Publications by authors named "Lorenzo Gaetani"

30 Publications

  • Page 1 of 1

Insights into the Pathophysiology of Psychiatric Symptoms in Central Nervous System Disorders: Implications for Early and Differential Diagnosis.

Int J Mol Sci 2021 Apr 23;22(9). Epub 2021 Apr 23.

Section of Neurology, Department of Medicine and Surgery, University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy.

Different psychopathological manifestations, such as affective, psychotic, obsessive-compulsive symptoms, and impulse control disturbances, may occur in most central nervous system (CNS) disorders including neurodegenerative and neuroinflammatory diseases. Psychiatric symptoms often represent the clinical onset of such disorders, thus potentially leading to misdiagnosis, delay in treatment, and a worse outcome. In this review, psychiatric symptoms observed along the course of several neurological diseases, namely Alzheimer's disease, fronto-temporal dementia, Parkinson's disease, Huntington's disease, and multiple sclerosis, are discussed, as well as the involved brain circuits and molecular/synaptic alterations. Special attention has been paid to the emerging role of fluid biomarkers in early detection of these neurodegenerative diseases. The frequent occurrence of psychiatric symptoms in neurological diseases, even as the first clinical manifestations, should prompt neurologists and psychiatrists to share a common clinico-biological background and a coordinated diagnostic approach.
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http://dx.doi.org/10.3390/ijms22094440DOI Listing
April 2021

Machine Learning Driven Profiling of Cerebrospinal Fluid Core Biomarkers in Alzheimer's Disease and Other Neurological Disorders.

Front Neurosci 2021 31;15:647783. Epub 2021 Mar 31.

Neurology 5/Neuropathology Unit, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy.

Amyloid-beta (Aβ) 42/40 ratio, tau phosphorylated at threonine-181 (p-tau), and total-tau (t-tau) are considered core biomarkers for the diagnosis of Alzheimer's disease (AD). The use of fully automated biomarker assays has been shown to reduce the intra- and inter-laboratory variability, which is a critical factor when defining cut-off values. The calculation of cut-off values is often influenced by the composition of AD and control groups. Indeed, the clinically defined AD group may include patients affected by other forms of dementia, while the control group is often very heterogeneous due to the inclusion of subjects diagnosed with other neurological diseases (OND). In this context, unsupervised machine learning approaches may overcome these issues providing unbiased cut-off values and data-driven patient stratification according to the sole distribution of biomarkers. In this work, we took advantage of the reproducibility of automated determination of the CSF core AD biomarkers to compare two large cohorts of patients diagnosed with different neurological disorders and enrolled in two centers with established expertise in AD biomarkers. We applied an unsupervised Gaussian mixture model clustering algorithm and found that our large series of patients could be classified in six clusters according to their CSF biomarker profile, some presenting a typical AD-like profile and some a non-AD profile. By considering the frequencies of clinically defined OND and AD subjects in clusters, we subsequently computed cluster-based cut-off values for Aβ42/Aβ40, p-tau, and t-tau. This approach promises to be useful for large-scale biomarker studies aimed at providing efficient biochemical phenotyping of neurological diseases.
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http://dx.doi.org/10.3389/fnins.2021.647783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044304PMC
March 2021

High performance liquid chromatography determination of L-glutamate, L-glutamine and glycine content in brain, cerebrospinal fluid and blood serum of patients affected by Alzheimer's disease.

Amino Acids 2021 Mar 22;53(3):435-449. Epub 2021 Feb 22.

Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Caserta, Italy.

Altered glutamatergic neurotransmission is thought to play a crucial role in the progression of Alzheimer's disease (AD). Accordingly, the identification of peculiar biochemical patterns reflecting AD-related synaptopathy in blood and cerebrospinal fluid (CSF) could have relevant diagnostic and prognostic implications. In this study, we measured by High-Performance Liquid Chromatography the amount of glutamate, glutamine and glycine in post-mortem brain samples of AD patients, as well as in CSF and blood serum of drug-free subjects encompassing the whole AD clinical spectrum (pre-clinical AD, n = 18, mild cognitive impairment-AD, n = 29, dementia AD, n = 30). Interestingly, we found that glutamate and glycine levels, as well as total tau protein content, were significantly reduced in the superior frontal gyrus of patients with AD, compared with non-demented controls. No significant change was also found in glutamate, glutamine and glycine CSF concentrations between AD patients and neurological controls. Remarkably, serum glutamate levels were significantly higher in patients affected by early AD phases compared to controls, and were negatively correlated with CSF total tau levels. Conversely, serum glutamine concentration was significantly increased in AD patients, with a negative correlation with MMSE performances. Finally, we reported a significant correlation between serum L-glutamate concentrations and CDR score in female but not in male cohort of AD subjects. Overall, our results suggest that serum glutamate and glutamine levels in AD patients could vary across disease stages, potentially reflecting the progressive alteration of glutamatergic signaling during neurodegenerative processes.
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http://dx.doi.org/10.1007/s00726-021-02943-7DOI Listing
March 2021

Defining the course of tumefactive multiple sclerosis: A large retrospective multicentre study.

Eur J Neurol 2021 Apr 12;28(4):1299-1307. Epub 2021 Jan 12.

Department of Clinical and Experimental Epilepsy, Queen Square, UCL Queen Square Institute of Neurology, London, UK.

Background And Purpose: Tumefactive multiple sclerosis (TuMS) (i.e., MS onset presenting with tumefactive demyelinating lesions [TDLs]) is a diagnostic and therapeutic challenge. We performed a multicentre retrospective study to describe the clinical characteristics and the prognostic factors of TuMS.

Methods: One hundred two TuMS patients were included in this retrospective study. Demographic, clinical, magnetic resonance imaging (MRI), laboratory data and treatment choices were collected.

Results: TuMS was found to affect women more than men (female:male: 2.4), with a young adulthood onset (median age: 29.5 years, range: 11-68 years, interquartile range [IQR]: 38 years). At onset, 52% of TuMS patients presented with the involvement of more than one functional system and 24.5% of them with multiple TDLs. TDLs most frequently presented with an infiltrative MRI pattern (38.7%). Cerebrospinal fluid immunoglobulin G oligoclonal bands were often demonstrated (76.6%). In 25.3% of the cases, more than one acute-phase treatment was administered, and almost one-half of the patients (46.6%) were treated with high-efficacy treatments. After a median follow-up of 2.3 years (range: 0.1-10.7 years, IQR: 3.4 years), the median Expanded Disability Status Scale (EDSS) score was 1.5 (range: 0-7, IQR: 2). Independent risk factors for reaching an EDSS score ≥3 were a higher age at onset (odds ratio [OR]: 1.08, 95% confidence interval [CI]: 1.03-1.14, p < 0.01), a higher number of TDLs (OR: 1.67, 95% CI: 1.02-2.74, p < 0.05) and the presence of infiltrative TDLs (OR: 3.34, 95% CI: 1.18-9.5, p < 0.001) at baseline.

Conclusions: The management of TuMS might be challenging because of its peculiar characteristics. Large prospective studies could help to define the clinical characteristics and the best treatment algorithms for people with TuMS.
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http://dx.doi.org/10.1111/ene.14672DOI Listing
April 2021

CSF and Blood Biomarkers in Neuroinflammatory and Neurodegenerative Diseases: Implications for Treatment.

Trends Pharmacol Sci 2020 12 27;41(12):1023-1037. Epub 2020 Oct 27.

Section of Neurology, Department of Medicine, University of Perugia, Perugia, Italy. Electronic address:

Neuroinflammatory and neurodegenerative diseases are characterized by the interplay of a number of molecular pathways that can be assessed through biofluids, especially cerebrospinal fluid and blood. Accordingly, the definition and classification of these disorders will move from clinical and pathological to biological criteria. The consequences of this biomarker-based diagnostic and prognostic approach are highly relevant to the field of drug development. Indeed, in view of the availability of disease-modifying drugs, fluid biomarkers offer a unique opportunity for improving the quality and applicability of results from clinical trials. Herein, we discuss the benefits of using fluid biomarkers for patient stratification, target engagement, and outcome assessment, as well as the most recent developments in neuroinflammatory and neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.tips.2020.09.011DOI Listing
December 2020

Cerebrospinal fluid and serum d-serine concentrations are unaltered across the whole clinical spectrum of Alzheimer's disease.

Biochim Biophys Acta Proteins Proteom 2020 12 5;1868(12):140537. Epub 2020 Sep 5.

Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Caserta, Italy; CEINGE Biotecnologie Avanzate, Naples, Italy. Electronic address:

The diagnosis of Alzheimer's disease (AD) relies on the presence of amyloidosis and tauopathy, as reflected in cerebrospinal fluid (CSF), independently from the clinical stage. Recently, CSF d-serine has been proposed as a possible new AD biomarker, reflecting dysfunctional activation of neuronal glutamatergic N-methyl-d-aspartate receptor (NMDAR). In this study, we measured blood serum and CSF concentration of two NMDAR modulators, such as d-serine and d-aspartate, in a cohort of drug-free subjects encompassing the whole AD clinical spectrum. In addition, we also analyzed d-serine levels in a cohort of post-mortem AD and control cortex samples. We reported unaltered serum and CSF concentrations of d-serine and d-aspartate in AD patients both during the AD progression and compared to non-demented controls. Accordingly, no correlation was detected between serum or CSF d-serine content and mini-mental state examination or Clinical Dementia Rating. Similarly, cortical d-serine levels were also unaltered in post-mortem samples of AD patients. Overall, our results failed to confirm previous findings indicating the CSF d-serine as a novel biomarker for AD.
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http://dx.doi.org/10.1016/j.bbapap.2020.140537DOI Listing
December 2020

Cognitive impairment in multiple sclerosis: lessons from cerebrospinal fluid biomarkers.

Neural Regen Res 2021 Jan;16(1):36-42

Section of Neurology, Department of Medicine, University of Perugia, Perugia, Italy.

Cognitive impairment is a common clinical manifestation of multiple sclerosis, but its pathophysiology is not completely understood. White and grey matter injury together with synaptic dysfunction do play a role. The measurement of biomarkers in the cerebrospinal fluid and the study of their association with cognitive impairment may provide interesting in vivo evidence of the biological mechanisms underlying multiple sclerosis-related cognitive impairment. So far, only a few studies on this topic have been published, giving interesting results that deserve further investigation. Cerebrospinal fluid biomarkers of different pathophysiological mechanisms seem to reflect different neuropsychological patterns of cognitive deficits in multiple sclerosis. The aim of this review is to discuss the studies that have correlated cerebrospinal fluid markers of immune, glial and neuronal pathology with cognitive impairment in multiple sclerosis. Although preliminary, these findings suggest that cerebrospinal fluid biomarkers show some correlation with cognitive performance in multiple sclerosis, thus providing interesting insights into the mechanisms underlying the involvement of specific cognitive domains.
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http://dx.doi.org/10.4103/1673-5374.286949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818856PMC
January 2021

Molecular profiling in Parkinsonian syndromes: CSF biomarkers.

Clin Chim Acta 2020 Jul 4;506:55-66. Epub 2020 Mar 4.

Section of Neurology, Department of Medicine, University of Perugia, Italy; Laboratory of Clinical Neurochemistry, Department of Medicine, University of Perugia, Italy.

An accurate and early diagnosis of degenerative parkinsonian syndromes is a major need for their correct and timely therapeutic management. The current diagnostic criteria are mostly based on clinical features and molecular imaging. However, diagnostic doubts often persist especially in the early stages of diseases when signs are slight, ambiguous and overlapping among different syndromes. Molecular imaging may not be altered in the early stages of diseases, also failing to discriminate among different syndromes. Cerebrospinal fluid (CSF) represents an ideal source of biomarkers reflecting different pathways of neuropathological changes taking place in the brain and preceding the clinical onset. The aim of this review is to provide un update on CSF biomarkers in parkinsonian disorders, discussing in detail their association with neuropathological correlates. Their potential contribution in differential diagnosis and prognostic assessment of different parkinsonian syndromes is also discussed. Before entering the clinical use both for diagnostic and prognostic purposes, these CSF biomarkers need to be thoroughly assessed in terms of pre-analytical and analytical variability, as well as to clinical validation in independent cohorts.
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http://dx.doi.org/10.1016/j.cca.2020.03.002DOI Listing
July 2020

Host and Microbial Tryptophan Metabolic Profiling in Multiple Sclerosis.

Front Immunol 2020 18;11:157. Epub 2020 Feb 18.

Department of Experimental Medicine, University of Perugia, Perugia, Italy.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that is associated with demyelination and neuronal loss. Over recent years, the immunological and neuronal effects of tryptophan (Trp) metabolites have been largely investigated, leading to the hypothesis that these compounds and the related enzymes are possibly involved in the pathophysiology of MS. Specifically, the kynurenine pathway of Trp metabolism is responsible for the synthesis of intermediate products with potential immunological and neuronal effects. More recently, Trp metabolites, originating also from the host microbiome, have been identified in MS, and it has been shown that they are differently regulated in MS patients. Here, we sought to discuss whether, in MS patients, a specific urinary signature of host/microbiome Trp metabolism can be potentially identified so as to select novel biomarkers and guide toward the identification of specific metabolic pathways as drug targets in MS.
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http://dx.doi.org/10.3389/fimmu.2020.00157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041364PMC
March 2021

The Challenge of Disease-Modifying Therapies in Parkinson's Disease: Role of CSF Biomarkers.

Biomolecules 2020 02 19;10(2). Epub 2020 Feb 19.

Section of Neurology, Department of Medicine, University of Perugia, 06132 Perugia, Italy.

The development of disease modifying strategies in Parkinson's disease (PD) largely depends on the ability to identify suitable populations after accurate diagnostic work-up. Therefore, patient molecular profiling and disease subtyping are mandatory. Thus far, in clinical trials, PD has been considered to be a "single entity". Conversely, in front of the common feature of nigro-striatal degeneration, PD is pathogenically heterogeneous with a series of several biological and molecular pathways that differently contribute to clinical development and progression. Currently available diagnostic criteria for PD mainly rely on clinical features and imaging biomarkers, thus missing to identify the contribution of pathophysiological pathways, also failing to catch abnormalities occurring in the early stages of disease. Cerebrospinal fluid (CSF) is a promising source of biomarkers, with the high potential for reflecting early changes occurring in PD brain. In this review, we provide an overview on CSF biomarkers in PD, discussing their association with different molecular pathways involved either in pathophysiology or progression in detail. Their potential application in the field of disease modifying treatments is also discussed.
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http://dx.doi.org/10.3390/biom10020335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072459PMC
February 2020

Positive allosteric modulation of indoleamine 2,3-dioxygenase 1 restrains neuroinflammation.

Proc Natl Acad Sci U S A 2020 02 5;117(7):3848-3857. Epub 2020 Feb 5.

Department of Experimental Medicine, University of Perugia, 06100 Perugia, Italy;

l-tryptophan (Trp), an essential amino acid for mammals, is the precursor of a wide array of immunomodulatory metabolites produced by the kynurenine and serotonin pathways. The kynurenine pathway is a paramount source of several immunoregulatory metabolites, including l-kynurenine (Kyn), the main product of indoleamine 2,3-dioxygenase 1 (IDO1) that catalyzes the rate-limiting step of the pathway. In the serotonin pathway, the metabolite -acetylserotonin (NAS) has been shown to possess antioxidant, antiinflammatory, and neuroprotective properties in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). However, little is known about the exact mode of action of the serotonin metabolite and the possible interplay between the 2 Trp metabolic pathways. Prompted by the discovery that NAS neuroprotective effects in EAE are abrogated in mice lacking IDO1 expression, we investigated the NAS mode of action in neuroinflammation. We found that NAS directly binds IDO1 and acts as a positive allosteric modulator (PAM) of the IDO1 enzyme in vitro and in vivo. As a result, increased Kyn will activate the ligand-activated transcription factor aryl hydrocarbon receptor and, consequently, antiinflammatory and immunoregulatory effects. Because NAS also increased IDO1 activity in peripheral blood mononuclear cells of a significant proportion of MS patients, our data may set the basis for the development of IDO1 PAMs as first-in-class drugs in autoimmune/neuroinflammatory diseases.
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http://dx.doi.org/10.1073/pnas.1918215117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035626PMC
February 2020

Cerebrospinal fluid free light chains compared to oligoclonal bands as biomarkers in multiple sclerosis.

J Neuroimmunol 2020 02 7;339:577108. Epub 2019 Nov 7.

Sezione di Neurologia, Dipartimento di Medicina, Università degli Studi di Perugia, Perugia, Italy. Electronic address:

Cerebrospinal fluid (CSF) free light chains (FLC) may be an alternative biomarker to oligoclonal bands (OCB) in multiple sclerosis (MS). Herein, we compared the diagnostic accuracy of CSF OCB and FLC and we tested the prognostic value of FLC in a cohort of 64 MS patients and 106 controls. A κ-index >7.83 was more sensitive but less specific than OCB in discriminating MS patients from controls. Additionally, a κ-index >10.61 performed better than OCB in the discrimination between MS and controls with inflammatory neurological diseases (p < .001). In clinically isolated syndrome (CIS) patients, a κ-index >10.61 significantly predicted time to conversion to MS (p = .020). κ-index might be a valid alternative to OCB as a diagnostic biomarker for MS and might also be a prognostic marker in CIS.
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http://dx.doi.org/10.1016/j.jneuroim.2019.577108DOI Listing
February 2020

Serum neurofilament light chain as a preclinical marker of neurodegeneration.

Lancet Neurol 2019 12;18(12):1070-1071

Section of Neurology, Department of Medicine, University of Perugia, Perugia, Italy.

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http://dx.doi.org/10.1016/S1474-4422(19)30405-3DOI Listing
December 2019

Cerebrospinal fluid neurofilament light chain predicts disease activity after the first demyelinating event suggestive of multiple sclerosis.

Mult Scler Relat Disord 2019 Oct 27;35:228-232. Epub 2019 Jul 27.

Section of Neurology, Department of Medicine, University of Perugia, piazzale Gambuli 1, 06156 Perugia (PG) Italy.

Background: The prediction of disease activity in patients with a first demyelinating event suggestive of multiple sclerosis (MS) is of high clinical relevance. Cerebrospinal fluid (CSF) neurofilament light chain (NfL) has shown to have prognostic value in MS patients. In this work, we measured CSF NfL in patients at the first demyelinating event in order to find a cut-off value able to discriminate patients who will have disease activity from those who will remain stable during the follow-up.

Methods: We included CSF samples collected within 30 days after the onset of the first demyelinating event from 32 patients followed-up for 3.8 ± 2.5 years. CSF NfL was measured with a newly developed in-house enzyme linked immunosorbent assay (ELISA).

Results: At the first demyelinating event, patients with subsequent disease activity had significantly higher baseline CSF NfL values compared to clinically and radiologically stable patients (median 812.5 pg/mL, range 205-2359 pg/mL vs 329.5 pg/mL, range 156-3492 pg/mL, p = 0.002). A CSF NfL cut-off value of 500 pg/mL significantly discriminated these two groups of patients with a 90% sensitivity and an 83.3% specificity.

Conclusion: Our results confirm that CSF NfL is a prognostic marker in the very early phases of MS. The validation of a cut-off value of 500 pg/mL could provide clinicians with a dichotomous variable that can simplify the prognostic assessment of patients at the first demyelinating event.
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http://dx.doi.org/10.1016/j.msard.2019.07.025DOI Listing
October 2019

Cerebrospinal fluid neurofilament light chain tracks cognitive impairment in multiple sclerosis.

J Neurol 2019 Sep 25;266(9):2157-2163. Epub 2019 May 25.

Section of Neurology, Department of Medicine, Santa Maria Della Misericordia Hospital, University of Perugia, 06132, Perugia, Italy.

Background: Cognitive impairment (CI) is a disabling symptom of multiple sclerosis (MS). Axonal damage disrupts neural circuits and may play a role in determining CI, but its detection and monitoring are not routinely performed. Cerebrospinal fluid (CSF) neurofilament light chain (NfL) is a promising marker of axonal damage in MS.

Objective: To retrospectively examine the relationship between CSF NfL and CI in MS patients.

Methods: CSF NfL concentration was measured in 28 consecutive newly diagnosed MS patients who underwent a neuropsychological evaluation with the Brief Repeatable Battery of Neuropsychological tests (BRBN).

Results: CSF NfL was higher in patients with overall CI (947.8 ± 400.7 vs 518.4 ± 424.7 pg/mL, p < 0.01), and with impairment in information processing speed (IPS) (820.8 ± 413.6 vs 513.6 ± 461.4 pg/mL, p < 0.05) and verbal fluency (1292 ± 511 vs 582.8 ± 395.4 pg/mL, p < 0.05), and it positively correlated with the number of impaired BRBN tests (r = 0.48, p = 0.01) and cognitive domains (r = 0.47, p = 0.01). Multivariate analyses taking into account potential confounders confirmed these findings.

Conclusion: CSF NfL is higher in MS patients with CI and impaired IPS and verbal fluency. Large myelinated axons injury, causing neural disconnection, may be an important determinant of CI in MS and can be reliably measured through CSF NfL.
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http://dx.doi.org/10.1007/s00415-019-09398-7DOI Listing
September 2019

CSF and blood biomarkers for Parkinson's disease.

Lancet Neurol 2019 06 10;18(6):573-586. Epub 2019 Apr 10.

Section of Neurology, Department of Medicine, University of Perugia, Perugia, Italy; IRCCS Fondazione Santa Lucia, Rome, Italy.

In the management of Parkinson's disease, reliable diagnostic and prognostic biomarkers are urgently needed. The diagnosis of Parkinson's disease mostly relies on clinical symptoms, which hampers the detection of the earliest phases of the disease-the time at which treatment with forthcoming disease-modifying drugs could have the greatest therapeutic effect. Reliable prognostic markers could help in predicting the response to treatments. Evidence suggests potential diagnostic and prognostic value of CSF and blood biomarkers closely reflecting the pathophysiology of Parkinson's disease, such as α-synuclein species, lysosomal enzymes, markers of amyloid and tau pathology, and neurofilament light chain. A combination of multiple CSF biomarkers has emerged as an accurate diagnostic and prognostic model. With respect to early diagnosis, the measurement of CSF α-synuclein aggregates is providing encouraging preliminary results. Blood α-synuclein species and neurofilament light chain are also under investigation because they would provide a non-invasive tool, both for early and differential diagnosis of Parkinson's disease versus atypical parkinsonian disorders, and for disease monitoring. In view of adopting CSF and blood biomarkers for improving Parkinson's disease diagnostic and prognostic accuracy, further validation in large independent cohorts is needed.
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http://dx.doi.org/10.1016/S1474-4422(19)30024-9DOI Listing
June 2019

Neurofilament light chain as a biomarker in neurological disorders.

J Neurol Neurosurg Psychiatry 2019 08 9;90(8):870-881. Epub 2019 Apr 9.

Institute of Neuroscience and Physiology Department of Psychiatry and Neurochemistry, The Sahlgrenska AcademyUniversity of Gothenburg, Mölndal, Sweden.

In the management of neurological diseases, the identification and quantification of axonal damage could allow for the improvement of diagnostic accuracy and prognostic assessment. Neurofilament light chain (NfL) is a neuronal cytoplasmic protein highly expressed in large calibre myelinated axons. Its levels increase in cerebrospinal fluid (CSF) and blood proportionally to the degree of axonal damage in a variety of neurological disorders, including inflammatory, neurodegenerative, traumatic and cerebrovascular diseases. New immunoassays able to detect biomarkers at ultralow levels have allowed for the measurement of NfL in blood, thus making it possible to easily and repeatedly measure NfL for monitoring diseases' courses. Evidence that both CSF and blood NfL may serve as diagnostic, prognostic and monitoring biomarkers in neurological diseases is progressively increasing, and NfL is one of the most promising biomarkers to be used in clinical and research setting in the next future. Here we review the most important results on CSF and blood NfL and we discuss its potential applications and future directions.
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http://dx.doi.org/10.1136/jnnp-2018-320106DOI Listing
August 2019

Finding a way to preserve mitochondria: new pathogenic pathways in experimental multiple sclerosis.

Neural Regen Res 2019 Jan;14(1):77-78

Clinica Neurologica, Dipartimento di Medicina, Università degli Studi di Perugia, Perugia, Italy.

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http://dx.doi.org/10.4103/1673-5374.243707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262986PMC
January 2019

2017 revisions of McDonald criteria shorten the time to diagnosis of multiple sclerosis in clinically isolated syndromes.

J Neurol 2018 Nov 8;265(11):2684-2687. Epub 2018 Sep 8.

Clinica Neurologica, Dipartimento di Medicina, Ospedale S. Maria della Misericordia, Università degli Studi di Perugia, 06156, Perugia, Italy.

Objectives: To investigate the impact of the 2017 revisions of McDonald criteria on the diagnosis of multiple sclerosis (MS) in a cohort of patients with clinically isolated syndrome (CIS) and dissemination in space (DIS) of demyelinating lesions.

Methods: We retrospectively analyzed 137 patients with CIS + DIS from two Italian MS centers.

Results: Application of the 2017 revisions of McDonald criteria in our cohort led to a diagnosis of MS in 82.5% of the patients who could have not been diagnosed with MS according to the previous criteria at the time of the first demyelinating event. After a follow-up of 3.8 ± 2.9 years, 85.8% of these patients eventually satisfied also the previous (2010) criteria.

Conclusions: Application of the 2017 revisions of McDonald criteria results in an earlier diagnosis of MS in a large percentage of CIS patients destined to convert to MS.
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http://dx.doi.org/10.1007/s00415-018-9048-8DOI Listing
November 2018

A new enzyme-linked immunosorbent assay for neurofilament light in cerebrospinal fluid: analytical validation and clinical evaluation.

Alzheimers Res Ther 2018 01 23;10(1). Epub 2018 Jan 23.

Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.

Background: Cerebrospinal fluid (CSF) neurofilament light (NfL) is a reliable marker of neuro-axonal damage in different neurological disorders that is related to disease severity. To date, all recent studies performed in human CSF have used the same enzyme-linked immunosorbent assay (ELISA). To confirm the large body of evidence for NfL, we developed a new ELISA method and here we present the performance characteristics of this new ELISA for CSF NfL in different neurological disorders.

Methods: We produced two monoclonal antibodies (NfL21 and NfL23) directed against the NfL core domain, and developed a novel sandwich ELISA method that we evaluated in patients with: 1) inflammatory demyelinating diseases (IDD; n = 97), including multiple sclerosis (MS; n = 59), clinically isolated syndrome (CIS; n = 32), and radiologically isolated syndrome (RIS; n = 6); 2) Alzheimer's disease (AD; n = 72), including mild cognitive impairment due to AD (MCI-AD, n = 36) and probable AD dementia (AD-dem; n = 36); 3) Parkinson's disease (PD; n = 30); and 4) other neurological noninflammatory and non-neurodegenerative diseases (OND; n = 30).

Results: Our new NfL ELISA showed a good analytical performance (inter-plate coefficient of variation (CV) < 13%), with no cross-reactivity with neurofilament medium and heavy (NfM and NfH). With respect to the other available ELISAs, CSF NfL showed the same range of values with a strong correlation (r = 0.9984, p < 0.001) between the two methods. CSF NfL levels were significantly higher in MCI-AD/AD-dem and IDD patients as compared with both PD and OND patients. The highest discriminative power was obtained between IDD and OND patients (area under the curve (AUC) 0.87, 95% confidence interval (CI) 0.80-0.95). Within the IDD group, CSF NfL positively correlated with several clinical and radiological disease severity parameters.

Conclusions: These results show a good analytical performance of the new ELISA for quantification of NfL concentrations in the CSF. CSF NfL is confirmed to be a reliable marker in AD and MS, and a disease-severity marker in MS patients.
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http://dx.doi.org/10.1186/s13195-018-0339-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389166PMC
January 2018

Treatment of multiple sclerosis relapses with high-dose methylprednisolone reduces the evolution of contrast-enhancing lesions into persistent black holes.

J Neurol 2018 Mar 11;265(3):522-529. Epub 2018 Jan 11.

Clinica Neurologica, Dipartimento di Medicina, Università degli Studi di Perugia, Ospedale S. Maria della Misericordia, 06156, Perugia, Italy.

Introduction: The MRI evidence of persistent black holes (pBHs) on T1-weighted images reflects brain tissue loss in multiple sclerosis (MS). The evolution of contrast-enhancing lesions (CELs) into pBHs probably depends on the degree and persistence of focal brain inflammation. The aim of our retrospective study was to evaluate the effect of a single cycle of intravenous methylprednisolone (IVMP), as for MS relapse treatment, on the risk of CELs' evolution into pBHs.

Patients And Methods: We selected 57 patients with CELs on the baseline MRI scan. We evaluated the evolution of CELs into pBHs on a follow-up MRI scan performed after ≥ 6 months in patients exposed and not exposed to IVMP for the treatment of relapse after the baseline MRI.

Results: In our cohort, 182 CELs were identified in the baseline MRI and 57 of them (31.3%) evolved into pBHs. In the multivariate analysis, the exposure of CELs to IVMP resulted to be a significant independent protective factor against pBHs' formation (OR 0.28, 95% CI 0.11-0.766, p = 0.005), while ring enhancement pattern and the fact of being symptomatic were significant risk factors for CELs' conversion into pBHs (OR 6.42, 95% CI 2.55-17.27, p < 0.001 and OR 13.19, 95% CI 1.56-288.87, p = 0.037).

Conclusions: The exposure of CELs to a cycle of IVMP as for relapse treatment is associated with a lower risk of CELs' evolution into pBHs. Future studies are required to confirm the potential independent protective effect of IVMP on CELs' evolution into pBHs.
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http://dx.doi.org/10.1007/s00415-017-8726-2DOI Listing
March 2018

Microglial activation and the nitric oxide/cGMP/PKG pathway underlie enhanced neuronal vulnerability to mitochondrial dysfunction in experimental multiple sclerosis.

Neurobiol Dis 2018 05 9;113:97-108. Epub 2018 Jan 9.

Clinica Neurologica, Dipartimento di Medicina, Università degli Studi di Perugia, Ospedale Santa Maria della Misericordia, S. Andrea delle Fratte, 06132 Perugia, Italy. Electronic address:

During multiple sclerosis (MS), a close link has been demonstrated to occur between inflammation and neuro-axonal degeneration, leading to the hypothesis that immune mechanisms may promote neurodegeneration, leading to irreversible disease progression. Energy deficits and inflammation-driven mitochondrial dysfunction seem to be involved in this process. In this work we investigated, by the use of striatal electrophysiological field-potential recordings, if the inflammatory process associated with experimental autoimmune encephalomyelitis (EAE) is able to influence neuronal vulnerability to the blockade of mitochondrial complex IV, a crucial component for mitochondrial activity responsible of about 90% of total cellular oxygen consumption. We showed that during the acute relapsing phase of EAE, neuronal susceptibility to mitochondrial complex IV inhibition is markedly enhanced. This detrimental effect was counteracted by the pharmacological inhibition of microglia, of nitric oxide (NO) synthesis and its intracellular pathway (involving soluble guanylyl cyclase, sGC, and protein kinase G, PKG). The obtained results suggest that mitochondrial complex IV exerts an important role in maintaining neuronal energetic homeostasis during EAE. The pathological processes associated with experimental MS, and in particular the activation of microglia and of the NO pathway, lead to an increased neuronal vulnerability to mitochondrial complex IV inhibition, representing promising pharmacological targets.
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http://dx.doi.org/10.1016/j.nbd.2018.01.002DOI Listing
May 2018

Visual pathway involvement in multiple sclerosis: Look straight in the eyes.

Mult Scler Relat Disord 2017 Oct 18;17:217-219. Epub 2017 Aug 18.

Clinica Neurologica, Dipartimento di Medicina, Università degli Studi di Perugia, Perugia, Italy. Electronic address:

Visual symptoms are a common clinical manifestation of multiple sclerosis (MS) and are frequently due to acute optic neuritis (ON). However, the entire visual pathway can be involved throughout the disease course. We describe the case of a young MS patient who experienced visual symptoms that were eventually found to be caused by retinal periphlebitis, an inflammatory process of the anterior visual pathway, which is common during MS, but rarely symptomatic. This case reinforces the concept that in all MS patients complaining visual symptoms, a complete work-up should be performed in order to rule out possible ON mimicries.
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http://dx.doi.org/10.1016/j.msard.2017.08.008DOI Listing
October 2017

High risk of early conversion to multiple sclerosis in clinically isolated syndromes with dissemination in space at baseline.

J Neurol Sci 2017 Aug 9;379:236-240. Epub 2017 Jun 9.

Dipartimento di Medicina, Clinica Neurologica, Università degli Studi di Perugia, Perugia, Italy. Electronic address:

Introduction: Multiple sclerosis (MS) usually presents at onset with a clinically isolated syndrome (CIS). According to 2010 McDonald criteria, a diagnosis of MS can be made if CIS patients satisfy clinical/MRI criteria of both dissemination in time (DIT) and space (DIS).

Objective: The aim of this study was to analyze the follow-up data and possible prognostic factors of CIS patients satisfying DIS MRI criteria.

Patients And Methods: We performed a retrospective, multicenter study across 2 Italian centers. Clinical, MRI, and laboratory assessments were performed according to real-life clinical workup.

Results: Out of the 137 enrolled patients, during a median follow-up time of 3.1years, 116 (84.7%) converted to MS with the large majority (78.4%) of the converters developing MS within 1year. In multivariate analysis, baseline predictors of an earlier conversion were a cerebellar/brainstem CIS (HR 2.00, 95% CI: 1.3-3.0, p=0.001) and the presence of all the Barkhof-Tintore MRI criteria (HR 1.67, 95% CI: 1.1-2.6, p=0.028).

Conclusions: Patients with CIS and DIS are at very high risk of an early conversion to MS. The onset with cerebellar/brainstem symptoms and the evidence of a higher MRI lesion load at baseline are the strongest independent predictors of an early conversion to MS.
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http://dx.doi.org/10.1016/j.jns.2017.06.008DOI Listing
August 2017

Extracranial Venous Drainage Pattern in Multiple Sclerosis and Healthy Controls: Application of the 2011 Diagnostic Criteria for Chronic Cerebrospinal Venous Insufficiency.

Eur Neurol 2016 7;76(1-2):62-8. Epub 2016 Jul 7.

Clinica Neurologica, Universitx00E0; degli Studi di Perugia, Perugia, Italy.

The etiology of multiple sclerosis (MS) is still largely unknown and it has been proposed that an impaired venous drainage from the central nervous system, defined as chronic cerebrospinal venous insufficiency (CCSVI), may play a role in this. We investigated the prevalence of extracranial venous drainage pattern alterations in a cohort of MS patients based on the 2011 revised diagnostic criteria for CCSVI. Thirty-nine MS patients and 18 healthy subjects underwent blinded extra-cranial venous echo-color Doppler sonography to reveal the presence of CCSVI. There was no statistically significant difference between MS patients and healthy controls regarding CCSVI prevalence (p value = 0.53). The results challenge the hypothesis that CCSVI plays a primary role in the pathogenesis of MS.
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http://dx.doi.org/10.1159/000445540DOI Listing
September 2017

Multiple sclerosis and chronic progressive external ophthalmoplegia associated with a large scale mitochondrial DNA single deletion.

J Neurol 2016 Jul 25;263(7):1449-51. Epub 2016 Apr 25.

Dipartimento di Medicina, Clinica Neurologica, Università degli Studi di Perugia, Ospedale S. Maria della Misericordia, 06156, Perugia, Italy.

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http://dx.doi.org/10.1007/s00415-016-8120-5DOI Listing
July 2016

Retinopathy during interferon-β treatment for multiple sclerosis: case report and review of the literature.

J Neurol 2016 Mar 21;263(3):422-7. Epub 2015 Aug 21.

Clinica Neurologica, Dipartimento di Medicina, Università degli Studi di Perugia, Ospedale S. Maria della Misericordia, 06132, Perugia, Italy.

The onset of new visual symptoms in patients with multiple sclerosis is often associated with a neuro-ophthalmologic manifestation of the disease. However, other possible differential diagnoses need to be ruled out, including drug-induced retinal side effects. Although uncommon, retinal side effects of interferon-beta formulations may occur, and need to be promptly recognized and treated by neurologists. In this manuscript, we report the case of a 37-year-old woman affected by multiple sclerosis diagnosed with interferon beta-associated retinopathy and we review the literature with regard to the epidemiology, clinical presentation, management and follow-up of interferon beta-associated retinopathy. Interferon-beta induced retinopathy seems to be an uncommon and a dose-related side effect in multiple sclerosis patients. Retinopathy tends to completely resolve after treatment discontinuation. Neurologists must be aware that immune-modulatory drugs, in particular interferon beta, have been reported to cause retinal side effects. In multiple sclerosis patients complaining of new visual symptoms during interferon-beta treatment, it is thus advisable to perform an ophthalmological assessment to rule out and properly manage retinopathy.
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http://dx.doi.org/10.1007/s00415-015-7879-0DOI Listing
March 2016

Synaptic plasticity and experimental autoimmune encephalomyelitis: implications for multiple sclerosis.

Brain Res 2015 Sep 12;1621:205-13. Epub 2014 Dec 12.

Clinica Neurologica, Dipartimento di Medicina, Università degli Studi di Perugia, Perugia, Italy; IRCCS Fondazione S Lucia, Rome, Italy.

Structural and functional neuronal plasticity could play a crucial role during the course of multiple sclerosis (MS). The immune system and the central nervous system (CNS) strictly interact in physiologic conditions and during inflammation to modulate neuroplasticity and in particular the ability of the synapses to undergo long-term changes in the efficacy of synaptic transmission, such as long-term potentiation (LTP). During MS, neuro-inflammation might deeply influence the ability of neuronal networks to express physiologic plasticity, reducing the plastic reserve of the brain, with a negative impact on symptoms progression and cognitive performances. In this manuscript we review the evidence on synaptic plasticity alterations in experimental autoimmune encephalomyelitis (EAE), the most diffuse and widely utilized experimental model of MS, together with their potential underlying mechanisms and clinical relevance. This article is part of a Special Issue entitled SI: Brain and Memory.
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http://dx.doi.org/10.1016/j.brainres.2014.12.004DOI Listing
September 2015