Pilar Maria Ferraro - Academia.edu (original) (raw)

Papers by Pilar Maria Ferraro

Zenodo (CERN European Organization for Nuclear Research), Feb 9, 2023

European Journal of Physical and Rehabilitation Medicine, May 1, 2024

Objective: To assess the patterns of cortical thinning and white matter (WM) tract abnormalities ... more Objective: To assess the patterns of cortical thinning and white matter (WM) tract abnormalities in relation to cognition and behavioural symptoms in patients with motor neuron disease (MND). Methods: 101 patients with motor neuron disease (MND) and 56 healthy subjects were studied. Patients were classified into MND with a pure motor syndrome (MND-motor) and those with cognitive/behavioural symptoms (MND-plus). A surface-based morphometry analysis was used to assess cortical thickness. Corticospinal tract (CST), corpus callosum (CC), and major association tracts diffusion tensor (DT) metrics were obtained. A Random Forest (RF) approach was used to identify the set of image features correlated with cognitive/behavioural deficits. Results: There were 48 MND-motor and 53 MND-plus patients. Relative to controls, both patient groups showed cortical thinning of the bilateral precentral and postcentral gyri, cingulate cortex, inferior temporal and parietal areas. In all regions, there was a trend towards a more extensive involvement in MND-plus vs MND-motor. Both patient groups showed a damage of the motor CC fibers, but such a damage was greater in MND-plus cases. MND-plus patients also showed a severe involvement of the extra-motor WM tracts bilaterally. RF analysis showed that the best predictors of cognitive deficits and behavioural symptoms in MND patients were the DT MRI metrics of the frontotemporal tracts. Conclusions: Cortical thinning and WM degeneration are highly dependent upon neuropsychological and behavioural symptoms in patients with MND. WM tract damage contributes to the severity of selective cognitive and behavioural manifestations more than cortical thinning. Study Supported by: Italian Ministry of Health (#RF-2010-2313220). Disclosure: Dr. Agosta has received personal compensation for activities with Biogen Idec and Serono Symposia International Foundation. Dr. Ferraro has nothing to disclose. Dr. Spinelli has nothing to disclose. Dr. Canu has nothing to disclose. Dr. Riva has nothing to disclose. Dr. Copetti has nothing to disclose. Dr. Prudente has nothing to disclose. Adriano Chio serves on a scientific advisory board for Biogen Idec, Cytokinetics and Italfamaco, Dr. Iannaccone has nothing to disclose. Dr. Falini has nothing to disclose. Dr. Comi has received personal compensation for activities with Teva, Novartis, Genzyme, Merck Serono, Biogen Idec, Bayer, Actelion Pharmaceuticals, Almirall, and Serono. Cure PSP, Alzheimer9s Drug Discovery Foundation, and the Jacques and Gloria Gossweiler

European Journal of Radiology Open, 2022

Purpose The partial volume effect (PVE) complicates PET studies of neurodegenerative diseases, si... more Purpose The partial volume effect (PVE) complicates PET studies of neurodegenerative diseases, since a decreased 18F-FDG retention might be influenced by atrophy-related changes of cortical regions. Multiple partial volume correction (PVC) methods have been therefore developed, but their application in amyotrophic lateral sclerosis (ALS) is still rare. Additionally, even if metabolic changes have been established in ALS, no study yet has investigated how these may be influenced by aging and disease course. The aim of the present study was therefore to apply and compare multiple PVC approaches to explore aging and disease course-related hypometabolism in ALS. Methods PET and MRI data from 15 ALS patients were analyzed using PETSurfer to implement 4 distinct PVC methods: noPVC, Meltzer (MZ), Müller-Gärtner (MG) and Symmetric Geometric Transfer Matrix (SGTM). For each method and Region of Interest (ROI), the 18F-FDG value was regressed against subject age and disease duration. Results MG/SGTM application almost halved the number of regions showing a significant age-related hypometabolism, while the same effect was not observed for disease course, where only the distribution of identified regions varied. Three distinct patterns emerged: regions showing a significant age/disease course-related effect across all the different methods, regions yielding significance only with MG/SGTM application, and regions maintaining significance only with noPVC/MZ application. Conclusions Significant changes in the distribution of aging and disease course-related hypometabolism were observed when the effect of the underlying structural status was considered, supporting the need for investigate the impact of PVE on PET-assessed metabolic changes in clinical and research settings.

Neurobiology of Aging, Aug 1, 2018

Amyotrophic lateral sclerosis (ALS) and the behavioural variant of frontotemporal dementia (bvFTD... more Amyotrophic lateral sclerosis (ALS) and the behavioural variant of frontotemporal dementia (bvFTD) commonly share the presence of TDP-43 inclusions. Structural MRI studies demonstrated evidence for TDP-43 pathology spread, but while structural imaging usually reveals overt neuronal loss, perfusion imaging may detect more subtle neural activity alterations. We evaluated perfusion as an early marker for incipient pathology associated brain alterations in TDP-43 proteinopathies. Cortical thickness (CT) and perfusion measurements were obtained in ALS (N=18), pathologically and/or genetically confirmed bvFTD-TDP (N=12), and healthy controls (N=33).

Objective. To test the diagnostic ability of the cortical thickness of the primary motor cortex (... more Objective. To test the diagnostic ability of the cortical thickness of the primary motor cortex (PMC) and diffusion tensor (DT) indices of the corticospinal tracts (CST) and corpus callosum (CC) in a large sample of patients with different motor neuron disease (MND) phenotypes. Background. There is no test available to make a reliable diagnosis and predict disease course early in amyotrophic lateral sclerosis (ALS) and other MND. MRI allows accurate measurements of cortical thickness and white matter (WM) abnormalities. Methods. 171 MND patients and 59 healthy controls underwent T1-weighted and DT MRI. We included 57 classic ALS, 22 bulbar ALS, 19 pyramidal ALS, 45 pure upper motor neuron (PUMN), and 28 pure lower motor neuron (PLMN). Cortical thickness of PMC bilaterally and DT MRI measures from the CST and CC fibers linking the PMC and supplementary motor area (SMA) were obtained. MRI feature individual classification was assessed. Results. Relative to controls, all MND groups showed thinning of the PMC, while damage to CST and CC motor fibers bilaterally was found in all phenotypes except for PLMN. MRI predictors providing optimal classification of each clinical phenotype were: CC-PMC FA (p<0.001) and right PMC thickness (p=0.005) with an accuracy of 71.2[percnt] in classic ALS; CC-PMC FA (p<0.001) with an accuracy of 93.2[percnt] in pyramidal ALS; CC-PMC FA (p<0.001) with an accuracy of 90.5[percnt] in PUMN; and right PMC thickness (p=0.02) with an accuracy of 71.5[percnt] in bulbar ALS and 71.9[percnt] in PLMN. The combination of DT MRI and cortical thickness measures provided an accuracy of 98[percnt] in distinguishing PUMN from PLMN. ALSFRS-R and UMN score correlated with CST and CC damage. Conclusions. Cortical thickness measures and DT MRI provide a sensitive quantitative method for distinguishing patients with MND at the individual level with high accuracy. Supported by: Italian Ministry of Health (#RF-2010-2313220). Disclosure: Dr. Ferraro has nothing to disclose. Dr. Agosta has received personal compensation for activities with Biogen Idec and Serono Symposia International Foundation. Dr. Spinelli has nothing to disclose. Dr. Riva has nothing to disclose. Dr. Copetti has nothing to disclose. Dr. Valsasina has nothing to disclose. Dr. Prudente has nothing to disclose. Adriano Chio serves on a scientific advisory board for Biogen Idec, Cytokinetics and Italfamaco, Dr. Iannaccone has nothing to disclose. Dr. Silani has nothing to disclose. Dr. Falini has nothing to disclose. Dr. Comi has received personal compensation for activities with Teva, Novartis, Genzyme, Merck Serono, Biogen Idec, Bayer, Actelion Pharmaceuticals, Almirall, and Serono. Cure PSP, Alzheimer9s Drug Discovery Foundation, and the Jacques and Gloria Gossweiler

Objective. To explore structural and functional abnormalities in C9orf72-positive (+) amyotrophic... more Objective. To explore structural and functional abnormalities in C9orf72-positive (+) amyotrophic lateral sclerosis (ALS) relative to C9orf72-negative (-) cases with or without a comparable amount of cognitive deficits. Background. Previous studies suggest an extensive frontotemporal involvement as the C9orf72 structural MRI signature in ALS. However, these findings were obtained comparing C9orf72(+) with C9orf72(-) ALS patients without cognitive impairment. Methods. 21 C9orf72(+) ALS patients were compared with: 22 healthy subjects; 31 C9orf72(-) ALS patients without cognitive impairment [C9orf72(-) motor] matched for demographics, ALSFRS-r score and disease duration; 26 C9orf72(-) ALS patients matched for ALSFRS-r score and cognitive/behavioral deficits [C9orf72(-) plus]. All subjects performed 3D T1-weighted, diffusion tensor (DT), and resting state (RS) fMRI. Results. Relative to C9orf72(-) plus, C9orf72(+) ALS patients were younger and had a shorter disease duration. All patients showed cortical thinning of the precentral, middle frontal, superior temporal and inferior parietal cortices bilaterally. In the majority of regions, thinning was greater in C9orf72(+) compared to C9orf72(-) motor patients, while no areas were more affected in C9orf72(+) compared to C9orf72(-) plus. All patients showed a damage of the motor callosal fibers and corticospinal tract. C9orf72(+) patients showed an additional involvement of the right superior longitudinal fasciculus. In the motor network, C9orf72(-) patients exhibited increased functional connectivity compared to controls, while C9orf72(+) patients showed decreased functional connectivity relative to C9orf72(-) plus patients. All patients showed decreased functional connectivity within the dorsal attention network compared to controls. Conclusions. C9orf72(+) ALS patients showed a structural cortical damage similar to older C9orf72(-) patients with comparable cognitive impairment and longer disease duration, implying that frontotemporal involvement appears earlier in C9orf72(+) than in other ALS patients. C9orf72(+) ALS patients showed divergent motor functional connectivity patterns relative to C9orf72(-) plus patients suggesting altered connectivity as part of C9orf72-ALS pathogenesis. Funding: Italian Ministry of Health (#RF-2010-2313220). Disclosure: Dr. Ferraro has nothing to disclose. Dr. Agosta has received personal compensation for activities with Biogen Idec and EXCEMED– Excellence in Medical Education. Dr. Riva has nothing to disclose. Dr. Domi has nothing to disclose. Dr. Copetti has nothing to disclose. Dr. Lunetta has nothing to disclose. Dr. Ferrari has nothing to disclose. Dr. Comi has received personal compensation for activities with Teva, Novartis, Genzyme, Merck Serono, Biogen, Bayer, Actelion, Almirall, and Serono Symposia International Foundation. Dr. Carrera has nothing to disclose. Dr. Falini has nothing to disclose. Dr. Quattrini has nothing to disclose. Dr. Filippi has received personal compensation for activities for consulting services and/or speaking activities from Biogen Idec, Excemed, Novartis, and Teva Pharmaceutical Industries.

Objective. To identify overlapping and unique grey (GM) and white matter (WM) signatures within t... more Objective. To identify overlapping and unique grey (GM) and white matter (WM) signatures within the frontotemporal lobar degeneration (FTLD) continuum, and discriminate likely FTLD-TAU and FTLD-TDP patients using structural and diffusion tensor (DT) MRI. Background. Our understanding of brain networks’ alterations in each FTLD syndrome has been fruitfully expanded in the past few years through the use of MRI. Despite the clinical, genetic and pathological overlap, patterns of brain damage across the whole continuum are still largely unexplored. Methods. T1-weighted and DT MRI were collected from 35 motor neuron disease (MND), 14 behavioral variant of frontotemporal dementia, 12 semantic and 11 nonfluent primary progressive aphasia, 21 progressive supranuclear palsy syndrome patients and 28 controls. Patterns of GM atrophy and WM tract damage were established. Results. All patient groups, with the exception of MND cases with a pure motor syndrome, shared a focal GM atrophy centered around the dorsolateral and medial frontal cortex and a largely overlapping pattern of WM damage involving the genu and body of the corpus callosum and ventral frontotemporal and dorsal frontoparietal WM pathways. Surrounding this common area, phenotype (symptom)-specific GM and WM regions of damage were found in each group. Patients with a high likelihood of an underlying FTLD-TAU had more severe WM damage relative to patients who are likely to harbor FTLD-TDP pathology, despite a similar pattern of GM atrophy. Conclusions. In the FTLD spectrum, WM damage is more severe than GM atrophy. Frontal cortex and WM pathways represent the common target of neurodegeneration in these conditions. The topographic pattern of damage supports a “prion-like” protein propagation through WM connections as underlying mechanism of the stereotyped progression of FTLD. Funding. This study was partially supported by the following grants: Italian Ministry of Healthy (#RF-2010-2313220, and #GR-2010-2303035); CurePSP Foundation (#MD505-12_001). Disclosure: Cure PSP, Alzheimer9s Drug Discovery Foundation, and the Jacques and Gloria Gossweiler Dr. Agosta has received personal compensation for activities with Biogen Idec and Serono Symposia International Foundation. Dr. Galantucci has nothing to disclose. Dr. Magnani has nothing to disclose. Dr. Marcone has nothing to disclose. Dr. Martinelli has nothing to disclose. Dr. Volonte has nothing to disclose. Dr. Riva has nothing to disclose. Dr. Iannaccone has nothing to disclose. Dr. Ferraro has nothing to disclose. Dr. Caso has nothing to disclose. Adriano Chio serves on a scientific advisory board for Biogen Idec, Cytokinetics and Italfamaco, Dr. Falini has nothing to disclose. Dr. Comi has received personal compensation for activities with Teva, Novartis, Genzyme, Merck Serono, Biogen Idec, Bayer, Actelion Pharmaceuticals, Almirall, and Serono.

Neurology, Apr 6, 2015

An overlap frequently occurs between major depression disorder (MDD) and generalized anxiety diso... more An overlap frequently occurs between major depression disorder (MDD) and generalized anxiety disorder (GAD). Aim of this study was to assess cortical and white matter (WM) alterations in MDD patients with or without GAD comorbidity. Seventy-one MDD patients and 71 controls were recruited. All subjects underwent T1weighted and diffusion tensor (DT)/MRI. MRI metrics of cortical thickness and WM integrity were obtained from atlas-based cortical regions and the interhemispheric and major long association WM tracts. Between-group MRI comparisons and multiple regressions with clinical scale scores were performed. Compared to controls, both MDD and MDD-GAD patients showed a cortical thinning of the middle frontal cortex bilaterally, left medial frontal gyrus and frontal pole. Compared to controls and MDD patients, MDD-GAD cases also showed a thinning of the right medial orbitofrontal and fusiform gyri, and left temporal pole and lateral occipital cortices. Compared to controls, MDD patients showed DT MRI abnormalities of the right parahippocampal tract and superior longitudinal fasciculus bilaterally, while no WM alterations were found in MDD-GAD. In all patients, brain abnormalities were related with symptom severity. MDD and MDD-GAD share a common pattern of cortical alterations located in the frontal regions. However, while both the cortex and WM integrity are affected in MDD, only the former is affected in MDD-GAD. These findings support the notion of MDD-GAD as a distinct clinical entity, providing insights into patient vulnerability for specific networks as well as into patient resilience factors reflected by the integrity of other cerebral circuits.

Life, Apr 21, 2023

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Neurology, Apr 5, 2016

Objective: To study longitudinally clinical, cognitive, and neuroimaging changes in patients with... more Objective: To study longitudinally clinical, cognitive, and neuroimaging changes in patients with progressive supranuclear palsy syndrome (PSPs). Background: There is great interest in the identification of reliable biomarkers of PSPs progression. Methods: We enrolled 21 patients with Richardson’s syndrome (PSP-RS) and 10 with PSP-parkinsonism (PSP-P). Patients underwent clinical and neuropsychological evaluation and MRI scan at baseline and after a mean follow-up (FU) of 1.4 years. At baseline, MRI was obtained from 35 healthy controls. Diffusion tensor (DT) metrics of white matter (WM) tracts were assessed in both PSPs groups. Cortical thickness changes were investigated in PSP-RS patients. Results: Both PSPs groups showed significant motor impairment and cognitive decline, that appeared more severe in PSP-RS than in PSP-P patients. Apathy worsened in both groups, while depression and behavioral changes in PSP-RS only. At study entry, PSP-RS patients presented focal thinning of fronto-temporal and cingulate cortical areas bilaterally, compared to controls. Over time, cortical thinning progressed in cingulate cortex bilaterally, left fronto-temporal and insular cortices. At baseline, PSP-RS patients showed a widespread WM damage in midbrain, superior cerebellar peduncles, corpus callosum and the main long-range tracts. During FU, WM damage progressed in these patients in the corpus callosum, frontotemporal/-parietal connections, but not in infratentorial WM. In PSP-RS, WM damage progression correlated with the worsening of disability and behavioral dysfunction. DT MRI analysis showed that, at baseline, PSP-P patients had WM damage in the anterior corpus callosum, external capsule, corona radiate, and superior longitudinal fasciculus bilaterally, compared to controls; these same regions showed a subtle progression of damage during FU. Conclusions: In PSPs patients, the progression of WM microstructural damage is prominent compared to cortical damage and it is related to the worsening of clinical symptoms. MRI differences between clinical phenotypes might reflect the different extent and distribution of the underlying tau pathology. Disclosure: Dr. Caso has nothing to disclose. Dr. Agosta has received personal compensation for activities with Biogen Idec and EXCEMED– Excellence in Medical Education. Dr. Jecmenica has nothing to disclose. Dr. Petrovic has nothing to disclose. Dr. Valsasina has nothing to disclose. Dr. Ferraro has nothing to disclose. Dr. Meani has nothing to disclose. Dr. Copetti has nothing to disclose. Dr. Kostic has received personal compensation for activities with Novartis, Boehringer Ingelheim Pharmaceuticals, Merck & Co., Inc., Lundbeck Research USA, Inc., GlaxoSmithKline, Hoffman-La Roche, Alkaloid, and AbbVie as a speaker. Dr. Filippi has received personal compensation for activities for consulting services and/or speaking activities from Biogen Idec, Excemed, Novartis, and Teva Pharmaceutical Industries.

Frontiers in Neuroscience, Aug 14, 2023

European Journal of Neurology

Background and purposeMild behavioral impairment (MBI) has been increasingly regarded as the neur... more Background and purposeMild behavioral impairment (MBI) has been increasingly regarded as the neurobehavioral axis of predementia risk states, but a specific investigation of its detection as a potential marker of prodromal dementia in motor neuron diseases (MNDs) is still lacking. The aims of our study were therefore to explore MBI in MNDs both at onset and over the disease course, and to evaluate its relationship with baseline and longitudinal cognitive features.MethodsSixty MND patients with cognitive/behavioral, mood, and motor examinations were recruited and followed longitudinally for up to 15 months. Associations between baseline MBI symptoms and clinical features were tested using the Spearman correlation coefficient. Based on longitudinal data, relative deltas of variation for each cognitive measure were generated, and linear regression models were then used to evaluate the role of baseline MBI symptoms in predicting longitudinal rates of cognitive decline.ResultsAt disease ...

Neurology, 2016

Objective. We investigated cortical and white matter (WM) alterations in a large sample of Kenned... more Objective. We investigated cortical and white matter (WM) alterations in a large sample of Kennedy’s disease (KD) patients compared to healthy subjects and amyotrophic lateral sclerosis (ALS) patients. Background. Diagnosis of KD might be challenging. Subtle MRI alterations have been reported in KD, but the extent of central nervous system (CNS) involvement relative to ALS still needs to be investigated. Methods. 19 patients with genetically confirmed KD were compared with 21 healthy subjects and 17 sporadic ALS patients matched for demographics and ALSFRS-r score. All patients underwent clinical assessment and Magnetic Resonance Imaging (MRI). Tract-based spatial statistics was applied to investigate WM damage and cortical thickness analysis to identify cortical atrophy. Results. KD patients were characterized by pronounced behavioral symptoms and only subtle cognitive deficits. Relative to controls, KD patients showed pronounced damage of the pontine crossing fibers, right frontot...

JAMA Neurology, 2021

IMPORTANCE Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by ag... more IMPORTANCE Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation. OBJECTIVE To identify the genetic variants associated with juvenile ALS. DESIGN, SETTING, AND PARTICIPANTS In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism. MAIN OUTCOMES AND MEASURES De novo variants present only in the index case and not in unaffected family members. RESULTS Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway. CONCLUSIONS AND RELEVANCE These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.