Author name cluster

Federica Agosta

Possible papers associated with this exact author name in Arrow. This page groups case-insensitive exact name matches and is not a full identity disambiguation profile.

26 papers

1 author row

YNICL Journal 2026 Journal Article

Resting-State EEG captures functional network correlates of plasma p-Tau-217 in Alzheimer’s disease

Giordano Cecchetti
Jacopo Lanzone
Luca Zanchi
Giulia Rugarli
Silvia Basaia
Marco Cursi
Federico Coraglia
Edoardo G. Spinelli

BACKGROUND: Scalable biomarkers are needed for early Alzheimer's disease (AD) detection. Plasma p-tau217 reflects AD pathology, while resting-state EEG captures functional brain alterations. Their relationship remains unclear. METHODS: We enrolled 128 patients with subjective cognitive decline (SCD), mild cognitive impairment due to AD (AD-MCI), or AD dementia (AD-DEM), who underwent 32-channel EEG and plasma biomarker assessment. EEG features included spectral, aperiodic, phase-amplitude coupling, and complexity metrics. Machine learning was used to classify p-tau217 positivity. RESULTS: AD-MCI and AD-DEM patients showed increased p-tau217 and spectral slowing (higher theta, lower alpha). While no correlations survived correction for multiple comparisons, stage-specific analyses revealed positive associations between theta power and p-tau217 in AD-MCI and AD-DEM. A random forest classifier achieved an AUC of 0.75 in predicting p-tau217 positivity. CONCLUSIONS: EEG captures functional alterations reflecting AD pathology beyond molecular measures, supporting its value as a complementary, non-invasive biomarker for early stratification in clinical settings.

YNICL Journal 2025 Journal Article

Multi-Center 3D CNN for Parkinson’s disease diagnosis and prognosis using clinical and T1-weighted MRI data

Silvia Basaia
Elisabetta Sarasso
Francesco Sciancalepore
Roberta Balestrino
Simona Musicco
Stefano Pisano
Iva Stankovic
Aleksandra Tomic

OBJECTIVE: Parkinson's disease (PD) presents challenges in early diagnosis and progression prediction. Recent advancements in machine learning, particularly convolutional-neural-networks (CNNs), show promise in enhancing diagnostic accuracy and prognostic capabilities using neuroimaging data. The aims of this study were: (i) develop a 3D-CNN based on MRI to distinguish controls and PD patients and (ii) employ CNN to predict the progression of PD. METHODS: Three cohorts were selected: 86 mild, 62 moderate-to-severe PD patients, and 60 controls; 14 mild-PD patients and 14 controls from Parkinson's Progression Markers Initiative database, and 38 de novo mild-PD patients and 38 controls. All participants underwent MRI scans and clinical evaluation at baseline and over 2-years. PD subjects were classified in two clusters of different progression using k-means clustering based on baseline and follow-up UDPRS-III scores. A 3D-CNN was built and tested on PD patients and controls, with binary classifications: controls vs moderate-to-severe PD, controls vs mild-PD, and two clusters of PD progression. The effect of transfer learning was also tested. RESULTS: CNN effectively differentiated moderate-to-severe PD from controls (74% accuracy) using MRI data alone. Transfer learning significantly improved performance in distinguishing mild-PD from controls (64% accuracy). For predicting disease progression, the model achieved over 70% accuracy by combining MRI and clinical data. Brain regions most influential in the CNN's decisions were visualized. CONCLUSIONS: CNN, integrating multimodal data and transfer learning, provides encouraging results toward early-stage classification and progression monitoring in PD. Its explainability through activation maps offers potential for clinical application in early diagnosis and personalized monitoring.

YNICL Journal 2023 Journal Article

C9orf72 ALS mutation carriers show extensive cortical and subcortical damage compared to matched wild-type ALS patients

Anna Nigri
Manera Umberto
Mario Stanziano
Stefania Ferraro
Davide Fedeli
Jean Paul Medina Carrion
Sara Palermo
Laura Lequio

OBJECTIVE: C9orf72 mutation carriers with different neurological phenotypes show cortical and subcortical atrophy in multiple different brain regions, even in pre-symptomatic phases. Despite there is a substantial amount of knowledge, small sample sizes, clinical heterogeneity, as well as different choices of image analysis may hide anatomical abnormalities that are unique to amyotrophic lateral sclerosis (ALS) patients with this genotype or that are indicative of the C9orf72-specific trait overlain in fronto-temporal dementia patients. METHODS: Brain structural and resting state functional magnetic imaging was obtained in 24 C9orf72 positive (ALSC9+) ALS patients paired for burden disease with 24 C9orf72 negative (ALSC9-) ALS patients. A comprehensive structural evaluation of cortical thickness and subcortical volumes between ALSC9+ and ALSC9- patients was performed while a region of interest (ROI)-ROI analysis of functional connectivity was implemented to assess functional alterations among abnormal cortical and subcortical regions. Results were corrected for multiple comparisons. RESULTS: Compared to ALSC9- patients, ALSC9+ patients exhibited extensive disease-specific patterns of thalamo-cortico-striatal atrophy, supported by functional alterations of the identified abnormal regions. Cortical thinning was most pronounced in posterior areas and extended to frontal regions. Bilateral atrophy of the mediodorsal and pulvinar nuclei was observed, emphasizing a focal rather than global thalamus atrophy. Volume loss in a large portion of bilateral caudate and left putamen was reported. The marked reduction of functional connectivity observed between the left posterior thalamus and almost all the atrophic cortical regions support the central role of the thalamus in the pathogenic mechanism of C9orf72-mediated disease. CONCLUSIONS: These findings constitute a coherent and robust picture of ALS patients with C9orf72-mediated disease, unveiling a specific structural and functional characterization of thalamo-cortico-striatal circuit alteration. Our study introduces new evidence in the characterization of the pathogenic mechanisms of C9orf72 mutation.

YNICL Journal 2022 Journal Article

Neurogenetic traits outline vulnerability to cortical disruption in Parkinson’s disease

Silvia Basaia
Federica Agosta
Ibai Diez
Elisenda Bueichekú
Federico d'Oleire Uquillas
Manuel Delgado-Alvarado
César Caballero-Gaudes
MariCruz Rodriguez-Oroz

The genetic traits that underlie vulnerability to neuronal damage across specific brain circuits in Parkinson's disease (PD) remain to be elucidated. In this study, we characterized the brain topological intersection between propagating connectivity networks in controls and PD participants and gene expression patterns across the human cortex - such as the SNCA gene. We observed that brain connectivity originated from PD-related pathology epicenters in the brainstem recapitulated the anatomical distribution of alpha-synuclein histopathology in postmortem data. We also discovered that the gene set most related to cortical propagation patterns of PD-related pathology was primarily involved in microtubule cellular components. Thus, this study sheds light on new avenues for enhancing detection of PD neuronal vulnerability via an evaluation of in vivo connectivity trajectories across the human brain and successful integration of neuroimaging-genetic strategies.

YNICL Journal 2022 Journal Article

Pallidal functional connectivity changes are associated with disgust recognition in pure motor amyotrophic lateral sclerosis

Veronica Castelnovo
Elisa Canu
Maria Antonietta Magno
Elena Gatti
Nilo Riva
Debora Pain
Gabriele Mora
Barbara Poletti

In the present study, we aimed to investigate the resting-state functional connectivity (RS-FC) of the globus pallidus (GP) in patients with amyotrophic lateral sclerosis (ALS) compared to healthy controls, and the relationship between RS-FC changes and disgust recognition. Twenty-six pure-motor ALS patients and 52 healthy controls underwent RS functional MRI and a neuropsychological assessment including the Comprehensive Affect Testing System. A seed-based RS-FC analysis was performed between the left and right GP and the rest of the brain and compared between groups. Correlations between RS-FC significant changes and subjects' performance in recognizing disgust were tested. Compared to controls, patients were significantly less able to recognize disgust. In ALS compared to controls, the seed-based analysis showed: reduced RS-FC between bilateral GP and bilateral middle and superior frontal and middle cingulate gyri, and increased RS-FC between bilateral GP and bilateral postcentral, supramarginal and superior temporal gyri and Rolandic operculum. Decreased RS-FC was further observed between left GP and left middle and inferior temporal gyri and bilateral caudate; and increased RS-FC was also shown between right GP and left lingual and fusiform gyri. In patients and controls, lower performance in recognizing disgust correlated with reduced RS-FC between left GP and left middle and inferior temporal gyri. In pure-motor ALS patients, we demonstrated altered RS-FC between GP and the rest of the brain. The reduced left pallidum-temporo-striatal RS-FC may have a role in the lower ability of patients in recognizing disgust.

YNICL Journal 2021 Journal Article

Brain activity of the emotional circuit in Parkinson’s disease patients with freezing of gait

Elisabetta Sarasso
Federica Agosta
Noemi Piramide
Elisa Canu
Maria Antonietta Volontè
Massimo Filippi

OBJECTIVE: Emotional processes might influence freezing of gait (FoG) in Parkinson's disease (PD) patients. We assessed brain functional MRI (fMRI) activity during a "FoG-observation-task" in PD-FoG patients relative to healthy controls. METHODS: Twenty-four PD-FoG patients and 18 age- and sex-matched healthy controls performed clinical and neuropsychological evaluations, and fMRI experiments including: i) "FoG-observation-task" consisting of watching a patient experiencing FoG during a walking task (usually evoking FoG); ii) "gait-observation-task" consisting of watching a healthy subject performing similar walking tasks without experiencing FoG. RESULTS: During both tasks, PD-FoG patients showed reduced activity of the fronto-parietal mirror neuron system (MNS) relative to controls. In the "FoG-observation-task" relative to the "gait-observation-task", PD-FoG patients revealed an increased recruitment of the anterior medial prefrontal cortex and a reduced recruitment of the dorsomedial prefrontal cortex and hippocampus relative to controls. Healthy controls in the "FoG-observation-task" relative to the "gait-observation-task" showed increased recruitment of cognitive empathy areas and decreased activity of the fronto-parietal MNS. CONCLUSION: Our results suggest that when PD-FoG patients observe a subject experiencing FoG, there is an increased activity of brain areas involved in self-reflection emotional processes and a reduced activity of areas related to motor programming, executive functions and cognitive empathy. These findings support previous evidence on the critical role of the emotional circuit in the mechanisms underlying FoG.

YNICL Journal 2021 Journal Article

Impaired recognition of disgust in amyotrophic lateral sclerosis is related to basal ganglia involvement

Veronica Castelnovo
Elisa Canu
Maria Antonietta Magno
Silvia Basaia
Nilo Riva
Barbara Poletti
Vincenzo Silani
Massimo Filippi

In the present study we investigated emotion recognition in pure motor amyotrophic lateral sclerosis (ALS) patients and its relationship with the integrity of basal ganglia, hippocampus and amygdala. Twenty ALS patients without either cognitive or behavioural impairment, and 52 matched healthy controls performed a neuropsychological assessment including the Comprehensive Affect Testing System (CATS) investigating emotion recognition. All participants underwent also a 3T brain MRI. Volumes of basal ganglia, hippocampus and amygdala bilaterally were measured using FIRST in FSL. Sociodemographic, cognitive and MRI data were compared between groups. In ALS patients, correlations between CATS significant findings, brain volumes, cognition, mood and behaviour were explored. ALS patients showed altered performances at the CATS total score and, among the investigated emotions, patients were significantly less able to recognize disgust compared with controls. No brain volumetric differences were observed between groups. In ALS patients, a lower performance in disgust recognition was related with a reduced volume of the left pallidum and a lower performance on the Edinburgh Cognitive and Behavioural ALS Screen. Cognitively/behaviourally unimpaired ALS patients showed impaired disgust recognition, which was associated with pallidum volume. The association with cognitive alterations may suggest impaired disgust recognition as an early marker of cognitive decline.

YNICL Journal 2021 Journal Article

Resting-state electroencephalographic biomarkers of Alzheimer’s disease

Giordano Cecchetti
Federica Agosta
Silvia Basaia
Camilla Cividini
Marco Cursi
Roberto Santangelo
Francesca Caso
Fabio Minicucci

OBJECTIVE: We evaluated the value of resting-state EEG source biomarkers to characterize mild cognitive impairment (MCI) subjects with an Alzheimer's disease (AD)-like cerebrospinal fluid (CSF) profile and to track neurodegeneration throughout the AD continuum. We further applied a resting-state functional MRI (fMRI)-driven model of source reconstruction and tested its advantage in terms of AD diagnostic accuracy. METHODS: Thirty-nine consecutive patients with AD dementia (ADD), 86 amnestic MCI, and 33 healthy subjects enter the EEG study. All ADD subjects, 37 out of 86 MCI patients and a distinct group of 53 healthy controls further entered the fMRI study. MCI subjects were divided according to the CSF phosphorylated tau/β amyloid-42 ratio (MCIpos: ≥ 0.13, MCIneg: < 0.13). Using Exact low-resolution brain electromagnetic tomography (eLORETA), EEG lobar current densities were estimated at fixed frequencies and analyzed. To combine the two imaging techniques, networks mostly affected by AD pathology were identified using Independent Component Analysis applied to fMRI data of ADD subjects. Current density EEG analysis within ICA-based networks at selected frequency bands was performed. Afterwards, graph analysis was applied to EEG and fMRI data at ICA-based network level. RESULTS: ADD patients showed a widespread slowing of spectral density. At a lobar level, MCIpos subjects showed a widespread higher theta density than MCIneg and healthy subjects; a lower beta2 density than healthy subjects was also found in parietal and occipital lobes. Evaluating EEG sources within the ICA-based networks, alpha2 band distinguished MCIpos from MCIneg, ADD and healthy subjects with good accuracy. Graph analysis on EEG data showed an alteration of connectome configuration at theta frequency in ADD and MCIpos patients and a progressive disruption of connectivity at alpha2 frequency throughout the AD continuum. CONCLUSIONS: Theta frequency is the earliest and most sensitive EEG marker of AD pathology. Furthermore, EEG/fMRI integration highlighted the role of alpha2 band as potential neurodegeneration biomarker.

YNICL Journal 2020 Journal Article

Functional brain connectome in posterior cortical atrophy

Raffaella Migliaccio
Federica Agosta
Silvia Basaia
Camilla Cividini
Marie-Odile Habert
Aurélie Kas
Maxime Montembeault
Massimo Filippi

This study investigated the functional brain connectome architecture in patients with Posterior Cortical Atrophy (PCA). Eighteen PCA patients and 29 age- and sex- matched healthy controls were consecutively recruited in a specialized referral center. Participants underwent neurologic examination, cerebrospinal fluid (CSF) examination for Alzheimer's disease (AD) biomarkers, cognitive assessment, and brain MRI. For a smaller subset of participants, FDG-PET examination was available. We assessed topological brain network properties and regional functional connectivity as well as intra- and inter-hemispheric connectivity, using graph analysis and connectomics. Supplementary analyses were performed to explore the association between the CSF AD profile and the connectome status, and taking into account hypometabolic, atrophic, and spared regions (nodes). PCA patients showed diffuse functional connectome alterations at both global and regional level, as well as a connectivity breakdown between the posterior brain nodes. They had a widespread loss of both intra- and inter-hemispheric connections, exceeding the structural damage, and including the frontal connections. In PCA, connectome alterations were identified in all the brain nodes irrespectively of their structural and metabolic classification and were associated with a connectivity breakdown between damaged and spared areas. Taken together, these findings suggest the potentially high sensitivity of graph-analysis and connectomic in capturing the progression and maybe early signs of neurodegeneration in PCA patients.

YNICL Journal 2020 Journal Article

Progression of brain functional connectivity and frontal cognitive dysfunction in ALS

Veronica Castelnovo
Elisa Canu
Davide Calderaro
Nilo Riva
Barbara Poletti
Silvia Basaia
Federica Solca
Vincenzo Silani

OBJECTIVE: To investigate the progression of resting-state functional connectivity (rs-FC) changes in patients with amyotrophic lateral sclerosis (ALS) and their relationship with frontal cognitive alterations. METHODS: This is a multicentre, observational and longitudinal study. At baseline and after six months, 25 ALS patients underwent 3D T1-weighted MRI, resting-state functional MRI (rs-fMRI), and the computerized Test of Attentional Performance (TAP). Using independent component analysis, rs-FC changes of brain networks involving connections to frontal lobes and their relationship with baseline cognitive scores and cognitive changes over time were assessed. With a seed-based approach, rs-FC longitudinal changes of the middle frontal gyrus (MFG) were also explored. RESULTS: After six months, ALS patients showed an increased rs-FC of the left anterior cingulate, left middle frontal gyrus (MFG) and left superior frontal gyrus within the frontostriatal network, and of the left MFG, left supramarginal gyrus and right angular gyrus within the left frontoparietal network. Within the frontostriatal network, a worse baseline performance at TAP divided attention task was associated with an increased rs-FC over time in the left MFG and a worse baseline performance at the category fluency index was related with increased rs-FC over time in the left frontal superior gyrus. After six months, the seed-based rs-FC analysis of the MFG with the whole brain showed decreased rs-FC of the right MFG with frontoparietal regions in patients compared to controls. CONCLUSIONS: Rs-FC changes in ALS patients progressed over time within the frontostriatal and the frontoparietal networks and are related to frontal-executive dysfunction. The MFG seems a potential core region in the framework of a frontoparietal functional breakdown, which is typical of frontotemporal lobar degeneration. These findings offer new potential markers for monitoring extra-motor progression in ALS.

YNICL Journal 2020 Journal Article

Progressive brain atrophy and clinical evolution in Parkinson’s disease

Massimo Filippi
Elisabetta Sarasso
Noemi Piramide
Tanja Stojkovic
Iva Stankovic
Silvia Basaia
Andrea Fontana
Aleksandra Tomic

Clinical manifestations and evolution are very heterogeneous among individuals with Parkinson's disease (PD). The aims of this study were to investigate the pattern of progressive brain atrophy in PD according to disease stage and to elucidate to what extent cortical thinning and subcortical atrophy are related to clinical motor and non-motor evolution. 154 patients at different PD stages were assessed over time using motor, non-motor and structural MRI evaluations for a maximum of 4 years. Cluster analysis defined clinical subtypes. Cortical thinning and subcortical atrophy were assessed at baseline in patients relative to 60 healthy controls. Longitudinal trends of brain atrophy progression were compared between PD clusters. The contribution of brain atrophy in predicting motor, non-motor, cognitive and mood deterioration was explored. Two main PD clusters were defined: mild (N = 87) and moderate-to-severe (N = 67). Two mild subtypes were further identified: mild motor-predominant (N = 43) and mild-diffuse (N = 44), with the latter group being older and having more severe non-motor and cognitive symptoms. The initial pattern of brain atrophy was more severe in patients with moderate-to-severe PD. Over time, mild-diffuse PD patients had the greatest brain atrophy accumulation in the cortex and the left hippocampus, while less distributed atrophy progression was observed in moderate-to-severe and mild motor-predominant patients. Baseline and 1-year cortical thinning was associated with long-term progression of motor, cognitive, non-motor and mood symptoms. Cortical and subcortical atrophy is accelerated early after the onset of PD and becomes prominent in later stages of disease according to the development of cognitive, non-motor and mood dysfunctions. Structural MRI may be useful for monitoring and predicting disease progression in PD.

YNICL Journal 2020 Journal Article

Structural MRI outcomes and predictors of disease progression in amyotrophic lateral sclerosis

Edoardo G. Spinelli
Nilo Riva
Paola M.V. Rancoita
Paride Schito
Alberto Doretti
Barbara Poletti
Clelia Di Serio
Vincenzo Silani

BACKGROUND AND AIMS: Considering the great heterogeneity of amyotrophic lateral sclerosis (ALS), the identification of accurate prognostic predictors is fundamental for both the clinical practice and the design of treatment trials. This study aimed to explore the progression of clinical and structural brain changes in patients with ALS, and to assess magnetic resonance imaging (MRI) measures of brain damage as predictors of subsequent functional decline. METHODS: 50 ALS patients underwent clinical evaluations and 3 T MRI scans at regular intervals for a maximum of 2 years (total MRI scans = 164). MRI measures of cortical thickness, as well as diffusion tensor (DT) metrics of microstructural damage along white matter (WM) tracts were obtained. Voxel-wise regression models and longitudinal mixed-effects models were used to test the relationship between clinical decline and baseline and longitudinal MRI features. RESULTS: The rate of decline of the ALS Functional Rating Scale revised (ALSFRS-r) was significantly associated with the rate of fractional anisotropy (FA) decrease in the body of the corpus callosum (CC). Corticospinal tract (CST) and CC-body alterations had a faster progression in patients with higher baseline ALSFRS-r scores and greater CC-body disruption at baseline. Lower FA of the cerebral peduncle was associated with faster subsequent clinical progression. CONCLUSIONS: In this longitudinal study, we identified a significant association between measures of WM damage of the motor tracts and functional decline in ALS patients. Our data suggest that a multiparametric approach including DT MRI measures of brain damage would provide an optimal method for an accurate stratification of ALS patients into prognostic classes.

YNICL Journal 2019 Journal Article

Automated classification of Alzheimer's disease and mild cognitive impairment using a single MRI and deep neural networks

Silvia Basaia
Federica Agosta
Luca Wagner
Elisa Canu
Giuseppe Magnani
Roberto Santangelo
Massimo Filippi

We built and validated a deep learning algorithm predicting the individual diagnosis of Alzheimer's disease (AD) and mild cognitive impairment who will convert to AD (c-MCI) based on a single cross-sectional brain structural MRI scan. Convolutional neural networks (CNNs) were applied on 3D T1-weighted images from ADNI and subjects recruited at our Institute (407 healthy controls [HC], 418 AD, 280 c-MCI, 533 stable MCI [s-MCI]). CNN performance was tested in distinguishing AD, c-MCI and s-MCI. High levels of accuracy were achieved in all the classifications, with the highest rates achieved in the AD vs HC classification tests using both the ADNI dataset only (99%) and the combined ADNI + non-ADNI dataset (98%). CNNs discriminated c-MCI from s-MCI patients with an accuracy up to 75% and no difference between ADNI and non-ADNI images. CNNs provide a powerful tool for the automatic individual patient diagnosis along the AD continuum. Our method performed well without any prior feature engineering and regardless the variability of imaging protocols and scanners, demonstrating that it is exploitable by not-trained operators and likely to be generalizable to unseen patient data. CNNs may accelerate the adoption of structural MRI in routine practice to help assessment and management of patients.

YNICL Journal 2018 Journal Article

Cortico-efferent tract involvement in primary lateral sclerosis and amyotrophic lateral sclerosis: A two-centre tract of interest-based DTI analysis

Hans-Peter Müller
Federica Agosta
Martin Gorges
Rebecca Kassubek
Edoardo Gioele Spinelli
Nilo Riva
Albert C. Ludolph
Massimo Filippi

BACKGROUND: After the demonstration of a corticoefferent propagation pattern in amyotrophic lateral sclerosis (ALS) by neuropathological studies, this concept has been used for in vivo staging of individual patients by diffusion tensor imaging (DTI) techniques, both in `classical` ALS and in restricted phenotypes such as primary lateral sclerosis (PLS). OBJECTIVE: The study was designed to investigate that microstructural changes according to the neuropathologically defined ALS alteration pattern in PLS patients could be confirmed to be identical to ´classical´ ALS patients. The novelty in this approach is that the results were independent of the subject samples and the data acquisition parameters (as was validated in two samples from two different centres). That way, reproducibility across (international) centres in addition to harmonisation/standardisation of data analysis has been addressed, for the possible use of MRI-based staging to stratify patients in clinical trials. METHODS: Tractwise analysis of fractional anisotropy (FA) maps according to the ALS-staging pattern was applied to DTI data (pooled from two ALS centres) of 88 PLS patients and 88 ALS patients with a 'classical' phenotype in comparison to 88 matched controls in order to identify white matter integrity alterations. RESULTS: In the tract-specific analysis, alterations were identical for PLS and ALS in the tract systems corresponding to the ALS staging pattern, independent of the subject samples and the data acquisition parameters. The individual categorisation into ALS stages did not differ between PLS and ALS patients. CONCLUSIONS: This DTI study in a two-centre setting demonstrated that the neuropathological stages can be mapped in vivo in PLS with high reproducibility and that PLS-associated cerebral propagation, although showing the same corticofugal patterns as ALS, might have a different time course of neuropathology, in analogy to its much slower clinical progression rates.

YNICL Journal 2018 Journal Article

Fast progressive lower motor neuron disease is an ALS variant: A two-centre tract of interest-based MRI data analysis

Hans-Peter Müller
Federica Agosta
Nilo Riva
Edoardo G. Spinelli
Giancarlo Comi
Albert C. Ludolph
Massimo Filippi
Jan Kassubek

BACKGROUND: The criteria for assessing upper motor neuron pathology in pure lower motor neuron disease (LMND) still remain a major issue of debate with respect to the clinical classification as an amyotrophic lateral sclerosis (ALS) variant. OBJECTIVE: The study was designed to investigate white matter damage by a hypothesis-guided tract-of-interest-based approach in patients with LMND compared with healthy controls and ´classical´ ALS patients in order to identify in vivo brain structural changes according to the neuropathologically defined ALS affectation pattern. Data were pooled from two previous studies at two different study sites (Ulm, Germany and Milano, Italy). METHODS: DTI-based white matter integrity mapping was performed by voxelwise statistical comparison and by a tractwise analysis of fractional anisotropy (FA) maps according to the ALS-staging pattern for 65 LMND patients (clinically differentiated in fast and slow progressors) vs. 92 matched controls and 101 ALS patients with a 'classical' phenotype to identify white matter structural alterations. RESULTS: The analysis of white matter structural connectivity by regional FA reductions demonstrated the characteristic alteration patterns along the CST and also in frontal and prefrontal brain areas in LMND patients compared to controls and ALS. Fast progressing LMND showed substantial involvement, like in ALS, while slow progressors showed less severe alterations. In the tract-specific analysis according to the ALS-staging pattern, fast progressing LMND showed significant alterations of ALS-related tract systems as compared to slow progressors and controls. CONCLUSIONS: This study showed an affectation pattern for corticoefferent fibers in LMND with fast disease progression as defined for ALS, that way confirming the hypothesis that fast progressing LMND is a phenotypical variant of ALS.

YNICL Journal 2018 Journal Article

Functional and structural brain networks in posterior cortical atrophy: A two-centre multiparametric MRI study

Federica Agosta
Gorana Mandic-Stojmenovic
Elisa Canu
Tanja Stojkovic
Francesca Imperiale
Francesca Caso
Elka Stefanova
Massimiliano Copetti

This study identified structural and functional brain connectivity alterations in two independent samples of patients along the posterior cortical atrophy (PCA) disease course. Twenty-one PCA patients and 44 controls were recruited from two expert centres. Microstructural damage of white matter (WM) tracts was assessed using probabilistic tractography; resting state (RS) functional connectivity of brain networks was explored using a model free approach; grey matter (GM) atrophy was investigated using voxel-based morphometry. Compared with controls, common patterns of damage across PCA patients included: GM atrophy in the occipital-temporal-parietal regions; diffusion tensor (DT) MRI alterations of the corpus callosum and superior (SLF) and inferior longitudinal fasciculi (ILF) bilaterally; and decreased functional connectivity of the occipital gyri within the visual network and the precuneus and posterior cingulum within the default mode network (DMN). In PCA patients with longer disease duration and greater disease severity, WM damage extended to the cingulum and RS functional connectivity alterations spread within the frontal, dorsal attentive and salience networks. In PCA, reduced DMN functional connectivity was associated with SLF and ILF structural alterations. PCA patients showed distributed WM damage. Altered RS functional connectivity extends with disease worsening from occipital to temporo-parietal and frontostriatal regions, and this is likely to occur through WM connections. Future longitudinal studies are needed to establish trajectories of damage spreading in PCA and whether a combined DT MRI/RS functional MRI approach is promising in monitoring the disease progression.

YNICL Journal 2017 Journal Article

Multimodal structural MRI in the diagnosis of motor neuron diseases

Pilar M. Ferraro
Federica Agosta
Nilo Riva
Massimiliano Copetti
Edoardo Gioele Spinelli
Yuri Falzone
Gianni Sorarù
Giancarlo Comi

This prospective study developed an MRI-based method for identification of individual motor neuron disease (MND) patients and test its accuracy at the individual patient level in an independent sample compared with mimic disorders. 123 patients with amyotrophic lateral sclerosis (ALS), 44 patients with predominantly upper motor neuron disease (PUMN), 20 patients with ALS-mimic disorders, and 78 healthy controls were studied. The diagnostic accuracy of precentral cortical thickness and diffusion tensor (DT) MRI metrics of corticospinal and motor callosal tracts were assessed in a training cohort and externally proved in a validation cohort using a random forest analysis. In the training set, precentral cortical thickness showed 0. 86 and 0. 89 accuracy in differentiating ALS and PUMN patients from controls, while DT MRI distinguished the two groups from controls with 0. 78 and 0. 92 accuracy. In ALS vs controls, the combination of cortical thickness and DT MRI metrics (combined model) improved the classification pattern (0. 91 accuracy). In the validation cohort, the best accuracy was reached by DT MRI (0. 87 and 0. 95 accuracy in ALS and PUMN vs mimic disorders). The combined model distinguished ALS and PUMN patients from mimic syndromes with 0. 87 and 0. 94 accuracy. A multimodal MRI approach that incorporates motor cortical and white matter alterations yields statistically significant improvement in accuracy over using each modality separately in the individual MND patient classification. DT MRI represents the most powerful tool to distinguish MND from mimic disorders.

YNICL Journal 2017 Journal Article

Multiparametric MRI to distinguish early onset Alzheimer's disease and behavioural variant of frontotemporal dementia

Elisa Canu
Federica Agosta
Gorana Mandic-Stojmenovic
Tanja Stojković
Elka Stefanova
Alberto Inuggi
Francesca Imperiale
Massimiliano Copetti

This prospective study explored whether an approach combining structural [cortical thickness and white matter (WM) microstructure] and resting state functional MRI can aid differentiation between 62 early onset Alzheimer's disease (EOAD) and 27 behavioural variant of frontotemporal dementia (bvFTD) patients. Random forest and receiver operator characteristic curve analyses assessed the ability of MRI in classifying the two clinical syndromes. All patients showed a distributed pattern of brain alterations relative to controls. Compared to bvFTD, EOAD patients showed bilateral inferior parietal cortical thinning and decreased default mode network functional connectivity. Compared to EOAD, bvFTD patients showed bilateral orbitofrontal and temporal cortical thinning, and WM damage of the corpus callosum, bilateral uncinate fasciculus, and left superior longitudinal fasciculus. Random forest analysis revealed that left inferior parietal cortical thickness (accuracy 0.78, specificity 0.76, sensitivity 0.83) and WM integrity of the right uncinate fasciculus (accuracy 0.81, specificity 0.96, sensitivity 0.43) were the best predictors of clinical diagnosis. The combination of cortical thickness and DT MRI measures was able to distinguish patients with EOAD and bvFTD with accuracy 0.82, specificity 0.76, and sensitivity 0.96. The diagnostic ability of MRI models was confirmed in a subsample of patients with biomarker-based clinical diagnosis. Multiparametric MRI is useful to identify brain alterations which are specific to EOAD and bvFTD. A severe cortical involvement is suggestive of EOAD, while a prominent WM damage is indicative of bvFTD.

YNIMG Journal 2017 Journal Article

The European DTI Study on Dementia — A multicenter DTI and MRI study on Alzheimer's disease and Mild Cognitive Impairment

Katharina Brueggen
Michel J. Grothe
Martin Dyrba
Andreas Fellgiebel
Florian Fischer
Massimo Filippi
Federica Agosta
Peter Nestor

The European DTI Study on Dementia (EDSD) is a multicenter framework created to study the diagnostic accuracy and inter-site variability of DTI-derived markers in patients with manifest and prodromal Alzheimer's disease (AD). The dynamically growing database presently includes 493 DTI, 512 T1-weighted MRI, and 300 FLAIR scans from patients with AD dementia, patients with Mild Cognitive Impairment (MCI) and matched Healthy Controls, acquired on 13 different scanner platforms. The imaging data is publicly available, along with the subjects' demographic and clinical characterization. Detailed neuropsychological information, cerebrospinal fluid information on biomarkers and clinical follow-up diagnoses are included for a subset of subjects. This paper describes the rationale and structure of the EDSD, summarizes the available data, and explains how to gain access to the database. The EDSD is a useful database for researchers seeking to investigate the contribution of DTI to dementia diagnostics.

YNIMG Journal 2013 Journal Article

Reduced limbic metabolism and fronto-cortical volume in rats vulnerable to alcohol addiction

Alessandro Gozzi
Federica Agosta
Maurizio Massi
Roberto Ciccocioppo
Angelo Bifone

Alcohol abuse is associated with long-term reductions in fronto-cortical volume and limbic metabolism. However, an unanswered question in alcohol research is whether these alterations are the sole consequence of chronic alcohol use, or contain heritable contributions reflecting biological propensity toward ethanol addiction. Animal models of genetic predisposition to alcohol dependence can be used to investigate the role of inborn brain abnormalities in the aetiology of alcoholism. Here we used magnetic resonance imaging (MRI) in the Marchigian–Sardinian (msP) alcohol-preferring rats to assess the presence of inherited structural or functional brain alterations. Alcohol-naïve msP (N=22) and control rats (N=26) were subjected to basal cerebral blood volume (bCBV) mapping followed by voxel-based morphometry (VBM) of grey matter and tract-based spatial statistics mapping of white matter fractional anisotropy. msP rats exhibited significantly reduced bCBV, an established marker of resting brain function, in focal cortico-limbic and thalamic areas, together with reduced grey matter volume in the thalamus, ventral tegmental area, insular and cingulate cortex. No statistically significant differences in fractional anisotropy were observed between groups. These findings highlight the presence of inborn grey matter and metabolic abnormalities in alcohol-naïve msP rats, the localization and sign of which are remarkably similar to those mapped in abstinent alcoholics and subjects at high risk for alcohol dependence. Collectively, these results point for a significant role of heritable neurofunctional brain alterations in biological propensity toward ethanol addiction, and support the translational use of advanced imaging methods to describe the circuital determinants of vulnerability to drug addiction.

YNIMG Journal 2008 Journal Article

Tactile-associated recruitment of the cervical cord is altered in patients with multiple sclerosis

Federica Agosta
Paola Valsasina
Domenico Caputo
Patrick W. Stroman
Massimo Filippi

Functional magnetic resonance imaging (fMRI) studies of the brain have shown that cortical reorganization might contribute to a more favourable clinical outcome of multiple sclerosis (MS). In order to assess whether fMRI changes can also be detected in the spinal cord from patients with MS, and to investigate their nature and extent, twenty-five patients and 12 matched healthy controls were scanned during a tactile stimulation of the palm of the right hand. The task-related mean signal change was computed for all activated voxels within the cervical cord and, separately, in the right and left anterior, right and left posterior, and middle cervical cord from C5 to C8. Cord lesion number, brain T2-weighted lesion load, gray matter mean diffusivity (MD), and normal appearing white matter MD and fractional anisotropy were also measured. One control and one patient were excluded prior to fMRI analysis due to motion artifacts. The task-related signal change of all cord activated voxels was 3. 2% (SD=0. 8) for controls and 3. 9% (SD=0. 9) for MS patients (p =0. 02). Compared with controls, MS patients showed a higher signal change in the following cord sections: right anterior at C5 (p =0. 05), right anterior (p =0. 04) and posterior (p =0. 04) at C6, and middle at C6 (p =0. 03) and C7/C8 (p =0. 01). MS patients showed a more frequent cord activity in the left posterior cervical cord at C5/C6 than controls (p =0. 02). No significant correlation was found between cord fMRI changes and brain structural MRI metrics. In MS patients, the over-recruitment of the ipsilateral posterior cervical cord associated to a reduced functional lateralization suggests an abnormal function of the spinal relay interneurons.

YNIMG Journal 2008 Journal Article

Voxel-based analysis derived from fractional anisotropy images of white matter volume changes with aging

Elisabetta Pagani
Federica Agosta
Maria A. Rocca
Domenico Caputo
Massimo Filippi

Although age-related effects on brain volume have been extensively investigated post mortem and in vivo using magnetic resonance imaging (MRI), regional and temporal patterns of white matter (WM) volume changes with aging are not defined yet. The aim of this study was to assess the topographical distribution of age-related WM volume changes using a recently developed voxel-based method to obtain estimates of WM fiber bundle volumes using diffusion tensor (DT) MRI. Brain conventional and DT MRI were obtained from 84 healthy subjects (mean age=44 years, range=13–70). Linear and non-linear relationships between age and WM fiber bundle volume changes were tested. A negative linear correlation was found between age and WM volume decline in the corona radiata, anterior cingulum, body and crus of the fornix and left superior cerebellar peduncle. A positive linear correlation was found between age and volume increase of the right deep temporal association fibers. The non-linear regression analysis also showed age-related changes of the genu of the corpus callosum and fitted better the volume changes of the right deep temporal association fibers. WM volume decline with age is unevenly distributed across brain regions. Our approach holds promise to gain additional information on the pathological changes associated to neurological disorders of the elderly.

YNIMG Journal 2007 Journal Article

Evidence for cervical cord tissue disorganisation with aging by diffusion tensor MRI

Federica Agosta
Marcella Laganà
Paola Valsasina
Stefania Sala
Luca Dall'Occhio
Maria P. Sormani
Elda Judica
Massimo Filippi

This study investigated the influence of normal aging on cervical cord volumetry and diffusivity changes and assessed whether magnetic resonance imaging (MRI) abnormalities of the aging cervical cord and brain are associated. Conventional and diffusion tensor (DT) MRI of the brain and cervical cord were acquired from 96 healthy subjects (age range=13–70 years). Cross-sectional area, mean diffusivity (MD) and fractional anisotropy (FA) of the cervical cord were measured. Volumetry and diffusivity metrics were also obtained for the brain white matter (WM) and grey matter (GM) (overall and cortical). No cervical cord lesions were seen on conventional MR images from all subjects. Degenerative vertebral column changes (not associated to cord compression) were found in 41 subjects (43%). Average FA of the cervical cord, but not average MD and cross-sectional area, was correlated with age (r =−0. 70, p <0. 001). Additionally, T2 brain lesion volume, normalised brain volume (NBV), normalised global and cortical brain GM volumes and average MD of the brain GM and WM also correlated with age (r values ranging from −0. 83 to 0. 62). Only brain WM average FA was weakly correlated with cervical cord average FA (r =0. 25, p =0. 02). The final multivariate model retained cord average FA (r =−0. 37, p <0. 001), normalised cortical GM volume (r =−0. 56, p <0. 001) and NBV (r =−0. 22, p =0. 04) as independent correlates of age (r 2 =0. 76). Cervical cord is vulnerable to aging. The decrease of FA, in the absence of atrophy and MD changes, suggests gliosis as the most likely pathological feature of the aging cord.

YNIMG Journal 2006 Journal Article

An fMRI study of the motor system in patients with neuropsychiatric systemic lupus erythematosus

Maria A. Rocca
Federica Agosta
Domenico M. Mezzapesa
Gianfranco Ciboddo
Andrea Falini
Giancarlo Comi
Massimo Filippi

Functional cortical changes have been demonstrated in patients with several neurological conditions, including stroke, tumors and MS. The correlation found between the extent of fMRI activations and the extent and severity of brain structural damage suggests an adaptive role of these functional changes. In this study, we assess, using fMRI, the brain pattern of movement-associated cortical activations in neuropsychiatric systemic lupus erythematosus (NPSLE) patients and investigate whether the extent of cortical reorganization is associated with the extent of brain pathology, measured on dual-echo and diffusion tensor (DT) MR images. From 14 right-handed NPSLE patients and 14 matched controls, we obtained: (a) fMRI during the performance of repetitive flexion–extension of the last four fingers of the right hand; (b) dual-echo and (c) pulsed-gradient spin-echo echo-planar sequence to calculate DT MRI maps of the normal-appearing white (NAWM) and gray (NAGM) matter. Brain T2-visible abnormalities were detected in 11 NPSLE patients. Compared with controls, NPSLE patients had significantly higher NAWM fractional anisotropy histogram peak height (P = 0. 005), and more significant activations of the contralateral primary sensorimotor cortex, putamen and dentate nucleus. They also had more significant activations of several regions located in the frontal and parietal lobes as well as of MT/V5 and the middle occipital gyrus, bilaterally. Strong correlations (r values ranging from 0. 79 to 0. 87) were found between relative activations of sensorimotor areas and the extent and severity of brain damage. Movement-associated functional cortical changes do occur in patients with NPSLE and might contribute to the maintenance of their normal functional capacities.

YNIMG Journal 2006 Journal Article

The level of spinal cord involvement influences the pattern of movement-associated cortical recruitment in patients with isolated myelitis

Maria A. Rocca
Federica Agosta
Vittorio Martinelli
Andrea Falini
Giancarlo Comi
Massimo Filippi

Using fMRI, an increased recruitment of the ipsilateral primary sensorimotor cortex (SMC), supplementary motor area, and middle frontal gyrus has been detected in patients with cervical cord myelitis of possible demyelinating origin. The aim of this study was to evaluate, using fMRI, whether the level of cord involvement influences cortical reorganization by comparing patients with isolated myelitis of the cervical and the dorsal portions of the cord, and to investigate whether the extent of cortical reorganization is associated with the extent of cervical cord pathology measured using magnetization transfer (MT) MRI. We studied 24 right-handed patients (14 with a previous involvement of the cervical cord and 10 with an involvement of the dorsal cord) in a chronic and clinically stable phase following an isolated myelitis of possible demyelinating origin and 15 sex- and age-matched healthy controls. During a single session, we obtained fMRI during repetitive flexion–extension of the last four fingers of the right and left hands and cervical cord MT MRI. Average cord MTR was lower in patients with cervical (P < 0. 0001) and dorsal (P = 0. 0001) myelitis than in controls. Compared to controls and for both tasks, patients with myelitis had an increased recruitment of the ipsilateral primary SMC, which was independent of the level of cord involvement. On the contrary, patients with cervical myelitis had a more widespread recruitment of frontal and parietal regions, whereas those with dorsal myelitis had a more widespread recruitment of temporal and cerebellar regions. Strong correlations (r values ranging from −0. 72 to −0. 88) were found between relative activations of cortical areas and the severity of cervical cord damage. Patients with isolated myelitis have different patterns of movement-associated cortical activations according to the level of cord involvement. This “level-dependent” functional reorganization of the cortex is likely to have an adaptive role in limiting the clinical outcome of cord damage and should be considered when designing rehabilitation strategies for these patients.

YNIMG Journal 2005 Journal Article

Mean diffusivity and fractional anisotropy histogram analysis of the cervical cord in MS patients

Paola Valsasina
Maria A. Rocca
Federica Agosta
Beatrice Benedetti
Mark A. Horsfield
Antonio Gallo
Marco Rovaris
Giancarlo Comi

The spinal cord is frequently involved in multiple sclerosis (MS), and cord damage may be an important contributor to disability. Diffusion tensor magnetic resonance imaging (DT-MRI) provides quantitative information about the structural and orientational features of the central nervous system. In order to assess whether diffusion tensor-derived measures of cord tissue damage are related to clinical disability, mean diffusivity (MD) and fractional anisotropy (FA) histograms from the cervical cord were acquired from a large cohort of MS patients. Diffusion-weighted sensitivity-encoded (SENSE) echo planar images of the cervical cord, and brain dual-echo and diffusion-weighted scans were acquired from 44 patients with MS and 17 healthy controls. Cord and brain MD and FA histograms were produced. An analysis of variance model, adjusting for cord volume and patient age, was used to compare cord DT-MRI parameters from controls and patients. A multivariate linear regression model was used to identify DT-MRI variables independently associated with disability. Average cervical cord FA was significantly lower in MS patients compared to controls. Cord cross-sectional area, average FA and average MD were all significantly correlated with the degree of disability (r values ranging from 0. 36 to 0. 51). The multivariate linear regression model retained average cord FA and average brain MD as variables independently associated with disability, with a correlation coefficient of 0. 73 (P < 0. 001). DT-MRI reveals a loss of cervical cord tissue structure in MS patients. The strong correlation found between a composite DT-MRI score and disability suggests that a full and accurate assessment of cervical cord damage in MS provides information that usefully contributes to an explanation of the clinical manifestations of the disease.