Correlations between hippocampal functional connectivity,structural changes,and clinical data in patients with relapsing-remitting multiple sclerosis: a case-control study using multimodal magnetic resonance imaging

Multiple sclerosis is associated with structural and functional brain alterations leading to cognitive impairments across multiple domains including attention,memory,and the speed of information processing.The hippocampus,which is a brain important structure involved in memory,undergoes microstructural changes in the early stage of multiple sclerosis.In this study,we analyzed hippocampal function and structure in patients with relapsing-remitting multiple sclerosis and explored correlations between the functional connectivity of the hippocampus to the whole brain,changes in local brain function and microstructure,and cognitive function at rest.We retrospectively analyzed data from 20 relapsing-remitting multiple sclerosis patients admitted to the Department of Neurology at the China-Japan Union Hospital of Jilin University,China,from April 2015 to November 2019.Sixteen healthy volunteers were recruited as the healthy control group.All participants were evaluated using a scale of extended disability status and the Montreal cognitive assessment within 1 week before and after head diffusion tensor imaging and functional magnetic resonance imaging.Compared with the healthy control group,the patients with relapsing-remitting multiple sclerosis had lower Montreal cognitive assessment scores and regions of simultaneously enhanced and attenuated whole-brain functional connectivity and local functional connectivity in the bilateral hippocampus.Hippocampal diffusion tensor imaging data showed that,compared with the healthy control group,patients with relapsing-remitting multiple sclerosis had lower hippocampal fractional anisotropy values and higher mean diffusivity values,suggesting abnormal hippocampal structure.The left hippocampus whole-brain functional connectivity was negatively correlated with the Montreal cognitive assessment score(r=-0.698,P=0.025),and whole-brain functional connectivity of the right hippocampus was negatively correlated with extended disability status scale score(r=-0.649,P=0.042).The mean diffusivity value of the left hippocampus was negatively correlated with the Montreal cognitive assessment score(r=-0.729,P=0.017)and positively correlated with the extended disability status scale score(r=0.653,P=0.041).The right hippocampal mean diffusivity value was positively correlated with the extended disability status scale score(r=0.684,P=0.029).These data suggest that the functional connectivity and presence of structural abnormalities in the hippocampus in patients with relapse-remission multiple sclerosis are correlated with the degree of cognitive function and extent of disability.This study was approved by the Ethics Committee of China-Japan Union Hospital of Jilin University,China(approval No.201702202)on February 22,2017.     

Screening for cognitive toxicity of anticholinergic drugs

Impairment of memory by muscarinic anticholinergic drugs has been demonstrated with a variety of agents using both acute administration in normal volunteers and chronic treatment in patients. Cognitive toxicity must be considered in the evaluation of the risks versus the benefits of psychopharmacologic treatment. The relationship between serum levels of anticholinergic drugs measured by radioreceptor assay and performance on the Buschke Selective Reminding Test were investigated to develop strategies for identifying patients with drug-related cognitive impairment. The radioreceptor assay may be of value in screening for patients at high risk for cognitive toxicity. However, there appears to be no alternative to careful longitudinal evaluation of learning and memory in patients after appropriate trial modifications of their medication regimens to identify patients with drug-related impairment.     

A short version of Rao's Brief Repeatable Battery as a screening tool for cognitive impairment in multiple sclerosis

Rao's Brief Repeatable Battery (BRB) is the most widely used instrument for cognitive evaluation in multiple sclerosis (MS). We assessed a short version of the BRB in 116 relapsing-remitting participants. We found that the administration of three tests, the Selective Reminding Test, the Paced Auditory Serial Addition Test-3 seconds and the Symbol Digit Modalities Test, was able to detect cognitive impairment with a sensitivity of 94%, a specificity of 84%, and an accuracy of 89%. On the basis of these results we developed a screening algorithm requiring 5 to 15 minutes, which may represent a highly sensitive and rapid tool to detect MS-associated cognitive impairment.     

The effects of 7-week cognitive training in patients with vascular cognitive impairment,no dementia (the Cog-VACCINE study): A randomized controlled trial

IntroductionEvidence for the efficacy of cognitive training in patients with subcortical vascular cognitive impairment no dementia is still lacking.MethodsA randomized, active controlled design using multidomain, adaptive, computerized cognitive training for 30 minutes, 5 days/week for 7 weeks. Assessments included global cognitive function and executive function (primary outcomes) and brain functional connectivity and structural changes (secondary outcomes).ResultsSixty patients were randomized across three medical centers in Beijing. At the end of the intervention, the cognitive training group showed significant improvement in Montreal Cognitive Assessment relative to the active control group (P = .013) and significantly increased functional connectivity between the left dorsolateral prefrontal cortex and medial prefrontal cortex, which was significantly correlated with Montreal Cognitive Assessment change (P = .017).DiscussionComputerized cognitive training significantly improved global cognitive function, which was supported by the improved brain plasticity. Incorporation of biomarkers should be implemented in cognitive training trials.     

Benefits from an autobiographical memory facilitation programme in relapsing-remitting multiple sclerosis patients: a clinical and neuroimaging study

While the efficacy of mental visual imagery (MVI) to alleviate autobiographical memory (AM) impairment in multiple sclerosis (MS) patients has been documented, nothing is known about the brain changes sustaining that improvement. To explore this issue, 20 relapsing-remitting MS patients showing AM impairment were randomly assigned to two groups, experimental (n?=?10), who underwent the MVI programme, and control (n?=?10), who followed a sham verbal programme. Besides the stringent AM assessment, the patients underwent structural and functional MRI sessions, consisting in retrieving personal memories, within a pre-/post-facilitation study design. Only the experimental group showed a significant AM improvement in post-facilitation, accompanied by changes in brain activation (medial and lateral frontal regions), functional connectivity (posterior brain regions), and grey matter volume (parahippocampal gyrus). Minor activations and functional connectivity changes were observed in the control group. The MVI programme improved AM in MS patients leading to functional and structural changes reflecting (1) an increase reliance on brain regions sustaining a self-referential process; (2) a decrease of those reflecting an effortful research process; and (3) better use of neural resources in brain regions sustaining MVI. Functional changes reported in the control group likely reflected ineffective attempts to use the sham strategy in AM.     

A divergent breakdown of neurocognitive networks in Parkinson's Disease mild cognitive impairment

Cognitive decline is a major disabling feature in Parkinson's disease (PD). Multimodal imaging studies have shown functional disruption in neurocognitive networks related to cognitive impairment. However, it remains unknown whether these changes are related to gray matter loss, or whether they outline network vulnerability in the early stages of cognitive impairment. In this work, we intended to assess functional connectivity and graph theoretical measures and their relation to gray matter loss in Parkinson's disease with mild cognitive impairment (PD‐MCI). We recruited 53 Parkinson's disease patients and classified them for cognitive impairment using Level‐1 Movement Disorders Society‐Task Force Criteria. Voxel‐based morphometry, functional connectivity and graph theoretical measures were obtained on a 3‐Tesla MRI scanner. Loss of gray matter was observed in the default mode network (bilateral precuneus), without a corresponding disruption of functional or graph theoretical properties. However, functional and graph theoretical changes appeared in salience network nodes, without evidence of gray matter loss. Global cognition and executive scores showed a correlation with node degree in the right anterior insula. We also found a correlation between visuospatial scores and right supramarginal gyrus node degree. Our findings highlight the loss of functional connectivity and topological features without structural damage in salience network regions in PD‐MCI. They also underline the importance of multimodal hubs in the transition to mild cognitive impairment. This functional disruption in the absence of gray matter atrophy suggests that the salience network is a key vulnerable system at the onset of mild cognitive impairment in PD.     

Comparison of two brief neuropsychological batteries in people with multiple sclerosis

BACKGROUND: We compared two brief neuropsychological batteries devised to assess people with multiple sclerosis (MS) and used them to assess the relationship between cognitive impairment and dinical characteristics. METHODS: We administered either the Brief Repeatable Battery of Neuropsychological Tests (BRBNT) or the Screening Examination for Cognitive Impairment (SEFCI) to 213 consecutive MS outpatients and 213 individually matched controls. RESULTS: Administration times were longer for BRBNT than SEFCI, for MS and controls (p=0.001). People with MS had lower scores in all individual tests than controls (p<0.001, BRBNT and SEFCI). By the criterion of poor performance on one or more tests, the sensitivity of BRBNT was 41.9% and that of SEFCI 31.5%. The corresponding figures by poor performance on two or more tests were 16.2% for BRBNT and 18.5% for SEFCI. The Buschke Selective Reminding and Paced Auditory Serial Addition were the tests best discriminating between people with MS and controls for BRBNT, and the Symbol Digit Modalities test for SEFCI. The only clinical variable independently associated with impaired performance on these batteries was EDSS. CONCLUSIONS: Both cognitive batteries were well accepted and easy to administer. Administration time for SEFCI was significantly shorter than for BRBNT; however, alternative forms for serial evaluation are available only for BRBNT. The BRBNT was slightly more sensitive in detecting impairment by the criterion of poor perfomance on one or more tests. EDSS score was the only clinical variable independently associated with cognitive impairment     

Preserved network functional connectivity underlies cognitive reserve in multiple sclerosis

Cognitive reserve is one's mental resilience or resistance to the effects of structural brain damage. Reserve effects are well established in people with multiple sclerosis (PwMS) and Alzheimer's disease, but the neural basis of this phenomenon is unclear. We aimed to investigate whether preservation of functional connectivity explains cognitive reserve. Seventy‐four PwMS and 29 HCs underwent neuropsychological assessment and 3 T MRI. Structural damage measures included gray matter (GM) atrophy and network white matter (WM) tract disruption between pairs of GM regions. Resting‐state functional connectivity was also assessed. PwMS exhibited significantly impaired cognitive processing speed (t = 2.14, p = .037) and visual/spatial memory (t = 2.72, p = .008), and had significantly greater variance in functional connectivity relative to HCs within relevant networks (p < .001, p < .001, p = .016). Higher premorbid verbal intelligence, a proxy for cognitive reserve, predicted relative preservation of functional connectivity despite accumulation of GM atrophy (standardized‐β = .301, p = .021). Furthermore, preservation of functional connectivity attenuated the impact of structural network WM tract disruption on cognition (β = ?.513, p = .001, for cognitive processing speed; β = ?.209, p = .066, for visual/spatial memory). The data suggests that preserved functional connectivity explains cognitive reserve in PwMS, helping to maintain cognitive capacity despite structural damage.     

A short version of Rao's Brief Repeatable Battery as a screening tool for cognitive impairment in multiple sclerosis

Rao's Brief Repeatable Battery (BRB) is the most widely used instrument for cognitive evaluation in multiple sclerosis (MS). We assessed a short version of the BRB in 116 relapsing–remitting participants. We found that the administration of three tests, the Selective Reminding Test, the Paced Auditory Serial Addition Test–3 seconds and the Symbol Digit Modalities Test, was able to detect cognitive impairment with a sensitivity of 94%, a specificity of 84%, and an accuracy of 89%. On the basis of these results we developed a screening algorithm requiring 5 to 15 minutes, which may represent a highly sensitive and rapid tool to detect MS-associated cognitive impairment.     

Altered cerebellar functional connectivity mediates potential adaptive plasticity in patients with multiple sclerosis

BACKGROUND: The cerebellum is of potential interest for understanding adaptive responses in motor control in patients with multiple sclerosis because of the high intrinsic synaptic plasticity of this brain region. OBJECTIVE: To assess the relative roles of interactions between the neocortex and the cerebellum using measures of functional connectivity. METHODS: A role for altered neocortical-cerebellar functional connectivity in adaptive responses to injury from multiple sclerosis was tested using 1.5 T functional magnetic resonance imaging (fMRI) during figure writing with the dominant right hand in patients with predominantly early relapsing-remitting multiple sclerosis. RESULTS: Patients (n = 14) showed a more bihemispheric pattern of activation in motor cortex than healthy controls (n = 11). Correlations between task related signal changes in neocortical and cerebellar regions of interest were used as a measure of functional connectivity. Healthy controls showed strong functional connectivity between the left motor cortex and the right cerebellar dentate nucleus. Significant connectivity between the left primary motor cortex and the right dentate was not found in patients. However, patients had significant connectivity between the left premotor neocortex and the ipsilateral (left) cerebellar cortex (crus I), which was not found in healthy controls. CONCLUSIONS: Changes in apparent cerebellar-neocortical functional connectivity may mediate potentially adaptive changes in brain motor control in patients with multiple sclerosis. Similar changes in the cerebellum and premotor cortex have been reported in the healthy brain during motor learning, suggesting that common mechanisms may contribute to normal motor learning and motor recovery after injury from multiple sclerosis.     

Correlation of global N-acetyl aspartate with cognitive impairment in multiple sclerosis

BACKGROUND: Whole-brain N-acetyl aspartate (NAA), a measure of neuronal function, can be assessed by multislice echo-planar spectroscopic imaging. OBJECTIVE: To test the hypothesis that the global brain NAA/creatine (Cr) ratio is a better predictor of cognitive dysfunction in multiple sclerosis than conventional magnetic resonance imaging measures. DESIGN: Survey. SETTING: Research-oriented hospitals. PATIENTS: Twenty patients, 16 women and 4 men (mean age, 36 years), with early relapsing-remitting multiple sclerosis (mean Expanded Disability Status Scale score, 2.5). MAIN OUTCOME MEASURES: Correlation between the global NAA/Cr ratio and a cognitive dysfunction factor comprising 16 measures from an extensive neuropsychological test battery that best distinguished patients with multiple sclerosis from healthy control subjects. RESULTS: A significant partial correlation between the global NAA/Cr ratio and the cognitive dysfunction factor was found (partial r = 0.62, P = .01), and 9 cognitively impaired patients had significantly lower global NAA/Cr ratios than 11 unimpaired patients (P = .04). No significant correlations were found between the cognitive dysfunction factor and conventional magnetic resonance imaging measures (ie, brain parenchymal fraction and lesion volume). CONCLUSIONS: Multislice echo-planar spectroscopic imaging provides global metabolic measures that distinguish between cognitively impaired and unimpaired patients with multiple sclerosis and correlate with a global cognitive measure. Standardization of the technique is needed, and larger-scale studies that include healthy controls are suggested.     

Paroxetine and fluoxetine effects on mood and cognitive functions in depressed nondemented elderly patients

BACKGROUND: A large proportion of the elderly population complains of depressive symptoms. The ideal antidepressant for these patients, who often suffer from numerous concomitant diseases, should not worsen their cognitive functions and should be free of contraindications. METHOD: To assess the effects of 2 selective serotonin reuptake inhibitors on cognitive functions in elderly depressed patients (ICD-10 criteria), we conducted a double-blind, randomized, parallel-group, multicenter study comparing paroxetine (20-40 mg daily) and fluoxetine (20-60 mg daily) treatment for 1 year. Cognitive performance was evaluated by means of the Buschke Selective Reminding Test, the Blessed Information and Memory Test, the Clifton Assessment Schedule, the Cancellation Task Test, and the Wechsler Paired Word Test; the Hamilton Rating Scale for Depression (HAM-D) and the Clinical Anxiety Scale were administered to assess the course of depressive and anxiety symptoms, respectively. RESULTS: 242 patients were enrolled (mean +/- SD age = 75.4 +/- 6.6 years). During the study, no deterioration of cognition was observed; on the contrary, most of the tested cognitive functions improved. Good antidepressant efficacy was maintained for over 1 year with both drugs, based on the percentage of responders to treatment (patients achieving a HAM-D total score < 10; 60%). Both drugs showed a good tolerability and safety profile. CONCLUSION: The 2 antidepressants proved to be suitable for the long-term treatment of depression in the elderly and to be devoid of detrimental effects on the tested cognitive functions.     

Combined Cognitive Training and Vortioxetine Mitigates Age-Related Declines in Functional Brain Network Integrity

ObjectiveAge-related cognitive decline is common and potentially modifiable with cognitive training. Combining cognitive training with pro-cognitive medication offers an opportunity to modify brain networks to mitigate age-related cognitive decline. We tested the hypothesis that the efficacy of cognitive training could be amplified by combining it with vortioxetine, a pro-cognitive and pro-neuroplastic multimodal antidepressant.MethodsWe evaluated the effects of 6 months of computerized cognitive training plus vortioxetine (versus placebo) on resting state functional connectivity in older adults (age 65+) with age-related cognitive decline. We first evaluated the association of functional connectivity with age and cognitive performance (N = 66). Then we compared the effects of vortioxetine plus cognitive training versus placebo plus cognitive training on connectivity changes over the training period (n = 20).ResultsAt baseline, greater age was significantly associated with lower within-network strength and network segregation, and poorer cognitive function. Cognitive training plus vortioxetine over 6 months positively impacted the relationship between age to mean network segregation. These effects were not observed in the placebo group. In contrast, vortioxetine did not modify the relationship of age to change in mean within-network strength. Exploratory analyses identified the cingulo-opercular network as the network most affected by cognitive training plus vortioxetine.ConclusionThis preliminary study provides evidence that combining cognitive training with pro-cognitive medication may modulate the effects of aging on functional brain networks. Results indicate that for older adults experiencing age-related cognitive decline, vortioxetine has a potentially beneficial effect on the correspondence between aging and functional brain network segregation. These results await replication in a larger sample.     

White-matter changes in early and late stages of mild cognitive impairment

Mild Cognitive Impairment (MCI) is characterized by cognitive deficits that exceed age-related decline, but not interfering with daily living activities. Amnestic type of the disorder (aMCI) is known to have a high risk to progress to Alzheimer’s Disease (AD), the most common type of dementia. Identification of very early structural changes in the brain related to the cognitive decline in MCI patients would further contribute to the understanding of the dementias. In the current study, we target to investigate whether the white-matter changes are related to structural changes, as well as the cognitive performance of MCI patients. Forty-nine MCI patients were classified as Early MCI (E-MCI, n = 24) and Late MCI (L-MCI, n = 25) due to their performance on The Free and Cued Selective Reminding Test (FCSRT). Age-Related White-Matter Changes (ARWMC) scale was used to evaluate the white-matter changes in the brain. Volumes of specific brain regions were calculated with the FreeSurfer program. Both group and correlation analyses were conducted to show if there was any association between white-matter hyperintensities (WMHs) and structural changes and cognitive performance. Our results indicate that, L-MCI patients had significantly more WMHs not in all but only in the frontal regions compared to E-MCI patients. Besides, ARWMC scores were not correlated with total hippocampal and white-matter volumes. It can be concluded that WMHs play an important role in MCI and cognitive functions are affected by white-matter changes of MCI patients, especially in the frontal regions.     

Evidence of cognitive compensation associated with educational level in early relapsing-remitting multiple sclerosis

BACKGROUND: Cognitive compensatory mechanisms may limit the cognitive dysfunction due to cerebral tissue destruction in multiple sclerosis (MS). OBJECTIVE: To explore the effect of educational status on cognitive performances in early relapsing-remitting (RR) MS. METHODS: 43 RRMS patients were individually matched for age, sex and educational level with 43 healthy controls. Each patient underwent neuropsychological tests, clinical assessment and magnetic resonance imaging (MRI). Cognitive scores of MS patients were compared to those of their paired controls according to educational level. RESULTS: Less educated patients had low performances on all but two neuropsychological tests, while more educated patients had low scores only for three tests. Cognitive performances of more educated patients but not those of less educated ones were strongly correlated with MRI parameters and decreased with the severity of cerebral tissue destruction. CONCLUSION: These different cognitive patterns suggest the existence of a cognitive compensation in more educated patients which is limited by the accumulation of tissue damage.     

Internet-based cognitive testing in multiple sclerosis

Cognitive impairment in multiple sclerosis is difficult to study because of the heterogeneity and variability of this disease. The gold standard for measurement of cognitive function in multiple sclerosis is a full battery of neurocognitive tests, which is time consuming and expensive. Some cognitive tests like the PASAT, a measure of working verbal memory and processing speed, have been proposed for screening and follow-up of cognitive function in clinical trials. We studied whether we could measure cognitive function in multiple sclerosis over the Internet. For this we used the Cognitive Stability Index (CSI)trade mark, developed for persons with known or suspected primary central nervous system illness. The CSI was compared with formal neurocognitive testing (NPsych) and the PASAT in a cross-sectional study of 40 consecutive multiple sclerosis patients with subjective cognitive complaints. NPsych revealed that only 18 of the 40 patients (46%) were cognitively impaired. Although both the CSI and the PASAT were equalivalent in their specificity (86%), the CSI was significantly more sensitive than the PASAT (83% versus 28%). We conclude that the CSI, because of its availability over the Internet, has great potential as a tool for screening and follow up of cognitive function in multiple sclerosis.     

Transcranial electrical stimulation improves cognitive training effects in healthy elderly adults with low cognitive performance

ObjectiveTo investigate the efficacy of transcranial direct (tDCS) or alternating current stimulation (tACS) in boosting cognitive training efficiency in healthy older adults. We further explored whether such improvements depend on general cognitive performance or age.MethodsIn this randomized, sham-controlled study, 59 healthy elderly participants (mean age 71.7) were assigned to receive computer-based cognitive training (10 sessions, 50 min, twice weekly) combined with tDCS (2 mA), tACS (5 Hz), or sham stimulation over the left dorsolateral prefrontal cortex (20 minutes). Cognitive performance was assessed with the Montreal Cognitive Assessment (MoCA), and a cognitive composite score derived from a broad neuropsychological test battery before and immediately after the intervention as well as at 6 and 12 months follow-ups.ResultsPerformance in the cognitive composite score improved significantly in all groups but was not further modulated by neurostimulation. Additional analyses revealed that participants with a low initial MoCA score (<1SD) improved significantly more in the tDCS than in the sham group.ConclusionTDCS increased the efficacy of cognitive training, but only in participants with initially low general cognitive performance.SignificanceCognitive interventions including tDCS should address baseline performance as modulating factor of cognitive outcomes.     

Compensatory cortical activation observed by fMRI during a cognitive task at the earliest stage of MS

Recent functional magnetic resonance imaging (fMRI) studies have suggested that functional cortical changes seen in patients with early relapsing-remitting multiple sclerosis (MS) can have an adaptive role to limit the clinical impact of tissue injury. To determine whether cortical reorganization occurs during high cognitive processes at the earliest stage of multiple sclerosis (MS), we performed an fMRI experiment using the conventional Paced Auditory Serial Addition Test (PASAT) as paradigm in a population of ten patients with clinically isolated syndrome suggestive of multiple sclerosis (CISSMS). At the time of the fMRI exploration, mean disease duration was 6.8 +/- 3.3 months. We compared these results to those obtained in a group of ten education-, age-, and sex-matched healthy controls. Subjects were explored on a 1.5 T MRI system using single-shot gradient-echo EPI sequence. Performances of the two groups during PASAT recorded inside the MR scanner were not different. Statistical assessment of brain activation was based on the random effect analysis (between-group analysis two-sample t-test P < 0.005 confirmed by individual analyses performed in the surviving regions P < 0.05 Mann Whitney U-test). Compared to controls, patients showed significantly greater activation in the right frontopolar cortex, the bilateral lateral prefrontal cortices, and the right cerebellum. Healthy controls did not show greater activation compared to CISSMS patients. The present study argues in favor of the existence of compensatory cortical activations at the earliest stage of MS mainly located in regions involved in executive processing in patients performing PASAT. It also suggests that fMRI can evidence the active processes of neuroplasticity contributing to mask the clinical cognitive expression of brain pathology at the earliest stage of MS.     

Multiple sclerosis-related cognitive changes: a review of cross-sectional and longitudinal studies

Prevalence estimates of cognitive impairment in multiple sclerosis (MS) range from 40% to 65%, depending on the research setting. Cognitive dysfunction virtually encompasses all the disease stages and types of clinical course, although it is generally less frequent in relapsing-remitting (RR) patients compared with secondary progressive (SP) patients, and tends to be less frequent in primary progressive (PP) patients. Moreover, it causes role limitations in work and social life, independently of the degree of physical disability. Relatively little is known about the evolution of cognitive impairment in MS, particularly starting from the early stages of the disease. Controlled studies, however, have clearly shown that cognitive deterioration tends to progress over time. Among clinical predictors, incipient cognitive decline seems to be the major risk factor for further deterioration in the short-term. In the long-term, the likelihood increases that also patients with initial cognitive preservation may deteriorate. As for magnetic resonance imaging (MRI), there are consistent, albeit moderate, correlations between the progression of cognitive impairment and increasing brain lesion load and brain atrophy. The aim of this paper is to provide a review of existing cross-sectional and longitudinal studies on cognitive deterioration in MS.     

Brain networks disconnection in early multiple sclerosis cognitive deficits: An anatomofunctional study

Severe cognitive impairment involving multiple cognitive domains can occur early during the course of multiple sclerosis (MS). We investigated resting state functional connectivity changes in large‐scale brain networks and related structural damage underlying cognitive dysfunction in patients with early MS. Patients with relapsing MS (3–5 years disease duration) were prospectively assigned to two groups based on a standardized neuropsychological evaluation: (1) cognitively impaired group (CI group, n = 15), with abnormal performances in at least 3 tests; (2) cognitively preserved group (CP group, n = 20) with normal performances in all tests. Patients and age‐matched healthy controls underwent a multimodal 3T magnetic resonance imaging (MRI) including anatomical T1 and T2 images, diffusion imaging and resting state functional MRI. Structural MRI analysis revealed that CI patients had a higher white matter lesion load compared to CP and a more severe atrophy in gray matter regions highly connected to networks involved in cognition. Functional connectivity measured by integration was increased in CP patients versus controls in attentional networks (ATT), while integration was decreased in CI patients compared to CP both in the default mode network (DMN) and ATT. An anatomofunctional study within the DMN revealed that functional connectivity was mostly altered between the medial prefrontal cortex (MPFC) and the posterior cingulate cortex (PCC) in CI patients compared to CP and controls. In a multilinear regression model, functional correlation between MPFC and PCC was best predicted by PCC atrophy. Disconnection in the DMN and ATT networks may deprive the brain of compensatory mechanisms required to face widespread structural damage. Hum Brain Mapp 35:4706–4717, 2014. © 2014 Wiley Periodicals, Inc .