Publications by authors named "Barbara Spanò"

43 Publications

Evidence for interhemispheric imbalance in stroke patients as revealed by combining transcranial magnetic stimulation and electroencephalography.

Hum Brain Mapp 2021 Apr 13;42(5):1343-1358. Epub 2021 Jan 13.

Non-Invasive Brain Stimulation Unit/Department of Behavioral and Clinical Neurology, Santa Lucia Foundation, Rome, Italy.

Interhemispheric interactions in stroke patients are frequently characterized by abnormalities, in terms of balance and inhibition. Previous results showed an impressive variability, mostly given to the instability of motor-evoked potentials when evoked from the affected hemisphere. We aim to find reliable interhemispheric measures in stroke patients with a not-evocable motor-evoked potential from the affected hemisphere, by combining transcranial magnetic stimulation (TMS) and electroencephalography. Ninteen stroke patients (seven females; 61.26 ± 9.8 years) were studied for 6 months after a first-ever stroke in the middle cerebral artery territory. Patients underwent four evaluations: clinical, cortical, corticospinal, and structural. To test the reliability of our measures, the evaluations were repeated after 3 weeks. To test the sensitivity, 14 age-matched healthy controls were compared to stroke patients. In stroke patients, stimulation of the affected hemisphere did not result in any inhibition onto the unaffected. The stimulation of the unaffected hemisphere revealed a preservation of the inhibition mechanism onto the affected. This resulted in a remarkable interhemispheric imbalance, whereas this mechanism was steadily symmetric in healthy controls. This result was stable when cortical evaluation was repeated after 3 weeks. Importantly, patients with a better recovery of the affected hand strength were the ones with a more stable interhemispheric balance. Finally, we found an association between microstructural integrity of callosal fibers, suppression of interhemispheric TMS-evoked activity and interhemispheric connectivity. We provide direct and sensitive cortical measures of interhemispheric imbalance in stroke patients. These measures offer a reliable means of distinguishing healthy and pathological interhemispheric dynamics.
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http://dx.doi.org/10.1002/hbm.25297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927297PMC
April 2021

Brain Connectivity Changes after Osteopathic Manipulative Treatment: A Randomized Manual Placebo-Controlled Trial.

Brain Sci 2020 Dec 11;10(12). Epub 2020 Dec 11.

Networks Unit, IMT School for Advanced Studies Lucca, 55100 Lucca, Italy.

The effects of osteopathic manipulative treatment (OMT) on functional brain connectivity in healthy adults is missing in the literature. To make up for this lack, we applied advanced network analysis methods to analyze resting state functional magnetic resonance imaging (fMRI) data, after OMT and Placebo treatment (P) in 30 healthy asymptomatic young participants randomized into OMT and placebo groups (OMTg; Pg). fMRI brain activity measures, performed before (T0), immediately after (T1) and three days after (T2) OMT or P were used for inferring treatment effects on brain circuit functional organization. Repeated measures ANOVA and post-hoc analysis demonstrated that Right Precentral Gyrus (F (2, 32) = 5.995, < 0.005) was more influential over the information flow immediately after the OMT, while decreased betweenness centrality in Left Caudate (F (2, 32) = 6.496, < 0.005) was observable three days after. Clustering coefficient showed a distinct time-point and group effect. At T1, reduced neighborhood connectivity was observed after OMT in the Left Amygdala (L-Amyg) (F (2, 32) = 7.269, < 0.005) and Left Middle Temporal Gyrus (F (2, 32) = 6.452, < 0.005), whereas at T2 the L-Amyg and Vermis-III (F (2, 32) = 6.772, < 0.005) increased functional interactions. Data demonstrated functional connectivity re-arrangement after OMT.
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http://dx.doi.org/10.3390/brainsci10120969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764238PMC
December 2020

Dual-Task Performance in Multiple Sclerosis' Patients: Cerebellum Matters?

Arch Clin Neuropsychol 2020 Oct 17. Epub 2020 Oct 17.

Neurology and Neurorehabilitation Unit, I.R.C.C.S. "Santa Lucia" Foundation, Rome, Italy.

Objective: Gait, cognitive impairments, and their mutual influence in dual tasking (cognitive-motor dual tasking, CM-DT) are important to address therapeutic approaches in patients with multiple sclerosis (PMS). CM-DT correlates have been widely investigated with variable and dissimilar results, due to differences in methods. However, although the cerebellum has recently shown to be involved in both motor and cognitive functions, few studies have explored its role in the integration of the concurrent execution of gait and cognition. This case-control study aims to explore the effects of adding a cognitive task to walking in PMS and to investigate the role of the cerebellum in the interfering process.

Methods: In total, 20 patients and 18 healthy controls (HC) underwent clinical assessments, dual task (DT), and 3 T magnetic resonance imaging (MRI). DT was composed by three 2-min trials requiring fast walking. In 2 of them 2 different cognitive tasks were added.

Results: Both groups evidenced the presence of cognitive-motor interference (CMI) for both cognitive conditions with a greater effect of word list generation task in PMS. Analysis of variance between HC and patients with high or low performances showed a significantly increased volume in Vermis lobules VIIIa and IX of high performers compared with HC.

Conclusion: Our results show that CMI is also present in healthy individuals but is significantly more disabling in PMS. Furthermore, MRI data point to the existence of an initial mechanism of cerebellar reorganization in PMS with lower interference. Subsequently, the failure of this mechanism due to the progression of disability leads to a more evident expression of symptoms.
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http://dx.doi.org/10.1093/arclin/acaa089DOI Listing
October 2020

Rates of depression and anxiety in Italian patients with cystic fibrosis and parent caregivers: Implementation of the Mental Health Guidelines.

Respir Med 2020 10 10;172:106147. Epub 2020 Sep 10.

Unit of Clinical Psychology, Bambino Gesù Pediatric Hospital, Rome, IT.

Background: Individuals with chronic respiratory conditions are at-risk for depression and anxiety. In the largest mental health screening study of over 6000 people with cystic fibrosis (CF) and 4000 parent caregivers (TIDES, 2014), rates of symptomatology were two to three times higher than in the general population. International guidelines recommend annual screening of mental health. This is the first study to implement these guidelines in one of the largest CF Centers in Italy.

Methods: All individuals with CF, 12 and older (n = 167) and caregivers of children with CF (n = 186), birth to 18, were screened. Health outcome data were also collected (i.e FEV, BMI, pulmonary exacerbations, CF-related diabetes). Prevalence data and associations between psychological symptoms and health outcomes were examined.

Results: A high percentage of patients and parent caregivers reported scored above the clinical cut-off for depression and anxiety (37%-48% of adolescents, 45%-46% of adults, 49%-66% of mothers and fathers). Most scores fell in the mild range, however, over 30% were in the moderate to severe range. Elevations in depression and anxiety were correlated. Adolescents who had more pulmonary exacerbations reported higher anxiety. Adults with recent events of hemoptysis reported higher symptoms of depression.

Conclusions: Symptoms of depression and anxiety were elevated in both individuals with CF and parents. Implementation of mental health screening was critical for identifying those in need of psychological interventions. These results strongly suggest that mental health should be integrated into physical health care for those with complex, chronic respiratory conditions, including COPD, PCD.
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http://dx.doi.org/10.1016/j.rmed.2020.106147DOI Listing
October 2020

Cerebral Perfusion Changes After Osteopathic Manipulative Treatment: A Randomized Manual Placebo-Controlled Trial.

Front Physiol 2019 5;10:403. Epub 2019 Apr 5.

IMT School for Advanced Studies Lucca, Lucca, Italy.

Osteopathic Manipulative Treatment (OMT) is a therapeutic approach aimed at enhancing the body's self-regulation focusing on somatic dysfunctions correction. Despite evidence of OMT effectiveness, the underlying neurophysiological mechanisms, as well as blood perfusion effects, are still poorly understood. The study aim was to address OMT effects on cerebral blood flow (CBF) in asymptomatic young volunteers as measured by Magnetic Resonance Arterial Spin Labeling (ASL) method. Thirty blinded participants were randomized to OMT or placebo, and evaluated with an MRI protocol before manual intervention (T0), immediately after (T1), and 3 days later (T2). After T0 MRI, participants received 45 min of OMT, focused on correcting whole body somatic dysfunctions, or placebo manual treatment, consisting of passive touches in a protocolled order. After treatment, participants completed a de-blinding questionnaire about treatment perception. Results show significant differences due to treatment only for the OMT group (OMTg): perfusion decreased (compared to T0) in a cluster comprising the left posterior cingulate cortex (PCC) and the superior parietal lobule, while increased at T2 in the contralateral PCC. Furthermore, more than 60% of participants believed they had undergone OMT. The CBF modifications at T2 suggest that OMT produced immediate but reversible effects on CBF.
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http://dx.doi.org/10.3389/fphys.2019.00403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460882PMC
April 2019

Left hemispatial neglect and overt orienting in naturalistic conditions: Role of high-level and stimulus-driven signals.

Cortex 2019 04 14;113:329-346. Epub 2019 Jan 14.

Neuroimaging Laboratory, Santa Lucia Foundation, Rome, Italy; ImpAct Team, Lyon Neuroscience Research Center, Lyon, France.

Deficits of visuospatial orienting in brain-damaged patients affected by hemispatial neglect have been extensively investigated. Nonetheless, spontaneous spatial orienting in naturalistic conditions is still poorly understood. Here, we investigated the role played by top-down and stimulus-driven signals in overt spatial orienting of neglect patients during free-viewing of short videos portraying everyday life situations. In Experiment 1, we assessed orienting when meaningful visual events competed on the left and right side of space, and tested whether sensory salience on the two sides biased orienting. In Experiment 2, we examined whether the spatial alignment of visual and auditory signals modulates orienting. The results of Experiment 1 showed that in neglect patients severe deficits in contralesional orienting were restricted to viewing conditions with bilateral visual events competing for attentional capture. In contrast, orienting towards the contralesional side was largely spared when the videos contained a single event on the left side. In neglect patients the processing of stimulus-driven salience was relatively spared and helped orienting towards the left side when multiple events were present. Experiment 2 showed that sounds spatially aligned with visual events on the left side improved orienting towards the otherwise neglected hemispace. Anatomical scans indicated that neglect patients suffered grey and white matter damages primarily in the ventral frontoparietal cortex. This suggests that the improvement of contralesional orienting associated with visual salience and audiovisual spatial alignment may be due to processing in the relatively intact dorsal frontoparietal areas. Our data show that in naturalistic environments, the presence of multiple meaningful events is a major determinant of spatial orienting deficits in neglect patients, whereas the salience of visual signals and the spatial alignment between auditory and visual signals can counteract spatial orienting deficits. These results open new perspectives to develop novel rehabilitation strategies based on the use of naturalistic stimuli.
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http://dx.doi.org/10.1016/j.cortex.2018.12.022DOI Listing
April 2019

Disruption of neurite morphology parallels MS progression.

Neurol Neuroimmunol Neuroinflamm 2018 Nov 26;5(6):e502. Epub 2018 Sep 26.

Neuroimaging Laboratory (B.S., G.G., M.B., M.C.), Santa Lucia Foundation, IRCCS; Department of Clinical and Behavioural Neurology (V.P., U.N., C.C.), Santa Lucia Foundation, IRCCS; Neurovascular Diagnosis Unit (M.M.), Department of Medical and Surgical Sciences and Biotechnology, Section of Neurology, Sapienza, University of Rome; Department of Neurology and Psychiatry (M.M., A.F.), Multiple Sclerosis Center, Sapienza, University of Rome, Italy; High Field Magnetic Resonance (E.T.), Max Planck Institute for Biological Cybernetics, Tuebingen, Germany; Department of System Medicine (U.N., C.C.), University of Rome "Tor Vergata," Italy; and Department of Neuroscience (M.B., M.C.), Brighton & Sussex Medical School, Falmer, United Kingdom.

Objectives: To apply advanced diffusion MRI methods to the study of normal-appearing brain tissue in MS and examine their correlation with measures of clinical disability.

Methods: A multi-compartment model of diffusion MRI called neurite orientation dispersion and density imaging (NODDI) was used to study 20 patients with relapsing-remitting MS (RRMS), 15 with secondary progressive MS (SPMS), and 20 healthy controls. Maps of NODDI were analyzed voxel-wise to assess the presence of abnormalities within the normal-appearing brain tissue and the association with disease severity. Standard diffusion tensor imaging (DTI) parameters were also computed for comparing the 2 techniques.

Results: Patients with MS showed reduced neurite density index (NDI) and increased orientation dispersion index (ODI) compared with controls in several brain areas ( < 0.05), with patients with SPMS having more widespread abnormalities. DTI indices were also sensitive to some changes. In addition, patients with SPMS showed reduced ODI in the thalamus and caudate nucleus. These abnormalities were associated with scores of disease severity ( < 0.05). The association with the MS functional composite score was higher in patients with SPMS compared with patients with RRMS.

Conclusions: NODDI and DTI findings are largely overlapping. Nevertheless, NODDI helps interpret previous findings of increased anisotropy in the thalamus of patients with MS and are consistent with the degeneration of selective axon populations.
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http://dx.doi.org/10.1212/NXI.0000000000000502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192688PMC
November 2018

Whole brain white matter histogram analysis of diffusion tensor imaging data detects microstructural damage in mild cognitive impairment and alzheimer's disease patients.

J Magn Reson Imaging 2018 Jan 21. Epub 2018 Jan 21.

Neuroimaging Laboratory, IRCCS Santa Lucia Foundation, Rome, Italy.

Background: Amnestic mild cognitive impairment (MCI) is a transitional stage between normal aging and Alzheimer's disease (AD). However, the clinical conversion from MCI to AD is unpredictable. Hence, identification of noninvasive biomarkers able to detect early changes induced by dementia is a pressing need.

Purpose: To explore the added value of histogram analysis applied to measures derived from diffusion tensor imaging (DTI) for detecting brain tissue differences between AD, MCI, and healthy subjects (HS).

Study Type: Prospective.

Population/subjects: A local cohort (57 AD, 28 MCI, 23 HS), and an Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort (41 AD, 58 MCI, 41 HS).

Field Strength: 3T. Dual-echo turbo spin echo (TSE); fluid-attenuated inversion recovery (FLAIR); modified-driven-equilibrium-Fourier-transform (MDEFT); inversion-recovery spoiled gradient recalled (IR-SPGR); diffusion tensor imaging (DTI).

Assessment: Normal-appearing white matter (NAWM) masks were obtained using the T -weighted volumes for tissue segmentation and T -weighted images for removal of hyperintensities/lesions. From DTI images, fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AXD), and radial diffusivity (RD) were obtained. NAWM histograms of FA, MD, AXD, and RD were derived and characterized estimating: peak height, peak location, mean value (MV), and quartiles (C25, C50, C75), which were compared between groups. Receiver operating characteristic (ROC) and area under ROC curves (AUC) were calculated. To confirm our results, the same analysis was repeated on the ADNI dataset.

Statistical Tests: One-way analysis of variance (ANOVA), post-hoc Student's t-test, multiclass ROC analysis.

Results: For the local cohort, C25 of AXD had the maximum capability of group discrimination with AUC of 0.80 for "HS vs. patients" comparison and 0.74 for "AD vs. others" comparison. For the ADNI cohort, MV of AXD revealed the maximum group discrimination capability with AUC of 0.75 for "HS vs. patients" comparison and 0.75 for "AD vs. others" comparison.

Data Conclusion: AXD of NAWM might be an early marker of microstructural brain tissue changes occurring during the AD course and might be useful for assessing disease progression.

Level Of Evidence: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2017.
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http://dx.doi.org/10.1002/jmri.25947DOI Listing
January 2018

Damage to the Frontal Aslant Tract Accounts for Visuo-Constructive Deficits in Alzheimer's Disease.

J Alzheimers Dis 2017 ;60(3):1015-1024

Neuroimaging Laboratory, IRCCS Santa Lucia Foundation, Rome, Italy.

The frontal aslant tract (FAT) has been described as a bundle connecting the Broca's area to the supplementary motor area (SMA) and the pre-SMA in both hemispheres. The functional properties of this tract and its role in degenerative dementia, such as Alzheimer's disease (AD), still need to be fully clarified. The aim of this study was to explore the microstructural integrity of the FAT in patients with AD and its potential relationship with cognitive functioning. Twenty-three patients with AD and 25 healthy subjects (HS) were enrolled. All subjects underwent cognitive and MRI examination. MRI, including diffusion sequences, was used for probabilistic tractography analysis. We reconstructed individual FATs bilaterally and assessed their microstructural integrity using fractional anisotropy (FA), computed as both mean tract value and voxel-wise using SPM-8. Mean FA values were then used to test for correlations with cognitive measures. Mean tract FA and voxel-wise analyses revealed that patients with AD, compared to HS, had decreased FA in the FAT bilaterally. In addition, positive associations were found between FA in the FATs and patients' performance at tests for constructional praxis and visuospatial logical reasoning. The present results reveal a bilateral damage of FAT in AD patients. The association between FATs' microscopic abnormalities and constructive abilities fits well with the knowledge of a functional involvement of SMA and pre-SMA in movement sequences when executing constructive praxis tasks. The FAT is an associative bundle critically involved in the network sub-serving constructional praxis in patients with AD.
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http://dx.doi.org/10.3233/JAD-170638DOI Listing
May 2018

Introducing axonal myelination in connectomics: A preliminary analysis of g-ratio distribution in healthy subjects.

Neuroimage 2018 11 14;182:351-359. Epub 2017 Sep 14.

Neuroimaging Laboratory, Santa Lucia Foundation, Rome, Italy; Department of Neuroscience, Brighton and Sussex Medical School, University of Sussex, Brighton, UK.

Microstructural imaging and connectomics are two research areas that hold great potential for investigating brain structure and function. Combining these two approaches can lead to a better and more complete characterization of the brain as a network. The aim of this work is characterizing the connectome from a novel perspective using the myelination measure given by the g-ratio. The g-ratio is the ratio of the inner to the outer diameters of a myelinated axon, whose aggregated value can now be estimated in vivo using MRI. In two different datasets of healthy subjects, we reconstructed the structural connectome and then used the g-ratio estimated from diffusion and magnetization transfer data to characterize the network structure. Significant characteristics of g-ratio weighted graphs emerged. First, the g-ratio distribution across the edges of the graph did not show the power-law distribution observed using the number of streamlines as a weight. Second, connections involving regions related to motor and sensory functions were the highest in myelin content. We also observed significant differences in terms of the hub structure and the rich-club organization suggesting that connections involving hub regions present higher myelination than peripheral connections. Taken together, these findings offer a characterization of g-ratio distribution across the connectome in healthy subjects and lay the foundations for further investigating plasticity and pathology using a similar approach.
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http://dx.doi.org/10.1016/j.neuroimage.2017.09.018DOI Listing
November 2018

Estimating multimodal brain connectivity in multiple sclerosis: an exploratory factor analysis.

Annu Int Conf IEEE Eng Med Biol Soc 2016 Aug;2016:1131-1134

Graph-theoretical approaches have become a popular way to model brain data collected using magnetic resonance imaging (MRI), both from the structural and the functional perspectives. In structural networks, tract-based mapping allows to model different aspects of brain structures by means of the specific characteristics of the different MRI modalities. However, there has been little effort to join the information carried by each modality and to understand what level of common variance is shown in these data. In this paper, we proposed a combined approach based on graph theory and factor analysis to model magnetization transfer and microstructural properties in 18 relapsing remitting multiple sclerosis (RRMS) patients and 17 healthy controls. After defining the common factors and outlining their relationships with MRI data, we evaluated between-group differences using global and local graph measures. The results showed that one common factor describes brain structures in terms of myelin and global integrity, and such factor is able to highlight specific between-group differences.
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http://dx.doi.org/10.1109/EMBC.2016.7590903DOI Listing
August 2016

Cognitive reserve and cognitive performance of patients with focal frontal lesions.

Neuropsychologia 2017 02 29;96:19-28. Epub 2016 Dec 29.

Department of Neuropsychology, National Hospital for Neurology and Neurosurgery, London, UK; Dipartimento di Scienze Psicologiche, Pedagogiche e della Formazione, Università degli Studi di Palermo, Palermo, Italy. Electronic address:

The Cognitive reserve (CR) hypothesis was put forward to account for the variability in cognitive performance of patients with similar degrees of brain pathology. Compensatory neural activity within the frontal lobes has often been associated with CR. For the first time we investigated the independent effects of two CR proxies, education and NART IQ, on measures of executive function, fluid intelligence, speed of information processing, verbal short term memory (vSTM), naming, and perception in a sample of 86 patients with focal, unilateral frontal lesions and 142 healthy controls. We fitted multiple linear regression models for each of the cognitive measures and found that only NART IQ predicted executive and naming performance. Neither education nor NART IQ predicted performance on fluid intelligence, processing speed, vSTM or perceptual abilities. Education and NART IQ did not modify the effect of lesion severity on cognitive impairment. We also found that age significantly predicted performance on executive tests and the majority of our other cognitive measures, except vSTM and GNT. Age was the only predictor for fluid intelligence. This latter finding suggests that age plays a role in executive performance over and above the contribution of CR proxies in patients with focal frontal lesions. Overall, our results suggest that the CR proxies do not appear to modify the relationship between cognitive impairment and frontal lesions.
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http://dx.doi.org/10.1016/j.neuropsychologia.2016.12.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5317176PMC
February 2017

Inhibition processes are dissociable and lateralized in human prefrontal cortex.

Neuropsychologia 2016 Dec 23;93(Pt A):1-12. Epub 2016 Sep 23.

Neuroimaging Laboratory, Santa Lucia Foundation, Rome, Italy.

The prefrontal cortex (PFC) is known to make fundamental contributions to executive functions. However, the precise nature of these contributions is incompletely understood. We focused on a specific executive function, inhibition, the ability to suppress a pre-potent response. Functional imaging and animal studies have studied inhibition. However, there are only few lesion studies, typically reporting discrepant findings. For the first time, we conducted cognitive and neuroimaging investigations on patients with focal unilateral PFC lesions across two widely used inhibitory tasks requiring a verbal response: The Hayling Part 2 and Stroop Colour-Word Tests. We systematically explored the relationship between inhibition, fluid intelligence and lesion location using voxel-based lesion symptom mapping (VLSM). We found that PFC patients were significantly impaired compared with healthy comparison group (HC) on both suppression measures of the Hayling and on the Stroop, even when performance on a fluid intelligence test was covaried. No significant relationship was found between patients' performance on each Hayling suppression measure and the Stroop, once fluid intelligence was partialled out, suggesting that the two tests may involve different kinds of inhibition. After accounting for fluid intelligence, we found a significant interaction between tests, Hayling or Stroop, and site, left or right, of PFC damage. This finding suggesting lateralized functional organization was complemented and extended by our VLSM results. We found that performance on both Hayling suppression measures significantly relied on the integrity of a similar and relatively circumscribed region within the right lateral PFC, in the right lateral superior and middle frontal gyri. In stark contrast, performance on the Stroop relies on the integrity of left lateral superior and middle frontal gyri. Thus, lesion location, right or left PFC, is critical in producing impairments on two inhibitory tasks loading similarly on verbal control. This suggests that the two suppression measures of the Hayling and the Stroop are likely to assess dissociable components of executive functions, related to anatomically defined and lateralized PFC circuits. Our findings also suggest that inhibition may actually comprise qualitatively different forms with different neural substrates. This has clinical implications for the diagnosis and treatment of disinhibition impairments, a common behavioural problem caused by PFC lesions. Our results highlight the need to assess inhibition using a variety of tasks and to develop different types of treatments.
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http://dx.doi.org/10.1016/j.neuropsychologia.2016.09.018DOI Listing
December 2016

Brain Connectivity Changes in Autosomal Recessive Parkinson Disease: A Model for the Sporadic Form.

PLoS One 2016 27;11(10):e0163980. Epub 2016 Oct 27.

Neuroimaging Laboratory, IRCCS Santa Lucia Foundation, Rome, Italy.

Biallelic genetic mutations in the Park2 and PINK1 genes are frequent causes of autosomal recessive PD. Carriers of single heterozygous mutations may manifest subtle signs of disease, thus providing a unique model of preclinical PD. One emerging hypothesis suggests that non-motor symptom of PD, such as cognitive impairment may be due to a distributed functional disruption of various neuronal circuits. Using resting-state functional MRI (RS-fMRI), we tested the hypothesis that abnormal connectivity within and between brain networks may account for the patients' cognitive status. Eight homozygous and 12 heterozygous carriers of either PINK1 or Park2 mutation and 22 healthy controls underwent RS-fMRI and cognitive assessment. RS-fMRI data underwent independent component analysis to identify five networks of interest: default-mode network, salience network, executive network, right and left fronto-parietal networks. Functional connectivity within and between each network was assessed and compared between groups. All mutation carriers were cognitively impaired, with the homozygous group reporting a more prominent impairment in visuo-spatial working memory. Changes in functional connectivity were evident within all networks between homozygous carriers and controls. Also heterozygotes reported areas of reduced connectivity when compared to controls within two networks. Additionally, increased inter-network connectivity was observed in both groups of mutation carriers, which correlated with their spatial working memory performance, and could thus be interpreted as compensatory. We conclude that both homozygous and heterozygous carriers exhibit pathophysiological changes unveiled by RS-fMRI, which can account for the presence/severity of cognitive symptoms.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0163980PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082970PMC
June 2017

CSF β-amyloid as a putative biomarker of disease progression in multiple sclerosis.

Mult Scler 2017 Jul 17;23(8):1085-1091. Epub 2016 Oct 17.

Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, "Dino Ferrari" Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Background: Neurodegeneration plays a major role in determining disability in multiple sclerosis (MS) patients. Hence, there is increasing need to identify reliable biomarkers, which could serve as prognostic measure of disease progression.

Objectives: To assess whether cerebrospinal fluid (CSF) tau and β-amyloid (Aβ) levels were altered in newly diagnosed MS patients and correlated with disability. Moreover, we investigated whether these CSF biomarkers associate with macroscopic brain tissue damage measures.

Methods: CSF Aβ and tau levels were determined by enzyme-linked immunosorbent assay in CSF samples from 48 newly diagnosed MS patients, followed-up clinically for 3 years by recording their Expanded Disability Status Scale score at 6-month intervals, and 45 controls. All patients underwent magnetic resonance imaging at baseline and at the end of follow-up to quantify their lesion load (LL).

Results: CSF Aβ levels were significantly reduced in patients compared to controls ( p < 0.001). Lower CSF Aβ levels at baseline were a disability predictor at 3-year follow-up ( p = 0.009). CSF tau levels correlated with T2- and T1-LL ( p < 0.001).

Conclusion: CSF Aβ reduction is a promising biomarker of neurodegeneration and may predict patients' clinical outcome. Therefore, CSF Aβ should be considered as a potential biomarker of prognostic value.
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http://dx.doi.org/10.1177/1352458516674566DOI Listing
July 2017

Network-Based Substrate of Cognitive Reserve in Alzheimer's Disease.

J Alzheimers Dis 2017 ;55(1):421-430

Neuroimaging Laboratory, IRCCS Santa Lucia Foundation, Rome, Italy.

Cognitive reserve (CR) is known to modulate the clinical features of Alzheimer's disease (AD). This concept may be critical for the development of non-pharmacological interventions able to slow down patients' cognitive decline in the absence of disease-modifying treatments. We aimed at identifying the neurobiological substrates of CR (i.e., neural reserve) over the transition between normal aging and AD, by assessing the underlying brain networks and their topological properties. A cohort of 154 participants (n = 68 with AD, n = 61 with amnestic mild cognitive impairment (aMCI), and 25 healthy subjects) underwent resting-state functional MRI and neuropsychological testing. Within each group, participants were classified as having high or low CR, and functional connectivity measures were compared, within group, between high and low CR individuals. Network-based statistics and topological network properties derived from graph theory were explored. Connectivity differences between high and low CR were evident only for aMCI patients, with participants with high CR showing a significant increase of connectivity in a network involving mainly fronto-parietal nodes. Conversely, they showed significantly decreased connectivity in a network involving fronto-temporo-cerebellar nodes. Consistently, changes to topological measures were observed in either direction, and were associated with measures of global cognitive function. These findings support the hypothesis that CR impacts on neurodegenerative process in the early phase of AD only. In addition, they fit with the existence of a "neural reserve", characterized by specific neural networks and their efficiency. It remains to be demonstrated whether interventions later in life can modulate this "neural reserve".
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http://dx.doi.org/10.3233/JAD-160735DOI Listing
February 2018

Brain Connectomics' Modification to Clarify Motor and Nonmotor Features of Myotonic Dystrophy Type 1.

Neural Plast 2016 25;2016:2696085. Epub 2016 May 25.

Neuroimaging Laboratory, IRCCS Santa Lucia Foundation, Via Ardeatina 306, 00179 Rome, Italy.

The adult form of myotonic dystrophy type 1 (DM1) presents with paradoxical inconsistencies between severity of brain damage, relative preservation of cognition, and failure in everyday life. This study, based on the assessment of brain connectivity and mechanisms of plasticity, aimed at reconciling these conflicting issues. Resting-state functional MRI and graph theoretical methods of analysis were used to assess brain topological features in a large cohort of patients with DM1. Patients, compared to controls, revealed reduced connectivity in a large frontoparietal network that correlated with their isolated impairment in visuospatial reasoning. Despite a global preservation of the topological properties, peculiar patterns of frontal disconnection and increased parietal-cerebellar connectivity were also identified in patients' brains. The balance between loss of connectivity and compensatory mechanisms in different brain networks might explain the paradoxical mismatch between structural brain damage and minimal cognitive deficits observed in these patients. This study provides a comprehensive assessment of brain abnormalities that fit well with both motor and nonmotor clinical features experienced by patients in their everyday life. The current findings suggest that measures of functional connectivity may offer the possibility of characterizing individual patients with the potential to become a clinical tool.
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http://dx.doi.org/10.1155/2016/2696085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4897716PMC
October 2017

"I Know that You Know that I Know": Neural Substrates Associated with Social Cognition Deficits in DM1 Patients.

PLoS One 2016 3;11(6):e0156901. Epub 2016 Jun 3.

Neuroimaging Laboratory, IRCCS Santa Lucia Foundation, Rome, Italy.

Myotonic dystrophy type-1 (DM1) is a genetic multi-systemic disorder involving several organs including the brain. Despite the heterogeneity of this condition, some patients with non-congenital DM1 can present with minimal cognitive impairment on formal testing but with severe difficulties in daily-living activities including social interactions. One explanation for this paradoxical mismatch can be found in patients' dysfunctional social cognition, which can be assessed in the framework of the Theory of Mind (ToM). We hypothesize here that specific disease driven abnormalities in DM1 brains may result in ToM impairments. We recruited 20 DM1 patients who underwent the "Reading the Mind in the Eyes" and the ToM-story tests. These patients, together with 18 healthy controls, also underwent resting-state functional MRI. A composite Theory of Mind score was computed for all recruited patients and correlated with their brain functional connectivity. This analysis provided the patients' "Theory of Mind-network", which was compared, for its topological properties, with that of healthy controls. We found that DM1 patients showed deficits in both tests assessing ToM. These deficits were associated with specific patterns of abnormal connectivity between the left inferior temporal and fronto-cerebellar nodes in DM1 brains. The results confirm the previous suggestions of ToM dysfunctions in patients with DM1 and support the hypothesis that difficulties in social interactions and personal relationships are a direct consequence of brain abnormalities, and not a reaction symptom. This is relevant not only for a better pathophysiological comprehension of DM1, but also for non-pharmacological interventions to improve clinical aspects and impact on patients' success in life.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0156901PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4892543PMC
August 2017

Longitudinal Changes in Functional Brain Connectivity Predicts Conversion to Alzheimer's Disease.

J Alzheimers Dis 2016 ;51(2):377-89

Neuroimaging Laboratory, IRCCS Santa Lucia Foundation, Rome, Italy.

This longitudinal study investigates the modifications in structure and function occurring to typical Alzheimer's disease (AD) brains over a 2-year follow-up, from pre-dementia stages of disease, with the aim of identifying biomarkers of prognostic value. Thirty-one patients with amnestic mild cognitive impairment were recruited and followed-up with clinical, neuropsychological, and MRI assessments. Patients were retrospectively classified as AD Converters or Non-Converters, and the data compared between groups. Cross-sectional MRI data at baseline, assessing volume and functional connectivity abnormalities, confirmed previous findings, showing a more severe pattern of regional grey matter atrophy and default-mode network disconnection in Converters than in Non-Converters. Longitudinally, Converters showed more grey matter atrophy in the frontotemporal areas, accompanied by increased connectivity in the precuneus. Discriminant analysis revealed that functional connectivity of the precuneus within the default mode network at baseline is the parameter able to correctly classify patients in Converters and Non-Converters with high sensitivity, specificity, and accuracy.
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http://dx.doi.org/10.3233/JAD-150961DOI Listing
December 2016

Different Patterns of Correlation between Grey and White Matter Integrity Account for Behavioral and Psychological Symptoms in Alzheimer's Disease.

J Alzheimers Dis 2016 ;50(2):591-604

Neuroimaging Laboratory, IRCCS Santa Lucia Foundation, Rome, Italy.

Behavioral disorders and psychological symptoms (BPSD) in Alzheimer's disease (AD) are known to correlate with grey matter (GM) atrophy and, as shown recently, also with white matter (WM) damage. WM damage and its relationship with GM atrophy are reported in AD, reinforcing the interpretation of the AD pathology in light of a disconnection syndrome. It remains uncertain whether this disconnection might account also for different BPSD observable in AD. Here, we tested the hypothesis of different patterns of association between WM damage of the corpus callosum (CC) and GM atrophy in AD patients exhibiting one of the following BPSD clusters: Mood (i.e., anxiety and depression; ADmood), Frontal (i.e., dishinibition and elation; ADfrontal), and Psychotic (delusions and hallucinations; ADpsychotic) related symptoms, as well as AD patients without BPSD. Overall, this study brings to light the strict relationship between WM alterations in different parts of the CC and GM atrophy in AD patients exhibiting BPSD, supporting the hypothesis that such symptoms are likely to be caused by characteristic patterns of neurodegeneration of WM and GM, rather than being a reactive response to accumulation of cognitive disabilities, and should therefore be regarded as potential markers of diagnostic and prognostic value in AD.
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http://dx.doi.org/10.3233/JAD-150612DOI Listing
November 2016

The Contursi Family 20 Years Later: Intrafamilial Phenotypic Variability of the SNCA p.A53T Mutation.

Mov Disord 2016 Feb 22;31(2):257-8. Epub 2016 Jan 22.

Morton and Gloria Shulman Movement Disorders Center and the Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1002/mds.26549DOI Listing
February 2016

How genetics affects the brain to produce higher-level dysfunctions in myotonic dystrophy type 1.

Funct Neurol 2015 Jan-Mar;30(1):21-31

Myotonic dystrophy type 1 (DM1) is a multisystemic disorder dominated by muscular impairment and brain dysfunctions. Although brain damage has previously been demonstrated in DM1, its associations with the genetics and clinical/neuropsychological features of the disease are controversial. This study assessed the differential role of gray matter (GM) and white matter (WM) damage in determining higher-level dysfunctions in DM1. Ten patients with genetically confirmed DM1 and 16 healthy How genetics affects the brain to produce higher-level dysfunctions in myotonic dystrophy type 1 matched controls entered the study. The patients underwent a neuropsychological assessment and quantification of CTG triplet expansion. All the subjects underwent MR scanning at 3T, with studies including T1-weighted volumes and diffusion-weighted images. Voxel-based morphometry and tractbased spatial statistics were used for unbiased quantification of regional GM atrophy and WM integrity. The DM1 patients showed widespread involvement of both tissues. The extent of the damage correlated with CTG triplet expansion and cognition. This study supports the idea that genetic abnormalities in DM1mainly target the WM, but GM involvement is also crucial in determining the clinical characteristics of DM1.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4520669PMC
April 2016

The effect of age on cognitive performance of frontal patients.

Neuropsychologia 2015 Aug 20;75:233-41. Epub 2015 Jun 20.

Institute of Cognitive Neuroscience, University College London, UK; International School for Advanced Studies (SISSA-ISAS), Trieste, Italy.

Age is known to affect prefrontal brain structure and executive functioning in healthy older adults, patients with neurodegenerative conditions and TBI. Yet, no studies appear to have systematically investigated the effect of age on cognitive performance in patients with focal lesions. We investigated the effect of age on the cognitive performance of a large sample of tumour and stroke patients with focal unilateral, frontal (n=68), or non-frontal lesions (n=45) and healthy controls (n=52). We retrospectively reviewed their cross sectional cognitive and imaging data. In our frontal patients, age significantly predicted the magnitude of their impairment on two executive tests (Raven's Advanced Progressive Matrices, RAPM and the Stroop test) but not on nominal (Graded Naming Test, GNT) or perceptual (Incomplete Letters) task. In our non-frontal patients, age did not predict the magnitude of their impairment on the RAPM and GNT. Furthermore, the exacerbated executive impairment observed in our frontal patients manifested itself from middle age. We found that only age consistently predicted the exacerbated executive impairment. Lesions to specific frontal areas, or an increase in global brain atrophy or white matter abnormalities were not associated with this impairment. Our results are in line with the notion that the frontal cortex plays a critical role in aging to counteract cognitive and neuronal decline. We suggest that the combined effect of aging and frontal lesions impairs the frontal cortical systems by causing its computational power to fall below the threshold needed to complete executive tasks successfully.
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http://dx.doi.org/10.1016/j.neuropsychologia.2015.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4542524PMC
August 2015

Strategic lesions in the anterior thalamic radiation and apathy in early Alzheimer's disease.

PLoS One 2015 1;10(5):e0124998. Epub 2015 May 1.

Neuroimaging Laboratory, Santa Lucia Foundation, IRCCS, Rome, Italy.

Background: Behavioural disorders and psychological symptoms of Dementia (BPSD) are commonly observed in Alzheimer's disease (AD), and strongly contribute to increasing patients' disability. Using voxel-lesion-symptom mapping (VLSM), we investigated the impact of white matter lesions (WMLs) on the severity of BPSD in patients with amnestic mild cognitive impairment (a-MCI).

Methods: Thirty-one a-MCI patients (with a conversion rate to AD of 32% at 2 year follow-up) and 26 healthy controls underwent magnetic resonance imaging (MRI) examination at 3T, including T2-weighted and fluid-attenuated-inversion-recovery images, and T1-weighted volumes. In the patient group, BPSD was assessed using the Neuropsychiatric Inventory-12. After quantitative definition of WMLs, their distribution was investigated, without an a priori anatomical hypothesis, against patients' behavioural symptoms. Unbiased regional grey matter volumetrics was also used to assess the contribution of grey matter atrophy to BPSD.

Results: Apathy, irritability, depression/dysphoria, anxiety and agitation were shown to be the most common symptoms in the patient sample. Despite a more widespread anatomical distribution, a-MCI patients did not differ from controls in WML volumes. VLSM revealed a strict association between the presence of lesions in the anterior thalamic radiations (ATRs) and the severity of apathy. Regional grey matter atrophy did not account for any BPSD.

Conclusions: This study indicates that damage to the ATRs is strategic for the occurrence of apathy in patients with a-MCI. Disconnection between the prefrontal cortex and the mediodorsal and anterior thalamic nuclei might represent the pathophysiological substrate for apathy, which is one of the most common psychopathological symptoms observed in dementia.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0124998PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4416903PMC
January 2016

Comparison of psychological functioning in children and their mothers living through a life-threatening and non life-threatening chronic disease: A pilot study.

J Child Health Care 2016 06 5;20(2):174-84. Epub 2015 Jan 5.

Sapienza University of Rome, Rome, Italy.

Childhood chronic illness is a potential source of distress and can be a traumatic experience both for the child and for the family. Several studies highlighted the importance of integrating psychosocial care and standard medical practice in the child's care. The current pilot study is the first investigation that compared distress in children and their mothers living through a life-threatening illness (cancer) and a non life-threatening (juvenile rheumatoid arthritis) chronic disease. Findings show that there are differences in the psychological functioning in children with respect to age. Moreover, the presence of posttraumatic stress symptoms in mothers of children with cancer seems to be a possible key to understanding the psychological response in this specific population.
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http://dx.doi.org/10.1177/1367493514563854DOI Listing
June 2016

The impact of different aetiologies on the cognitive performance of frontal patients.

Neuropsychologia 2015 Feb 31;68:21-30. Epub 2014 Dec 31.

Neuroimaging Laboratory, Santa Lucia Foundation, Rome, Italy.

Neuropsychological group study methodology is considered one of the primary methods to further understanding of the organisation of frontal 'executive' functions. Typically, patients with frontal lesions caused by stroke or tumours have been grouped together to obtain sufficient power. However, it has been debated whether it is methodologically appropriate to group together patients with neurological lesions of different aetiologies. Despite this debate, very few studies have directly compared the performance of patients with different neurological aetiologies on neuropsychological measures. The few that did included patients with both anterior and posterior lesions. We present the first comprehensive retrospective comparison of the impact of lesions of different aetiologies on neuropsychological performance in a large number of patients whose lesion solely affects the frontal cortex. We investigated patients who had a cerebrovascular accident (CVA), high (HGT) or low grade (LGT) tumour, or meningioma, all at the post-operative stage. The same frontal 'executive' (Raven's Advanced Progressive Matrices, Stroop Colour-Word Test, Letter Fluency-S; Trail Making Test Part B) and nominal (Graded Naming Test) tasks were compared. Patients' performance was compared across aetiologies controlling for age and NART IQ scores. Assessments of focal frontal lesion location, lesion volume, global brain atrophy and non-specific white matter (WM) changes were undertaken and compared across the four aetiology. We found no significant difference in performance between the four aetiology subgroups on the 'frontal' executive and nominal tasks. However, we found strong effects of premorbid IQ on all cognitive tasks and robust effects of age only on the frontal tasks. We also compared specific aetiology subgroups directly, as previously reported in the literature. Overall we found no significant differences in the performance of CVA and tumour patients, or LGT and HGT patients or LGT, HGT and meningioma's on our four frontal tests. No difference was found with respect to the location of frontal lesions, lesion volume, global brain atrophy and non-specific WM changes between the subgroups. Our results suggest that the grouping of frontal patients caused by different aetiologies is a pragmatic, justified methodological approach that can help to further understanding of the organisation of frontal executive functions.
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http://dx.doi.org/10.1016/j.neuropsychologia.2014.12.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4410793PMC
February 2015

Functional Anatomy of the Thalamus as a Model of Integrated Structural and Functional Connectivity of the Human Brain In Vivo.

Brain Topogr 2015 Jul 31;28(4):548-58. Epub 2014 Dec 31.

Neuroimaging Laboratory, Istituto Di Ricovero e Cura a Carattere Scientifico, Santa Lucia Foundation, Rome, Italy,

While methods of measuring non-invasively both, functional and structural brain connectivity are available, the degree of overlap between them is still unknown. In this paper this issue is addressed by investigating the connectivity pattern of a brain structure with many, well characterized structural connections, namely the thalamus. Diffusion-weighted and resting state (RS) functional MRI (fMRI) data were collected in a group of 38 healthy participants. Probabilistic tractography was performed to parcellate the thalamus into regions structurally connected to different cortical areas. The resulting regions were used as seeds for seed-based analysis of RS fMRI data. The tractographic parcellation was thus cross-validated against functional connectivity data by evaluating the overlap between the functional and structural thalamo-cortical connections originating from the parcellated regions. Our data show only a partial overall correspondence between structural and functional connections, in the same group of healthy individuals, thus suggesting that the two approaches provide complementary and not overlapping information. Future studies are warranted to extend the results we obtained in the thalamus to other structures, and to confirm that the mechanisms behind functional connectivity are more complex than just expressing structural connectivity.
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http://dx.doi.org/10.1007/s10548-014-0422-2DOI Listing
July 2015

Cognitive reserve and the risk for Alzheimer's disease: a longitudinal study.

Neurobiol Aging 2015 Feb 16;36(2):592-600. Epub 2014 Oct 16.

Neuroimaging Laboratory, IRCCS Santa Lucia Foundation, Rome, Italy. Electronic address:

This study investigates how cognitive reserve (CR) interacts with neurodegeneration (quantified by medial temporal atrophy, MTA) and macroscopic white matter lesions (WMLs) in delaying the conversion from amnestic mild cognitive impairment to Alzheimer's disease (AD). Forty-two amnestic mild cognitive impairment patients were consecutively recruited. They underwent magnetic resonance imaging and a comprehensive questionnaire to classify them as individuals with low or high CR. Patients were then clinically followed-up for 2 years. The patients' risk for conversion to AD because of CR was estimated by controlling for cognitive efficiency, MTA, and WMLs at baseline. Global cognition was the best predictor of conversion to AD in low CR patients. Conversely, in high CR patients only, WMLs (but not MTA) highly contributed in increasing the risk for conversion to AD. In conclusion, CR interacts with both patients' cognitive features and WMLs in modulating the impact of AD pathology. This seems relevant for clinical prognosis and therapeutic strategies.
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http://dx.doi.org/10.1016/j.neurobiolaging.2014.10.010DOI Listing
February 2015

The impact of cognitive reserve on brain functional connectivity in Alzheimer's disease.

J Alzheimers Dis 2015 ;44(1):243-50

Neuroimaging Laboratory, IRCSS Santa Lucia, Rome, Italy Clinical Imaging Sciences Centre, Brighton and Sussex Medical School, Falmer, East Sussex, United Kingdom.

One factor believed to impact brain resilience to the pathological damage of Alzheimer's disease (AD) is the so-called "cognitive reserve" (CR). A critical issue that still needs to be fully understood is the mechanism by which environmental enrichment interacts with brain plasticity to determine resilience to AD pathology. Previous work using PET suggests that increased brain connectivity might be at the origin of the compensatory mechanisms implicated in this process. This study aims to further clarify this issue using resting-state functional MRI. Resting-state functional MRI was collected for 11 patients with AD, 18 with mild cognitive impairment (MCI), and 16 healthy controls, and analyzed to isolate the default mode network (DMN). A quantitative score of CR was obtained by combining information about number of years of education and type of schools attended. Consistent with previous reports, education was found to modulate functional connectivity in the posterior cingulate cortex, whose disconnection with the temporal lobes is known to be critical for the conversion from MCI to AD. This effect was highly significant in AD patients, less so in patients with MCI, and absent in healthy subjects. These findings show the potential neural mechanisms underlying the individual's ability to cope with brain damage, although they should be treated with some caution based on small numbers.
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http://dx.doi.org/10.3233/JAD-141824DOI Listing
September 2015