Publications by authors named "Marco Bozzali"

153 Publications

The distinct roles of monoamines in multiple sclerosis: a bridge between the immune and nervous systems?

Brain Behav Immun 2021 Mar 1. Epub 2021 Mar 1.

Department of Neuroscience, Brighton and Sussex Medical School, University of Sussex, United Kingdom; Rita Levi Montalcini Department of Neuroscience, University of Torino, Turin, Italy.

The monoaminergic neurotransmitters dopamine, noradrenaline, and serotonin are pivotal actors of the interplay between the nervous and the immune system due to their ability of binding to cell-receptors of both systems, crucially regulating their function within the central nervous system and the periphery. As monoamines are dysfunctional in many neurological and psychiatric diseases, they have been successfully used as pharmacological targets. Multiple sclerosis (MS) is one of the best examples of neurological disease caused by an altered interaction between the nervous and immune system and emerging evidence supports a dysregulation of monoaminergic systems in the pathogenesis of MS, secondary to both inflammation-induced reduction of monoamines' synthesis and structural damage to monoaminergic pathways within the brain. Here we review the evidence for monoamines being key mediators of neuroimmune interaction, affecting MS pathogenesis and course. Moreover, we discuss how the reduction/dysfunction of monoamines in MS may contribute to some clinical features typical of the disease, particularly fatigue and depression. Finally, we summarize different drugs targeting monoamines that are currently under evaluation for their potential efficacy to treat MS, as well as to alleviate fatigue and depression in MS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbi.2021.02.030DOI Listing
March 2021

Disruption of brainstem monoaminergic fibre tracts in multiple sclerosis as a putative mechanism for cognitive fatigue: a fixel-based analysis.

Neuroimage Clin 2021 Feb 12;30:102587. Epub 2021 Feb 12.

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

In multiple sclerosis (MS), monoaminergic systems are altered as a result of both inflammation-dependent reduced synthesis and direct structural damage. Aberrant monoaminergic neurotransmission is increasingly considered a major contributor to fatigue pathophysiology. In this study, we aimed to compare the integrity of the monoaminergic white matter fibre tracts projecting from brainstem nuclei in a group of patients with MS (n = 68) and healthy controls (n = 34), and to investigate its association with fatigue. Fibre tracts integrity was assessed with the novel fixel-based analysis that simultaneously estimates axonal density, by means of 'fibre density', and white matter atrophy, by means of fibre 'cross section'. We focused on ventral tegmental area, locus coeruleus, and raphe nuclei as the main source of dopaminergic, noradrenergic, and serotoninergic fibres within the brainstem, respectively. Fourteen tracts of interest projecting from these brainstem nuclei were reconstructed using diffusion tractography, and compared by means of the product of fibre-density and cross-section (FDC). Finally, correlations of monoaminergic axonal damage with the modified fatigue impact scale scores were evaluated in MS. Fixel-based analysis revealed significant axonal damage - as measured by FDC reduction - within selective monoaminergic fibre-tracts projecting from brainstem nuclei in MS patients, in comparison to healthy controls; particularly within the dopaminergic-mesolimbic pathway, the noradrenergic-projections to prefrontal cortex, and serotoninergic-projections to cerebellum. Moreover, we observed significant correlations between severity of cognitive fatigue and axonal damage within the mesocorticolimbic tracts projecting from ventral tegmental area, as well as within the locus coeruleus projections to prefrontal cortex, suggesting a potential contribution of dopaminergic and noradrenergic pathways to central fatigue in MS. Our findings support the hypothesis that axonal damage along monoaminergic pathways contributes to the reduction/dysfunction of monoamines in MS and add new information on the mechanisms by which monoaminergic systems contribute to MS pathogenesis and fatigue. This supports the need for further research into monoamines as therapeutic targets aiming to combat and alleviate fatigue in MS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nicl.2021.102587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903010PMC
February 2021

Lesion distribution and substrate of white matter damage in myotonic dystrophy type 1: Comparison with multiple sclerosis.

Neuroimage Clin 2021 14;29:102562. Epub 2021 Jan 14.

Clinical Imaging Sciences Centre, Brighton and Sussex Medical School, Brighton, United Kingdom; UOC Neurologia e Neurofisiopatologia, AO San Camillo Forlanini, Rome, Italy. Electronic address:

Myotonic Dystrophy type 1 (DM1) is an autosomal dominant condition caused by expansion of the CTG triplet repeats within the myotonic dystrophy protein of the kinase (DMPK) gene. The central nervous system is involved in the disease, with multiple symptoms including cognitive impairment. A typical feature of DM1 is the presence of widespread white matter (WM) lesions, whose total volume is associated with CTG triplet expansion. The aim of this study was to characterize the distribution and pathological substrate of these lesions as well as the normal appearing WM (NAWM) using quantitative magnetization transfer (qMT) MRI, and comparing data from DM1 patients with those from patients with multiple sclerosis (MS). Twenty-eight patients with DM1, 29 patients with relapsing-remitting MS, and 15 healthy controls had an MRI scan, including conventional and qMT imaging. The average pool size ratio (F), a proxy of myelination, was computed within lesions and NAWM for every participant. The lesion masks were warped into MNI space and lesion probability maps were obtained for each patient group. The lesion distribution, total lesion load and the tissue-specific mean F were compared between groups. The supratentorial distribution of lesions was similar in the 2 patient groups, although mean lesion volume was higher in MS than DM1. DM1 presented higher prevalence of anterior temporal lobe lesions, but none in the cerebellum and brainstem. Significantly reduced F values were found within DM1 lesions, suggesting a loss of myelin density. While F was reduced in the NAWM of MS patients, it did not differ between DM1 and controls. Our results provide further evidence for a need to compare histology and imaging using new MRI techniques in DM1 patients, in order to further our understanding of the underlying disease process contributing to WM disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nicl.2021.102562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848627PMC
January 2021

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hbm.25297DOI Listing
April 2021

White Matter Hyperintensities Are No Major Confounder for Alzheimer's Disease Cerebrospinal Fluid Biomarkers.

J Alzheimers Dis 2021 ;79(1):163-175

Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Centre, Radboud University Medical Center, Nijmegen, the Netherlands.

Background: The cerebrospinal fluid (CSF) biomarkers amyloid-β 1-42 (Aβ42), total and phosphorylated tau (t-tau, p-tau) are increasingly used to assist in the clinical diagnosis of Alzheimer's disease (AD). However, CSF biomarker levels can be affected by confounding factors.

Objective: To investigate the association of white matter hyperintensities (WMHs) present in the brain with AD CSF biomarker levels.

Methods: We included CSF biomarker and magnetic resonance imaging (MRI) data of 172 subjects (52 controls, 72 mild cognitive impairment (MCI), and 48 AD patients) from 9 European Memory Clinics. A computer aided detection system for standardized automated segmentation of WMHs was used on MRI scans to determine WMH volumes. Association of WMH volume with AD CSF biomarkers was determined using linear regression analysis.

Results: A small, negative association of CSF Aβ42, but not p-tau and t-tau, levels with WMH volume was observed in the AD (r2 = 0.084, p = 0.046), but not the MCI and control groups, which was slightly increased when including the distance of WMHs to the ventricles in the analysis (r2 = 0.105, p = 0.025). Three global patterns of WMH distribution, either with 1) a low, 2) a peak close to the ventricles, or 3) a high, broadly-distributed WMH volume could be observed in brains of subjects in each diagnostic group.

Conclusion: Despite an association of WMH volume with CSF Aβ42 levels in AD patients, the occurrence of WMHs is not accompanied by excess release of cellular proteins in the CSF, suggesting that WMHs are no major confounder for AD CSF biomarker assessment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-200496DOI Listing
January 2021

Automatic multispectral MRI segmentation of human hippocampal subfields: an evaluation of multicentric test-retest reproducibility.

Brain Struct Funct 2021 Jan 24;226(1):137-150. Epub 2020 Nov 24.

Center for Mind/Brain Sciences (CIMeC), University of Trento, Rovereto, Italy.

Accurate and reproducible automated segmentation of human hippocampal subfields is of interest to study their roles in cognitive functions and disease processes. Multispectral structural MRI methods have been proposed to improve automated hippocampal subfield segmentation accuracy, but the reproducibility in a multicentric setting is, to date, not well characterized. Here, we assessed test-retest reproducibility of FreeSurfer 6.0 hippocampal subfield segmentations using multispectral MRI analysis pipelines (22 healthy subjects scanned twice, a week apart, at four 3T MRI sites). The harmonized MRI protocol included two 3D-T1, a 3D-FLAIR, and a high-resolution 2D-T2. After within-session T1 averaging, subfield volumes were segmented using three pipelines with different multispectral data: two longitudinal ("long_T1s" and "long_T1s_FLAIR") and one cross-sectional ("long_T1s_FLAIR_crossT2"). Volume reproducibility was quantified in magnitude (reproducibility error-RE) and space (DICE coefficient). RE was lower in all hippocampal subfields, except for hippocampal fissure, using the longitudinal pipelines compared to long_T1s_FLAIR_crossT2 (average RE reduction of 0.4-3.6%). Similarly, the longitudinal pipelines showed a higher spatial reproducibility (1.1-7.8% of DICE improvement) in all hippocampal structures compared to long_T1s_FLAIR_crossT2. Moreover, long_T1s_FLAIR provided a small but significant RE improvement in comparison to long_T1s (p = 0.015), whereas no significant DICE differences were found. In addition, structures with volumes larger than 200 mm had better RE (1-2%) and DICE (0.7-0.95) than smaller structures. In summary, our study suggests that the most reproducible hippocampal subfield FreeSurfer segmentations are derived from a longitudinal pipeline using 3D-T1s and 3D-FLAIR. Adapting a longitudinal pipeline to include high-resolution 2D-T2 may lead to further improvements.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00429-020-02172-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817563PMC
January 2021

Detection of Alzheimer's Disease using cortical diffusion tensor imaging.

Hum Brain Mapp 2021 Mar 11;42(4):967-977. Epub 2020 Nov 11.

Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.

The aim of this research was to test a novel in-vivo brain MRI analysis method that could be used in clinical cohorts to investigate cortical architecture changes in patients with Alzheimer's Disease (AD). Three cohorts of patients with probable AD and healthy volunteers were used to assess the results of the method. The first group was used as the "Discovery" cohort, the second as the "Test" cohort and the last "ATN" (Amyloid, Tau, Neurodegeneration) cohort was used to test the method in an ADNI 3 cohort, comparing to amyloid and Tau PET. The method can detect altered quality of cortical grey matter in AD patients, providing an additional tool to assess AD, distinguishing between these and healthy controls with an accuracy range between good and excellent. These new measurements could be used within the "ATN" framework as an index of cortical microstructure quality and a marker of Neurodegeneration. Further development may aid diagnosis, patient selection, and quantification of the "Neurodegeneration" component in response to therapies in clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hbm.25271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856641PMC
March 2021

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/arclin/acaa089DOI Listing
October 2020

The Role of Amyloid-β in White Matter Damage: Possible Common Pathogenetic Mechanisms in Neurodegenerative and Demyelinating Diseases.

J Alzheimers Dis 2020 ;78(1):13-22

Department of Neuroscience 'Rita Levi Montalcini', University of Torino, Turin, Italy.

Just as multiple sclerosis (MS) has long been primarily considered a white matter (WM) disease, Alzheimer's disease (AD) has for decades been regarded only as a grey matter disorder. However, convergent evidences have suggested that WM abnormalities are also important components of AD, at the same extent as axonal and neuronal loss is critically involved in MS pathophysiology since early clinical stages. These observations have motivated a more thorough investigation about the possible mechanisms that could link neuroinflammation and neurodegeneration, focusing on amyloid-β (Aβ). Neuroimaging studies have found that patients with AD have widespread WM abnormalities already at the earliest disease stages and prior to the presence of Aβ plaques. Moreover, a correlation between cerebrospinal fluid (CSF) Aβ levels and WM lesion load was found. On the other hand, recent studies suggest a predictive role for CSF Aβ levels in MS, possibly due in the first instance to the reduced capacity for remyelination, consequently to a higher risk of WM damage progression, and ultimately to neuronal loss. We undertook a review of the recent findings concerning the involvement of CSF Aβ levels in the MS disease course and of the latest evidence of AD related WM abnormalities, with the aim to discuss the potential causes that may connect WM damage and amyloid pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-200868DOI Listing
January 2020

Neurological comorbidity and severity of COVID-19.

J Neurol 2021 Mar 4;268(3):762-769. Epub 2020 Aug 4.

Department of Neuroscience "Rita Levi Montalcini", University of Turin, Via Cherasco 15, 10126, Turin, Italy.

Objective: Neurological symptoms of COVID-19 patients have been recently described. However, no comprehensive data have been reported on pre-existing neurological comorbidities and COVID-19. This study aims at evaluating the prevalence of neurological comorbidities, and their association with COVID-19 severity.

Methods: We evaluated all consecutive patients admitted to the Emergency Room (ER) of our hospital between the 3rd March and the 14th April 2020, and diagnosed with COVID-19. Data on neurological and non-neurological diseases were extracted, as well as data on demographic characteristics and on severity degree of COVID-19. The prevalence of neurological comorbidities was calculated, and multivariate binary logistic regression analyses were used to estimate the association between neurological diseases and COVID-19 severity.

Results: We included 344 patients. Neurological comorbidities accounted for 22.4% of cases, with cerebrovascular diseases and cognitive impairment being the most frequent. Neurological comorbidity resulted independently associated with severe COVID-19 (OR 2.305; p = 0.012), as well as male gender (p = 0.001), older age (p = 0.001), neoplastic diseases (p = 0.039), and arterial hypertension (p = 0.045). When neurological comorbidity was associated with non-neurological comorbidities, the OR for severe COVID-19 rose to 7.394 (p = 0.005). Neurological patients, in particular cerebrovascular and cognitively impaired ones, received more respiratory support indication.

Conclusion: Neurological comorbidities represent a significant determinant of COVID-19 severity, deserving a thorough evaluation since the earliest phases of infection. The vulnerability of patients affected by neurological diseases should suggest a greater attention in targeting this population for proactive viral screening.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00415-020-10123-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400751PMC
March 2021

Behavioral psychological symptoms of dementia and functional connectivity changes: a network-based study.

Neurobiol Aging 2020 10 16;94:196-206. Epub 2020 Jun 16.

Department of Neuroscience, Brighton & Sussex Medical School, University of Sussex, Brithon, UK; Department of Neuroscience "Rita Levi Montalcini", University of Torino, Turin, Italy.

Behavioral and psychological symptoms of dementia (BPSD) are commonly observed since the early stage of Alzheimer's disease (AD) associated with structural brain changes. It is conceivable that they may also relate to functional brain changes. This resting-state functional MRI (RS-fMRI) study investigated the alterations within functional brain networks of a cohort of AD patients at different clinical stages who presented with BPSD. One hundred one AD patients and 56 patients with amnestic mild cognitive impairment underwent a neuropsychological evaluation including the Neuropsychiatry Inventory-12 (NPI-12). All patients and 35 healthy controls (HS) underwent 3T-MRI. Factor analysis was used to extract the principal factors from NPI-12, while RS-fMRI data were processed using graph theory to investigate functional connectivity. Five factors were extracted from NPI-12. Sixty-two percent of patients showed BPSD and functional brain connectivity changes in various networks compared to those without BPSD and HS. These changes contributed to account for patients' BPSD. This work opens new perspectives in terms of nonpharmacological interventions that might be designed to modulate brain connectivity and improve patients' BPSD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neurobiolaging.2020.06.009DOI Listing
October 2020

The impact of lacosamide on mood disorders in adult patients with epilepsy: A systematic review.

Epilepsy Behav 2020 10 10;111:107179. Epub 2020 Jun 10.

Clinical Imaging Sciences Centre, Brighton and Sussex Medical School, University of Sussex, Brighton, UK; Neuroscience Research Centre, St. George's University of London, London, UK.

Mood disorders such as depression and anxiety have a high prevalence in adult patients with epilepsy, and their evaluation is crucial in choosing the most appropriate antiepileptic drug (AED) with regard to side effects, which can account for long-term discontinuation, poor compliance, and ultimately, failure of seizure control. While more evidence is provided for older AEDs on their effect on mood changes, newer AEDs such as lacosamide have not yet been extensively studied. We performed a systematic review of the literature available on the impact of lacosamide on mood in adult patients with epilepsy. A literature search on MEDLINE, COCHRANE, Scielo, and Clinicaltrials.gov databases was performed, and articles where mood scales where specifically reported as primary or secondary outcome measures were included. Articles differed greatly in terms of inclusion criteria, concomitant AEDs, seizure reduction control, and outcome measures. If lacosamide is used as add-on, two studies point towards a beneficial effect on depressive and anxiety symptoms, two studies claim no effects on mood, and one reports a positive effect only in patients with major depressive symptoms at baseline. Additional evidence from either retrospective or comparative drug studies indicates no effects of lacosamide on mood. Even though presently, a negative effect on mood seems unlikely, whether lacosamide could exert a beneficial impact on mood remains controversial. Multicenter, randomized, controlled, double-blind studies are needed to assess the impact on lacosamide on mood disorders, given the low evidence level (Class III and IV) of currently available studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yebeh.2020.107179DOI Listing
October 2020

Changes in functional connectivity in people with HIV switching antiretroviral therapy.

J Neurovirol 2020 10 4;26(5):754-763. Epub 2020 Jun 4.

Department of Global Health and Infection, Brighton and Sussex Medical School, Brighton, BN1 9PX, UK.

We assessed changes in functional connectivity by fMRI (functional magnetic resonance imaging) and cognitive measures in otherwise neurologically asymptomatic people with HIV (PWH) switching combination antiretroviral therapy (cART). In a prospective study (baseline and follow-up after at least 4 months), virologically suppressed PWH switched non-nuclease reverse-transcriptase inhibitors (NNRTI; tenofovir-DF/emtricitabine with efavirenz to rilpivirine) and integrase-strand-transfer inhibitors (INSTI; tenofovir-DF/emtricitabine with raltegravir to dolutegravir). PWH were assessed by resting-state fMRI and stop-signal reaction time (SSRT) task fMRI as well as with a cognitive battery (CogState™) at baseline and follow-up. Switching from efavirenz to rilpivirine (n = 10) was associated with increased functional connectivity in the dorsal attention network (DAN) and a reduction in SSRTs (p = 0.025) that positively correlated with the time previously on efavirenz (mean = 4.8 years, p = 0.02). Switching from raltegravir to dolutegravir (n = 12) was associated with increased connectivity in the left DAN and bilateral sensory-motor and associative visual networks. In the NNRTI study, significant improvements in the cognitive domains of executive function, working memory and speed of visual processing were observed, whereas no significant changes in cognitive function were observed in the INSTI study. Changes in fMRI are evident in PWH without perceived neuropsychiatric complaints switching cART. fMRI may be a useful tool in assisting to elucidate the underlying pathogenic mechanisms of cART-related neuropsychiatric effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13365-020-00853-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532134PMC
October 2020

Ventral tegmental area dysfunction affects decision-making in patients with myotonic dystrophy type-1.

Cortex 2020 07 8;128:192-202. Epub 2020 Apr 8.

Neuroimaging Laboratory, IRCCS Fondazione Santa Lucia, Rome, Italy; Department of Neuroscience, Brighton & Sussex Medical School, University of Sussex, Brighton, East Sussex, United Kingdom. Electronic address:

The clinical manifestations of Myotonic Dystrophy type-1 (DM1) are associated with a complex mixture of multisystem features including cognitive dysfunctions that strongly impact on patients' social and occupational functioning. Decision making, a function controlled by dopaminergic circuitry, is critical for succeeding in one's social and professional life. We tested here the hypothesis that altered connectivity of the ventral tegmental area (VTA), one of the major sources of diffuse dopaminergic projections in the brain, might account for some higher-level dysfunctions observed in patients with DM1. In this case-control study, we recruited 31 patients with DM1 and 26 healthy controls who underwent the IOWA Gambling task and resting-state functional MRI (RS-fMRI) at 3T. Functional connectivity of the VTA was assessed using RS-fMRI. VTA connectivity was compared between 25 DM1 patients and all the controls, and the presence of associations between VTA connectivity and IOWA Gambling task performance was also investigated. DM1 patients performed significantly worse than controls at the IOWA Gambling task. A significant increase of functional connectivity was observed between VTA and the left supramarginal and superior temporal gyri in DM1 patients. Patients' IOWA Gambling task net-scores were strictly associated with VTA-driven functional connectivity in the bilateral supplementary motor area and right precentral gyrus. This study demonstrates a prominent deficit of decision-making in patients with DM1. It might be related to increased connectivity between VTA and brain areas critically involved in the reward/punishment system and social cognition. These findings indicate that dopaminergic function is a potential target for pharmacological and non-pharmacological interventions in DM1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cortex.2020.03.022DOI Listing
July 2020

Abnormal Cortical Thickness Is Associated With Deficits in Social Cognition in Patients With Myotonic Dystrophy Type 1.

Front Neurol 2020 28;11:113. Epub 2020 Feb 28.

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

To investigate the cortical thickness in myotonic dystrophy type 1 (DM1) and its potential association with patients' genetic triplet expansion and social cognition deficits. Thirty patients with DM1 underwent the Social Cognition Battery Test and magnetic resonance imaging (MRI) scanning at 3 T. Twenty-five healthy subjects (HSs) were enrolled in the study to serve as a control group for structural MRI data. To assess changes in cortical thickness in DM1 patients, they were compared to HSs using a -test model. Correlations were used to assess potential associations between genetic and clinical characteristics and social cognition performances in the patient group. Additionally, multiple regression models were used to explore associations between cortical thickness, CTG triplet expansion size, and scores obtained by DM1 patients on the Social Cognition Battery. DM1 patients showed low performances in several subtests of the Social Cognition Battery. Specifically, they obtained pathological scores at Emotion Attribution Test (i.e., Sadness, Embarrassment, Happiness, and Anger) and at the Social Situations Test (i.e., recognition of normal situation, recognition of aberrant behavior). Significant negative correlations were found between CTG triplet expansion size and Embarrassment, and Severity of Aberrant Behavior. Similarly, a negative correlation was found between patients' MIRS scores and Sadness. DM1 patients compared to HSs showed reduced thickness in the right premotor cortex, angular gyrus, precuneus, and inferior parietal lobule. Significant associations were found between patients' CTG triplet expansion size and thickness in left postcentral gyrus and in the left primary somatosensory cortex, in the posterior cingulate cortex bilaterally, and in the right lingual gyrus. Finally, significant associations were found between cortical thickness and sadness in the superior temporal gyrus, the right precentral gyrus, the right angular gyrus, and the left medial frontal gyrus bilaterally. DM1 patients showed a negative correlation between cortical thickness in the bilateral precuneus and in the left lateral occipital cortex and performance at the Social Situations Test. Finally, DM1 patients showed a negative correlation between cortical thickness in the left precuneus and in the superior frontal gyrus and scores at the Moral Distinction Test. The present study shows both cortical thickness changes in DM1 patients compared to controls and significant associations between cortical thickness and patients' social cognition performances. These data confirm the presence of widespread brain damages associated with cognitive impairment in DM1 patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2020.00113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059122PMC
February 2020

Cerebello-Cortical Alterations Linked to Cognitive and Social Problems in Patients With Spastic Paraplegia Type 7: A Preliminary Study.

Front Neurol 2020 25;11:82. Epub 2020 Feb 25.

Ataxia Laboratory, IRCCS Fondazione Santa Lucia, Rome, Italy.

Spastic paraplegia type 7 (SPG7), which represents one of the most common forms of autosomal recessive spastic paraplegia (MIM#607259), often manifests with a complicated phenotype, characterized by progressive spastic ataxia with evidence of cerebellar atrophy on brain MRI. Recent studies have documented the presence of peculiar dentate nucleus hyperintensities on T2-weighted images and frontal executive dysfunction in neuropsychological tests in SPG7 patients. Therefore, we decided to assess whether any particular MRI pattern might be specifically associated with SPG7 mutations and possibly correlated with patients' cognitive profiles. For this purpose, we evaluated six SPG7 patients, studying the cerebello-cortical network by MRI voxel-based morphometry and functional connectivity techniques, compared to 30 healthy control subjects. In parallel, we investigated the cognitive and social functioning of the SPG7 patients. Our results document specific cognitive alterations in language, verbal memory, and executive function in addition to an impairment of social task and emotional functions. The MRI scans showed a diffuse symmetric reduction in the cerebellar gray matter of the right lobule V, right Crus I, and bilateral lobule VI, together with a cerebral gray matter reduction in the lingual gyrus, precuneus, thalamus, and superior frontal gyrus. The evidence of an over-connectivity pattern between both the right and left cerebellar dentate nuclei and specific cerebral regions (the lateral occipital cortex, precuneus, left supramarginal gyrus, and left superior parietal lobule) confirms the presence of cerebello-cortical dysregulation in different networks involved in cognition and social functioning in SPG7 patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2020.00082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053515PMC
February 2020

Right fronto-parietal white matter disruption contributes to speech impairments in amyotrophic lateral sclerosis.

Brain Res Bull 2020 05 28;158:77-83. Epub 2020 Feb 28.

Department of Neuroscience, University of Sheffield, Sheffield, United Kingdom. Electronic address:

Introduction: Non-linguistic properties of speech are widely heterogeneous and require complex neurological integration. The association between white matter integrity and the severity of dysarthria was investigated in a group of patients diagnosed with amyotrophic lateral sclerosis (ALS).

Methods: Thirty-six patients diagnosed with amyotrophic lateral sclerosis completed a magnetic resonance imaging protocol inclusive of diffusion-weighted images. A clinical assessment of pneumo-phono-articulatory abilities was conducted for each patient, and a composite score of residual speech capacity was calculated. Tract-Based Spatial Statistics was carried out to model the potential association between residual speech capacity and microstructural properties of white matter (fractional anisotropy, mean and radial diffusivity).

Results: A significant negative association was found between residual speech capacity and mean diffusivity in a large white matter cluster located in frontal, parietal and right temporal regions. These subcortical areas were characterised by pathological microstructural disruption, as revealed by post hoc analyses.

Conclusions: Non-linguistic aspects of speech are associated with microstructural integrity of frontal, parietal and right temporal white matter in amyotrophic lateral sclerosis. Such mapping is consistent with the centres responsible of volitional control of speech and sensory feedback during non-linguistic speech production.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.brainresbull.2020.02.016DOI Listing
May 2020

Cerebellar dentate nucleus functional connectivity with cerebral cortex in Alzheimer's disease and memory: a seed-based approach.

Neurobiol Aging 2020 05 15;89:32-40. Epub 2020 Jan 15.

Neuroimaging Laboratory, Fondazione Santa Lucia-IRCCS, Rome, Italy; Clinical Imaging Sciences Center, Brighton and Sussex Medical School, Brighton, UK.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by specific patterns of gray and white matter damage and cognitive/behavioral manifestations. The cerebellum has also been implicated in the pathophysiology of AD. Because the cerebellum is known to have strong functional connectivity (FC) with associative cerebral cortex regions, it is possible to hypothesize that it is incorporated into intrinsic FC networks relevant to cognitive manifestation of AD. In the present study, the cerebellar dentate nucleus, the largest cerebellar nucleus and the major output channel to the cerebral cortex, was chosen as the region of interest to test potential cerebellocerebral FC alterations and correlations with patients' memory impairment in a group of patients with AD. Compared to controls, patients with AD showed an increase in FC between the dentate nucleus and regions of the lateral temporal lobe. This study demonstrates that lower memory performances in AD may be related to altered FC within specific cerebellocortical functional modules, thus suggesting the cerebellar contribution to AD pathophysiology and typical memory dysfunctions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neurobiolaging.2019.10.026DOI Listing
May 2020

Cerebellar White Matter Disruption in Alzheimer's Disease Patients: A Diffusion Tensor Imaging Study.

J Alzheimers Dis 2020 ;74(2):615-624

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

The cognitive role of the cerebellum has recently gained much attention, and its pivotal role in Alzheimer's disease (AD) has now been widely recognized. Diffusion tensor imaging (DTI) has been used to evaluate the disruption of the microstructural milieu in AD, and though several white matter (WM) tracts such as corpus callosum, inferior and superior longitudinal fasciculus, cingulum, fornix, and uncinate fasciculus have been evaluated in AD, data on cerebellar WM tracts are currently lacking. We performed a tractography-based DTI reconstruction of the middle cerebellar peduncle (MCP), and the left and right superior cerebellar peduncles separately (SCPL and SCPR) and addressed the differences in fractional anisotropy (FA), axial diffusivity (Dax), radial diffusivity (RD), and mean diffusivity (MD) in the three tracts between 50 patients with AD and 25 healthy subjects. We found that AD patients showed a lower FA and a higher RD compared to healthy subjects in MCP, SCPL, and SCPR. Moreover, higher MD was found in SCPR and SCPL and higher Dax in SCPL. This result is important as it challenges the traditional view that WM bundles in the cerebellum are unaffected in AD and might identify new targets for therapeutic interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-191125DOI Listing
January 2020

Evolutionary modifications in human brain connectivity associated with schizophrenia.

Brain 2019 12;142(12):3991-4002

Center for Translational Social Neuroscience, Emory University, Atlanta, GA, USA.

The genetic basis and human-specific character of schizophrenia has led to the hypothesis that human brain evolution may have played a role in the development of the disorder. We examined schizophrenia-related changes in brain connectivity in the context of evolutionary changes in human brain wiring by comparing in vivo neuroimaging data from humans and chimpanzees, one of our closest living evolutionary relatives and a species with which we share a very recent common ancestor. We contrasted the connectome layout between the chimpanzee and human brain and compared differences with the pattern of schizophrenia-related changes in brain connectivity as observed in patients. We show evidence of evolutionary modifications of human brain connectivity to significantly overlap with the cortical pattern of schizophrenia-related dysconnectivity (P < 0.001, permutation testing). We validated these effects in three additional, independent schizophrenia datasets. We further assessed the specificity of effects by examining brain dysconnectivity patterns in seven other psychiatric and neurological brain disorders (including, among others, major depressive disorder and obsessive-compulsive disorder, arguably characterized by behavioural symptoms that are less specific to humans), which showed no such associations with modifications of human brain connectivity. Comparisons of brain connectivity across humans, chimpanzee and macaques further suggest that features of connectivity that evolved in the human lineage showed the strongest association to the disorder, that is, brain circuits potentially related to human evolutionary specializations. Taken together, our findings suggest that human-specific features of connectome organization may be enriched for changes in brain connectivity related to schizophrenia. Modifications in human brain connectivity in service of higher order brain functions may have potentially also rendered the brain vulnerable to brain dysfunction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awz330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906591PMC
December 2019

Testing for the Myth of Cognitive Reserve: Are the Static and Dynamic Cognitive Reserve Indexes a Representation of Different Reserve Warehouses?

J Alzheimers Dis 2019 ;72(1):111-126

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

Background: Cognitive reserve (CR) explains the individual resilience to neurodegeneration. Years of formal education express the static measure of reserve (sCR). A dynamic aspect of CR (dCR) has been recently proposed.

Objective: The aim of the study was to compare sCR and dCR indexes, respectively, to detect brain abnormalities in Alzheimer's disease (AD) patients.

Methods: 117 individuals [39 AD, 40 amnestic mild cognitive impairment (aMCI), 38 healthy subjects (HS)] underwent neuropsychological evaluation and a 3T-MRI. T1-weighted volumes were used for manual segmentation of the hippocampus and of the parahippocampal cortices. Years of formal education were used as an index of sCR. Partial Least Square analysis was used to decompose the variance of individual MMSE scores, considered as a dCR index. In aMCI and AD patients, the brain abnormalities have been assessed comparing individuals with high and low levels of sCR and dCR in turn. Moreover, we investigated the effect of the different CR indexes in mediating the relationship between changes in brain volumes and memory performances.

Results: sCR and dCR indexes classified differently individuals having high or low levels of CR. Smaller hippocampal and parahippocampal volumes in high dCR patients were found. The sCR and dCR indexes mediated significantly the relationship between brain abnormalities and memory in patients.

Conclusions: CR mediated the relationship between brain and memory dysfunctions. We hypothesized that sCR and dCR indexes are a representation of different warehouses of reserve not operating in parallel but forming a complex system, in which crystalized cognitive abilities and actual cognitive efficiency interact with brain atrophy impacting on memory.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-190716DOI Listing
November 2020

Shared vulnerability for connectome alterations across psychiatric and neurological brain disorders.

Nat Hum Behav 2019 09 5;3(9):988-998. Epub 2019 Aug 5.

Connectome Lab, Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands.

Macroscale white matter pathways are the infrastructure for large-scale communication in the human brain and a prerequisite for healthy brain function. Disruptions in the brain's connectivity architecture play an important role in many psychiatric and neurological brain disorders. Here we show that connections important for global communication and network integration are particularly vulnerable to brain alterations across multiple brain disorders. We report on a cross-disorder connectome study comprising in total 1,033 patients and 1,154 matched controls across 8 psychiatric and 4 neurological disorders. We extracted disorder connectome fingerprints for each of these 12 disorders and combined them into a 'cross-disorder disconnectivity involvement map' describing the level of cross-disorder involvement of each white matter pathway of the human brain network. Network analysis revealed connections central to global network communication and integration to display high disturbance across disorders, suggesting a general cross-disorder involvement and the importance of these pathways in normal function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41562-019-0659-6DOI Listing
September 2019

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

Neuropsychologia 2019 09 11;132:107143. Epub 2019 Jul 11.

Ataxia Laboratory, IRCCS Fondazione Santa Lucia, Rome, Italy; Department of Psychology, Sapienza University of Rome, Rome, Italy.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuropsychologia.2019.107143DOI Listing
September 2019

Thalamocortical disconnection affects the somatic marker and social cognition: a case report.

Neurocase 2019 Feb - Apr;25(1-2):1-9. Epub 2019 Mar 31.

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

Thalamo-cortical connectivity was characterised in a patient with bilateral infarct of the thalami, without evidence of cognitive deficits in everyday life. Patient underwent social and emotional tests, Iowa Gambling Task (IGT), with and without concomitant heart rate variability (HRV) recording and at 3T-MRI to assess thalamo-cortical connectivity. Patient showed impairment at the IGT, in somatic marker, in emotions and theory of mind. MRI documented a bilateral damage of the centromedian-parafascicular complex. Patient's thalamic lesions disconnected brain areas involved in decision-making and autonomic regulation, affecting the somatic marker and resulting in the neuropsychological deficit exhibited by L.C.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/13554794.2019.1599025DOI Listing
December 2019

Ventral tegmental area disruption in Alzheimer's disease.

Aging (Albany NY) 2019 03;11(5):1325-1326

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

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/aging.101852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428109PMC
March 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cortex.2018.12.022DOI Listing
April 2019

The Cerebellar Predictions for Social Interactions: Theory of Mind Abilities in Patients With Degenerative Cerebellar Atrophy.

Front Cell Neurosci 2018 8;12:510. Epub 2019 Jan 8.

Ataxia Laboratory, IRCCS Fondazione Santa Lucia, Rome, Italy.

Recent studies have focused on the role of the cerebellum in the social domain, including in Theory of Mind (ToM). ToM, or the "mentalizing" process, is the ability to attribute mental states, such as emotion, intentions and beliefs, to others to explain and predict their behavior. It is a fundamental aspect of social cognition and crucial for social interactions, together with more automatic mechanisms, such as emotion contagion. Social cognition requires complex interactions between limbic, associative areas and subcortical structures, including the cerebellum. It has been hypothesized that the typical cerebellar role in adaptive control and predictive coding could also be extended to social behavior. The present study aimed to investigate the social cognition abilities of patients with degenerative cerebellar atrophy to understand whether the cerebellum acts in specific ToM components playing a role as predictive structure. To this aim, an social cognition battery was administered to 27 patients with degenerative cerebellar pathology and 27 healthy controls. In addition, 3D T1-weighted and resting-state fMRI scans were collected to characterize the structural and functional changes in cerebello-cortical loops. The results evidenced that the patients were impaired in lower-level processes of immediate perception as well as in the more complex conceptual level of mentalization. Furthermore, they presented a pattern of GM reduction in cerebellar portions that are involved in the social domain such as crus I-II, lobule IX and lobule VIIIa. These areas showed decreased functional connectivity with projection cerebral areas involved in specific aspects of social cognition. These findings boost the idea that the cerebellar modulatory function on the cortical projection areas subtends the social cognition process at different levels. Particularly, regarding the lower-level processes, the cerebellum may act by implicitly matching the external information (i.e., expression of the eyes) with the respective internal representation to guarantee an immediate judgment about the mental state of others. Otherwise, at a more complex conceptual level, the cerebellum seems to be involved in the construction of internal models of mental processes during social interactions in which the prediction of sequential events plays a role, allowing us to anticipate the other person's behavior.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fncel.2018.00510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332472PMC
January 2019

Consensus-based care recommendations for adults with myotonic dystrophy type 1.

Neurol Clin Pract 2018 Dec;8(6):507-520

Purpose Of Review: Myotonic dystrophy type 1 (DM1) is a severe, progressive genetic disease that affects between 1 in 3,000 and 8,000 individuals globally. No evidence-based guideline exists to inform the care of these patients, and most do not have access to multidisciplinary care centers staffed by experienced professionals, creating a clinical care deficit.

Recent Findings: The Myotonic Dystrophy Foundation (MDF) recruited 66 international clinicians experienced in DM1 patient care to develop consensus-based care recommendations. MDF created a 2-step methodology for the project using elements of the Single Text Procedure and the Nominal Group Technique. The process generated a 4-page Quick Reference Guide and a comprehensive, 55-page document that provides clinical care recommendations for 19 discrete body systems and/or care considerations.

Summary: The resulting recommendations are intended to help standardize and elevate care for this patient population and reduce variability in clinical trial and study environments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/CPJ.0000000000000531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294540PMC
December 2018

Age-related microstructural and physiological changes in normal brain measured by MRI γ-metrics derived from anomalous diffusion signal representation.

Neuroimage 2019 03 21;188:654-667. Epub 2018 Dec 21.

Institute for Complex Systems, CNR, Rome, Italy; Neuroimaging Laboratory, Santa Lucia Foundation, Rome, Italy.

Nowadays, increasing longevity associated with declining cerebral nervous system functions, suggests the need for continued development of new imaging contrast mechanisms to support the differential diagnosis of age-related decline. In our previous papers, we developed a new imaging contrast metrics derived from anomalous diffusion signal representation and obtained from diffusion-weighted (DW) data collected by varying diffusion gradient strengths. Recently, we highlighted that the new metrics, named γ-metrics, depended on the local inhomogeneity due to differences in magnetic susceptibility between tissues and diffusion compartments in young healthy subjects, thus providing information about myelin orientation and iron content within cerebral regions. The major structural modifications occurring in brain aging are myelinated fibers damage in nerve fibers and iron accumulation in gray matter nuclei. Therefore, we investigated the potential of γ-metrics in relation to other conventional diffusion metrics such as DTI, DKI and NODDI in detecting age-related structural changes in white matter (WM) and subcortical gray matter (scGM). DW-images were acquired in 32 healthy subjects, adults and elderly (age range 20-77 years) using 3.0T and 12 b-values up to 5000 s/mm. Association between diffusion metrics and subjects' age was assessed using linear regression. A decline in mean γ (Mγ) in the scGM and a complementary increase in radial γ (γ) in frontal WM, genu of corpus callosum and anterior corona radiata with advancing age were found. We suggested that the increase in γ⊥ might reflect declined myelin density, and Mγ decrease might mirror iron accumulation. An increase in D and a decrease in the orientation dispersion index (ODI) were associated with axonal loss in the pyramidal tracts, while their inverted trends within the thalamus were thought to be linked to reduced architectural complexity of nerve fibers. γ-metrics together with conventional diffusion-metrics can more comprehensively characterize the complex mechanisms underlining age-related changes than conventional diffusion techniques alone.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuroimage.2018.12.044DOI Listing
March 2019

Patterns of Cerebellar Gray Matter Atrophy Across Alzheimer's Disease Progression.

Front Cell Neurosci 2018 20;12:430. Epub 2018 Nov 20.

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

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fncel.2018.00430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6255820PMC
November 2018