Authors: Agostini, Simone | Mancuso, Roberta | Hernis, Ambra | Costa, Andrea Saul | Nemni, Raffaello | Clerici, Mario
Article Type: Research Article
Abstract: Human Herpes Simplex Virus type 1 (HSV-1) infection is suggested to play a role in the development of Alzheimer’s disease (AD). Immunoglobulin G (IgG) neutralize HSV-1 activity, but the virus can evade IgG-mediated immune responses by expressing receptor that efficiently binds the Fc portion of all IgG subclasses with the exception of IgG3 . We analyzed HSV-1-specific IgG subclasses and IgG-mediated serum neutralization activity against HSV-1 in individuals with a diagnosis of either AD or mild cognitive impairment (MCI), comparing the results with those obtained in age-matched healthy controls (HC). 186 individuals were enrolled in the study: 67 AD, 58 …MCI, and 61 HC. HSV-1 IgG titers and subclasses, neutralizing antibody (NAb) titers, and complement C3 concentration—critical component of antibody-mediated effector activity—were measured in sera by ELISA; IgG neutralizing activity was performed on HSV-1 infected Vero cells. Results showed that, whereas HSV-1-specific IgG1 , IgG2 , and IgG4 titers as well as complement C3 serum concentration were comparable in all groups of individuals, IgG3 were more frequently detected in MCI (89%) compared to AD (75%; p < 0.05) and HC (68%; p = 0.003), whereas the titer is similar among the three groups (AD: 0.66±0.21 OD; MCI: 0.68±0.24 OD; HC: 0.72±0.28 OD). Notably, HSV-1 specific neutralizing ability of AD sera was reduced even in the presence of high quantity of IgG3 . As IgG3 plays a key role in counteracting the ability of HSV-1 to evade immune responses, these data reinforce the hypothesis of a pathogenetic role of HSV-1 in AD. Show more
Keywords: Alzheimer’s disease, HSV-1, HSV-1-IgG subclasses, mild cognitive impairment, neutralization activity
DOI: 10.3233/JAD-170966
Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 131-138, 2018
Authors: Mancuso, Roberta | Baglio, Francesca | Cabinio, Monia | Calabrese, Elena | Hernis, Ambra | Nemni, Raffaello | Clerici, Mario
Article Type: Short Communication
Abstract: HSV-1 infection of the central nervous system targets the same brain regions most affected in Alzheimer's disease (AD) and could play a pathogenic role in AD. HSV-1 serum IgG titers were analyzed in patients with mild AD (n = 83) and healthy controls (HC, n = 51); results were correlated with cortical grey matter (GM) volumes as analyzed by MRI. Seroprevalence and antibody (Ab) titers were comparable between AD and HC; elevated Ab titers (>75th percentile) were nevertheless significantly more frequent in AD and were positively correlated with cortical bilateral temporal and orbitofrontal GM volumes. HSV-1-specific-Ab could possibly play a …protective role in the early stages of AD. Show more
Keywords: Alzheimer's disease, HSV-1, humoral immunity, magnetic resonance imaging
DOI: 10.3233/JAD-130977
Citation: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 741-745, 2014
Authors: Cabinio, Monia | Saresella, Marina | Piancone, Federica | LaRosa, Francesca | Marventano, Ivana | Guerini, Franca Rosa | Nemni, Raffaello | Baglio, Francesca | Clerici, Mario
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative condition characterized by memory impairment and general decrease in cognitive functions and daily living competences, that leads to a complete loss of autonomy. The pathogenesis of AD is characterized by the deposition of amyloid-β plaques (Aβ plaques) and neurofibrillary tangles, initially involving cortical and hippocampal structures, and neuroinflammation. To date, no studies have investigated the topological association between neuroinflammation and hippocampal shape in AD. Objective: The aim of the present study is to assess the association between hippocampal shape, cognitive profile, and neuroinflammation in a group of AD patients in the mild stage …of the disease. Methods: Thirty-one patients with typical onset AD (mild stage) underwent MRI examination (1.5T scanner); hippocampal structures were segmented using a vertex-wise analysis (FSL-FIRST). Immune parameters were evaluated on peripheral blood mononuclear cells by flow-cytometry. Correlation analyses were performed between hippocampal shape and both cognitive profile (ADAS-Cog and MMSE scores), and neuro-inflammatory variables (i.e., circulating monocytes, cytokines). Results: Statistically significant correlations (p < 0.05FWE ) between right hippocampal shape and cognitive measurements and between left hippocampal shape and inflammatory indices were detected. The hippocampal field mostly involved was the lateral portion of bilateral hippocampi, mainly overlapping with Cornu Ammonis, extending along the entire longitudinal axis. Conclusions: A topological relationship between hippocampal atrophy and both cognitive profile and neuroinflammation is found; the association with neuroinflammatory indices is in line with the pattern of AD-associated neuronal death, whereas the association with cognitive test might account for residual cognitive functions. Show more
Keywords: Alzheimer’s disease, brain, flow cytometry, hippocampus, inflammation, Magnetic Resonance Imaging (MRI)
DOI: 10.3233/JAD-180250
Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 1131-1144, 2018
Authors: Costa, Andrea Saul | Guerini, Franca Rosa | Arosio, Beatrice | Galimberti, Daniela | Zanzottera, Milena | Bianchi, Anna | Nemni, Raffaello | Clerici, Mario
Article Type: Research Article
Abstract: The SNARE complex plays a crucial role in the synaptic exocytosis of neurotransmitters, a process involved in the Alzheimer’s disease (AD), the most common form of dementia. SNAP-25, STX1a, and VAMP2 are the core proteins of the SNARE complex, and changes in protein level are suggested to contribute to cognitive impairment and neuropsychiatric disorders. Single nucleotide polymorphisms (SNPs) in SNARE complex genes were shown to be associated with different diseases and different cognitive impairments. Chi-square analysis was used to compare case-control difference of ApoE4, SNAP-25 rs363039, rs363043, rs363950, STX1a rs4717806, rs2293489, and VAMP2 26bp Ins/Del genotype distribution in 192 AD, …187 mild cognitive impairment (MCI), and 200 healthy controls (HC). Results of genotype and allelic distribution of SNAP-25 rs363050 showed that AA genotype (AD versus HC: p = 1.5×10–4 ; MCI versus HC: p = 8.7×10–3 ) as well as A allele (AD versus HC: p = 6.0×10–4 ; MCI versus HC: p = 5.7×10–3 ) are significantly more frequent in AD and MCI compared to HC. Genotype distribution of STX1a rs4717806 and rs2293489 resulted significantly different in AD compared to HC (p = 0.032 and p = 0.047, respectively). Moreover, distribution of the STX1a rs4717806 allele in SNAP-25 rs363050 AA carriers was significantly different between MCI and HC (p = 0.018). Notably, in MCI, visual selective attention impairment was associated with the STX1a rs4717806 AA (pc = 0.027) genotype as well as the SNAP-25/STX1a rs363050/rs4717806 AA/A (pc = 0.022) combination. These data suggest that SNPs in SNARE complex genes may interfere and/or modulate the activity of the SNARE complex resulting in impairments of neurotransmission that involve attention brain areas. Show more
Keywords: Alzheimer’s disease, cognitive impairment, gene polymorphisms, mild cognitive impairment, SNAP-25, SNARE, SNPs, STX1a, VAMP2
DOI: 10.3233/JAD-190147
Citation: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 179-188, 2019
Authors: Saresella, Marina | Marventano, Ivana | Calabrese, Elena | Piancone, Federica | Rainone, Veronica | Gatti, Andrea | Alberoni, Margherita | Nemni, Raffaello | Clerici, Mario
Article Type: Research Article
Abstract: An impairment of the microglial catabolic mechanisms allows amyloid-β (Aβ) accumulation in plaques within the brain in Alzheimer's disease (AD). Monocytes/macrophages (M/M) are activated in AD and migrate thorough the blood-brain barrier (BBB) trying to improve Aβ clearing. In the attempt to shed light on the role of M/M in AD, these cells were analyzed in patients with AD or mild cognitive impairment (MCI) and in age-matched healthy controls. Results obtained in Aβ42 -stimulated cell cultures showed that significantly higher percentages of inflammatory M/M (CD14+ CD16− CCR2++ CX3CR1low ) expressing toll like receptors (TLR) 2 and 4, as well as …IL-6 and CCR2, a chemokine favoring M/M migration through the BBB, are seen in AD. Confocal microscopy suggested the presence of MHC-II/Aβ42 complexes on AD M/M alone. Finally, TRL3- and TLR8-expressing and IL-23-producing M/M were increased in both AD and MCI compared to HC. These data indicate that M/M in AD are characterized by an inflammatory profile and are involved in the induction of both innate immune responses via TLR stimulation and of acquired immunity possibly secondarily to the presentation of Aβ peptides in an MHC-restricted fashion. Therapeutic approaches designed to interrupt these mechanism might prove beneficial. Show more
Keywords: Alzheimer's disease, cytokines, monocytes, neuroinflammation, toll-like receptors
DOI: 10.3233/JAD-131160
Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 403-413, 2014
Authors: Saresella, Marina | Calabrese, Elena | Marventano, Ivana | Piancone, Federica | Gatti, Andrea | Calvo, Maria Gaetana | Nemni, Raffaello | Clerici, Mario
Article Type: Research Article
Abstract: Regulatory T lymphocytes (Treg ) play a fundamental importance in modulating the relative balance between inflammation and immune tolerance, and alterations of these cells are observed in inflammatory diseases. To better characterize the neuroinflammatory processes suggested to be associated with Alzheimer's disease (AD) and to clarify the possible role of Treg cells in this process, we extensively analyzed these cells (CD4 + CD25high Foxp3+) in patients with either severe AD (n = 25) or mild cognitive impairment (MCI) (n = 25), comparing the results with those of two groups of healthy controls (HC) (n = 55). Because the intra- or …extracellular expression of programmed death receptor 1 (PD1) identifies functionally diverse subsets of Treg we also analyzed such subpopulations. Results showed that, whereas both Treg and PD1pos Treg are increased in MCI and AD patients compared to HC, PD1neg Treg , the subpopulation of Treg cells endowed with the strongest suppressive ability, are significantly augmented in MCI patients alone. In these patients amyloid-β-stimulated-T cells proliferation was reduced and Treg -mediated suppression was more efficient compared to both AD and HC. The observation that PD1neg Treg , cells are increased in MCI patients reinforces the inflammatory origin of AD and supports a possible beneficial role of these cells in MCI that is lost in patients with full-blown AD. Show more
Keywords: Alzheimer's disease, immunology, mild cognitive impairment, PD1, T regulatory cells
DOI: 10.3233/JAD-2010-091696
Citation: Journal of Alzheimer's Disease, vol. 21, no. 3, pp. 927-938, 2010
Authors: Costa, Andrea Saul | Agostini, Simone | Guerini, Franca Rosa | Mancuso, Roberta | Zanzottera, Milena | Ripamonti, Enrico | Racca, Vittorio | Nemni, Raffaello | Clerici, Mario
Article Type: Research Article
Abstract: Herpes simplex virus type 1 (HSV-1) has long been suspected to play a role in Alzheimer’s disease (AD), the most common form of dementia. IFN-lambda (IFN-λ ) is one of the key cytokine in innate antiviral defenses and, in particular, has an appreciable antiviral activity against HSV-1 infection. IFN-λ expression is regulated by the interaction between two different proteins: Mediator Complex 23 (MED23) and Interferon-Responsive Transcription Factor 7 (IRF7); single nucleotide polymorphisms (SNPs) in these genes as well as in IFNL3 were shown to be differently distributed in AD patients. In this study, allelic discrimination analysis for IFNL3 rs12979860, MED23 …rs3756784, and IRF7 rs6598008, as well as IFN-λ serum concentration and anti-HSV-1 antibody (Ab) titers were performed in 79 AD patients, 57 mild cognitive impairment (MCI) individuals, and 81 healthy controls (HC) who were HSV-1-seropositive. Results showed that INF-λ serum concentration was increased in AD and MCI carrying the IFNL3 T allele compared to HC (AD versus HC: p = 0.014; MCI versus HC: p = 0.029), with the highest anti-HSV-1 Ab titers seen in AD patients carrying the IFNL3 CC genotype (p = 0.012 versus HC). Notably, anti-HSV-1 Ab titers were higher in AD and MCI individuals carrying the IRF7 AA genotype compared to HC (p = 0.018 for both). MED23 polymorphisms did not show any statistical association either with serum IFN-λ or with anti-HSV-1 Ab. Data herein suggest that the IFNL3 rs12979860 and IRF7 rs6598008 polymorphisms modulate immune responses against HSV-1 via their effect on the IFN-λ pathway. These results help to clarify the possible role of HSV-1 infection in AD pathogenesis. Show more
Keywords: Alzheimer’s disease, gene polymorphisms, HSV-1, IRF7, MED23, Interferon lambda, mild cognitive impairment, SNP
DOI: 10.3233/JAD-170520
Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 1055-1063, 2017
Authors: Agostini, Simone | Mancuso, Roberta | Baglio, Francesca | Cabinio, Monia | Hernis, Ambra | Guerini, Franca Rosa | Calabrese, Elena | Nemni, Raffaello | Clerici, Mario
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD), the most common form of dementia worldwide, is associated with impairment in the mechanisms of the clearing of amyloid-β within a scenario of neuroinflammation. The etiopathogenesis of the AD is unclear, but a role for viral infection is suspected to play a role in initiating the disease. We recently described a positive correlation between high titers of HSV-1-specific antibodies (Ab) and the volumes of brain regions typically affected in disease. Objective: The exploration of a possible role for Herpesviridae in AD was extended by analyzing HHV-6-specific humoral immunity in individuals with AD or a diagnosis of …amnestic mild cognitive impairment (aMCI), a condition that is often prodromic of the development of AD. Methods: 59 AD, 60 aMCI, and 61 age-matched healthy controls were enrolled in the study. Serum HHV-6 IgG antibody titers and avidity index were tested by ELISA. Two randomly selected subgroups of AD and aMCI in whom HHV-6 serum antibodies were detected underwent brain magnetic resonance imaging (MRI) by 1.5 T scanner. Results: HHV-6 seroprevalence, antibody titers, and avidity were similar in the three groups. No correlation was found between Ab titers or avidity and brain volumes, either overall or in the regions typically affected by disease. Conclusions: The lack of any relation between humoral immune response against HHV-6 and AD and aMCI seems to rule out a role for this virus in the pathogenesis of AD. Show more
Keywords: Alzheimer’s disease, HHV-6, humoral immunity, magnetic resonance imaging
DOI: 10.3233/JAD-150464
Citation: Journal of Alzheimer's Disease, vol. 49, no. 1, pp. 229-235, 2016
Authors: Gironi, Maira | Borgiani, Bruno | Farina, Elisabetta | Mariani, Enrica | Cursano, Cristina | Alberoni, Margherita | Nemni, Raffaello | Comi, Giancarlo | Buscema, Massimo | Furlan, Roberto | Grossi, Enzo
Article Type: Research Article
Abstract: Alzheimer's disease (AD) is the most common form of dementia, while mild cognitive impairment (MCI) causes a slight but measurable decline in cognitive abilities. A person with MCI has an increased risk of developing AD or another dementia. Thus, it is of medical interest to develop predictive tools to assess this risk. A growing awareness exists that pro-oxidative state and neuro-inflammation are both involved in AD. However, the extent of this relationship is still a matter of debate. Due to the expected non-linear correlations between oxidative and inflammatory markers, traditional statistics is unsuitable to dissect their relationship with the disease. …Artificial neural networks (ANNs) are computational models inspired by central nervous system networks, capable of machine learning and pattern recognition. The aim of this work was to disclose the relationship between immunological and oxidative stress markers in AD and MCI by the application of ANNs. Through a machine learning approach, we were able to construct an algorithm to classify MCI and AD with high accuracy. Such an instrument, requiring a small amount of immunological and oxidative-stress parameters, would be useful in the clinical practice. Moreover, applying an innovative non-linear mathematical technique, a global immune deficit was shown to be associated with cognitive impairment. Surprisingly, both adaptive and innate immunity were peripherally defective in AD and MCI patients. From this study, new pathogenetic aspects of these diseases could emerge. Show more
Keywords: Artificial neural network, machine learning, oxidative-stress, neurodegeneration, pattern recognition, relationships
DOI: 10.3233/JAD-141116
Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1199-1213, 2015
Authors: Guerini, Franca Rosa | Agliardi, Cristina | Sironi, Manuela | Arosio, Beatrice | Calabrese, Elena | Zanzottera, Milena | Bolognesi, Elisabetta | Ricci, Cristian | Costa, Andrea Saul | Galimberti, Daniela | Griffanti, Ludovica | Bianchi, Anna | Savazzi, Federica | Mari, Daniela | Scarpini, Elio | Baglio, Francesca | Nemni, Raffaello | Clerici, Mario
Article Type: Research Article
Abstract: Synaptosomal-associated protein of 25 kDa (SNAP-25) is an age-regulated vesicular SNARE protein involved in the exocytosis of neurotransmitters from synapses, a process that is altered in Alzheimer's disease (AD). Changes in SNAP-25 levels are suggested to contribute to age-related decline of cognitive function, and single nucleotide polymorphisms (SNPs) in the SNAP-25 gene are present in neuropsychiatric conditions and play a role in determining IQ phenotypes. To verify a possible role of SNAP-25 in AD, we analyzed five gene polymorphisms in patients with AD (n = 607), replicating the study in subjects with amnestic mild cognitive impairment (aMCI) (n = 148) …and in two groups of age-matched healthy controls (HC1: n = 615 and HC2: n = 310). Results showed that the intronic rs363050 (A) and rs363043 (T) alleles, as well as the rs363050/rs363043 A-T haplotype are significantly more frequent in AD and aMCI and are associated with pathological scores of categorical fluency in AD. Notably, functional MRI analyses indicated that SNAP-25 genotypes correlate with a significantly decreased brain activity in the cingulate cortex and in the frontal (middle and superior gyri) and the temporo-parietal (angular gyrus) area. SNAP-25 polymorphisms may be associated with AD and correlate with alterations in categorical fluency and a reduced localized brain activity. SNAP-25 polymorphisms could be used as surrogate markers for the diagnosis of AD and of cognitive deficit; these SNPs might also have a possible predictive role in the natural history of AD. Show more
Keywords: Alzheimer's disease, categorical fluency, cognitive impairment, functional MRI, genetic polymorphisms, SNAP-25
DOI: 10.3233/JAD-140057
Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 1015-1028, 2014