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Marco Onofrj

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Loughborough University

The University of Sheffield

Professor Dr. Loutfy H . Madkour

Al-Baha University, Kingdom of Saudi Arabia

Uwamere O Edeghor

University of Calabar, Calabar, Nigeria.

UNIVERSITY OF JOS, NIGERIA

Burdwan University

University of Brighton

OSUNTOKUN OLUDARE TEMITOPE (Orcid ID.0000-0002-3954-6778), Web of Science ResearcherID -L-4314-2016

Adekunle Ajasin University, Akungba-Akoko, Nigeria

University of East London

Gwen Robbins Schug

University of North Carolina at Greensboro

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Papers by Marco Onofrj

Mitochondrial Involvement in Neurodegenerative Dementia

Gribkoff/The Functions, Disease-Related Dysfunctions, and Therapeutic Targeting of Neuronal Mitochondria, 2015

Delirium in COVID-19 patients: a multicentric observational study in Italy

Neurological Sciences

Introduction Although recent data show that SARS-CoV-2 infection seems to affect the central nerv... more Introduction Although recent data show that SARS-CoV-2 infection seems to affect the central nervous system (CNS), little is known about the neuropsychiatric effects resulting from this condition. In addition to the well-known neurotrophism of coronaviruses, recent evidence shows also that the "cytokine storm" induced by the infection is at the basis of the neuroinflammation of the CNS. Furthermore, prolonged hospitalization, polypharmacotherapy, and isolation could be at the basis of the onset of delirium in hospitalized COVID patients. This multicentric observational study explores the incidence of the onset of delirium in an Italian cohort of SARS-CoV-2 positive inpatients. Methods Data were collected in the COVIDhospitals of Brescia, Bergamo, Chieti, and Genova. Different socio-demographic, medical, neurological, and pharmacological parameters were collected. As a rapid screening for delirium, the 4AT scale was used. Eighty COVID-19 inpatients (mean age 74.7 ± 14.5 years) met the inclusion criteria (confirmed positivity to the SARS-CoV-2 virus; the presence of delirium and/or psychomotor agitation and/or new onset of other neuropsychiatric symptoms during hospitalization). Results Themajority of these patients (68.8%) had "hyperactive delirium" subtype. Polypharmacotherapy, current treatment with corticosteroids, and higher age were associated with delirium severity. Conclusion These data provide an insight into the onset of delirium among COVID-19 patients underlining the need for monitoring, especially in elderly patients, the neuropsychiatric symptoms, and the therapy in order to have shorter hospitalization times and better outcomes.

Classification of Patients with Alzheimer’s Disease and Dementia with Lewy Bodies using Resting EEG Selected Features at Sensor and Source Levels: A proof-of-concept study

Current Alzheimer Research

Background: Early differentiation between Alzheimer’s disease (AD) and Dementia with Lewy Bodies ... more Background: Early differentiation between Alzheimer’s disease (AD) and Dementia with Lewy Bodies (DLB) is important for accurate prognosis, as DLB patients typically show faster disease progression. Cortical neural networks, necessary for human cognitive function, may be disrupted differently in DLB and AD patients, allowing diagnostic differentiation between AD and DLB. Objective: This proof-of-concept study assessed whether the application of machine learning techniques to data derived from resting-state electroencephalographic (rsEEG) rhythms (discriminant sensor power, 19 electrodes) and source connectivity (between five cortical regions of interest) allowed differentiation between DLB and AD. Methods: Clinical, demographic, and rsEEG datasets from DLB patients (N=30), AD patients (N=30), and control seniors (NOld, N=30), matched for age, sex, and education, were taken from our international database. Individual (delta, theta, alpha) and fixed (beta) rsEEG frequency bands were i...

Status epilepticus and COVID-19: A systematic review

Journal of the Neurological Sciences

SARS-CoV-2 serology after COVID-19 in multiple sclerosis: An international cohort study

Multiple Sclerosis Journal

Background: The MuSC-19 project is an Italian cohort study open to international partners that co... more Background: The MuSC-19 project is an Italian cohort study open to international partners that collects data on multiple sclerosis (MS) patients with COVID-19. During the second wave of the pandemic, serological tests became routinely available. Objective: To evaluate the seroprevalence of anti-SARS-CoV-2 antibodies according to the use of disease-modifying therapy (DMT) in a subset of patients included in the MuSC-19 data set who had undergone a serological test. Methods: We evaluated the association between positive serological test results and time elapsed since infection onset, age, sex, Expanded Disability Status Scale score, comorbidities and DMT exposure using a multivariable logistic model. Results: Data were collected from 423 patients (345 from Italy, 61 from Turkey and 17 from Brazil) with a serological test performed during follow-up. Overall, 325 out of 423 tested patients (76.8%) had a positive serological test. At multivariate analysis, therapy with anti-CD20 was sign...

Long-term outcomes in patients presenting with optic neuritis: Analyses of the MSBase registry

Journal of the Neurological Sciences

Inflammatory polyradiculoneuropathies: Clinical and immunological aspects, current therapies, and future perspectives

European Journal of Inflammation

Inflammatory polyradiculoneuropathies are heterogeneous disorders characterized by immune-mediate... more Inflammatory polyradiculoneuropathies are heterogeneous disorders characterized by immune-mediated leukocyte infiltration of peripheral nerves and nerve roots leading to demyelination or axonal degeneration or both. Inflammatory polyradiculoneuropathies can be divided into acute and chronic: Guillain–Barré syndrome and chronic inflammatory demyelinating polyneuropathy and their variants. Despite major advances in immunology and molecular biology have been made in the last years, the pathogenesis of these disorders is not completely understood. This review summarizes the current literature of the clinical features and pathogenic mechanisms of inflammatory polyradiculoneuropathies and focuses on current therapies and new potential treatment for the future.

Tumour-like presentation of atypical posterior reversible encephalopathy syndrome with prominent brainstem involvement

BMJ Case Reports

Typical posterior reversible encephalopathy syndrome (PRES) is a clinical-neuroradiological entit... more Typical posterior reversible encephalopathy syndrome (PRES) is a clinical-neuroradiological entity characterised by bilateral white matter oedema, which is usually symmetrical and totally reversible in 2–3 weeks. A 46-year-old man presented with a persistent headache and visual blurring in the right eye. On admission, the clinical examination revealed minimal unsteadiness of gait and elevated blood pressure. A brain MRI showed a hyperintense signal on T2-weighted sequences in the whole brainstem, extended to the spinal cord (C2–C6), the left insula and the right cerebellum. When his blood pressure was controlled, his symptoms gradually improved. The follow-up MRI scan at 3 weeks revealed a dramatic regression of the hyperintense lesions on T2-weighted sequences. The differential diagnosis of PRES is very wide, especially in the case of conspicuous brainstem involvement. Treatable causes of white matter oedema should be always kept in mind to avoid misdiagnosis and prevent complicati...

Phase 2A Randomized, Double-Blind, Placebo-Controlled Trial of the Histone Deacetylase Inhibitor (Hdaci), FRM-0334, in Asymptomatic Carriers Of, or Patients with Frontotemporal Lobar Degeneration (FTLD) Due To, Progranulin Gene Mutations

Alzheimer's & Dementia

What Electrophysiology Tells Us About Alzheimer’s Disease: A Window into the Synchronization and Connectivity of Brain Neurons

Neurobiology of Aging

The Characterization of Regulatory T-Cell Profiles in Alzheimer’s Disease and Multiple Sclerosis

Scientific Reports

Regulatory T Cells (Tregs) are a T-lymphocyte subset involved in the maintenance of immune periph... more Regulatory T Cells (Tregs) are a T-lymphocyte subset involved in the maintenance of immune peripheral tolerance. Despite evidence of the adaptive immune system's role in Alzheimer's Disease (AD), the involvement of Tregs is still not clear. We focused on the Flow-Cytometry analysis of the Treg frequencies and phenotypes in the AD. The aim of the study is to analyse similarities and differences in Tregs profile between Alzheimer's Disease and Multiple Sclerosis. Regulatory T Cells (CD4+/CD25high/ CD127low-neg) were identified using an innovative Flow Cytometry method and subtyped as Resting (analysed CD45RApos/CD25dim), Activated (CD45RAneg/CD25bright) and Secreting (CD45RAneg/ CD25dim) cells. Our data demonstrate a significant decrease in the total and Resting Tregs in AD patients when compared to healthy subjects. The percentage of the results of the Resting Tregs were also reduced in MS patients together with a parallel frequency increase of Activated Tregs. Our data suggest that altered Treg phenotypes observed in both diseases could play a role in the impairment of the Treg-mediated immunological tolerance, recalling a possible link between the two pathologies. Given that this study was conducted on a restricted population, if confirmed by a further and enlarged study, the implications of the autoimmune mechanisms in AD pathophysiology could open new immunotherapeutic perspectives based on Treg modulation. Alzheimer's Disease (AD) is the most common kind of neurodegenerative dementia in the elderly population, characterized by both cognitive and behavioural dysfunctions 1,2. The Alzheimer's Disease neuropathology is characterized by the Amyloid beta (Ab) deposition, as amyloid plaques within some specific brain regions, as well as by microglial activation and local inflammatory responses. When the microglia fails to remove the Ab peptide, this first immune-related event is not decisive, therefore the microglial activation becomes chronic as does the related production of pro-inflammatory cytokines 3. The consequent chronic neuro-inflammation status is associated with a toxic cascade, leading to neuronal death and resulting in neurodegeneration 4. Accumulating evidence suggests a relationship among adaptive immunity, neuroinflammation, and neurodegenerative pathologies 5-7. Adaptive immunity, also known as acquired immunity, encloses the humoral and the cell-mediated response. These events are both involved in the immune surveillance and in homeostasis balance 8,9. Under neurodegenerative conditions, as in the AD or in Parkinson's Disease (PD) 10,11 , T lymphocytes are recruited into specific brain regions 11,12 and high frequencies of reactive T lymphocytes have been found in the bloodstream of these patients, suggesting their key role in the physiopathology of neurodegenerative disorders 13. According to their phenotypes and functions, T cells are subtyped as CD8+ Cytotoxic Lymphocytes (CTL), CD4+ helper T lymphocytes (Th, subtyped as Th1 and Th2 subsets), CD4+ regulatory T lymphocytes (Tregs, including natural occurring Tregs and adaptively induced Tregs) and conventional T cells (effector T cells and memory T cells) 13-15. In the central nervous system, the CD4+ T cells orchestrate both innate and adaptive immune responses, through a complex network of cellular interactions involved in the control of tissue homeostasis 13. Various studies that have been

Integrated Lipidomics and Metabolomics Analysis of Tears in Multiple Sclerosis: An Insight into Diagnostic Potential of Lacrimal Fluid

International Journal of Molecular Sciences

Metabolomics based on mass spectrometry represents an innovative approach to characterize multifa... more Metabolomics based on mass spectrometry represents an innovative approach to characterize multifactorial diseases, such as multiple sclerosis (MuS). To date, the most important biomarker source for MuS diagnosis is the cerebrospinal fluid. However, an important goal for research is to identify new molecules in more easily accessible biological fluids. A very interesting biofluid in MuS is represented by tears, considered as an intermediate fluid between the cerebrospinal fluid and serum. In this work, we developed a merged strategy for the analysis of lipids containing choline by Liquid Chromatography coupled to Tandem Mass Spectrometry (LC-MS/MS), as well as for the targeted analysis of free carnitine, acylcarnitines and aminoacids by direct infusion mass spectrometry. Samples for both metabolomics and lipidomics approaches were obtained in a single extraction procedure from tears of patients affected by MuS and healthy controls. Tear lipidomics showed 30 phospholipids significantl...

Abnormalities Of Functional Cortical Source Connectivity Of Resting State Electroencephalographic Alpha Rhythms Are Similar In Patients With Mild Cognitive Impairment Due Alzheimer's And Lewy Body Diseases

Neurobiology of Aging

Cortical Network Topology in Prodromal and Mild Dementia Due to Alzheimer’s Disease: Graph Theory Applied to Resting State EEG

Brain Topography

Graph theory analysis on resting state electroencephalographic rhythms disclosed topological prop... more Graph theory analysis on resting state electroencephalographic rhythms disclosed topological properties of cerebral network. In Alzheimer's disease (AD) patients, this approach showed mixed results. Granger causality matrices were used as input to the graph theory allowing to estimate the strength and the direction of information transfer between electrode pairs. The number of edges (degree), the number of inward edges (in-degree), of outgoing edges (out-degree) were statistically compared among healthy controls, patients with mild cognitive impairment due to AD (AD-MCI) and AD patients with mild dementia (ADD) to evaluate if degree abnormality could involve low and/or high degree vertices, the so called hubs, in both prodromal and over dementia stage. Clustering coefficient and local efficiency were evaluated as measures of network segregation, path length and global efficiency as measures of integration, the assortativity coefficient as a measure of resilience. Degree, indegree and out-degree values were lower in AD-MCI and ADD than the control group for non-hubs and hubs vertices. The number of edges was preserved for frontal electrodes, where patients' groups showed an additional hub in F3. Clustering coefficient was lower in ADD compared with AD-MCI in the right occipital electrode, and it was positively correlated with mini mental state examination. Local and global efficiency values were lower in patients' than control groups. Our results show that the topology of the network is altered in AD patients also in its prodromal stage, begins with the reduction of the number of edges and the loss of the local and global efficiency.

The predictive power of transcranial sonography in movement disorders: a longitudinal cohort study

Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 2018

Transcranial sonography (TCS) is a noninvasive, easily performed, and commonly available neuroima... more Transcranial sonography (TCS) is a noninvasive, easily performed, and commonly available neuroimaging technique useful for the study of brain parenchyma in movement disorders. This tool has been increasingly used in the diagnosis of Parkinson's disease and atypical parkinsonism. The aim of the study was to evaluate the applicability of this technique as supportive tool in the early diagnosis of movement disorders. We performed TCS on 315 individuals which were diagnosed as healthy controls or affected by idiopathic Parkinson's disease, monogenetic subtypes of Parkinson's disease, atypical parkinsonism, and Dementia with Lewy bodies. Five TCS diagnostic patterns were defined on the basis of substantia nigra's and lenticular nuclei's echogenicity. TCS evaluations were performed by two blinded neuro-sonographers. Clinical diagnosis on all individuals was performed at baseline and at 4-year follow-up. The concordance rate between TCS patterns and clinical diagnosis a...

Metabolomic Signature in Sera of Multiple Sclerosis Patients during Pregnancy

International Journal of Molecular Sciences

Multiple sclerosis (MuS) is an autoimmune disease of the central nervous system characterized by ... more Multiple sclerosis (MuS) is an autoimmune disease of the central nervous system characterized by neuroinflammation, neurodegeneration, and degradation of the myelin sheath. Epidemiological studies have shown that the female gender is more susceptible than the male gender to MuS development, with a female-to-male ratio of 2:1. Despite this high onset, women have a better prognosis than men, and the frequency of the relapsing phase decreases during pregnancy, while it increases soon after birth. Therefore, it is interesting to investigate hormonal fluctuations during pregnancy and whether they correlate with metabolic signatures. To gain a deeper inside into the biochemical mechanism of such a multifactorial disease, we adopted targeted metabolomics approaches for the determination of many serum metabolites in 12 pregnant women affected by MuS by mass spectrometry analysis. Our data show a characteristic hormonal fluctuation for estrogens and progesterone, as expected. They also highl...

Levodopa may affect cortical excitability in Parkinson's disease patients with cognitive deficits as revealed by reduced activity of cortical sources of resting state electroencephalographic rhythms

Neurobiology of aging, Jan 30, 2018

We hypothesized that dopamine neuromodulation might affect cortical excitability in Parkinson&#39... more We hypothesized that dopamine neuromodulation might affect cortical excitability in Parkinson's disease (PD) patients set in quiet wakefulness, as revealed by resting state eyes-closed electroencephalographic (rsEEG) rhythms at alpha frequencies (8-12 Hz). Clinical and rsEEG rhythms in PD with dementia (N = 35), PD with mild cognitive impairment (N = 50), PD with normal cognition (N = 35), and normal (N = 50) older adults were available from an international archive. Cortical rsEEG sources were estimated by exact low-resolution brain electromagnetic tomography. Compared with the normal older group, the PD groups showed reduced occipital alpha sources and increased widespread delta (<4 Hz) sources. Widespread frontal and temporal alpha sources exhibited an increase in PD with dementia compared with PD with mild cognitive impairment and PD with normal cognition groups, as function of dopamine depletion severity, typically greater in the former than the latter groups. A daily do...

LRP10 genetic variants in familial Parkinson's disease and dementia with Lewy bodies: a genome-wide linkage and sequencing study

The Lancet. Neurology, 2018

Most patients with Parkinson's disease, Parkinson's disease dementia, and dementia with L... more Most patients with Parkinson's disease, Parkinson's disease dementia, and dementia with Lewy bodies do not carry mutations in known disease-causing genes. The aim of this study was to identify a novel gene implicated in the development of these disorders. Our study was done in three stages. First, we did genome-wide linkage analysis of an Italian family with dominantly inherited Parkinson's disease to identify the disease locus. Second, we sequenced the candidate gene in an international multicentre series of unrelated probands who were diagnosed either clinically or pathologically with Parkinson's disease, Parkinson's disease dementia, or dementia with Lewy bodies. As a control, we used gene sequencing data from individuals with abdominal aortic aneurysms (who were not examined neurologically). Third, we enrolled an independent series of patients diagnosed clinically with Parkinson's disease and controls with no signs or family history of Parkinson's dis...

Post Traumatic Stress Disorder Heralding the Onset of Semantic Frontotemporal Dementia

Journal of Alzheimer's disease : JAD, 2018

Post traumatic stress disorder (PTSD) is associated with cognitive decline. The dementia type fol... more Post traumatic stress disorder (PTSD) is associated with cognitive decline. The dementia type following PTSD is unclear. To assess whether PTSD is associated with a specific dementia. Prospective study: 46 PTSD patients (DSM-IV-TR) were followed for 6-10 years with clinical, neuropsychological, imaging evaluations for possible development of dementia.Retrospective study:849 dementia patients followed during 1999-2014 (509 Alzheimer's disease, AD; 207 dementia with Lewy bodies, DLB; 90 vascular dementia, VaD; 43 frontotemporal dementia, FTD) and 287 patients with any neurological condition (including patients with/without dementia) were evaluated for the presence of PTSD in their history. Prospective study: 8 patients developed dementia; 1 AD, 1 DLB, 6 semantic FTD (13.0% of the PTSD population). Retrospective study: 38 patients (4.5%) had a history of PTSD; 3.5% of AD, 4.3% of DLB, 14.0% of FTD, 5.6% of VaD. The percentage was higher in FTD than in AD or DLB (χ2 = 10, p = 0.001,...

Simultaneous early-onset severe autoimmune hemolytic anemia and albuminuria during alemtuzumab treatment for multiple sclerosis

Multiple sclerosis (Houndmills, Basingstoke, England), 2018

Alemtuzumab, approved for multiple sclerosis (MS), can cause secondary autoimmune adverse events ... more Alemtuzumab, approved for multiple sclerosis (MS), can cause secondary autoimmune adverse events including thyroid disorders, immune thrombocytopenia (ITP), and glomerular nephropathies. Non-ITP autoimmune cytopenias are rarely reported. To report a case of autoimmune hemolytic anemia (AIHA) and nephropathy in a MS patient treated with alemtuzumab. A 34-year-old man with MS developed albuminuria and AIHA after the first and only alemtuzumab treatment, with positive Coombs' direct and indirect tests and IgG autoantibodies. Both AIHA and nephropathy resolved 1 month after treatment with steroids and intravenous immunoglobulins. Our report adds to literature on AIHA and nephropathy after alemtuzumab treatment and suggests to add Coombs' tests to the screening panel required for alemtuzumab treatment.

Mitochondrial Involvement in Neurodegenerative Dementia

Gribkoff/The Functions, Disease-Related Dysfunctions, and Therapeutic Targeting of Neuronal Mitochondria, 2015

Delirium in COVID-19 patients: a multicentric observational study in Italy

Neurological Sciences

Introduction Although recent data show that SARS-CoV-2 infection seems to affect the central nerv... more Introduction Although recent data show that SARS-CoV-2 infection seems to affect the central nervous system (CNS), little is known about the neuropsychiatric effects resulting from this condition. In addition to the well-known neurotrophism of coronaviruses, recent evidence shows also that the "cytokine storm" induced by the infection is at the basis of the neuroinflammation of the CNS. Furthermore, prolonged hospitalization, polypharmacotherapy, and isolation could be at the basis of the onset of delirium in hospitalized COVID patients. This multicentric observational study explores the incidence of the onset of delirium in an Italian cohort of SARS-CoV-2 positive inpatients. Methods Data were collected in the COVIDhospitals of Brescia, Bergamo, Chieti, and Genova. Different socio-demographic, medical, neurological, and pharmacological parameters were collected. As a rapid screening for delirium, the 4AT scale was used. Eighty COVID-19 inpatients (mean age 74.7 ± 14.5 years) met the inclusion criteria (confirmed positivity to the SARS-CoV-2 virus; the presence of delirium and/or psychomotor agitation and/or new onset of other neuropsychiatric symptoms during hospitalization). Results Themajority of these patients (68.8%) had "hyperactive delirium" subtype. Polypharmacotherapy, current treatment with corticosteroids, and higher age were associated with delirium severity. Conclusion These data provide an insight into the onset of delirium among COVID-19 patients underlining the need for monitoring, especially in elderly patients, the neuropsychiatric symptoms, and the therapy in order to have shorter hospitalization times and better outcomes.

Classification of Patients with Alzheimer’s Disease and Dementia with Lewy Bodies using Resting EEG Selected Features at Sensor and Source Levels: A proof-of-concept study

Current Alzheimer Research

Background: Early differentiation between Alzheimer’s disease (AD) and Dementia with Lewy Bodies ... more Background: Early differentiation between Alzheimer’s disease (AD) and Dementia with Lewy Bodies (DLB) is important for accurate prognosis, as DLB patients typically show faster disease progression. Cortical neural networks, necessary for human cognitive function, may be disrupted differently in DLB and AD patients, allowing diagnostic differentiation between AD and DLB. Objective: This proof-of-concept study assessed whether the application of machine learning techniques to data derived from resting-state electroencephalographic (rsEEG) rhythms (discriminant sensor power, 19 electrodes) and source connectivity (between five cortical regions of interest) allowed differentiation between DLB and AD. Methods: Clinical, demographic, and rsEEG datasets from DLB patients (N=30), AD patients (N=30), and control seniors (NOld, N=30), matched for age, sex, and education, were taken from our international database. Individual (delta, theta, alpha) and fixed (beta) rsEEG frequency bands were i...

Status epilepticus and COVID-19: A systematic review

Journal of the Neurological Sciences

SARS-CoV-2 serology after COVID-19 in multiple sclerosis: An international cohort study

Multiple Sclerosis Journal

Background: The MuSC-19 project is an Italian cohort study open to international partners that co... more Background: The MuSC-19 project is an Italian cohort study open to international partners that collects data on multiple sclerosis (MS) patients with COVID-19. During the second wave of the pandemic, serological tests became routinely available. Objective: To evaluate the seroprevalence of anti-SARS-CoV-2 antibodies according to the use of disease-modifying therapy (DMT) in a subset of patients included in the MuSC-19 data set who had undergone a serological test. Methods: We evaluated the association between positive serological test results and time elapsed since infection onset, age, sex, Expanded Disability Status Scale score, comorbidities and DMT exposure using a multivariable logistic model. Results: Data were collected from 423 patients (345 from Italy, 61 from Turkey and 17 from Brazil) with a serological test performed during follow-up. Overall, 325 out of 423 tested patients (76.8%) had a positive serological test. At multivariate analysis, therapy with anti-CD20 was sign...

Long-term outcomes in patients presenting with optic neuritis: Analyses of the MSBase registry

Journal of the Neurological Sciences

Inflammatory polyradiculoneuropathies: Clinical and immunological aspects, current therapies, and future perspectives

European Journal of Inflammation

Inflammatory polyradiculoneuropathies are heterogeneous disorders characterized by immune-mediate... more Inflammatory polyradiculoneuropathies are heterogeneous disorders characterized by immune-mediated leukocyte infiltration of peripheral nerves and nerve roots leading to demyelination or axonal degeneration or both. Inflammatory polyradiculoneuropathies can be divided into acute and chronic: Guillain–Barré syndrome and chronic inflammatory demyelinating polyneuropathy and their variants. Despite major advances in immunology and molecular biology have been made in the last years, the pathogenesis of these disorders is not completely understood. This review summarizes the current literature of the clinical features and pathogenic mechanisms of inflammatory polyradiculoneuropathies and focuses on current therapies and new potential treatment for the future.

Tumour-like presentation of atypical posterior reversible encephalopathy syndrome with prominent brainstem involvement

BMJ Case Reports

Typical posterior reversible encephalopathy syndrome (PRES) is a clinical-neuroradiological entit... more Typical posterior reversible encephalopathy syndrome (PRES) is a clinical-neuroradiological entity characterised by bilateral white matter oedema, which is usually symmetrical and totally reversible in 2–3 weeks. A 46-year-old man presented with a persistent headache and visual blurring in the right eye. On admission, the clinical examination revealed minimal unsteadiness of gait and elevated blood pressure. A brain MRI showed a hyperintense signal on T2-weighted sequences in the whole brainstem, extended to the spinal cord (C2–C6), the left insula and the right cerebellum. When his blood pressure was controlled, his symptoms gradually improved. The follow-up MRI scan at 3 weeks revealed a dramatic regression of the hyperintense lesions on T2-weighted sequences. The differential diagnosis of PRES is very wide, especially in the case of conspicuous brainstem involvement. Treatable causes of white matter oedema should be always kept in mind to avoid misdiagnosis and prevent complicati...

Phase 2A Randomized, Double-Blind, Placebo-Controlled Trial of the Histone Deacetylase Inhibitor (Hdaci), FRM-0334, in Asymptomatic Carriers Of, or Patients with Frontotemporal Lobar Degeneration (FTLD) Due To, Progranulin Gene Mutations

Alzheimer's & Dementia

What Electrophysiology Tells Us About Alzheimer’s Disease: A Window into the Synchronization and Connectivity of Brain Neurons

Neurobiology of Aging

The Characterization of Regulatory T-Cell Profiles in Alzheimer’s Disease and Multiple Sclerosis

Scientific Reports

Regulatory T Cells (Tregs) are a T-lymphocyte subset involved in the maintenance of immune periph... more Regulatory T Cells (Tregs) are a T-lymphocyte subset involved in the maintenance of immune peripheral tolerance. Despite evidence of the adaptive immune system's role in Alzheimer's Disease (AD), the involvement of Tregs is still not clear. We focused on the Flow-Cytometry analysis of the Treg frequencies and phenotypes in the AD. The aim of the study is to analyse similarities and differences in Tregs profile between Alzheimer's Disease and Multiple Sclerosis. Regulatory T Cells (CD4+/CD25high/ CD127low-neg) were identified using an innovative Flow Cytometry method and subtyped as Resting (analysed CD45RApos/CD25dim), Activated (CD45RAneg/CD25bright) and Secreting (CD45RAneg/ CD25dim) cells. Our data demonstrate a significant decrease in the total and Resting Tregs in AD patients when compared to healthy subjects. The percentage of the results of the Resting Tregs were also reduced in MS patients together with a parallel frequency increase of Activated Tregs. Our data suggest that altered Treg phenotypes observed in both diseases could play a role in the impairment of the Treg-mediated immunological tolerance, recalling a possible link between the two pathologies. Given that this study was conducted on a restricted population, if confirmed by a further and enlarged study, the implications of the autoimmune mechanisms in AD pathophysiology could open new immunotherapeutic perspectives based on Treg modulation. Alzheimer's Disease (AD) is the most common kind of neurodegenerative dementia in the elderly population, characterized by both cognitive and behavioural dysfunctions 1,2. The Alzheimer's Disease neuropathology is characterized by the Amyloid beta (Ab) deposition, as amyloid plaques within some specific brain regions, as well as by microglial activation and local inflammatory responses. When the microglia fails to remove the Ab peptide, this first immune-related event is not decisive, therefore the microglial activation becomes chronic as does the related production of pro-inflammatory cytokines 3. The consequent chronic neuro-inflammation status is associated with a toxic cascade, leading to neuronal death and resulting in neurodegeneration 4. Accumulating evidence suggests a relationship among adaptive immunity, neuroinflammation, and neurodegenerative pathologies 5-7. Adaptive immunity, also known as acquired immunity, encloses the humoral and the cell-mediated response. These events are both involved in the immune surveillance and in homeostasis balance 8,9. Under neurodegenerative conditions, as in the AD or in Parkinson's Disease (PD) 10,11 , T lymphocytes are recruited into specific brain regions 11,12 and high frequencies of reactive T lymphocytes have been found in the bloodstream of these patients, suggesting their key role in the physiopathology of neurodegenerative disorders 13. According to their phenotypes and functions, T cells are subtyped as CD8+ Cytotoxic Lymphocytes (CTL), CD4+ helper T lymphocytes (Th, subtyped as Th1 and Th2 subsets), CD4+ regulatory T lymphocytes (Tregs, including natural occurring Tregs and adaptively induced Tregs) and conventional T cells (effector T cells and memory T cells) 13-15. In the central nervous system, the CD4+ T cells orchestrate both innate and adaptive immune responses, through a complex network of cellular interactions involved in the control of tissue homeostasis 13. Various studies that have been

Integrated Lipidomics and Metabolomics Analysis of Tears in Multiple Sclerosis: An Insight into Diagnostic Potential of Lacrimal Fluid

International Journal of Molecular Sciences

Metabolomics based on mass spectrometry represents an innovative approach to characterize multifa... more Metabolomics based on mass spectrometry represents an innovative approach to characterize multifactorial diseases, such as multiple sclerosis (MuS). To date, the most important biomarker source for MuS diagnosis is the cerebrospinal fluid. However, an important goal for research is to identify new molecules in more easily accessible biological fluids. A very interesting biofluid in MuS is represented by tears, considered as an intermediate fluid between the cerebrospinal fluid and serum. In this work, we developed a merged strategy for the analysis of lipids containing choline by Liquid Chromatography coupled to Tandem Mass Spectrometry (LC-MS/MS), as well as for the targeted analysis of free carnitine, acylcarnitines and aminoacids by direct infusion mass spectrometry. Samples for both metabolomics and lipidomics approaches were obtained in a single extraction procedure from tears of patients affected by MuS and healthy controls. Tear lipidomics showed 30 phospholipids significantl...

Abnormalities Of Functional Cortical Source Connectivity Of Resting State Electroencephalographic Alpha Rhythms Are Similar In Patients With Mild Cognitive Impairment Due Alzheimer's And Lewy Body Diseases

Neurobiology of Aging

Cortical Network Topology in Prodromal and Mild Dementia Due to Alzheimer’s Disease: Graph Theory Applied to Resting State EEG

Brain Topography

Graph theory analysis on resting state electroencephalographic rhythms disclosed topological prop... more Graph theory analysis on resting state electroencephalographic rhythms disclosed topological properties of cerebral network. In Alzheimer's disease (AD) patients, this approach showed mixed results. Granger causality matrices were used as input to the graph theory allowing to estimate the strength and the direction of information transfer between electrode pairs. The number of edges (degree), the number of inward edges (in-degree), of outgoing edges (out-degree) were statistically compared among healthy controls, patients with mild cognitive impairment due to AD (AD-MCI) and AD patients with mild dementia (ADD) to evaluate if degree abnormality could involve low and/or high degree vertices, the so called hubs, in both prodromal and over dementia stage. Clustering coefficient and local efficiency were evaluated as measures of network segregation, path length and global efficiency as measures of integration, the assortativity coefficient as a measure of resilience. Degree, indegree and out-degree values were lower in AD-MCI and ADD than the control group for non-hubs and hubs vertices. The number of edges was preserved for frontal electrodes, where patients' groups showed an additional hub in F3. Clustering coefficient was lower in ADD compared with AD-MCI in the right occipital electrode, and it was positively correlated with mini mental state examination. Local and global efficiency values were lower in patients' than control groups. Our results show that the topology of the network is altered in AD patients also in its prodromal stage, begins with the reduction of the number of edges and the loss of the local and global efficiency.

The predictive power of transcranial sonography in movement disorders: a longitudinal cohort study

Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 2018

Transcranial sonography (TCS) is a noninvasive, easily performed, and commonly available neuroima... more Transcranial sonography (TCS) is a noninvasive, easily performed, and commonly available neuroimaging technique useful for the study of brain parenchyma in movement disorders. This tool has been increasingly used in the diagnosis of Parkinson's disease and atypical parkinsonism. The aim of the study was to evaluate the applicability of this technique as supportive tool in the early diagnosis of movement disorders. We performed TCS on 315 individuals which were diagnosed as healthy controls or affected by idiopathic Parkinson's disease, monogenetic subtypes of Parkinson's disease, atypical parkinsonism, and Dementia with Lewy bodies. Five TCS diagnostic patterns were defined on the basis of substantia nigra's and lenticular nuclei's echogenicity. TCS evaluations were performed by two blinded neuro-sonographers. Clinical diagnosis on all individuals was performed at baseline and at 4-year follow-up. The concordance rate between TCS patterns and clinical diagnosis a...

Metabolomic Signature in Sera of Multiple Sclerosis Patients during Pregnancy

International Journal of Molecular Sciences

Multiple sclerosis (MuS) is an autoimmune disease of the central nervous system characterized by ... more Multiple sclerosis (MuS) is an autoimmune disease of the central nervous system characterized by neuroinflammation, neurodegeneration, and degradation of the myelin sheath. Epidemiological studies have shown that the female gender is more susceptible than the male gender to MuS development, with a female-to-male ratio of 2:1. Despite this high onset, women have a better prognosis than men, and the frequency of the relapsing phase decreases during pregnancy, while it increases soon after birth. Therefore, it is interesting to investigate hormonal fluctuations during pregnancy and whether they correlate with metabolic signatures. To gain a deeper inside into the biochemical mechanism of such a multifactorial disease, we adopted targeted metabolomics approaches for the determination of many serum metabolites in 12 pregnant women affected by MuS by mass spectrometry analysis. Our data show a characteristic hormonal fluctuation for estrogens and progesterone, as expected. They also highl...

Levodopa may affect cortical excitability in Parkinson's disease patients with cognitive deficits as revealed by reduced activity of cortical sources of resting state electroencephalographic rhythms

Neurobiology of aging, Jan 30, 2018

We hypothesized that dopamine neuromodulation might affect cortical excitability in Parkinson&#39... more We hypothesized that dopamine neuromodulation might affect cortical excitability in Parkinson's disease (PD) patients set in quiet wakefulness, as revealed by resting state eyes-closed electroencephalographic (rsEEG) rhythms at alpha frequencies (8-12 Hz). Clinical and rsEEG rhythms in PD with dementia (N = 35), PD with mild cognitive impairment (N = 50), PD with normal cognition (N = 35), and normal (N = 50) older adults were available from an international archive. Cortical rsEEG sources were estimated by exact low-resolution brain electromagnetic tomography. Compared with the normal older group, the PD groups showed reduced occipital alpha sources and increased widespread delta (<4 Hz) sources. Widespread frontal and temporal alpha sources exhibited an increase in PD with dementia compared with PD with mild cognitive impairment and PD with normal cognition groups, as function of dopamine depletion severity, typically greater in the former than the latter groups. A daily do...

LRP10 genetic variants in familial Parkinson's disease and dementia with Lewy bodies: a genome-wide linkage and sequencing study

The Lancet. Neurology, 2018

Most patients with Parkinson's disease, Parkinson's disease dementia, and dementia with L... more Most patients with Parkinson's disease, Parkinson's disease dementia, and dementia with Lewy bodies do not carry mutations in known disease-causing genes. The aim of this study was to identify a novel gene implicated in the development of these disorders. Our study was done in three stages. First, we did genome-wide linkage analysis of an Italian family with dominantly inherited Parkinson's disease to identify the disease locus. Second, we sequenced the candidate gene in an international multicentre series of unrelated probands who were diagnosed either clinically or pathologically with Parkinson's disease, Parkinson's disease dementia, or dementia with Lewy bodies. As a control, we used gene sequencing data from individuals with abdominal aortic aneurysms (who were not examined neurologically). Third, we enrolled an independent series of patients diagnosed clinically with Parkinson's disease and controls with no signs or family history of Parkinson's dis...

Post Traumatic Stress Disorder Heralding the Onset of Semantic Frontotemporal Dementia

Journal of Alzheimer's disease : JAD, 2018

Post traumatic stress disorder (PTSD) is associated with cognitive decline. The dementia type fol... more Post traumatic stress disorder (PTSD) is associated with cognitive decline. The dementia type following PTSD is unclear. To assess whether PTSD is associated with a specific dementia. Prospective study: 46 PTSD patients (DSM-IV-TR) were followed for 6-10 years with clinical, neuropsychological, imaging evaluations for possible development of dementia.Retrospective study:849 dementia patients followed during 1999-2014 (509 Alzheimer's disease, AD; 207 dementia with Lewy bodies, DLB; 90 vascular dementia, VaD; 43 frontotemporal dementia, FTD) and 287 patients with any neurological condition (including patients with/without dementia) were evaluated for the presence of PTSD in their history. Prospective study: 8 patients developed dementia; 1 AD, 1 DLB, 6 semantic FTD (13.0% of the PTSD population). Retrospective study: 38 patients (4.5%) had a history of PTSD; 3.5% of AD, 4.3% of DLB, 14.0% of FTD, 5.6% of VaD. The percentage was higher in FTD than in AD or DLB (χ2 = 10, p = 0.001,...

Simultaneous early-onset severe autoimmune hemolytic anemia and albuminuria during alemtuzumab treatment for multiple sclerosis

Multiple sclerosis (Houndmills, Basingstoke, England), 2018

Alemtuzumab, approved for multiple sclerosis (MS), can cause secondary autoimmune adverse events ... more Alemtuzumab, approved for multiple sclerosis (MS), can cause secondary autoimmune adverse events including thyroid disorders, immune thrombocytopenia (ITP), and glomerular nephropathies. Non-ITP autoimmune cytopenias are rarely reported. To report a case of autoimmune hemolytic anemia (AIHA) and nephropathy in a MS patient treated with alemtuzumab. A 34-year-old man with MS developed albuminuria and AIHA after the first and only alemtuzumab treatment, with positive Coombs' direct and indirect tests and IgG autoantibodies. Both AIHA and nephropathy resolved 1 month after treatment with steroids and intravenous immunoglobulins. Our report adds to literature on AIHA and nephropathy after alemtuzumab treatment and suggests to add Coombs' tests to the screening panel required for alemtuzumab treatment.