Publications by authors named "Chiara Fenoglio"

146 Publications

Role of Oxidative Damage in Alzheimer's Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery.

Antioxidants (Basel) 2021 Aug 26;10(9). Epub 2021 Aug 26.

Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy.

Alzheimer's disease (AD) is a neurodegenerative disorder accounting for over 50% of all dementia patients and representing a leading cause of death worldwide for the global ageing population. The lack of effective treatments for overt AD urges the discovery of biomarkers for early diagnosis, i.e., in subjects with mild cognitive impairment (MCI) or prodromal AD. The brain is exposed to oxidative stress as levels of reactive oxygen species (ROS) are increased, whereas cellular antioxidant defenses are decreased. Increased ROS levels can damage cellular structures or molecules, leading to protein, lipid, DNA, or RNA oxidation. Oxidative damage is involved in the molecular mechanisms which link the accumulation of amyloid-β and neurofibrillary tangles, containing hyperphosphorylated tau, to microglia response. In this scenario, microglia are thought to play a crucial role not only in the early events of AD pathogenesis but also in the progression of the disease. This review will focus on oxidative damage products as possible peripheral biomarkers in AD and in the preclinical phases of the disease. Particular attention will be paid to biological fluids such as blood, CSF, urine, and saliva, and potential future use of molecules contained in such body fluids for early differential diagnosis and monitoring the disease course. We will also review the role of oxidative damage and microglia in the pathogenesis of AD and, more broadly, in neurodegeneration.
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http://dx.doi.org/10.3390/antiox10091353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8471953PMC
August 2021

Niemann-Pick Type C 1 (NPC1) and NPC2 Gene Variability in Demented Patients with Evidence of Brain Amyloid Deposition.

J Alzheimers Dis 2021 ;83(3):1313-1323

Fondazione IRCCS Ca' Granda, Ospedale Policlinico, Milan, Italy.

Background: Variants in Niemann-Pick Type C genes (NPC1 and NPC2) have been suggested to play a role as risk or disease modifying factors for Alzheimer's disease (AD).

Objective: The aim of this study was to analyze NPC1 and NPC2 variability in demented patients with evidence of brain amyloid-β 1-42 (Aβ) deposition and to correlate genetic data with clinical phenotypes.

Methods: A targeted Next Generation Sequencing panel was customized to screen NPC1, NPC2, and main genes related to neurodegenerative dementias in a cohort of 136 demented patients with cerebrospinal fluid (CSF) low Aβ levels or positive PET with Aβ tracer and 200 non-demented geriatric subjects.

Results: Seven patients were carriers of NPC variants in heterozygosis. Four of them displayed pathogenic variants previously found in NPC patients and one AD patient had a novel variant. The latter was absent in 200 non-demented elderly subjects. Five of seven patients (70%) exhibited psychiatric symptoms at onset or later as compared with 43%in non-carriers (p > 0.05).

Conclusion: The frequency of NPC1 and NPC2 heterozygous variants in patients with CSF evidence of Aβ deposition is higher than in the general population.
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http://dx.doi.org/10.3233/JAD-210453DOI Listing
January 2021

Extracellular Vesicles in Multiple Sclerosis: Role in the Pathogenesis and Potential Usefulness as Biomarkers and Therapeutic Tools.

Cells 2021 07 8;10(7). Epub 2021 Jul 8.

Fondazione IRCCS Ca' Granda, Ospedale Policlinico, 20122 Milan, Italy.

Although extracellular vesicles (EVs) were initially relegated to a waste disposal role, nowadays, they have gained multiple fundamental functions working as messengers in intercellular communication as well as exerting active roles in physiological and pathological processes. Accumulating evidence proves the involvement of EVs in many diseases, including those of the central nervous system (CNS), such as multiple sclerosis (MS). Indeed, these membrane-bound particles, produced in any type of cell, carry and release a vast range of bioactive molecules (nucleic acids, proteins, and lipids), conferring genotypic and phenotypic changes to the recipient cell. This means that not only EVs per se but their content, especially, could reveal new candidate disease biomarkers and/or therapeutic agents. This review is intended to provide an overview regarding current knowledge about EVs' involvement in MS, analyzing the potential versatility of EVs as a new therapeutic tool and source of biomarkers.
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http://dx.doi.org/10.3390/cells10071733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303489PMC
July 2021

More Atypical than Atypical Alzheimer's Disease Phenotypes: A Treviso Dementia (TREDEM) Registry Case Report.

J Alzheimers Dis Rep 2021 May 3;5(1):365-374. Epub 2021 May 3.

Department of Neuroscience Imaging and Clinical Sciences and CESI, University G D'Annunzio of Chieti-Pescara, Chieti, Italy.

Background: A 57-year-old right-handed man was admitted to the Treviso Memory Clinic due to the presence of memory forgetfulness, repetition of the same questions, episodes of confusion, initial difficulties in performing complex tasks and easy distraction over the past two years, as well as recurrent and never-happened-before car accidents.

Objective: We report a peculiar case of an early onset Alzheimer's disease (AD) with an unusual symptomatology, apparently not fitting in any of the categorized atypical forms of AD nor being representative of a typical amnestic AD.

Methods: The patient underwent a neuropsychological, structural, and metabolic cerebral evaluation by MRI and F-FDG PET, together with the search for cerebral amyloid (amyloid PET), a genetic testing for dementia related genes and the dosage of CSF protein biomarkers of neurodegenerative conditions.

Results: We observed a convergence of predominant frontal (dysexecutive, verbal disinhibition) and posterior (visuospatial) features of cognitive impairment. Structural MRI sequences showed subarachnoid spaces of the vault enlarged in the fronto-parietal region with anterior and posterior cortical atrophy. The hippocampus appeared preserved. The F-FDG PET scans showed hypometabolism in the prefrontal, lateral temporal, posterior parietal, and occipital regions bilaterally. The F-Flutemetamol scan showed a diffused uptake of the amyloid tracer at the cerebral cortex. CSF biomarkers were compatible with Alzheimer's disease (AD).

Conclusion: This case report presented with clinical phenotypic aspects atypical of AD, both frontal and posterior, never described as concomitant in the most accredited criteria for atypical AD, and appeared therefore more atypical than each of the atypical AD phenotypes already reported.
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http://dx.doi.org/10.3233/ADR-210009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203287PMC
May 2021

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Nat Commun 2021 06 7;12(1):3417. Epub 2021 Jun 7.

Servei de Neurologia, Hospital Universitari i Politècnic La Fe, Valencia, Spain.

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
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http://dx.doi.org/10.1038/s41467-021-22491-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184987PMC
June 2021

Analysis of C9orf72 Intermediate Alleles in a Retrospective Cohort of Neurological Patients: Risk Factors for Alzheimer's Disease?

J Alzheimers Dis 2021 ;81(4):1445-1451

Fondazione IRCCS Ca' Granda, Ospedale Policlinico, Milan, Italy.

Background: C9orf72 hexanucleotide GGGGCC (G4C2) large repeat expansions within the first intron of the gene are a major cause of familial frontotemporal dementia, but also of apparently sporadic cases. Alleles with > 30 repeats are often considered pathogenic, but the repeat length threshold is still undefined. It is also unclear if C9orf72 intermediate alleles (9-30 repeats) have clinically significant effects.

Objectives: We correlated the presence of C9orf72 intermediate alleles with clinical diagnoses in a perspective cohort referred to a secondary memory clinic.

Methods: All samples were genotyped with AmplideXPCR/CE C9ORF72 Kit (Asuragen, Inc), an optimized C9orf72 PCR amplification reagent.

Results: We showed that in patients with Alzheimer's disease (AD) the frequency of the intermediate repeat alleles was significantly increased versus controls (34/54, 63%AD versus 16/39, 41%CTRLs, *p = 0.01, OR 2.91 CI 95%1.230-6.077), whereas no significant differences (p > 0.05) were observed when comparing all other dementias with non-demented individuals.

Conclusion: Our findings suggest that C9orf72 intermediate repeat units may represent a genetic risk factor, contributing to the occurrence of AD. Nevertheless, further longitudinal studies, including larger cohort of subjects with intermediate alleles with long-term follow-up, would be needed to confirm these results.
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http://dx.doi.org/10.3233/JAD-210249DOI Listing
September 2021

Detection of the SQSTM1 Mutation in a Patient with Early-Onset Hippocampal Amnestic Syndrome.

J Alzheimers Dis 2021 ;79(2):477-481

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Genetics has a major role in early-onset dementia, but the correspondence between genotype and phenotype is largely tentative. We describe a 54-year-old with familial early-onset slowly-progressive episodic memory impairment with the P392L-variant in SQSTM1. The patient showed cortical atrophy and hypometabolism in the temporal lobes, but no amyloidosis biomarkers. As symptoms/neuroimaging were suggestive for Alzheimer's disease-but biomarkers were not-and considering the family-history, genetic analysis was performed, revealing the P392L-variant in SQSTM1, which encodes for sequestosome-1/p62. Increasing evidence suggests a p62 involvement in neurodegeneration and SQSTM1 mutations have been found to cause amyotrophic lateral sclerosis/frontotemporal dementia. Our report suggests that the clinical spectrum of SQSTM1 variants is wider.
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http://dx.doi.org/10.3233/JAD-201231DOI Listing
September 2021

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

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

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

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

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

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

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

Conclusion: Despite an association of WMH volume with CSF Aβ42 levels in AD patients, the occurrence of WMHs is not accompanied by excess release of cellular proteins in the CSF, suggesting that WMHs are no major confounder for AD CSF biomarker assessment.
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http://dx.doi.org/10.3233/JAD-200496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902951PMC
September 2021

MiRNA Profiling in Plasma Neural-Derived Small Extracellular Vesicles from Patients with Alzheimer's Disease.

Cells 2020 06 10;9(6). Epub 2020 Jun 10.

Neurodegenerative Diseases Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy.

Small extracellular vesicles (EVs) are able to pass from the central nervous system (CNS) into peripheral blood and contain molecule markers of their parental origin. The aim of our study was to isolate and characterize total and neural-derived small EVs (NDEVs) and their micro RNA (miRNA) cargo in Alzheimer's disease (AD) patients. Small NDEVs were isolated from plasma in a population consisting of 40 AD patients and 40 healthy subjects (CTRLs) using high throughput Advanced TaqMan miRNA OpenArrays, which enables the simultaneous determination of 754 miRNAs. MiR-23a-3p, miR-223-3p, miR-100-3p and miR-190-5p showed a significant dysregulation in small NDEVs from AD patients as compared with controls (1.16 ± 0.49 versus 7.54 ± 2.5, = 0.026; 9.32 ± 2.27 versus 0.66 ± 0.18, <0.0001; 0.069 ± 0.01 versus 0.5 ± 0.1, < 0.0001 and 2.9 ± 1.2 versus 1.93 ± 0.9, < 0.05, respectively). A further validation analysis confirmed that miR-23a-3p, miR-223-3p and miR-190a-5p levels in small NDEVs from AD patients were significantly upregulated as compared with controls ( = 0.008; = 0.016; = 0.003, respectively) whereas miR-100-3p levels were significantly downregulated ( = 0.008). This is the first study that carries out the comparison between total plasma small EV population and NDEVs, demonstrating the presence of a specific AD NDEV miRNA signature.
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http://dx.doi.org/10.3390/cells9061443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349735PMC
June 2020

IL-33 and its decoy sST2 in patients with Alzheimer's disease and mild cognitive impairment.

J Neuroinflammation 2020 Jun 6;17(1):174. Epub 2020 Jun 6.

IRCCS Fondazione Don Carlo Gnocchi, Laboratory of Molecular Medicine and Biotechnology, Via Capecelatro, 66, 20148, Milan, Italy.

Background: Interleukin-33 is a cytokine endowed with pro- and anti-inflammatory properties that plays a still poorly defined role in the pathogenesis of a number of central nervous system (CNS) conditions including Alzheimer's disease (AD). We analyzed this cytokine and its decoy receptor sST2 in Alzheimer's disease (AD) and mild cognitive impairment (MCI).

Method: IL-33 and sST2 were analyzed in serum and CSF of AD and MCI patients, comparing the results to those obtained in age-matched healthy controls (HC). Because of the ambiguous role of IL-33 in inflammation, the concentration of both inflammatory (IL-1β and IL-6) and anti-inflammatory (IL-10) cytokines was analyzed as well in serum and cerebrospinal fluid (CSF) of the same individuals. Finally, the effect of IL-33 on in vitro Aβ-stimulated monocytes of AD, MCI, and HC individuals was examined.

Results: As compared to HC, (1) IL-33 was significantly decreased in serum and CSF of AD and MCI, (2) sST2 was increased in serum of AD and MCI but was undetectable in CSF, (3) serum and CSF IL-1β concentration was significantly increased and that of IL-10 was reduced in AD and MCI, whereas no differences were observed in IL-6. In vitro addition of IL-33 to LPS+Aβ -stimulated monocytes downregulated IL-1β generation in MCI and HC, but not in AD, and stimulated IL-10 production in HC alone. IL-33 addition also resulted in a significant reduction of NF-kB nuclear translocation in LPS+Aβ-stimulated monocytes of HC alone.

Conclusions: These data support the hypothesis that IL-33 plays a complex anti-inflammatory role that is lost in AD- and MCI-associated neuroinflammation; results herein also suggest a possible use of IL-33 as a novel therapeutic approach in AD and MCI.
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http://dx.doi.org/10.1186/s12974-020-01806-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276088PMC
June 2020

Evidence of retinal anterograde neurodegeneration in the very early stages of multiple sclerosis: a longitudinal OCT study.

Neurol Sci 2020 Nov 30;41(11):3175-3183. Epub 2020 Apr 30.

Neurodegenerative Diseases Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122, Milan, Italy.

Background: Neurodegenerative processes are present since the early stages of multiple sclerosis (MS), constituting the primary substrate of disability. As part of the CNS, retinal damage could be considered a reliable prognostic biomarker of neurodegeneration in MS.

Objectives: To characterize longitudinal changes in the retinal layers' thickness and to investigate correlations between retinal atrophy and other prognostic biomarkers, i.e., cerebrospinal fluid (CSF) β-amyloid (Aβ) levels.

Methods: Forty-two eyes without a history of optic neuritis of 23 MS patients were recruited. All patients underwent spectral-domain-OCT scans (SD-OCT), brain magnetic resonance imaging (MRI), and lumbar puncture at baseline. SD-OCT and brain MRI were repeated after 12 months. Ten controls underwent the same OCT procedure.

Results: At baseline, macular ganglion cell/inner plexiform layer (mGCIPL) thickness was reduced in patients compared to controls (p = 0.008), without retinal nerve fiber layer (RNFL) thinning, that was revealed only at follow-up (p = 0.005). Patients with lower CSF Aβ levels displayed reduced RNFL thickness values, both at baseline and follow-up.

Conclusions: At very early clinical stages, mGCIPL thickness values were reduced without a concomitant peripapillary RNFL thinning. The longitudinal assessment demonstrated a RNFL loss in patients compared to HC, together with a plateau of mGCIPL thinning. Aβ subgroup of patients showed a reduction of retinal nerve fiber layer thickness.
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http://dx.doi.org/10.1007/s10072-020-04431-4DOI Listing
November 2020

Anti-Cholinergic Derangement of Cortical Metabolism on 18F-FDG PET in a Patient with Frontotemporal Lobar Degeneration Dementia: A Case of the TREDEM Registry.

J Alzheimers Dis 2020 ;74(4):1107-1117

Department of Neuroscience Imaging and Clinical Sciences and CESI, University G D'Annunzio of Chieti-Pescara, Chieti, Italy.

We present the case of a patient with an atypical course of frontotemporal lobar degeneration (FTLD) complicated by the use of an anticholinergic drug. A 70-year-old patient, followed by psychiatrists for depression and behavioral disorders, received a diagnosis of dementia with Lewy bodies (DLB) at another Center due to auditory hallucinations, gait impairment, and tendency to fall. He was then admitted to our Memory Clinic Unit for behavioral disturbances, such as delusional thinking, auditory hallucinations, and memory complaints. At that time, the patient's therapy included Lorazepam, Quetiapine, Promazine, and Biperiden. The latter was immediately suspended for the absence of extrapyramidal signs and to avoid the anticholinergic cognitive side effects. A 18F-FDG PET showed a derangement of cortical metabolism with diffusely reduced activity, and limited areas of hyperactivity involving lateral frontal and lateral temporal inferior regions bilaterally. The patient underwent a series of exams, including neuropsychological tests, 123I-MIBG scintigraphy, cerebrospinal fluid examination, and genetic analysis. A second 18F-FDG PET showed an extensive remodulation of metabolic activity: relative higher concentration of the tracer in the prefrontal and inferior temporal cortex was no more detectable. Similarly, the diffuse reduced metabolic activity could not be traced anymore. Nonetheless, the metabolic activity still appeared reduced in the frontal lobe, in the anterior cingulate bilaterally, and in the anterior part of the hemispheric fissure. Taken together, clinical and neuroimaging features would point to a FTLD-like form. Furthermore, the diagnostic work-up was likely confounded by the anticholinergic drug on 18F-FDG PET, highlighting the importance of carefully checking the patient's pharmacology during the diagnostic process.
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http://dx.doi.org/10.3233/JAD-191290DOI Listing
May 2021

CLIC1 Protein Accumulates in Circulating Monocyte Membrane during Neurodegeneration.

Int J Mol Sci 2020 Feb 21;21(4). Epub 2020 Feb 21.

Dipartimento di Bioscienze, Università degli Studi di Milano, 20133 Milano, Italy.

Pathologies that lead to neurodegeneration in the central nervous system (CNS) represent a major contemporary medical challenge. Neurodegenerative processes, like those that occur in Alzheimer's disease (AD) are progressive, and at the moment, they are unstoppable. Not only is an adequate therapy missing but diagnosis is also extremely complicated. The most reliable method is the measurement of beta amyloid and tau peptides concentration in the cerebrospinal fluid (CSF). However, collecting liquid samples from the CNS is an invasive procedure, thus it is not suitable for a large-scale prevention program. Ideally, blood testing is the most manageable and appropriate diagnostic procedure for a massive population screening. Recently, a few candidates, including proteins or microRNAs present in plasma/serum have been identified. The aim of the present work is to propose the chloride intracellular channel 1 (CLIC1) protein as a potential marker of neurodegenerative processes. CLIC1 protein accumulates in peripheral blood mononuclear cells (PBMCs), and increases drastically when the CNS is in a chronic inflammatory state. In AD patients, both immunolocalization and mRNA quantification are able to show the behavior of CLIC1 during a persistent inflammatory state of the CNS. In particular, confocal microscopy analysis and electrophysiological measurements highlight the significant presence of transmembrane CLIC1 (tmCLIC1) in PBMCs from AD patients. Recent investigations suggest that tmCLIC1 has a very specific role. This provides an opportunity to use blood tests and conventional technologies to discriminate between healthy individuals and patients with ongoing neurodegenerative processes.
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http://dx.doi.org/10.3390/ijms21041484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073046PMC
February 2020

Low CSF β-amyloid levels predict early regional grey matter atrophy in multiple sclerosis.

Mult Scler Relat Disord 2019 Dec 19;39:101899. Epub 2019 Dec 19.

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Dino Ferrari Center, Milan, Italy; University of Milan, Milan, Italy.

Background And Purpose: Grey matter (GM) atrophy is present from the earliest stages of multiple sclerosis (MS) and occurs largely in a nonrandom manner. However, the biological mechanisms underlying the progression of regional atrophy are still unclear. Aim of this study is to investigate whether amyloid pathology might be involved in determining the pattern of GM atrophy over time.

Methods: Forty-six subjects were recruited: 31 newly diagnosed relapsing-remitting (RR-) MS patients and 15 age- and sex-matched healthy controls (HC). Aβ levels were determined in CSF samples from all subjects. All participants underwent brain magnetic resonance imaging (MRI) at baseline, and 23 out of 31 patients at one year follow-up. T1-weighted scans were segmented using the Geodesic Information Flows software. Non-parametric statistical tests were used for between-group comparisons and multiple regression analyses.

Results: CSF Aβ concentration was the best predictor of global GM loss over time after age (β = 0.403; p = 0.024), in particular in the left precuneus (p = 0.045), in the left middle cingulate gyrus (p = 0.009), in the left precentral gyrus (p = 0.021) and in the right angular gyrus (p = 0.029).

Conclusions: CSF Aβ levels seem to be crucial in MS early brain volume loss as GM atrophy manifests in regions particularly vulnerable to early Aβ deposition.
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http://dx.doi.org/10.1016/j.msard.2019.101899DOI Listing
December 2019

CSF β-amyloid predicts early cerebellar atrophy and is associated with a poor prognosis in multiple sclerosis.

Mult Scler Relat Disord 2020 Jan 21;37:101462. Epub 2019 Oct 21.

Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy; University of Milan, Milan, Italy; Dino Ferrari Center, Milan, Italy.

Background: Neurodegeneration is present from the earliest stages of multiple sclerosis (MS) and is critically involved in MS related clinical disability. Aim of the present study was to assess the connection between amyloid burden and early cerebellar grey matter (GM) atrophy compared to early brain GM atrophy in MS patients.

Methods: Forty newly diagnosed relapsing-remitting (RR-) MS patients were recruited. β-amyloid1-42 (Aβ) levels were determined in cerebrospinal fluid (CSF) samples from all subjects. All participants underwent neurological examination and brain magnetic resonance imaging (MRI) at baseline. Twenty-nine out of 40 patients repeated a brain MRI at 1-year follow-up. T1-weighted scans were segmented using the Voxel-Based Morphometry (VBM) protocol and the Spatially Unbiased Infratentorial Toolbox (SUIT) from Statistical Parametric Mapping (SPM12).

Results: Between-group comparison of cerebellar parenchymal fraction (GM+WM/total cerebellar volume%) showed significant differences between Aβ and Aβ at baseline (p < 0.0001) and follow-up (p = 0.02). Similarly, a between-group comparison of cerebellar GM fraction (GMF) showed significant differences between Aβ and Aβ at baseline (p = 0.002) and follow-up (p = 0.04). The multiple regression analysis showed CSF Aβ concentration as the best predictor of GMF both at baseline and over time (β = 0.505, β=0.377; p < 0.05). No significant results were found regarding global brain atrophy and CSF Aβ concentration.

Conclusions: Early cerebellar atrophy seems to be crucial in predicting a poor prognosis in MS, more than early global brain atrophy.
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http://dx.doi.org/10.1016/j.msard.2019.101462DOI Listing
January 2020

Testing the 2018 NIA-AA research framework in a retrospective large cohort of patients with cognitive impairment: from biological biomarkers to clinical syndromes.

Alzheimers Res Ther 2019 10 15;11(1):84. Epub 2019 Oct 15.

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122, Milan, Italy.

Background: According to the 2018 NIA-AA research framework, Alzheimer's disease (AD) is not defined by the clinical consequences of the disease, but by its underlying pathology, measured by biomarkers. Evidence of both amyloid-β (Aβ) and phosphorylated tau protein (p-tau) deposition-assessed interchangeably with amyloid-positron emission tomography (PET) and/or cerebrospinal fluid (CSF) analysis-is needed to diagnose AD in a living person. Our aim was to test the new NIA-AA research framework in a large cohort of cognitively impaired patients to evaluate correspondence between the clinical syndromes and the underlying pathologic process testified by biomarkers.

Methods: We retrospectively analysed 628 subjects referred to our centre in suspicion of dementia, who underwent CSF analysis, together with neuropsychological assessment and neuroimaging, and were diagnosed with different neurodegenerative dementias according to current criteria, or as cognitively unimpaired. Subjects were classified considering CSF biomarkers, and the prevalence of normal, AD-continuum and non-AD profiles in each clinical syndrome was calculated. The positivity threshold of each CSF biomarker was first assessed by receiver operating characteristic analysis, using Aβ-positive/negative status as determined by amyloid-PET visual reads. The agreement between CSF and amyloid-PET data was also evaluated.

Results: Among patients with a clinical diagnosis of AD, 94.1% were in the AD-continuum, whereas 5.5% were classified as non-AD and 0.4% were normal. The AD-continuum profile was found also in 26.2% of frontotemporal dementia, 48.6% of Lewy body dementia, 25% of atypical parkinsonism and 44.7% of vascular dementia. Biomarkers' profile did not differ in amnestic and not amnestic mild cognitive impairment. CSF Aβ levels and amyloid-PET tracer binding negatively correlated, and the concordance between the two Aβ biomarkers was 89%.

Conclusions: The examination of the 2018 NIA-AA research framework in our clinical setting revealed a good, but incomplete, correspondence between the clinical syndromes and the underlying pathologic process measured by CSF biomarkers. The AD-continuum profile resulted to be a sensitive, but non-specific biomarker with regard to the clinical AD diagnosis. CSF and PET Aβ biomarkers were found to be not perfectly interchangeable to quantify the Aβ burden, possibly because they measure different aspects of AD pathology.
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http://dx.doi.org/10.1186/s13195-019-0543-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794758PMC
October 2019

Exosome Determinants of Physiological Aging and Age-Related Neurodegenerative Diseases.

Front Aging Neurosci 2019 28;11:232. Epub 2019 Aug 28.

Neurodegenerative Diseases Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.

Aging is consistently reported as the most important independent risk factor for neurodegenerative diseases. As life expectancy has significantly increased during the last decades, neurodegenerative diseases became one of the most critical public health problem in our society. The most investigated neurodegenerative diseases during aging are Alzheimer disease (AD), Frontotemporal Dementia (FTD) and Parkinson disease (PD). The search for biomarkers has been focused so far on cerebrospinal fluid (CSF) and blood. Recently, exosomes emerged as novel biological source with increasing interest for age-related neurodegenerative disease biomarkers. Exosomes are tiny Extracellular vesicles (EVs; 30-100 nm in size) released by all cell types which originate from the endosomal compartment. They constitute important vesicles for the release and transfer of multiple (signaling, toxic, and regulatory) molecules among cells. Initially considered with merely waste disposal function, instead exosomes have been recently recognized as fundamental mediators of intercellular communication. They can move from the site of release by diffusion and be retrieved in several body fluids, where they may dynamically reflect pathological changes of cells present in inaccessible sites such as the brain. Multiple evidence has implicated exosomes in age-associated neurodegenerative processes, which lead to cognitive impairment in later life. Critically, consolidated evidence indicates that pathological protein aggregates, including Aβ, tau, and α-synuclein are released from brain cells in association with exosomes. Importantly, exosomes act as vehicles between cells not only of proteins but also of nucleic acids [DNA, mRNA transcripts, miRNA, and non-coding RNAs (ncRNAs)] thus potentially influencing gene expression in target cells. In this framework, exosomes could contribute to elucidate the molecular mechanisms underneath neurodegenerative diseases and could represent a promising source of biomarkers. Despite the involvement of exosomes in age-associated neurodegeneration, the study of exosomes and their genetic cargo in physiological aging and in neurodegenerative diseases is still in its infancy. Here, we review, the current knowledge on protein and ncRNAs cargo of exosomes in normal aging and in age-related neurodegenerative diseases.
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http://dx.doi.org/10.3389/fnagi.2019.00232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722391PMC
August 2019

C9ORF72 hexanucleotide repeat expansion frequency in patients with Paget's disease of bone.

Neurobiol Aging 2020 01 21;85:154.e1-154.e3. Epub 2019 Aug 21.

Department of Neuroscience and Mental Health, A.O.U. Città della Salute e della Scienza di Torino, Italy; Department of Neuroscience "Rita Levi Montalcini", University of Torino, Torino, Italy.

Paget's disease of bone (PDB) is a focal bone disorder affecting the skeleton segmentally. A strong genetic component has been shown in PDB, and variants in several genes, such as SQSTM1, VCP, and OPTN, have been associated with the disease. Mutations in the same genes have also been reported in patients with frontotemporal dementia and amyotrophic lateral sclerosis. Hexanucleotide repeat expansions in the C9ORF72 gene have been shown to be responsible for both familial and sporadic frontotemporal dementia/amyotrophic lateral sclerosis. Thence, we evaluated the frequency of the C9ORF72 hexanucleotide repeat expansions in a cohort of 191 Italian PDB patients and in 106 controls. The pathogenic repeat expansion was detected in 2 PDB patients (1.0%). During the follow-up period, both PDB patients did not develop any sign of mental decline and/or motor neuron disease. Our study suggests that repeat expansions in the C9ORF72 gene are rare in patients with PDB.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.08.014DOI Listing
January 2020

Cerebrospinal Fluid Level of Aquaporin4: A New Window on Glymphatic System Involvement in Neurodegenerative Disease?

J Alzheimers Dis 2019 ;69(3):663-669

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, UOSD Neurologia - Malattie Neurodegenerative, Milan, Italy.

Aquaporin4 (AQP4) is a water channel protein located at astrocyte foot processes that plays a role in glymphatic system, a highly organized fluid transport pathway which seems to be involved in Alzheimer's disease (AD) and normal pressure hydrocephalus (NPH) pathophysiology. Cerebrospinal fluid (CSF) AQP4 levels were determined in 11 patients with AD, 10 patients with NPH, and 9 controls. We found significantly reduced AQP4 in AD patients, a trend in reduction in NPH patients, and a correlation between AQP4 and amyloid-β CSF levels. This study indicates the potential role of AQP4 and glymphatic system in neurodegenerative diseases pathophysiology.
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http://dx.doi.org/10.3233/JAD-190119DOI Listing
September 2020

Overlap Between Frontotemporal Dementia and Dementia with Lewy Bodies: A Treviso Dementia (TREDEM) Registry Case Report.

J Alzheimers Dis 2019 ;69(3):839-847

Cognitive Impairment Center, Local Health Authority n.2 Marca Trevigiana, Treviso, Italy.

In the present work, we report the case of a patient presenting signs of Lewy body dementia (DLB) and frontotemporal dementia (FTD) throughout different phases of the disease. In January 2017, a 79-year-old right-handed living man was admitted to our Memory Clinic for the presence of behavioral disturbances and progressive cognitive decline. For the previous six years, he was monitored by other Neurological Clinics for the onset of extrapyramidal features. Indeed, through the first phase of the disease (2011-2014), the patient predominantly showed: extrapyramidal features, initial cognitive decline, sleep disturbances, and visual hallucinations, together with a reduced dopamine transporter uptake in basal ganglia at the DATscan, suggesting a diagnosis of DLB. In a second phase (2015-2017), while his extrapyramidal features remained substantially stable, his cognitive profile deteriorated, with an additional development of severe behavioral and neuropsychiatric disturbances. Again, a subsequent DATscan study was positive and slightly worse than the preceding one; however, the 18F-FDG PET showed reduced metabolic activity in the frontal and temporal lobes, with the occipital regions left spared. Genetic analysis revealed a hexanucleotide expansion in C9ORF72 (6//38 repeats; ITALSGEN NV <30). In conclusion, we report the case of a patient presenting, firstly, with probable DLB and, in a second phase, with predominant bvFTD features with stable parkinsonism. Even though some clinical and neuropsychological aspects can co-exist in different neurodegenerative diseases, we find such a significant intersection of clinical features to be fairly atypical. Moreover, what is challenging to define is whether the two clinical phenotypes are somehow lying on a continuum, or if they are two individual entities.
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http://dx.doi.org/10.3233/JAD-181298DOI Listing
September 2020

Exploring the role of BDNF DNA methylation and hydroxymethylation in patients with obsessive compulsive disorder.

J Psychiatr Res 2019 07 6;114:17-23. Epub 2019 Apr 6.

University of Milan, Department of Biomedical and Clinical Sciences Luigi Sacco, Milano, Italy; CRC "Aldo Ravelli", University of Milan, Milano, Italy; Department of Psychiatry and Behavioral Sciences, Stanford University, CA, USA. Electronic address:

Obsessive-compulsive disorder (OCD) is a clinically heterogeneous neuropsychiatric condition associated with profound disability, whose susceptibility, stemming from genetic and environmental factors that intersect with each other, is still under investigation. In this perspective, we sought to explore the transcriptional regulation of Brain Derived Neurotrophic Factor (BDNF), a promising candidate biomarker in both development and etiology of different neuropsychiatric conditions, in peripheral blood mononuclear cells from OCD patients and healthy controls. In particular, we focused on BDNF gene expression and interrogated in depth DNA methylation and hydroxymethylation at gene promoters (exons I, IV and IX) in a sample of OCD patients attending a tertiary OCD Clinic to receive guidelines-recommended treatment, and matched controls. Our preliminary data showed a significant increase in BDNF gene expression and a significant correlation with changes in the two epigenetic modifications selectively at promoter exon I, with no changes in the other promoters under study. We can conclude that transcriptional regulation of BDNF in OCD engages epigenetic mechanisms, and can suggest that this is likely evoked by the long-term pharmacotherapy. It is important to underline that many different factors need to be taken into account (i.e. age, sex, duration of illness, treatment), and thus further studies are mandatory to investigate their role in the epigenetic regulation of BDNF gene. Of note, we provide unprecedented evidence for the importance of analyzing 5-hydroxymethylcytosine levels to correctly evaluate 5-methylcytosine changes.
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http://dx.doi.org/10.1016/j.jpsychires.2019.04.006DOI Listing
July 2019

Lag-time in Alzheimer's disease patients: a potential plasmatic oxidative stress marker associated with ApoE4 isoform.

Immun Ageing 2019 1;16. Epub 2019 Apr 1.

1Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milan, Italy.

In the brain, Oxidative Stress (OS) contribute to structural and functional changes associated with vascular aging, such as endothelial dysfunction, extracellular matrix degradation, resulting in age-related reduced vasodilatation in response to agonists. For this reason, OS is considered a key factor in Alzheimer's Disease (AD) development and recent evidence correlated oxidative stress with vascular lesion in the pathogenesis of AD, but the mechanism still need to be fully clarified. The etiology of AD is still not completely understood and is influenced by several factors including Apolipoprotein E (ApoE) genotype. In particular, the Apo ε4 isoform is considered a risk factor for AD development. This study was aimed to evaluate the possible relationship between three plasmatic OS marker and Apo ε4 carrier status. Plasmatic soluble receptor for advanced glycation end products (sRAGE) levels, plasma antioxidant total defenses (by lag-time method) and plasmatic Reactive Oxygen species (ROS) levels were evaluated in 25 AD patients and in 30 matched controls. ROS were significantly higher while plasma antioxidant total defenses and sRAGE levels were significantly lower in AD patients compared to controls. In AD patients lag-time values show a significant positive linear correlation with sRAGE levels and a (even not significant) negative correlation with ROS levels. Lag-time is significantly lower in ε4 carrier ( = 13) than in ε4 non-carrier ( = 12). Our result confirms the substantial OS in AD. Lag-time levels showed a significant positive correlation with sRAGE levels and a significant association with ε4 carrier status suggesting that plasmatic lag-time evaluation can be considered as a potential useful OS risk marker in AD.
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http://dx.doi.org/10.1186/s12979-019-0147-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444862PMC
April 2019

A Case with Early Onset Alzheimer's Disease, Frontotemporal Hypometabolism, ApoE Genotype ɛ4/ɛ4 and C9ORF72 Intermediate Expansion: A Treviso Dementia (TREDEM) Registry Case Report.

J Alzheimers Dis 2019 ;67(3):985-993

Cognitive Impairment Center, Local Health Autority n.2 Marca Trevigiana, Treviso, Italy.

We report the case of a woman firstly referred to our Memory Clinic at the age of 61, following the development of cognitive complaints and difficulties in sustained attention. The investigation that was performed showed: predominant executive dysfunctions at the neuropsychological evaluation, with mild, partial and stable involvement of the memory domain; cortical and subcortical atrophy with well-preserved hippocampal structures at MRI; marked fronto-temporal and moderate parietal hypometabolism from 18F-FDG PET study with a sparing of the posterior cingulate and precuneus; positivity of amyloid-β at 18F-Flutemetamol PET; an hexanucleotide intermediate repeats expansion of C9ORF72 gene (12//38 repeats) and ApoE genotype ɛ4/ɛ4. The patient was diagnosed with probable early onset frontal variant of Alzheimer's disease (AD), presenting with a major executive function impairment. The lack of specific areas of brain atrophy, as well as the failure to meet the clinical criteria for any frontotemporal dementia, drove us to perform the aforementioned investigations, which yielded our final diagnosis. The present case highlights the need to take into consideration a diagnosis of frontal variant of AD when the metabolic and the clinical picture are somehow dissonant.
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http://dx.doi.org/10.3233/JAD-180715DOI Listing
May 2020

Monozygotic Twins with Frontotemporal Dementia Due To Thr272fs GRN Mutation Discordant for Age At Onset.

J Alzheimers Dis 2019 ;67(4):1173-1179

University of Milan, "Dino Ferrari" Center, Milan, Italy.

We report the case of two monozygotic twins with Thr272fs mutation in progranulin gene. Both patients developed frontotemporal dementia with 5 years difference in age at onset (Twin 1:73 years, Twin 2:68 years), with early behavioral, language, dysexecutive, and memory problems. They had the same formal education (5 years), but while Twin 1 dedicated more to social and leisure activity, Twin 2 worked all her life. At neuroimaging (MRI for Twin 1 and CT for Twin 2), they both showed asymmetric atrophy with left predominance. The two were discordant for total tau levels in cerebrospinal fluid, neuropsychological testing, and smoking habits. The description of the twins can help identify environmental factors that influence the onset and phenotype of frontotemporal dementia.
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http://dx.doi.org/10.3233/JAD-180723DOI Listing
May 2020

Amyloid PET as a marker of normal-appearing white matter early damage in multiple sclerosis: correlation with CSF β-amyloid levels and brain volumes.

Eur J Nucl Med Mol Imaging 2019 02 21;46(2):280-287. Epub 2018 Oct 21.

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122, Milan, Italy.

Purpose: The disease course of multiple sclerosis (MS) is unpredictable, and reliable prognostic biomarkers are needed. Positron emission tomography (PET) with β-amyloid tracers is a promising tool for evaluating white matter (WM) damage and repair. Our aim was to investigate amyloid uptake in damaged (DWM) and normal-appearing WM (NAWM) of MS patients, and to evaluate possible correlations between cerebrospinal fluid (CSF) β-amyloid (Aβ) levels, amyloid tracer uptake, and brain volumes.

Methods: Twelve MS patients were recruited and divided according to their disease activity into active and non-active groups. All participants underwent neurological examination, neuropsychological testing, lumbar puncture, brain magnetic resonance (MRI) imaging, and F-florbetapir PET. Aβ levels were determined in CSF samples from all patients. MRI and PET images were co-registered, and mean standardized uptake values (SUV) were calculated for each patient in the NAWM and in the DWM. To calculate brain volumes, brain segmentation was performed using statistical parametric mapping software. Nonparametric statistical analyses for between-group comparisons and regression analyses were conducted.

Results: We found a lower SUV in DWM compared to NAWM (p < 0.001) in all patients. Decreased NAWM-SUV was observed in the active compared to non-active group (p < 0.05). Considering only active patients, NAWM volume correlated with NAWM-SUV (p = 0.01). Interestingly, CSF Aβ concentration was a predictor of both NAWM-SUV (r = 0.79; p = 0.01) and NAWM volume (r = 0.81, p = 0.01).

Conclusions: The correlation between CSF Aβ levels and NAWM-SUV suggests that the predictive role of β-amyloid may be linked to early myelin damage and may reflect disease activity and clinical progression.
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http://dx.doi.org/10.1007/s00259-018-4182-1DOI Listing
February 2019

CSF pro-orexin and amyloid-β38 expression in Alzheimer's disease and frontotemporal dementia.

Neurobiol Aging 2018 12 25;72:171-176. Epub 2018 Aug 25.

Centre for Translational Omics, Genetics & Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, UK. Electronic address:

There is an unmet need for markers that can stratify different forms and subtypes of dementia. Because of similarities in clinical presentation, it can be difficult to distinguish between Alzheimer's disease (AD) and frontotemporal dementia (FTD). Using a multiplex targeted proteomic LC-MS/MS platform, we aimed to identify cerebrospinal fluid proteins differentially expressed between patients with AD and FTD. Furthermore analysis of 2 confirmed FTD genetic subtypes carrying progranulin (GRN) and chromosome 9 open reading frame 72 (C9orf72) mutations was performed to give an insight into the differing pathologies of these forms of FTD. Patients with AD (n = 13) demonstrated a significant (p < 0.007) 1.24-fold increase in pro-orexin compared to FTD (n = 32). Amyloid beta-38 levels in patients with AD were unaltered but demonstrated a >2-fold reduction (p < 0.0001) in the FTD group compared to controls and a similar 1.83-fold reduction compared to the AD group (p < 0.001). Soluble TREM2 was elevated in both dementia groups but did not show any difference between AD and FTD. A further analysis comparing FTD subgroups revealed slightly lower levels of proteins apolipoprotein E, CD166, osteopontin, transthyretin, and cystatin C in the GRN group (n = 9) compared to the C9orf72 group (n = 7). These proteins imply GRN FTD elicits an altered inflammatory response to C9orf72 FTD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.08.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221294PMC
December 2018

Frontotemporal Dementia Misdiagnosed for Post-Treatment Lyme Disease Syndrome or vice versa? A Treviso Dementia (TREDEM) Registry Case Report.

J Alzheimers Dis 2018 ;66(2):445-451

Cognitive Impairment Center, Local Health Autority n.2 Marca Trevigiana, Treviso, Italy.

We describe the case of a 61-year-old woman diagnosed with Borreliosis at the age of 57. Subsequently, the patient developed depression, anxiety, and behavioral disturbances. A lumbar puncture excluded the condition of Neuroborreliosis. The diagnostic workup included: an MRI scan, a 18F-FDG PET, a 123I-ioflupane-SPECT, an amyloid-β PET, a specific genetic analysis, and a neuropsychological evaluation. Based on our investigation, the patient was diagnosed with probable behavioral-frontotemporal dementia (bvFTD), whereas in the previous years, the patient had been considered firstly as a case of Post-Treatment-Lyme Disease and, secondly, a psychiatric patient. We believe that, in the present case, such initial symptoms of Borrelia infection may have superimposed on those of bvFTD rather than playing as a contributory cause.
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http://dx.doi.org/10.3233/JAD-180524DOI Listing
October 2019

LncRNAs expression profile in peripheral blood mononuclear cells from multiple sclerosis patients.

J Neuroimmunol 2018 11 27;324:129-135. Epub 2018 Aug 27.

University of Milan, Dino Ferrari Center, Milan, Italy; Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy. Electronic address:

LncRNA PCR arrays containing 90 common LncRNAs were used to screen lncRNA expression levels in PBMC from a discovery population of patients with MS. Data from discovery and replications cohorts showed a generalized dysregulation of lncRNA levels in MS patients compared with controls. MALAT1, MEG9, NRON, ANRIL, TUG1, XIST, SOX2OT, GOMAFU, HULC, BACE-1AS were significantly downregulated in MS patients in comparison with controls. Therefore, we performed a validation analysis in an independent cohort of Belgian origin. In this study, NRON and TUG1 downregulations in MS patients compared with controls were confirmed (p ≤ .05 and p ≤ .0001 respectively), whereas considering the other lncRNAs, the statistical threshold was not reached. LncRNAs profiling could thus represent a new challenge in the research of easy detectable biomarkers of disease susceptibility and progression.
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http://dx.doi.org/10.1016/j.jneuroim.2018.08.008DOI Listing
November 2018

CSF β-amyloid predicts prognosis in patients with multiple sclerosis.

Mult Scler 2019 08 7;25(9):1223-1231. Epub 2018 Aug 7.

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy/University of Milan, Dino Ferrari Center, Milan, Italy.

Background: The importance of predicting disease progression in multiple sclerosis (MS) has increasingly been recognized, and hence reliable biomarkers are needed.

Objectives: To investigate the prognostic role of cerebrospinal fluid (CSF) amyloid beta (Aβ) levels by the determination of a cut-off value to classify patients in slow and fast progressors. To evaluate possible association with white matter (WM) and grey matter (GM) damage at early disease stages.

Methods: Sixty patients were recruited and followed up for 3-5 years. Patients underwent clinical assessment, brain magnetic resonance imaging (MRI; at baseline and after 1 year), and CSF analysis to determine Aβ levels. T1-weighted volumes were calculated. T2-weighted scans were used to quantify WM lesion loads.

Results: Lower CSF Aβ levels were observed in patients with a worse follow-up Expanded Disability Status Scale (EDSS;  = -0.65,  < 0.001). The multiple regression analysis confirmed CSF Aβ concentration as a predictor of patients' EDSS increase ( = -0.59,  < 0.0001). Generating a receiver operating characteristic curve, a cut-off value of 813 pg/mL was determined as the threshold able to identify patients with worse prognosis (95% confidence interval (CI): 0.690-0.933,  = 0.0001). No differences in CSF tau and neurofilament light chain (NfL) levels were observed ( > 0.05).

Conclusion: Low CSF Aβ levels may represent a predictive biomarker of disease progression in MS.
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http://dx.doi.org/10.1177/1352458518791709DOI Listing
August 2019

Progranulin as a therapeutic target for dementia.

Expert Opin Ther Targets 2018 07 22;22(7):579-585. Epub 2018 Jun 22.

a Neurodegenerative Diseases Unit, University of Milan, Centro Dino Ferrari, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico , Milan , Italy.

Introduction: Progranulin (PGRN) is an acrosomal glycoprotein that is synthesized during spermatogenesis. It is overexpressed in tumors and has anti-inflammatory properties. The protein may be cleaved into granulins which display pro-inflammatory properties. In 2006, mutations in progranulin gene (GRN) that cause haploinsufficiency were found in familial cases of frontotemporal dementia (FTD). Patients with null mutations in GRN display very low-plasma PGRN levels; this analysis is useful for identifying mutation carriers, independent of the clinical presentation, and in those before the appearance of symptoms. Areas covered: Here, we review the current knowledge of PGRN physiological functions and GRN mutations associated with FTD; we also summarize state of the art clinical trials and those compounds able to replace PGRN loss in preclinical models. Expert opinion: PGRN represents a promising therapeutic target for FTD. Cohorts suitable for treatment, ideally at the preclinical stage, where pathogenic mechanisms ongoing in the brain are targeted, are available. However, PGRN may have side effects, such as the risk of tumorigenesis, and the risk/benefit ratio of any intervention cannot be predicted. Furthermore, at present, the situation is complicated by the absence of adequate outcome measures.
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http://dx.doi.org/10.1080/14728222.2018.1487951DOI Listing
July 2018
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