disease experience (Damjanovic et al, 2017;Eshaghi et al, 2018;Ontaneda et al, 2017;Scalfari et al, 2018). Despite this profound clinical importance, our understanding of the mechanisms underlying cortical pathology in progressive MS remains poor, in part because modelling gray matter inflammation has been difficult.…”

Section: Introductionmentioning

confidence: 99%

Localized calcium accumulations prime synapses for phagocyte removal in cortical neuroinflammation

Jafari

Schumacher

Snaidero

et al. 2019

Preprint

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Cortical pathology contributes to chronic cognitive impairment of patients suffering from the neuroinflammatory disease multiple sclerosis (MS). How such gray matter inflammation affects neuronal structure and function is not well understood. Here we use functional and structural in vivo imaging in a mouse model of cortical MS to demonstrate that bouts of cortical 5 inflammation disrupt cortical circuit activity coincident with a widespread but transient loss of dendritic spines. Spines destined for removal show a local calcium accumulation and are subsequently removed by invading macrophages and activated microglia. Targeting phagocyte activation with a new antagonist of the colony-stimulating factor 1 receptor prevents cortical synapse loss. Overall, our study identifies synapse loss as a key pathological feature of 10 inflammatory gray matter lesions that is amenable to immunomodulatory therapy. HIGHLIGHTS:• Widespread, but transient loss of synapses in inflammatory lesions and beyond • Reversible impairment of neuronal firing and circuit function in the inflamed cortex • Calcium dyshomeostasis of single spines precedes swift synapse loss 20• Phagocyte-mediated spine pruning as targetable mechanism of synapse loss Jafari, Schumacher, Snaidero et al.2

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Hippocampal and Deep Gray Matter Nuclei Atrophy Is Relevant for Explaining Cognitive Impairment in MS: A Multicenter Study

Cited by 86 publications

References 37 publications

Gray matter integrity predicts white matter network reorganization in multiple sclerosis

Gray matter integrity predicts white matter network reorganization in multiple sclerosis

Targeting Cognitive Impairment in Multiple Sclerosis—The Road toward an Imaging-based Biomarker

Localized calcium accumulations prime synapses for phagocyte removal in cortical neuroinflammation

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