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52. Brain imaging of the cortex in ADHD: A coordinated analysis of large-scale clinical and population-based samples

Author

Hoogman, M., Muetzel, R., Guimaraes, J.P., Shumskaya, E., Mennes, M., Zwiers, M.P., Jahanshad, N., Sudre, G., Wolfers, T., Earl, E.A., oliva Vila, J.C. S, Vives-Gilabert, Y., Khadka, S., Novotny, S.E., Hartman, Catharina, Heslenfeld, D.J., Schweren, L.J., Ambrosino, S., Oranje, B., Zeeuw, P. de, Chaim-Avancini, T.M., Rosa, P.G., Zanetti, M.V., Malpas, C.B., Kohls, G., Polier, G.G. von, Seitz, J., Biederman, J., Doyle, A.E., Dale, A.M., Erp, T.G. van, Epstein, J.N., Jernigan, T.L., Baur-Streubel, R., Ziegler, G.C., Zierhut, K.C., Schrantee, A., Hovik, M.F., Lundervold, A.J., Kelly, C., McCarthy, H., Skokauskas, N., O'Gorman Tuura, R.L., Calvo, A., Lera-Miguel, S., Nicolau, R., Chantiluke, K.C., Christakou, A., Vance, A., Cercignani, M., Gabel, M.C., Asherson, P., Baumeister, S., Brandeis, D., Hohmann, S., Bramati, I.E., Tovar-Moll, F., Fallgatter, A.J., Kardatzki, B., Schwarz, L., Anikin, A., Baranov, A., Gogberashvili, T., Kapilushniy, D., Solovieva, A., Marroun, H. El, White, T., Karkashadze, G., Namazova-Baranova, L., Ethofer, T., Mattos, P., Banaschewski, T., Coghill, D., Plessen, K.J., Kuntsi, J., Mehta, M.A., Paloyelis, Y., Harrison, N.A., Bellgrove, M.A., Silk, T.J., Cubillo, A.I., Rubia, K., Lazaro, L., Brem, S., Walitza, S., Frodl, T., Zentis, M., Castellanos, F.X., Yoncheva, Y.N., Haavik, J., Reneman, L., Conzelmann, A., Lesch, K.P., Pauli, P., Reif, A., Tamm, L., Konrad, K., Oberwelland Weiss, E., Busatto, G.F., Louza, M.R., Durston, S., Hoekstra, P.J., Oosterlaan, J., Stevens, M.C., Ramos-Quiroga, J.A., Vilarroya, O., Fair, D.A., Nigg, J.T., Thompson, P.M., Buitelaar, J.K., Faraone, S.V, Shaw, P., Tiemeier, H., Bralten, J., Franke, B., Hoogman, M., Muetzel, R., Guimaraes, J.P., Shumskaya, E., Mennes, M., Zwiers, M.P., Jahanshad, N., Sudre, G., Wolfers, T., Earl, E.A., oliva Vila, J.C. S, Vives-Gilabert, Y., Khadka, S., Novotny, S.E., Hartman, Catharina, Heslenfeld, D.J., Schweren, L.J., Ambrosino, S., Oranje, B., Zeeuw, P. de, Chaim-Avancini, T.M., Rosa, P.G., Zanetti, M.V., Malpas, C.B., Kohls, G., Polier, G.G. von, Seitz, J., Biederman, J., Doyle, A.E., Dale, A.M., Erp, T.G. van, Epstein, J.N., Jernigan, T.L., Baur-Streubel, R., Ziegler, G.C., Zierhut, K.C., Schrantee, A., Hovik, M.F., Lundervold, A.J., Kelly, C., McCarthy, H., Skokauskas, N., O'Gorman Tuura, R.L., Calvo, A., Lera-Miguel, S., Nicolau, R., Chantiluke, K.C., Christakou, A., Vance, A., Cercignani, M., Gabel, M.C., Asherson, P., Baumeister, S., Brandeis, D., Hohmann, S., Bramati, I.E., Tovar-Moll, F., Fallgatter, A.J., Kardatzki, B., Schwarz, L., Anikin, A., Baranov, A., Gogberashvili, T., Kapilushniy, D., Solovieva, A., Marroun, H. El, White, T., Karkashadze, G., Namazova-Baranova, L., Ethofer, T., Mattos, P., Banaschewski, T., Coghill, D., Plessen, K.J., Kuntsi, J., Mehta, M.A., Paloyelis, Y., Harrison, N.A., Bellgrove, M.A., Silk, T.J., Cubillo, A.I., Rubia, K., Lazaro, L., Brem, S., Walitza, S., Frodl, T., Zentis, M., Castellanos, F.X., Yoncheva, Y.N., Haavik, J., Reneman, L., Conzelmann, A., Lesch, K.P., Pauli, P., Reif, A., Tamm, L., Konrad, K., Oberwelland Weiss, E., Busatto, G.F., Louza, M.R., Durston, S., Hoekstra, P.J., Oosterlaan, J., Stevens, M.C., Ramos-Quiroga, J.A., Vilarroya, O., Fair, D.A., Nigg, J.T., Thompson, P.M., Buitelaar, J.K., Faraone, S.V, Shaw, P., Tiemeier, H., Bralten, J., and Franke, B.

Abstract

Contains fulltext : 204879.pdf (publisher's version ) (Closed access) Contains fulltext : 204879pos.pdf (postprint version ) (Open Access), OBJECTIVE: Neuroimaging studies show structural alterations of various brain regions in children and adults with attention deficit hyperactivity disorder (ADHD), although nonreplications are frequent. The authors sought to identify cortical characteristics related to ADHD using large-scale studies. METHODS: Cortical thickness and surface area (based on the Desikan-Killiany atlas) were compared between case subjects with ADHD (N=2,246) and control subjects (N=1,934) for children, adolescents, and adults separately in ENIGMA-ADHD, a consortium of 36 centers. To assess familial effects on cortical measures, case subjects, unaffected siblings, and control subjects in the NeuroIMAGE study (N=506) were compared. Associations of the attention scale from the Child Behavior Checklist with cortical measures were determined in a pediatric population sample (Generation-R, N=2,707). RESULTS: In the ENIGMA-ADHD sample, lower surface area values were found in children with ADHD, mainly in frontal, cingulate, and temporal regions; the largest significant effect was for total surface area (Cohen's d=-0.21). Fusiform gyrus and temporal pole cortical thickness was also lower in children with ADHD. Neither surface area nor thickness differences were found in the adolescent or adult groups. Familial effects were seen for surface area in several regions. In an overlapping set of regions, surface area, but not thickness, was associated with attention problems in the Generation-R sample. CONCLUSIONS: Subtle differences in cortical surface area are widespread in children but not adolescents and adults with ADHD, confirming involvement of the frontal cortex and highlighting regions deserving further attention. Notably, the alterations behave like endophenotypes in families and are linked to ADHD symptoms in the population, extending evidence that ADHD behaves as a continuous trait in the population. Future longitudinal studies should clarify individual lifespan trajectories that lead to nons

Published
2019

53. Non-linear spelling in writing after a pure cerebellar lesion

Author

Lupo, M., Siciliano, L., Olivito, G., Masciullo, M., Bozzali, M., Molinari, M., Cercignani, M., Silveri, Maria Caterina, Leggio, M., Silveri M. C. (ORCID:0000-0001-5012-0682), Lupo, M., Siciliano, L., Olivito, G., Masciullo, M., Bozzali, M., Molinari, M., Cercignani, M., Silveri, Maria Caterina, Leggio, M., and Silveri M. C. (ORCID:0000-0001-5012-0682)

Abstract

The most common deficits in processing written language result from damage to the graphemic buffer system and refer to semantic and lexical problems or difficulties in phoneme-graphene conversion. However, a writing disorder that has not yet been studied in depth is the non-linear spelling phenomenon. Indeed, although some cases have been described, no report has exhaustively explained the cognitive mechanism and the anatomical substrates underlying this process. In the present study, we analyzed the modality of non-linear writing in a patient affected by a focal cerebellar lesion, who presented with an alteration of the normal trend to write the order of the letters. Based on this evidence, we analyzed the functional connectivity between the cerebellum and the brain network that subtends handwriting and demonstrated how the cerebellar lesion of the patient affected the connections between the cerebellum and cortical areas that support the anatomical system of writing. This is the first report of non-linear spelling in a patient with a lesion outside the fronto-parietal network, specifically with a focal cerebellar lesion. We propose that non-linear writing can be interpreted in view of the role of the cerebellum in timing and sequential processing. Thus, considering the current functional connectivity data, we hypothesize that the cerebellum might be relevant in the mechanism that allows the correct activation timing of letters within a string and placement of the letters in a specific sequential writing order.

Published
2019

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

Author

Giulietti, G., Torso, M., Serra, L., Spano, B., Marra, Camillo, Caltagirone, C., Cercignani, M., Bozzali, M., Marra C. (ORCID:0000-0003-3994-4044), Giulietti, G., Torso, M., Serra, L., Spano, B., Marra, Camillo, Caltagirone, C., Cercignani, M., Bozzali, M., and Marra C. (ORCID:0000-0003-3994-4044)

Abstract

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 T1-weighted volumes for tissue segmentation and T2-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 o

Published
2018

59. Patterns of cerebellar gray matter atrophy across Alzheimer’s disease progression

Author

Toniolo, S., Serra, L., Olivito, G., Marra, Camillo, Bozzali, M., Cercignani, M., Marra C. (ORCID:0000-0003-3994-4044), Toniolo, S., Serra, L., Olivito, G., Marra, Camillo, Bozzali, M., Cercignani, M., and Marra C. (ORCID:0000-0003-3994-4044)

Abstract

The role of the cerebellum in cognitive function has been broadly investigated in the last decades from an anatomical, clinical, and functional point of view and new evidence points toward a significant contribution of the posterior lobes of the cerebellum in cognition in Alzheimer’s disease (AD). In the present work we used SUIT-VBM (spatially unbiased infratentorial template, voxel-based morphometry) to perform an analysis of the pattern of cerebellar gray matter (GM) atrophy in amnestic mild cognitive impairment (a-MCI) and AD dementia patients compared to healthy subjects (HS), in order to follow the changes of non-motor features of cerebellar degeneration throughout disease progression. This template has been validated to guarantee a significant improvement in voxel-to-voxel alignment of the individual fissures and the deep cerebellar nuclei compared to Montreal Neurological Institute (MNI) whole-brain template. Our analysis shows a progression of cerebellar GM volume changes throughout a continuous spectrum from early to late clinical stages of AD. In particular vermis and paravermian areas of the anterior (I-V) and posterior (VI) lobes are involved since the a-MCI stage, with a later involvement of the hemispheric part of the posterior lobes (VI lobule) and Crus I in AD dementia patients only. These findings support the role of the cerebellum in higher-level functions, and whilst confirming previous data on the involvement of Crus I in AD dementia, provide new evidence of an involvement of the vermis in the early stages of the disease.

Published
2018

60. In vivo mapping of brainstem nuclei functional connectivity disruption in Alzheimer's disease

Author

Serra, L., D'Amelio, M., Di Domenico, C., Dipasquale, O., Marra, Camillo, Mercuri, N. B., Caltagirone, C., Cercignani, M., Bozzali, M., Marra C. (ORCID:0000-0003-3994-4044), Serra, L., D'Amelio, M., Di Domenico, C., Dipasquale, O., Marra, Camillo, Mercuri, N. B., Caltagirone, C., Cercignani, M., Bozzali, M., and Marra C. (ORCID:0000-0003-3994-4044)

Abstract

We assessed here functional connectivity changes in the locus coeruleus (LC) and ventral tegmental area (VTA) of patients with Alzheimer's disease (AD). We recruited 169 patients with either AD or amnestic mild cognitive impairment due to AD and 37 elderly controls who underwent cognitive and neuropsychiatric assessments and resting-state functional magnetic resonance imaging at 3T. Connectivity was assessed between LC and VTA and the rest of the brain. In amnestic mild cognitive impairment patients, VTA disconnection was predominant with parietal regions, while in AD patients, it involved the posterior nodes of the default-mode network. We also looked at the association between neuropsychiatric symptoms (assessed by the neuropsychiatric inventory) and VTA connectivity. Symptoms such as agitation, irritability, and disinhibition were associated with VTA connectivity with the parahippocampal gyrus and cerebellar vermis, while sleep and eating disorders were associated with VTA connectivity to the striatum and the insular cortex. This suggests a contribution of VTA degeneration to AD pathophysiology and to the occurrence of neuropsychiatric symptoms. We did not find evidence of LC disconnection, but this could be explained by the size of this nucleus, which makes it difficult to isolate. These results are consistent with animal findings and have potential implications for AD prognosis and therapies.

Published
2018

61. Binge drinking differentially affects cortical and subcortical microstructure

Author

Morris, LS, Dowell, NG, Cercignani, M, Harrison, NA, Voon, V, Voon, Valerie [0000-0001-6790-1776], and Apollo - University of Cambridge Repository

Subjects
Adult, Cerebral Cortex, Male, Adolescent, Brain, QP0351, Dendrites, Q1, Binge Drinking, Frontal Lobe, Young Adult, Diffusion Magnetic Resonance Imaging, Case-Control Studies, Ventral Striatum, Neurites, Humans, Female, Gray Matter
Abstract

Young adult binge drinkers represent a model for endophenotypic risk factors for alcohol misuse and early exposure to repeated binge cycles. Chronic or harmful alcohol use leads to neurochemical, structural and morphological neuroplastic changes, particularly in regions associated with reward processing and motivation. We investigated neural microstructure in 28 binge drinkers compared with 38 matched healthy controls. We used a recently developed diffusion magnetic resonance imaging acquisition and analysis, which uses three-compartment modelling (of intracellular, extracellular and cerebrospinal fluid) to determine brain tissue microstructure features including neurite density and orientation dispersion index (ODI). Binge drinkers had reduced ODI, a proxy of neurite complexity, in frontal cortical grey matter and increased ODI in parietal grey matter. Neurite density was higher in cortical white matter in adjacent regions of lower ODI in binge drinkers. Furthermore, binge drinkers had higher ventral striatal grey matter ODI that was positively correlated with binge score. Healthy volunteers showed no such relationships. We demonstrate disturbed dendritic complexity of higher-order prefrontal and parietal regions, along with higher dendritic complexity of a subcortical region known to mediate reward-related motivation. The findings illustrate novel microstructural abnormalities that may reflect an infnce of alcohol bingeing on critical neurodevelopmental processes in an at-risk young adult group.

Published
2017
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65. Acute changes in striatal microstructure predict the development of interferon-alpha induced fatigue

Author

Dowell, N. G., Cooper, E. A., Tibble, J., Voon, V., Critchley, H. D., Cercignani, M., and Harrison, N. A.

Abstract

Interferon-alpha (IFN-α) is a key mediator of antiviral immune responses used clinically for hepatitis C treatment. Though effective, IFN-α induces marked behavioral changes that, when severe, can appear indistinguishable from major depression. Curiously, fatigue and motivational impairment evolve rapidly, suggesting acute engagement of immune-brain communicatory pathways, yet mood impairments typically emerge later, after weeks of treatment. Whether this reflects prolonged modulation of motivational processes underpinning fatigue or separate neurobiological mechanisms is currently unclear.Here, we used quantitative magnetization transfer (qMT) imaging, an advanced microstructural neuroimaging technique sensitive to effects of inflammation, in a prospective study design to measure acute brain changes to IFN-α and relate these to later development of discrete behavioral changes. Twenty-three patients initiating IFN-α treatment for hepatitis C underwent qMT imaging and blood sampling at baseline and 4 hours after their first IFN-α injection. Comprehensive behavioral and psychological assessments were completed at both scanning sessions and at treatment weeks 4, 8, 12, and 24.IFN-α injection stimulated an acute inflammatory cytokine response and evoked fatigue that peaked between 4 and 12 weeks, preceding mood change by 4 weeks. In the brain, IFN-α induced an acute change in striatal microstructure that additionally predicted development of fatigue but not mood symptoms.Our findings highlight qMT as an in vivo biomarker of central effects of peripheral inflammation. We demonstrate exquisite sensitivity of the striatum to IFN-α, implicate striatal perturbation in IFN-α-induced fatigue, and dissociate this from mechanisms underlying IFN-α-induced mood symptoms, providing empirical support for distinct neural substrates mediating actions on motivation and mood.

Published
2016

67. Quantitative magnetization transfer imaging as a biomarker for effects of systemic inflammation on the brain

Author

Harrison, N.A., Cooper, E., Dowell, N.G., Keramida, G., Voon, V., Critchley, H.D., and Cercignani, M.

Abstract

BackgroundSystemic inflammation impairs brain function and is increasingly implicated in the etiology of common mental illnesses, particularly depression and Alzheimer’s disease. Immunotherapies selectively targeting proinflammatory cytokines demonstrate efficacy in a subset of patients with depression. However, efforts to identify patients most vulnerable to the central effects of inflammation are hindered by insensitivity of conventional structural magnetic resonance imaging.MethodsWe used quantitative magnetization transfer (qMT) imaging, a magnetic resonance imaging technique that enables quantification of changes in brain macromolecular density, together with experimentally induced inflammation to investigate effects of systemic inflammatory challenge on human brain microstructure. Imaging with qMT was performed in 20 healthy participants after typhoid vaccination and saline control injection. An additional 20 participants underwent fluorodeoxyglucose positron emission tomography following the same inflammatory challenge.ResultsThe qMT data demonstrated that inflammation induced a rapid change in brain microstructure, reflected in increased magnetization exchange from free (water) to macromolecular-bound protons, within a discrete region of insular cortex implicated in representing internal physiologic states including inflammation. The functional significance of this change in insular microstructure was demonstrated by correlation with inflammation-induced fatigue and fluorodeoxyglucose positron emission tomography imaging, which revealed increased resting glucose metabolism within this region following the same inflammatory challenge.ConclusionsTogether these observations highlight a novel structural biomarker of the central physiologic and behavioral effects of mild systemic inflammation. The widespread clinical availability of magnetic resonance imaging supports the viability of qMT imaging as a clinical biomarker in trials of immunotherapeutics, both to identify patients vulnerable to the effects of systemic inflammation and to monitor neurobiological responses.

Published
2015

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

Author

Serra, L, Mancini, M, Silvestri, Gabriella, Petrucci, A, Masciullo, M, Spanò, B, Torso, M, Mastropasqua, C, Giacanelli, M, Caltagirone, C, Cercignani, M, Meola, G, Bozzali, M., Silvestri, Gabriella (ORCID:0000-0002-1950-1468), Serra, L, Mancini, M, Silvestri, Gabriella, Petrucci, A, Masciullo, M, Spanò, B, Torso, M, Mastropasqua, C, Giacanelli, M, Caltagirone, C, Cercignani, M, Meola, G, Bozzali, M., and Silvestri, Gabriella (ORCID:0000-0002-1950-1468)

Abstract

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

Published
2016

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

Author

Serra, L, Cercignani, M, Bruschini, M, Cipolotti, L, Mancini, M, Silvestri, Gabriella, Petrucci, A, Bucci, E, Antonini, G, Licchelli, L, Spanò, B, Giacanelli, M, Caltagirone, C, Meola, G, Bozzali, M., Silvestri, Gabriella (ORCID:0000-0002-1950-1468), Serra, L, Cercignani, M, Bruschini, M, Cipolotti, L, Mancini, M, Silvestri, Gabriella, Petrucci, A, Bucci, E, Antonini, G, Licchelli, L, Spanò, B, Giacanelli, M, Caltagirone, C, Meola, G, Bozzali, M., and Silvestri, Gabriella (ORCID:0000-0002-1950-1468)

Abstract

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.

Published
2016

73. The Impact of Cognitive Reserve on Brain Functional Connectivity in Alzheimer's Disease

Author

Bozzali, M, Dowling, C, Serra, L, Spanò, B, Torso, Mario, Marra, Camillo, Castelli, Daniela, Dowell, Ng, Koch, Giacomo, Caltagirone, C, Cercignani, M., Marra, Camillo (ORCID:0000-0003-3994-4044), Bozzali, M, Dowling, C, Serra, L, Spanò, B, Torso, Mario, Marra, Camillo, Castelli, Daniela, Dowell, Ng, Koch, Giacomo, Caltagirone, C, Cercignani, M., and Marra, Camillo (ORCID:0000-0003-3994-4044)

Abstract

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.

Published
2015

74. Inter-sequence and inter-imaging unit variability of diffusion tensor MR imaging histogram-derived metrics of the brain in healthy volunteers

Author

Cercignani, M., Bammer, R., Sormani, M. P., Fazekas, F., Massimo Filippi, Cercignani, M, Bammer, R, Sormani, Mp, Fazekas, F, and Filippi, Massimo

Subjects
Analysis of Variance, Diffusion Magnetic Resonance Imaging, Image Processing, Computer-Assisted, Brain, Humans, Multicenter Studies as Topic, Reproducibility of Results, Longitudinal Studies, Reference Standards
Abstract

BACKGROUND AND PURPOSE: Diffusion tensor MR imaging has the potential to improve our ability to monitor several neurologic conditions. As a preliminary step to the assessment of the role of diffusion tensor MR imaging in the context of longitudinal and multicenter studies, we evaluated the effect of sequence-, imaging unit-, and imaging-reimaging-induced variations on diffusion tensor MR imaging quantities derived from histogram analysis of a large portion of the central brain of healthy volunteers. METHODS: Each of eight healthy volunteers underwent imaging on two MR imaging units using three different pulsed gradient spin-echo single shot echo-planar pulse sequences (each of them having a different diffusion gradient scheme). Four additional healthy participants underwent imaging twice on the same imaging unit to assess imaging-reimaging variability. RESULTS: For mean diffusivity histograms, the differences between inter-sequence and inter-imaging unit coefficients of variation were significant for all the considered quantities with P values ranging from .003 to

Published
2003

75. Age-related Changes in Conventional, Magnetization Transfer, and Diffusion-Tensor MR Imaging Findings: Study with Whole-Brain Tissue Histogram Analysis

Author

Rovaris, M, Iannucci, G, Cercignani, M, Sormani, MARIA PIA, DE STEFANO, N, Gerevini, S, Comi, G, AGE RELATED, FILIPPI M., Rovaris, M, Iannucci, G, Cercignani, M, Sormani, Mp, De Stefano, N, Gerevini, S, Comi, G, and Filippi, M

Subjects
Adult, Male, aging, brain, atrophy, brain, MR, magnetic resonance (MR), diffusion tensor, magnetic resonance (MR), magnetization transfer, brain, diffusion tensor, aging, MR, Magnetic Resonance Imaging, Diffusion Magnetic Resonance Imaging, atrophy, Image Processing, Computer-Assisted, Humans, Regression Analysis, Female, magnetic resonance (MR)
Abstract

To investigate the influence of aging on conventional magnetic resonance (MR) imaging-, magnetization transfer MR imaging-, and diffusion-tensor MR imaging-derived measurements.Dual-echo T1-weighted magnetization transfer and diffusion-tensor MR images of the brain were obtained in 89 healthy subjects. Normalized brain parenchymal volume (NBV) was measured by using a fully automated technique. Magnetization transfer ratio (MTR), apparent diffusion coefficient (ADC), and fractional anisotropy (FA) histograms were created for the whole brain (MTR values) or for a large representative portion of it (ADC and FA values). Bivariate correlations were assessed by using the Spearman rank correlation coefficient. A stepwise selection procedure was used to identify the combination of variables that were most influenced by subject age in a multivariate regression model.Significant correlations were found between subject age and the following variables: number of hyperintense areas in the brain at T2-weighted MR imaging (r = 0.63, P.001), NBV (r = -0.79, P.001), mean ADC (r = 0.34, P =.001), ADC peak height (r = -0.34, P =.001), and FA peak height (r = -0.57, P.001). NBV correlated significantly with number of hyperintense areas (P.001), MTR peak height (P.001), mean ADC (P =.001), ADC peak height (P =.001), and FA peak height (P.001). The final multivariable regression model included NBV and number of hyperintense areas at T2-weighted MR imaging as independent predictors of subject age.In addition to the extent of T2-weighted MR imaging hyperintense areas and the measurement of NBV, diffusion-tensor MR imaging provides additional in vivo information about microstructural age-related brain tissue changes.

Published
2003

79. A new approach to structural integrity assessment based on axial and radial diffusivities

Author

Ca, Wheeler-Kingshott, Olga Ciccarelli, Schneider T, Dc, Alexander, and Cercignani M

Subjects
Adult, Male, Diffusion Tensor Imaging, Anisotropy, Brain, Humans, Female, Original Articles, Middle Aged, Nerve Fibers, Myelinated
Abstract

This study describes a method for performing diffusivity measures along and across a specific direction, derived from white matter in healthy controls. The diffusion tensor (DT) assigns a principal eigenvector (v₁) and eigenvalue (axial diffusivity, d(ax)) to each voxel. The average of the second and third eigenvalues is the radial diffusivity, d(rad) v₁ may be affected by pathology, therefore when comparing d(ax) and d(rad) in patients one has to consider the direction of the measurement and underlying anatomy. Here we created a representative super-DT dataset, DT(ref), whose eigenvector, v(1,ref), was considered the most likely direction of diffusivity per voxel. We defined the projected axial diffusivity, d(p-ax), as the projection of individual DTs along v(1,ref) and the projected radial diffusivity, d(p-rad), as the average of the projections along the second and third eigenvectors of DT(ref). The projected diffusivities are promising new parameters for studying white matter pathology.

Published
2012

82. A comparison of MR imaging with fast-FLAIR, HASTE-FLAIR, and EPI-FLAIR sequences in the assessment of patients with multiple sclerosis

Author

Massimo Filippi, Rocca, Ma, Wiessmann, M., Mennea, S., Cercignani, M., Yousry, Ta, Sormani, Mp, Comi, G., Filippi, Massimo, Rocca, Ma, Wiessmann, M, Mennea, S, Cercignani, M, Yousry, Ta, Sormani, Mp, and Comi, Giancarlo

Subjects
Adult, Male, Multiple Sclerosis, Fourier Analysis, Echo-Planar Imaging, Brain, Humans, Female, Middle Aged, Image Enhancement, Magnetic Resonance Imaging, Sensitivity and Specificity
Abstract

BACKGROUND AND PURPOSE: Fast fluid-attenuated inversion-recovery (FLAIR) sequences are sensitive for detecting lesions in patients with multiple sclerosis (MS). More rapid fast-FLAIR imaging of the brain can be achieved by the concomitant use of half-Fourier acquisition single-shot turbo spin-echo (HASTE-FLAIR) and echo-planar imaging (EPI-FLAIR). The present study was performed in a large cohort of subjects to assess and compare the number and volume of brain lesions detected by the fast-FLAIR, HASTE-FLAIR, and EPI-FLAIR sequences in patients with MS. METHODS: Fast-FLAIR, HASTE-FLAIR, and EPI-FLAIR sequences were obtained from 46 consecutive MS patients. Lesions seen on each type of sequence were counted and classified by consensus by two observers. Lesion volumes were measured using a semiautomated segmentation technique based on local thresholding. RESULTS: The quality of the fast-FLAIR images was significantly better than that of HASTE-FLAIR and EPI-FLAIR images. Fast-FLAIR revealed significantly more lesions and higher lesion volumes than did HASTE-FLAIR and EPI-FLAIR. A similar number of large lesions was detected by the three sequences, but HASTE-FLAIR and EPI-FLAIR showed significantly fewer small and intermediate lesions than did fast-FLAIR. The number of lesions seen on HASTE-FLAIR and EPI-FLAIR images was similar. CONCLUSION: HASTE-FLAIR and EPI-FLAIR sequences revealed as many large MS lesions as fast-FLAIR. Because their acquisition times are only a fraction of that needed for fast-FLAIR sequences, they may be useful for making a rapid diagnosis of MS in uncooperative patients. Their reduced ability to detect smaller lesions indicates that they should not be used as a routine approach to imaging patients with MS.

Published
1999

83. Relevance of hypointense lesions on fast fluid-attenuated inversion recovery MR images as a marker of disease severity in cases of multiple sclerosis

Author

Rovaris, M., Comi, G., Maria A Rocca, Cercignani, M., Colombo, B., Santuccio, G., Filippi, M., Rovaris, M, Comi, G, Rocca, Ma, Cercignani, M, Colombo, B, Santuccio, G, and Filippi, M

Subjects
Adult, Male, Multiple Sclerosis, Recurrence, Disease Progression, Brain, Humans, Female, Middle Aged, Magnetic Resonance Imaging, Aged
Abstract

BACKGROUND AND PURPOSE: Hypointense lesions can be visible on fast fluid-attenuated inversion recovery (FLAIR) MR images of the brain of patients with multiple sclerosis (MS), and they may be produced by severely damaged white matter. To test the role of these lesions as an MR marker of MS severity, we assessed their relationship with clinical findings and other MR measures. METHODS: Using a 1.5-T scanner, dual-echo rapid acquisition with relaxation enhancement, fast FLAIR, and T1-weighted MR images (24 axial, 5-mm-thick contiguous interleaved sections) were obtained from 50 patients (32 with relapsing-remitting and 18 with secondary progressive MS). RESULTS: Hypointense lesions were visible on the fast FLAIR images of 19 patients (mean number of lesions, 7.8; range 1–22); their median load was 1.4 mL (range, 0.05–12.6 mL). The median lesion load was significantly higher in patients with secondary progressive MS than in those with relapsing-remitting MS on the T1-weighted images. Both the number and the load of hypointense lesions shown by fast FLAIR imaging were significantly higher in patients with secondary progressive MS. Significant correlations were found between Expanded Disability Status Scale scores and MR lesion load. A multivariate analysis showed that only the presence of hypointense lesions on fast FLAIR images significantly separated cases of relapsing-remitting MS from cases of secondary progressive MS (relative risk, 7.1; 95% confidence interval, 2.0–25.9). CONCLUSION: The presence of hypointense lesions on fast FLAIR images was a strong predictor of disease severity in cases of MS, although the low sensitivity of this approach might limit its use for the assessment of MS evolution.

Published
1999

90. Widespread alterations in functional brain network architecture in amnestic mild cognitive impairment

Author

Minati, L, Chan, D, Mastropasqua, C, Serra, L, Spanò, B, Marra, Camillo, Caltagirone, C, Cercignani, M, Bozzali, M., Marra, Camillo (ORCID:0000-0003-3994-4044), Minati, L, Chan, D, Mastropasqua, C, Serra, L, Spanò, B, Marra, Camillo, Caltagirone, C, Cercignani, M, Bozzali, M., and Marra, Camillo (ORCID:0000-0003-3994-4044)

Abstract

We investigated changes in functional network architecture in amnestic mild cognitive impairment using graph-based analysis of task-free functional magnetic resonance imaging and fine cortical parcellation. Widespread disconnection was observed primarily in cortical hubs known to manifest early Alzheimer's disease pathology, namely precuneus, parietal lobules, supramarginal and angular gyri, and cuneus, with additional involvement of subcortical regions, sensorimotor cortex and insula. The connectivity changes determined using graph-based analysis significantly exceed those detected using independent component analysis both in amplitude and topographical extent, and are largely decoupled from the presence of overt atrophy. This superior ability of graph-based analysis to detect disease-related disconnection highlights its potential use in the determination of biomarkers of early dementia. Graph-based analysis source code is provided as supplementary material.

Published
2014

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

Author

Serra, L, Musicco, M, Cercignani, M, Torso, Mario, Spanò, B, Mastropasqua, C, Giulietti, G, Marra, Camillo, Bruno, G, Koch, Giacomo, Caltagirone, C, Bozzali, M., Marra, Camillo (ORCID:0000-0003-3994-4044), Serra, L, Musicco, M, Cercignani, M, Torso, Mario, Spanò, B, Mastropasqua, C, Giulietti, G, Marra, Camillo, Bruno, G, Koch, Giacomo, Caltagirone, C, Bozzali, M., and Marra, Camillo (ORCID:0000-0003-3994-4044)

Abstract

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.

Published
2014

92. Constructional apraxia as a distinctive cognitive and structural brain feature of pre-senile Alzheimer's disease

Author

Serra, L, Fadda, L, Perri, R, Spanò, B, Marra, Camillo, Castelli, D, Torso, Mario, Makovac, E, Cercignani, M, Caltagirone, C, Bozzali, M., Marra, Camillo (ORCID:0000-0003-3994-4044), Serra, L, Fadda, L, Perri, R, Spanò, B, Marra, Camillo, Castelli, D, Torso, Mario, Makovac, E, Cercignani, M, Caltagirone, C, Bozzali, M., and Marra, Camillo (ORCID:0000-0003-3994-4044)

Abstract

Constructional apraxia (CA) is often, but not always, observed in patients with Alzheimer's disease (AD). CA is usually explained by impairment of either basic perceptual and motor abilities, or executive functions. This study aims to evaluate the structural correlates of CA in AD. Forty-eight patients with AD and 20 healthy age-matched controls underwent a thorough neuropsychological investigation and an MRI scan to collect high-resolution T1-weighted data. Patients were classified as having (ADca) or not having (ADnonca) CA based on performance on the Freehand copying of drawings task. T1-weighted volumes were process according to the voxel based morphometry protocol, to assess the presence of significant differences in local to grey matter volumes in patients compared to controls and in ADca compared to ADnonca. Post-hoc, the mean grey matter volume of clusters that resulted significantly different between groups was regressed against the neuropsychological scores in which the two patient groups performed differently. A pre-senile disease onset was significantly more frequent in patients with CA compared to ADnonca. ADca patients also showed worse performances than patients with ADnonca at some tests requiring the processing of visuo-spatial data and testing working memory. They also showed widespread reductions in grey matter volume, mainly located in areas known to be implicated in object recognition and localization, and in maintenance and re-orienting of spatial attention. These findings suggest that the occurrence of CA in AD is often associated with a peculiar clinical onset (i.e., pre-senile), neuropsychological profile, and distribution of grey matter atrophy.

Published
2014

93. Abnormal Functional Brain Connectivity and Personality Traits in Myotonic Dystrophy Type 1

Author

Silvestri, Gabriella, Serra, Laura, Petrucci, Antonio, Masciullo, Marcella, Basile, B, Makovac, E, Torso, M, Spanò, B, Mastropasqua, C, Harrison, Na, Bianchi, Maria Laura Ester, Caltagirone, C, Cercignani, M, Giacanelli, M., Silvestri, Gabriella (ORCID:0000-0002-1950-1468), Silvestri, Gabriella, Serra, Laura, Petrucci, Antonio, Masciullo, Marcella, Basile, B, Makovac, E, Torso, M, Spanò, B, Mastropasqua, C, Harrison, Na, Bianchi, Maria Laura Ester, Caltagirone, C, Cercignani, M, Giacanelli, M., and Silvestri, Gabriella (ORCID:0000-0002-1950-1468)

Abstract

IMPORTANCE Myotonic dystrophy type 1 (DM1), the most common muscular dystrophy observed in adults, is a genetic multisystem disorder affecting several other organs besides skeletal muscle, including the brain. Cognitive and personality abnormalities have been reported; however, no studies have investigated brain functional networks and their relationship with personality traits/disorders in patients with DM1. OBJECTIVE To use resting-state functional magnetic resonance imaging to assess the potential relationship between personality traits/disorders and changes to functional connectivity within the default mode network (DMN) in patients with DM1. DESIGN, SETTING, AND PARTICIPANTS We enrolled 27 patients with genetically confirmed DM1 and 16 matched healthy control individuals. Patients underwent personality assessment using clinical interview and Minnesota Multiphasic Personality Inventory-2 administration; all participants underwent resting-state functional magnetic resonance imaging. Investigations were conducted at the Istituto di Ricovero e Cura a Carattere Scientifico Santa Lucia Foundation, Catholic University of Sacred Heart, and Azienda Ospedaliera San Camillo Forlanini. INTERVENTION Resting-state functional magnetic resonance imaging. MAIN OUTCOMES AND MEASURES Measures of personality traits in patients and changes in functional connectivity within the DMN in patients and controls. Changes in functional connectivity and atypical personality traits in patients were correlated. RESULTS We combined results obtained from the Minnesota Multiphasic Personality Inventory-2 and clinical interview to identify a continuum of atypical personality profiles ranging from schizotypal personality traits to paranoid personality disorder within our DM1 patients. We also demonstrated an increase in functional connectivity in the bilateral posterior cingulate and left parietal DMN nodes in DM1 patients compared with controls. Moreover, patients with DM1 showed strong associati

Published
2014

99. Mild cognitive impairment: same identity for different entities

Author

Serra, L, Giulietti, G, Cercignani, M, Spanò, B, Torso, Mario, Castelli, D, Perri, R, Fadda, L, Marra, Camillo, Caltagirone, C, Bozzali, M., Marra, Camillo (ORCID:0000-0003-3994-4044), Serra, L, Giulietti, G, Cercignani, M, Spanò, B, Torso, Mario, Castelli, D, Perri, R, Fadda, L, Marra, Camillo, Caltagirone, C, Bozzali, M., and Marra, Camillo (ORCID:0000-0003-3994-4044)

Abstract

This study investigates whether different patterns of grey matter (GM) loss may account for the different neuropsychological profiles observed in patients with amnestic (a-) and non-amnestic (na-) mild cognitive impairment (MCI), and may predict patients' clinical evolution. Fifty-five consecutive individuals complaining of cognitive dysfunction (referred to specialist dementia clinics) were screened and included in the study if they met the diagnostic criteria for MCI on a neurodegenerative basis. After an extensive neuropsychological assessment, patients were classified as suffering from a-MCI or na-MCI. Twenty-eight healthy individuals were also recruited and served as controls. All participants underwent magnetic resonance imaging at 3T, including conventional images and volumetric scans. Volumetric data were processed using voxel-based morphometry to assess between-group differences in regional GM volumes and correlations with neuropsychological performances. When compared to controls, a-MCI patients showed prominent GM volume reductions in the medial temporal lobes, while those with na-MCI showed reduced GM volumes in the orbito-frontal cortex and basal ganglia. In a-MCI patients, significant associations were found between verbal long-term memory performance and GM volumes in the hippocampus. Conversely, in na-MCI patients, associations were found between scores at tests exploring executive functions and GM volumes in the orbito-frontal cortex. At one-year follow-up, conversions were recorded exclusively toward Alzheimer's disease (AD) in the a-MCI group, and toward non-AD dementia in the na-MCI group. This study confirms that MCI is a heterogeneous clinical identity including different neurodegenerative entities; specific patterns of regional GM loss appear to account for specific neuropsychological features and are likely to predict patients' clinical evolution.

Published
2013

100. Widespread Alterations in Functional Brain Network Architecture in Amnestic Mild Cognitive Impairment

Author

Minati, L, Chan, D, Mastropasqua, C, Serra, L, Spanò, B, Marra, Camillo, Caltagirone, C, Cercignani, M, Bozzali, M., Marra, Camillo (ORCID:0000-0003-3994-4044), Minati, L, Chan, D, Mastropasqua, C, Serra, L, Spanò, B, Marra, Camillo, Caltagirone, C, Cercignani, M, Bozzali, M., and Marra, Camillo (ORCID:0000-0003-3994-4044)

Abstract

We investigated changes in functional network architecture in amnestic mild cognitive impairment using graph-based analysis of task-free functional magnetic resonance imaging and fine cortical parcellation. Widespread disconnection was observed primarily in cortical hubs known to manifest early Alzheimer's disease pathology, namely precuneus, parietal lobules, supramarginal and angular gyri, and cuneus, with additional involvement of subcortical regions, sensorimotor cortex and insula. The connectivity changes determined using graph-based analysis significantly exceed those detected using independent component analysis both in amplitude and topographical extent, and are largely decoupled from the presence of overt atrophy. This superior ability of graph-based analysis to detect disease-related disconnection highlights its potential use in the determination of biomarkers of early dementia. Graph-based analysis source code is provided as supplementary material.

Published
2013

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