Special Issue "Epigenetics in Neurodegenerative Diseases".

Epigenetic mechanisms inducing phenotypic changes without altering the DNA genome are increasingly recognized as key factors modulating gene expression and, consequently, cell functions [...].

Evaluation of serum miRNAs expression in frail and robust subjects undergoing multicomponent exercise protocol (VIVIFRAIL).

BACKGROUND: Frailty, defined as physical performance impairment, is a common condition in older adults and can anticipate the development of sarcopenia, a geriatric syndrome characterized by loss of muscle strength and mass. microRNAs (miRNAs) are short molecules of RNA endowed with the ability to modulate gene expression; miRNAs are present in serum and are considered potential biomarkers for several diseases. Serum concentration of miR-451a, miR-93-5p, miR-155-5p, miR-421-3p, miR-425-5p, miR-495-3p and miR-744-5p was recently shown to be altered in sarcopenic patients. METHODS: We verified if a particular miRNAs pattern could be detected in frailty as well by analyzing these molecules in 50 frail and 136 robust subjects. Additionally, a subgroup of these subjects (15 frail and 30 robust) underwent a 12-week program based on a multicomponent exercise protocol (VIVIFRAIL) consisting of resistance training, gait retraining, and balance training. After the program, serum miRNAs concentration was measured again, to verify whether the physical activity had an effect on their concentration. Moreover, clinical characteristics and indicators of physical performance of all subjects were compared before and after intervention to verify the effect of the VIVIFRAIL program. RESULTS: At the end of the multicomponent exercise program, Short Physical Performance Battery (SPPB) score as well right and left handgrip (p < 0.05) were significantly increased in frail subjects; right and left handgrip significantly were increased also in robust subjects (p < 0.05). Interestingly, the variation of SPPB was significantly higher in frail compared to robust subjects (p < 0.0001). Moreover, at the end of the program, in frail compared to robust subjects: miR-451a serum concentration was significantly increased (frail: 6.59 × 104; 1.12 × 104-2.5 × 105 c/ng; robust: 2.31 × 104; 1.94 × 103-2.01 × 105 c/ng) (p < 0.05); and 2) miR-93-5p and miR-495-3p serum concentration was reduced, whereas that of miR-155-5p was significantly increased (p < 0.05 in both cases). Serum concentration of miR-93-5p and miR-495-3p was decreased, and that of miR-155-5p was increased at the end of the program in robust subjects alone, statistical significance being reached for miR-93-5p alone (p = 0.02). CONCLUSION: These results suggest that serum miR-451a should be investigated as a potential biomarker for frailty and show that the VIVIFRAIL multicomponent program modulates circulatory miRNAs expression, at least in older adults.

Computer-aided diagnosis in prostate cancer: a retrospective evaluation of the Watson Elementary® system for preoperative tumor characterization in patients treated with robot-assisted radical prostatectomy.

PURPOSE: Computer-aided diagnosis (CAD) may improve prostate cancer (PCa) detection and support multiparametric magnetic resonance imaging (mpMRI) readers for better characterization. We evaluated Watson Elementary® (WE®) CAD system results referring to definitive pathological examination in patients treated with robot-assisted radical prostatectomy (RARP) in a tertiary referral center. METHODS: Patients treated with RARP between 2020 and 2021 were selected. WE® calculates the Malignancy Attention Index (MAI), starting from the information contained in the mpMRI images. Outcome measures were the capability to predict the presence of PCa, to correctly locate the dominant lesion, to delimit the largest diameter of the dominant lesion, and to predict the extraprostatic extension (EPE). RESULTS: Overall, tumor presence was confirmed in 46 (92%) WE® highly suspicious areas, while it was confirmed in 43 (86%) mpMRI PI-RADS ≥ 4 lesions. The WE® showed a positive agreement with mpMRI of 92%. In 98% of cases, visible tumor at WE® showed that the highly suspicious areas were within the same prostate sector of the dominant tumor nodule at pathology. WE® showed a 2.5 mm median difference of diameter with pathology, compared with a 3.8 mm of mpMRI versus pathology (p = 0.019). In prediction of EPE, WE® and mpMRI showed sensitivity, specificity, positive and negative predictive value of 0.81 vs 0.71, 0.56 vs 0.60, 0.88 vs 0.85 and 0.42 vs 0.40, respectively. CONCLUSION: The WE® system resulted accurate in the PCa dominant lesion detection, localization and delimitation providing additional information concerning EPE prediction.

TREM2 Expression and Amyloid-Beta Phagocytosis in Alzheimer's Disease.

Alzheimer's Disease is the most common form of dementia; its key pathological findings include the deposition of extracellular-neurotoxic-plaques composed of amyloid-beta (Ab). AD-pathogenesis involves mechanisms that operate outside the brain, and new researches indicate that peripheral inflammation is an early event in the disease. Herein, we focus on a receptor known as triggering-receptor-expressed-on-myeloid-cells2 (TREM2), which promotes the optimal immune cells function required to attenuate AD-progression and is, therefore, a potential target as peripheral diagnostic and prognostic-biomarker for Alzheimer's Disease. The objective of this exploratory study was to analyze: (1) soluble-TREM2 (sTREM2) plasma and cerebrospinal fluid concentration, (2) TREM2-mRNA, (3) the percentage of TREM2-expressing monocytes, and (4) the concentration of miR-146a-5p and miR-34a-5p suspected to influence TREM2 transcription. Experiments were performed on PBMC collected by 15AD patients and 12age-matched healthy controls that were unstimulated or treated in inflammatory (LPS) conditions and Ab42 for 24 h; Aß42-phagocytosis was also analyzed by AMNIS FlowSight. Results although preliminary, due to limitations by the small sample-size, showed that in AD compared to HC: TREM2 expressing monocytes were reduced, plasma sTREM2 concentration and TREM2-mRNA were significantly upregulated and Ab42-phagocytosis was diminished (for all p < 0.05). miR-34a-5p expression was reduced (p = 0.02) as well in PBMC of AD, and miR-146 was only observed in AD cells (p = 0.0001).

Sarcopenia associates with SNAP-25 SNPs and a miRNAs profile which is modulated by structured rehabilitation treatment.

BACKGROUND: Sarcopenia is a loss of muscle mass and strength causing disability, morbidity, and mortality in older adults, which is characterized by alterations of the neuromuscular junctions (NMJs). SNAP-25 is essential for the maintenance of NMJ integrity, and the expression of this protein was shown to be modulated by the SNAP-25 rs363050 polymorphism and by a number of miRNAs. METHODS: We analysed these parameters in a cohort of sarcopenic patients undergoing structured rehabilitation. The rs363050 genotype frequency distribution was analyzed in 177 sarcopenic patients and 181 healthy controls (HC). The concentration of seven miRNAs (miR-451a, miR-425-5p, miR155-5p, miR-421-3p, miR-495-3p, miR-744-5p and miR-93-5p), identified by mouse brain miRNome analysis to be differentially expressed in wild type compared to SNAP-25± heterozygous mice, was analyzed as well by droplet digital PCR (ddPCR) in a subgroup of severe sarcopenic patients undergoing rehabilitation. RESULTS: The SNAP-25 rs363050 AA genotype was significantly more common in sarcopenic patients compared to HC (pc = 0.01); miR-451a was significantly up-regulated in these patients before rehabilitation. Rehabilitation modified miRNAs expression, as miR-155-5p, miR-421-3p, miR-451a, miR-425-5p, miR-744-5p and miR-93-5p expression was significantly up-regulated (p < 0.01), whereas that of miR-495-3p was significantly down-regulated (p < 0.001) by rehabilitation. Notably, rehabilitation-associated improvement of the muscle-skeletal SPPB score was significantly associated with the reduction of miR-451a expression. CONCLUSION: These results support the hypothesis of a role for SNAP-25 in sarcopenia and suggest SNAP-25-associated miRNAs as circulatory biomarkers of rehabilitative outcome for sarcopenia.

Deregulation of IL-37 and its miRNAs modulators in sarcopenic patients after rehabilitation.

BACKGROUND: sarcopenia is a highly prevalent condition in elderly individuals which is characterized by loss of muscle mass and functions; recent results showed that it is also associated with inflammation. Rehabilitation protocols for sarcopenia are designed to improve physical conditions, but very scarce data are available on their effects on inflammation We verified whether in sarcopenic patients the inflammation is reduced by rehabilitation and investigated the biological correlates of such effect. METHODS: Twenty-one sarcopenic patients undergoing a specifically-designed rehabilitation program were enrolled in the study. Physical, cognitive and nutritional parameters, as well as the concentration of C-Reactive Protein (CRP), pro-and anti-inflammatory cytokines and cytokine production-modulating miRNAs were measured at the beginning (T0) and at end (30-days; T1) of the rehabilitation. RESULTS: Rehabilitation resulted in a significant improvement of physical and cognitive conditions; this was accompanied by a significant reduction of CRP (p = 0.04) as well as of IL-18 (p = 0.008) and IL-37 (p = 0.009) concentration. Notably, the concentration of miR-335-3p (p = 0.007) and miR-657, the two known post-transcriptional regulators of IL-37 production, was increased by the rehabilitation protocol. CONCLUSIONS: Results herein confirm that successful rehabilitation for sarcopenia results in a reduction of the inflammatory milieu, raise the possibility that IL-37 may be a key target to monitor the rehabilitation-associated improvement in sarcopenia, and suggest that this cytokine could be a therapeutic target in sarcopenic patients.

Contrast-enhanced ultrasound (CEUS) imaging for active surveillance of small renal masses.

PURPOSE: To assess the safety and efficacy of contrast-enhanced ultrasound (CEUS) imaging for monitoring small (< 4 cm) renal masses (SRM) in patients undergoing active surveillance (AS). METHODS: We retrospectively selected all consecutive patients with SRMs who underwent AS for at least 6 months at our Institution between January 2014 and December 2018. CEUS imaging was performed by two experienced genitourinary radiologists at established time points. The accuracy of CEUS for monitoring SRM size was compared with that of CT scan. For solid SRMs, four enhancement patterns (EP) were recorded. Radiological progression was defined as SRM growth rate ≥ 5 mm/year. RESULTS: Overall, 158/1049 (15.1%) patients with SRMs underwent AS. At a median follow-up of 25 months (IQR 13-39), no patient died due to renal cell carcinoma (RCC). No patients experienced CEUS-related adverse events. There was a large variability in the pattern of growth of SRMs (overall median growth rate: 0.40 mm/year), with 9.5% of SRMs showing radiological progression. The median SRM size was comparable between CEUS and CT scan examinations at all time points. The vast majority (92.7%) of SRMs did not show a change in their EP over time; and there was no association between the SRM's EP and radiological progression or SRM size. Overall, 43 (27.2%) patients underwent delayed intervention (DI); median SRM size, and median growth rate were significantly higher in these patients as compared to those continuing AS. CONCLUSION: In experienced hands, CEUS is a safe and effective strategy for active monitoring of SRMs in well-selected patients undergoing AS.

Relation between FCGRIIB rs1050501 and HSV-1 specific IgG antibodies in Alzheimer's disease.

BACKGROUND: Alzheimer's Disease (AD) is a chronic neurodegenerative disorder characterized by extracellular plaques, intracellular neurofibrillary tangles and neuronal loss in the central nervous system (CNS). Pathogens are suspected to have a role in the development of AD; herpes simplex virus type 1 (HSV-1), in particular, is suggested to be a risk factor for the disease. The gamma receptor for the Fc portion of IgG molecules (FCGRs) plays a crucial role in regulating immune responses, and among FCGRs, FCGRIIB is endowed with an inhibitory function. Notably, the rs1050501 polymorphism of FCGRIIB gene associates with autoimmune diseases and with neuronal uptake and interneuronal accumulation of amyloid beta in animal AD models. METHODS: Genotype and allelic distribution of ApoE4 and FCGRIIB rs1050501 were evaluated in a case-control population of 225 AD patients, 93 MCI individuals and 201 sex and age matched healthy controls (HC). HSV-1 total IgG titers and IgG subclasses were detected and quantified in a subgroup of the main study population by ELISA. RESULTS: Genotype and allelic distribution of FCGRIIB was comparable in the study population. HSV-1-specific antibody titers were significantly higher in AD and MCI compared to HC (p < 0.01 for both); IgG3 titers, in particular, were increased in MCI compared to AD (p = 0.04). Analyses of possible correlations between the FCGRIIB rs1050501 genotype polymorphism and IgG subclasses showed that the presence of IgG3 was more frequent in MCI carrying the FCGRIIB TT (94.1%) compared to those carrying the CT genotype (63.6%) (p = 0.03). CONCLUSION: Results herein show an association between humoral immune response against HSV-1 and FCGRIIB rs1050501 genetic variation in the first stage of the disease.

COS-7 cells are a cellular model to monitor polyomavirus JC miR-J1-5p expression.

Polyomavirus JC (JCPyV) is a ubiquitous human neurotropic virus that can cause progressive multifocal leukoencephalopathy (PML), sometimes as a consequence of drug treatment for disabling diseases, including Multiple Sclerosis. JCPyV expresses microRNAs (miRNAs), and in particular miR-J1-5p, but at now we have limited knowledge regarding this aspect. In the present study the expression of JCPyV miR-J1-5p was measured in infected COS-7, to verify if and when this miRNA is expressed in a cell model of JCPyV-MAD-4 strain infection. Results showed that miR-J1-5p expression was relatively constant inside the cells from 11 days to 35 days after infection (mean: 4.13 × 105 copies/µg), and became measurable in supernatants 18 days after infection (mean: 7.20 × 104 copies/µl). miR-J1-5p expression in supernatants peaked (3.76 × 105 copies/µl) 25 days after infection and started to decrease 32 days after infection (7.20 × 104 copies/µl). These data show that COS-7 cells, already used as model for JCPyV replication cycle, can be also utilized to study JCPyV miRNAs expression, potentially opening new research avenues for diseases in which current therapeutic approaches could result in severe adverse effects (e.g. Natalizumab-associated JCPyV reactivation in Multiple Sclerosis patients). In these situations monitoring of miR-J1-5p may shed light on the mechanisms of virus reactivation and may help the clarification of the mechanisms responsible for such severe side effects.

Herpes simplex virus-1 (HSV-1) infection induces a potent but ineffective IFN-λ production in immune cells of AD and PD patients.

BACKGROUND: The sequential activation of immediate early (IE), early (E) and late (L) genes is required to allow productive herpes simplex virus type 1 (HSV-1) infection. Several evidences suggest that, together with inflammation, an immunological response incapable to counteract HSV-1 reactivation plays a role in the pathogenesis of Alzheimer's (AD) and Parkinson's (PD) diseases. IFN-lambda (IFN-λ), a cytokine endowed with a robust antiviral activity, contains HSV-1 reactivation. HSV-1-induced IFN-λ, IL-10 and IL-1ß as well as the expression of viral IE, E and L genes were analyzed in vitro in peripheral blood mononuclear cells (PBMC) of AD and PD patients as well as of healthy controls (HC). METHODS: PBMC of AD, PD and HC were in vitro infected with one multiplicity of infection (1 MOI) HSV-1. IE, E, and L viral genes transcription as well as IFN-λ, IL-10 and IL-1ß production were analyzed. RESULTS: In HSV-1-infected cells of AD and PD patients compared to HC: (1) transcription of IE (ICP0, ICP27) genes was reduced whereas that of E (UL41, UL29) and L (UL48, LAT) genes was increased; (2) IFN-λ mRNA expression was increased. IL-1ß was augmented and IL-10 was reduced in unstimulated cells of AD and PD compared to HC; HSV-1 infection significantly increased IL-10 production in HC alone. CONCLUSIONS: Data herein show that a proinflammatory condition is present in AD and PD, in whom attempts to obstacle viral replication via an initial, possibly more potent IFN-λ-mediated control of IE viral genes is unsuccessful.

The PILRA G78R Variant Correlates with Higher HSV-1-Specific IgG Titers in Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by a progressive decline in cognitive performance; Mild Cognitive Impairment (MCI) is instead an objective decline in cognitive performance that does not reach pathology. Paired immunoglobulin-like type 2 receptor alpha (PILRA) is a cell surface inhibitory receptor that was recently suggested to be involved in AD pathogenesis. In particular, the arginine-to-glycine substitution in position 78 (R78, rs1859788) was shown to be protective against AD. Herpes simplex virus type 1 (HSV-1) infection is suspected as well to be involved in AD. Interestingly, HSV-1 uses PILRA to infect cells, and HSV-1 infects more efficiently PIRLA G78 compared to R78 macrophages. We analyzed PILRA rs1859788 polymorphism and HSV-1 humoral immune responses in AD (n = 61) and MCI patients (n = 48), and in sex and age matched healthy controls (HC; n = 57). The rs1859788 PILRA genotype distribution was similar among AD, MCI and HC; HSV-1 antibody (Ab) titers were increased in AD and MCI compared to HC (p < 0.05 for both comparisons). Notably, HSV-1-specific IgG1 were significantly increased in AD patients carrying PILRA R78 rs1859788 AA than in those carrying G78 AG or GG (p = 0.01 for both comparisons), and the lowest titers of HSV-1-specific IgG1 were observed in rs1859788 GG AD. HSV-1 IgG are increased in AD patients with the protective R78 PILRA genotype. Because in AD patients brain atrophy is inversely correlated with HSV-1-specific IgG titers, results herein suggest a possible link between two important genetic and infective factors suspected to be involved in AD pathogenesis.

Correction to: The diagnosis and treatment of urogenital schistosomiasis in Italy in a retrospective cohort of immigrants from Sub-Saharan Africa.

The original version of this article unfortunately contained a mistake. The given name and family name of Filippo Parretti was transposed in the original publication. The correct name is as shown above.

The diagnosis and treatment of urogenital schistosomiasis in Italy in a retrospective cohort of immigrants from Sub-Saharan Africa.

OBJECTIVES: To evaluate ultrasound and praziquantel to, respectively, assess and reduce urogenital schistosomiasis (UGS)-associated morbidity in migrants from Sub-Saharan Africa (SSA). METHODS: Migrants from SSA with UGS attending three Italian centres for tropical diseases during 2011-2016 were retrospectively enrolled. Data on clinical symptoms, routine laboratory, parasitological tests, and ultrasound reported as per the WHO-Niamey protocol were collected at baseline and at available follow-up visits after treatment with praziquantel 40 mg/kg/day for 3 days. RESULTS: One hundred and seventy patients with UGS were enrolled and treated with praziquantel. Baseline ultrasonography showed urinary tract abnormalities in 115/169 patients (68%); the mean global Schistosoma haematobium score was 2.29 (SD 2.84, IQR 0-2), the mean urinary bladder intermediate score 1.75 (SD 1.73, IQR 0-2), and the mean upper urinary tract intermediate score 0.54 (SD 2.37, IQR 1-10). Abnormalities were more common among the 111 (65%) who were symptomatic (p < 0.02; OR 2.53; 95% CI 1.19-5.35). Symptoms started in 94/111 (85%) before arriving (median 63 months, IQR 12-119). At follow-up, we observed a significant reduction in the prevalence of UGS-related symptoms, blood, urine, and ultrasound abnormalities. CONCLUSIONS: Our study results support the use of ultrasound and praziquantel for assessing and reducing UGS-associated morbidity in migrants. Health-seeking behaviour, diagnostic, and treatment delays contribute to the advanced pathology and qualified treatment success. To ensure earlier treatment, based on our findings, clinical experience, and available literature, we propose an algorithm for the diagnosis and clinical management of UGS. Multicentre studies are needed to improve the management of subjects with UGS in non-endemic countries.

A simple and universal enzyme-free approach for the detection of multiple microRNAs using a single nanostructured enhancer of surface plasmon resonance imaging.

Here we describe a simple approach for the simultaneous detection of multiple microRNAs (miRNAs) using a single nanostructured reagent as surface plasmon resonance imaging (SPRi) enhancer and without using enzymatic reactions, sequence specific enhancers or multiple enhancing steps as normally reported in similar studies. The strategy involves the preparation and optimisation of neutravidin-coated gold nanospheres (nGNSs) functionalised with a previously biotinylated antibody (Ab) against DNA/RNA hybrids. The Ab guarantees the recognition of any miRNA sequence adsorbed on a surface properly functionalised with different DNA probes; at the same time, gold nanoparticles permit to detect this interaction, thus producing enough SPRi signal even at a low ligand concentration. After a careful optimisation of the nanoenhancer and after its characterisation, the final assay allowed the simultaneous detection of four miRNAs with a limit of detection (LOD) of up to 0.5 pM (equal to 275 attomoles in 500 µL) by performing a single enhancing injection. The proposed strategy shows good signal specificity and permits to discriminate wild-type, single- and triple-mutated sequences much better than non-enhanced SPRi. Finally, the method works properly in complex samples (total RNA extracted from blood) as demonstrated by the detection of four miRNAs potentially related to multiple sclerosis used as case study. This proof-of-concept study confirms that the approach provides the possibility to detect a theoretically unlimited number of miRNAs using a simple protocol and an easily prepared enhancing reagent, and may further facilitate the development of affordable multiplexing miRNA screening for clinical purposes.

Acute penile trauma: imaging features in the emergency setting.

In an emergency department, penile traumas are uncommon and a prompt diagnosis is necessary. Penile injury may result from penetrating and non-penetrating trauma. Non-penetrating injuries can produce cavernosal hematomas or fractures: if not treated promptly, these lesions can result in fibrosis or erectile dysfunction. Penile traumatic lesions need a clinical approach first, but a radiological study is often required: ultrasonography with color and spectral Doppler study is usually the first approach. In some cases, magnetic resonance imaging may be performed to better recognize even small discontinuity of the tunica albuginea. Radiologists have to be aware of the various radiological patterns of penile traumatic lesions, in order to establish a prompt and correct diagnosis.

HLA alleles modulate EBV viral load in multiple sclerosis.

BACKGROUND: The etiopathology of multiple sclerosis (MS) is believed to include genetic and environmental factors. Human leukocyte antigen (HLA) alleles, in particular,  are associated with disease susceptibility, whereas Epstein Barr Virus (EBV) infection has long been suspected to play a role in disease pathogenesis. The aim of the present study is to evaluate correlations between HLA alleles and EBV infection in MS. METHODS: HLA alleles, EBV viral load (VL) and serum anti-EBV antibody titers were evaluated in EBV-seropositive MS patients (N = 117) and age- and sex-matched healthy controls (HC; N = 89). RESULTS: Significantly higher DNA viral loads (p = 0.048) and EBNA-1 antibody titer (p = 0.0004) were seen in MS compared to HC. EBV VL was higher in HLA-B*07+ (p = 0.02) and HLA-DRB1*15+ (p = 0.02) MS patients, whereas it was lower in HLA-A*02+ (p = 0.04) subjects. EBV VL was highest in HLA-A*02-/B*07+/DRB1*15+ patients and lowest in HLA-A*A02+/B*07-/DRB1*15- individuals (p < 0.0001). HLA-B*07 resulted the most associated allele to EBV VL after multiple regression analysis considering altogether the three alleles, (p = 0.0001). No differences were observed in anti-EBV antibody titers in relationship with HLA distribution. CONCLUSIONS: Host HLA-B*07 allele influence EBV VL in MS. As HLA-class I molecules present antigens to T lymphocytes and initiate immune response against viruses, these results could support a role for EBV in MS.

NCAM1 is the Target of miRNA-572: Validation in the Human Oligodendroglial Cell Line.

The neural cell adhesion molecule 1 (NCAM1) is a fundamental protein in cell-cell interaction and in cellular developmental processes, and its dysregulation is involved in a number of diseases including multiple sclerosis. Studies in rats suggest that the modulation of NCAM1 expression is regulated by miRNA-572, but no data are available confirming such interaction in the human system. We analyzed whether this is the case using a human oligodendroglial cell line (MO3.13). MO3.13 cells were transfected with miRNA-572 mimic and inhibitor separately; NCAM1 mRNA and protein expression levels were analyzed at different time points after transfection. Results indicated that NCAM1 expression is increased after transfection with miRNA-572 inhibitor, whereas it is decreased after transfection with the mimic (p < 0.005). The interaction between NCAM1 and miRNA-572 was subsequently confirmed in a Vero cell line that does not express NCAM1, by luciferase assay after transfection with NCAM1. These results confirm that miRNA-572 regulates NCAM1 and for the first time demonstrate that this interaction regulates NCAM1 expression in human cells. Data herein also support the hypothesis that miRNA-572 is involved in diseases associated with NCAM1 deregulation, suggesting its possible use as a biomarker in these diseases.

High avidity HSV-1 antibodies correlate with absence of amnestic Mild Cognitive Impairment conversion to Alzheimer's disease.

Amnestic Mild Cognitive Impairment (aMCI) is an alteration in cognitive abilities that can progress to Alzheimer's disease (AD), a condition in which herpes simplex type 1 (HSV-1) infection might play a pathogenetic role. Prognostic indexes capable of predicting aMCI conversion to AD are only partially understood. The objective of the present work is to verify whether HSV-1 immune responses is involved in conversion of aMCI to AD and correlate with grey matter brain morphometry. Two homogeneous groups of individuals who did or did not convert to AD over a 24-months period were selected after retrospective analysis of a cohort of patients with a diagnosis of aMCI. The selection of subjects was based on: a) clinical follow-up; b) neurocognitive evaluation at baseline and after 24months; c) availability of serum and DNA samples at baseline. 36 aMCI individuals, 21 of whom did (aMCI-converters) and 15 of whom did not (aMCI-non-converters) convert to AD, were included in the study. HSV-1 antibody (Ab) titers, avidity index and APOE genotyping were performed in all the enrolled individuals at baseline. Brain magnetic resonance imaging (MRI) by 1.5T scanner results at baseline were available as well in most (29/36) of these individuals. HSV-1-specific Ab titers were increased at baseline in aMCI-non-converters, and the avidity of these Ab was significantly higher in aMCI-non-converter compared to aMCI-converter (p=0.0018). Receiver operating characteristics analysis showed that HSV-1 avidity had a predictive value in distinguishing between aMCI-non-converters and aMCI-converters (p<0.0001). Notably, a positive correlation was detected as well between HSV-1 antibody titers and MRI-evaluated cortical volumes in the left hippocampus and amigdala (pcorr<0.05). In conclusion, stronger HSV-1-specific humoral responses associate with protection against AD conversion and better-preserved cortical volumes. These results reinforce the hypothesis for a role for HSV-1 in the pathogenesis of AD.