Cortical Lesions and Atrophy Associated With Cognitive Impairment in Relapsing-Remitting Multiple Sclerosis

Calabrese, Massimiliano; Agosta, Federica; Rinaldi, Francesca; Mattisi, Irene; Grossi, Paola; Favaretto, Alice; Atzori, Manfredo; Bernardi, Valentina; Barachino, Luigi; Rinaldi, Luciano; Perini, Paola; Gallo, Paolo; Filippi, Massimo

doi:10.1001/archneurol.2009.174

Cited by 490 publications

(379 citation statements)

References 44 publications

(74 reference statements)

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“…These results are consistent with recent MR imaging studies that detected cortical lesions from the earliest clinical stages of MS, even in patients with clinically isolated syn- drome. 13,14,[30][31][32] We found a trend toward higher number and volume of cortical lesions with disease duration and progression when comparing Early RR versus Late RR versus SP subgroups (Table). However, these differences did not reach statistical significance, possibly because of small sample sizes.…”

Section: Discussionmentioning

confidence: 83%

Identification and Clinical Impact of Multiple Sclerosis Cortical Lesions as Assessed by Routine 3T MR Imaging

Mike¹,

Glanz²,

Hildenbrand³

et al. 2011

AJNR Am J Neuroradiol

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Section: Discussionmentioning

confidence: 83%

Identification and Clinical Impact of Multiple Sclerosis Cortical Lesions as Assessed by Routine 3T MR Imaging

Mike¹,

Glanz²,

Hildenbrand³

et al. 2011

AJNR Am J Neuroradiol

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Section: Conclusion: Leukocortical (Type I) and Subpial (Iii-iv) Clsmentioning

confidence: 81%

“…5,6 These findings are not entirely unexpected because MS neuropathology has highlighted the cortex as a major location of demyelination. 7 Although 3T DIR is an innovative improvement over conventional imaging of cortical demyelination, ultra-high-field (7T) MRI using an optimized fast low-angle shot (FLASH)-T2* sequence detects more than 5 to 7 times the number of in vivo CLs differentiated by neuropathologic type-allowing identification of subpial lesions not easily detectable on DIR imaging, and which are thought to be associated with disease progression.…”

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confidence: 81%

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Contribution of cortical lesion subtypes at 7T MRI to physical and cognitive performance in MS

et al. 2013

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Objectives: Evaluate cross-sectionally the contribution of focal cortical lesion (CL) subtypes at ultra-high-field MRI and traditional MRI metrics of brain damage to neurologic disability and cognitive performance in a heterogeneous multiple sclerosis (MS) cohort.Methods: Thirty-four patients with early or established disease including clinically isolated syndrome, relapsing-remitting MS, and secondary progressive MS were scanned on a human 7-tesla (7T) (Siemens) scanner to acquire fast low-angle shot (FLASH) T2*-weighted images for characterization of white matter and deep gray matter lesion volume, and CL types. Patients also underwent anatomical 3T MRI for cortical thickness estimation, and neuropsychological testing within 1 week of the 7T scan. Twenty-seven patient scans were acceptable for further analysis. Neurologic disability was measured using the Expanded Disability Status Scale.Results: Type III-IV CLs had the strongest relationship to physical disability (r 5 0.670, p , 0.0001).White matter lesion volume and type I CLs are each significantly associated with 6 of 11 neuropsychological test variables. Type III-IV CLs significantly correlate with 4 of 11 neuropsychological test variables whereas type II CLs, deep gray matter lesion volume, and cortical thickness metrics are less frequently associated with cognitive performance. Cognitive dysfunction is a common but frequently overlooked clinical manifestation of multiple sclerosis (MS). 1 Frequently affected cognitive domains include executive function, processing speed, and memory. 2 Cognitive impairment in MS deleteriously affects social and vocational activities, may result in unemployment, and appears to lead to an increased vulnerability to psychiatric illness. 3 Despite the impact of cognitive dysfunction in MS, our understanding of its pathophysiology is limited. Conclusions: Leukocortical (type I) and subpial (III-IV) CLs identified on 7T FLASH-T2Conventional and quantitative MRI have identified potential biomarkers and better defined the pathophysiology of cognitive dysfunction in MS. 4 To date, global rather than regional metrics of cortical atrophy and cortical lesion (CL) volume using double inversion recovery (DIR) sequences at 3 tesla (3T) better account for the variance seen in cognitive performance in MS-supplanting conventional white matter (WM) MRI metrics. 5,6 These findings are not entirely unexpected because MS neuropathology has highlighted the cortex as a major location of demyelination. 7 Although 3T DIR is an innovative improvement over conventional imaging

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“…MS affects over 2 million individuals worldwide, and ∼40-65% of all MS patients experience cognitive impairment (4). The most commonly and severely affected facets of cognition in MS patients are anterograde episodic memory, working memory, and processing speed (5)(6)(7), and these impairments strongly contribute to the high frequency of unemployment in MS patient populations (8).…”

mentioning

confidence: 99%

Inhibition of Glutamate Carboxypeptidase II (GCPII) activity as a treatment for cognitive impairment in multiple sclerosis

Rahn

Watkins

Alt³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Half of all patients with multiple sclerosis (MS) experience cognitive impairment, for which there is no pharmacological treatment. Using magnetic resonance spectroscopy (MRS), we examined metabolic changes in the hippocampi of MS patients, compared the findings to performance on a neurocognitive test battery, and found that N-acetylaspartylglutamate (NAAG) concentration correlated with cognitive functioning. Specifically, MS patients with cognitive impairment had low hippocampal NAAG levels, whereas those with normal cognition demonstrated higher levels. We then evaluated glutamate carboxypeptidase II (GCPII) inhibitors, known to increase brain NAAG levels, on cognition in the experimental autoimmune encephalomyelitis (EAE) model of MS. Whereas GCPII inhibitor administration did not affect physical disabilities, it increased brain NAAG levels and dramatically improved learning and memory test performance compared with vehicle-treated EAE mice. These data suggest that NAAG is a unique biomarker for cognitive function in MS and that inhibition of GCPII might be a unique therapeutic strategy for recovery of cognitive function.G lutamate carboxypeptidase II (GCPII), previously called Nacetylated-α-linked acidic dipeptidase (NAALADase), is a membrane-bound enzyme expressed on the surface of astrocytes that catalyzes the cleavage of N-acetylaspartylglutamate (NAAG) into N-acetylaspartate (NAA) and glutamate ( Fig. 1) (1, 2). NAAG, the most abundant neuropeptide in the mammalian brain, is a selective agonist for metabotropic glutamate receptor 3 (mGluR3) (1, 2). mGluR3s are expressed on the surface of presynaptic neurons and astrocytes in the CNS. Activation of mGluR3s by NAAG reduces cAMP and cGMP levels, inhibits glutamate release, and stimulates a release of transforming growth factor beta (1, 2). A recent study reported impaired performance on spatial reference and working memory tasks in mGluR2/3 knockout mice (3), suggesting a role for group II mGluRs in cognitive function.Cognitive impairment is a frequent comorbidity of many neurological diseases, including multiple sclerosis (MS). MS affects over 2 million individuals worldwide, and ∼40-65% of all MS patients experience cognitive impairment (4). The most commonly and severely affected facets of cognition in MS patients are anterograde episodic memory, working memory, and processing speed (5-7), and these impairments strongly contribute to the high frequency of unemployment in MS patient populations (8). Global brain atrophy, candidate genetic risk factors, accelerated inflammatory processes (7), and dysregulated signaling pathways (9) have been implicated as contributing factors, but an incomplete understanding of the molecular mechanisms behind cognitive impairment in MS has prevented the development and Food and Drug Administration (FDA) approval of drug therapies.The most widely used animal model of MS, experimental autoimmune encephalomyelitis (EAE), is a valuable tool for developing treatments for MS. Three FDA-approved disease-modifying agents were deve...

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Cortical Lesions and Atrophy Associated With Cognitive Impairment in Relapsing-Remitting Multiple Sclerosis

Cited by 490 publications

References 44 publications

Identification and Clinical Impact of Multiple Sclerosis Cortical Lesions as Assessed by Routine 3T MR Imaging

Identification and Clinical Impact of Multiple Sclerosis Cortical Lesions as Assessed by Routine 3T MR Imaging

Contribution of cortical lesion subtypes at 7T MRI to physical and cognitive performance in MS

Inhibition of Glutamate Carboxypeptidase II (GCPII) activity as a treatment for cognitive impairment in multiple sclerosis

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