Publications by authors named "Arianna Sala"

43 Publications

virucidal efficacy of a dry steam disinfection system against Human Coronavirus, Human Influenza Virus, and Echovirus.

J Occup Environ Hyg 2021 Oct 20:1-6. Epub 2021 Oct 20.

Department of Surgery Medicine Dentistry and Morphological Sciences with an Interest in Transplant Oncology, University of Modena and Reggio Emilia, Modena, Italy.

This study was aimed to assess the efficacy of dry steam in inactivating Human Coronavirus OC43 (HCoV-OC43) as surrogate of SARS-CoV-2, Human Influenza Virus A/H1N1/WSN/33 and Echovirus 7 on stainless steel, polypropylene, and cotton. The virus models were chosen on the basis of their transmission route and environmental resistance. Tests were carried out under a laminar flow cabinet, where two panels of each material were contaminated with a viral suspension. The inocula were left to dry and then the virus on untreated panel (control) was collected by swabbing in order to determine the initial titer. The other panel was treated using a professional vacuum cleaner equipped with a dry steam generator. Dry steam is generated in a boiler where tap water is heated up to 155 °C at 5.5 bar pressure and then during the passage along the flexible hose the temperature decreases to a value between 100 °C and 110 °C at the output. The dry steam was applied for four sec with a window wiper on metal and plastic panels or a brush covered by a microfiber cap on cotton, simulating the steam application during routine cleaning. After the treatment, infectious virus possibly remained on the surface was collected following the same swabbing procedure applied for controls. HCoV-OC43 and Echovirus 7 were titrated by end-point method on HCT-8 line cells and Vero cells, respectively, while Human Influenza Virus was quantified by plaque reduction assay on MDCK cells. Dry steam resulted effective against the three viruses on all tested materials, achieving a mean Log reduction factor ≥4 in viral titer of treated samples compared with controls according to UNI EN 14476:2019. Thus, dry steam may be proposed as an ease to use, effective, fast, and nontoxic alternative to chemicals for surface disinfection without damaging materials. Therefore, this device could be employed not only in healthcare facilities but also in occupational, domestic, and community settings, with advantages for environment and human health.
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http://dx.doi.org/10.1080/15459624.2021.1989442DOI Listing
October 2021

Static versus Functional PET: Making Sense of Metabolic Connectivity.

Cereb Cortex 2021 Aug 19. Epub 2021 Aug 19.

Department of Nuclear Medicine, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich 81675, Germany.

Recently, Jamadar et al. (2021, Metabolic and hemodynamic resting-state connectivity of the human brain: a high-temporal resolution simultaneous BOLD-fMRI and FDG-fPET multimodality study. Cereb Cortex. 31(6), 2855-2867) compared the patterns of brain connectivity or covariance as obtained from 3 neuroimaging measures: 1) functional connectivity estimated from temporal correlations in the functional magnetic resonance imaging blood oxygen level-dependent signal, metabolic connectivity estimated, 2) from temporal correlations in 16-s frames of dynamic [18F]-fluorodeoxyglucose-positron emission tomography (FDG-PET), which they designate as functional FDG-PET (fPET), and 3) from intersubject correlations in static FDG-PET images (sPET). Here, we discuss a number of fundamental issues raised by the Jamadar study. These include the choice of terminology, the interpretation of cross-modal findings, the issue of group- to single-subject level inferences, and the meaning of metabolic connectivity as a biomarker. We applaud the methodological approach taken by the authors, but wish to present an alternative perspective on their findings. In particular, we argue that sPET and fPET can both provide valuable information about brain connectivity. Certainly, resolving this conundrum calls for further experimental and theoretical efforts to advance the developing framework of PET-based brain connectivity indices.
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http://dx.doi.org/10.1093/cercor/bhab271DOI Listing
August 2021

Validation of FDG-PET datasets of normal controls for the extraction of SPM-based brain metabolism maps.

Eur J Nucl Med Mol Imaging 2021 07 10;48(8):2486-2499. Epub 2021 Jan 10.

Vita-Salute San Raffaele University, Milan, Italy.

Purpose: An appropriate healthy control dataset is mandatory to achieve good performance in voxel-wise analyses. We aimed at evaluating [18F]FDG PET brain datasets of healthy controls (HC), based on publicly available data, for the extraction of voxel-based brain metabolism maps at the single-subject level.

Methods: Selection of HC images was based on visual rating, after Cook's distance and jack-knife analyses, to exclude artefacts and/or outliers. The performance of these HC datasets (ADNI-HC and AIMN-HC) to extract hypometabolism patterns in single patients was tested in comparison with the standard reference HC dataset (HSR-HC) by means of Dice score analysis. We evaluated the performance and comparability of the different HC datasets in the assessment of single-subject SPM-based hypometabolism in three independent cohorts of patients, namely, ADD, bvFTD and DLB.

Results: Two-step Cook's distance analysis and the subsequent jack-knife analysis resulted in the selection of n = 125 subjects from the AIMN-HC dataset and n = 75 subjects from the ADNI-HC dataset. The average concordance between SPM hypometabolism t-maps in the three patient cohorts, as obtained with the new datasets and compared to the HSR-HC standard reference dataset, was 0.87 for the AIMN-HC dataset and 0.83 for the ADNI-HC dataset. Pattern expression analysis revealed high overall accuracy (> 80%) of the SPM t-map classification according to different statistical thresholds and sample sizes.

Conclusions: The applied procedures ensure validity of these HC datasets for the single-subject estimation of brain metabolism using voxel-wise comparisons. These well-selected HC datasets are ready-to-use in research and clinical settings.
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http://dx.doi.org/10.1007/s00259-020-05175-1DOI Listing
July 2021

Longitudinal pathways of cerebrospinal fluid and positron emission tomography biomarkers of amyloid-β positivity.

Mol Psychiatry 2020 Dec 11. Epub 2020 Dec 11.

Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.

Mismatch between CSF and PET amyloid-β biomarkers occurs in up to ≈20% of preclinical/prodromal Alzheimer's disease individuals. Factors underlying mismatching results remain unclear. In this study we hypothesized that CSF/PET discordance provides unique biological/clinical information. To test this hypothesis, we investigated non-demented and demented participants with CSF amyloid-β and [18F]Florbetapir PET assessments at baseline (n = 867) and at 2-year follow-up (n = 289). Longitudinal trajectories of amyloid-β positivity were tracked simultaneously for CSF and PET biomarkers. In the longitudinal cohort (n = 289), we found that participants with normal CSF/PET amyloid-β biomarkers progressed more frequently toward CSF/PET discordance than to full CSF/PET positivity (χ = 5.40; p < 0.05). Progression to CSF+/PET+ status was ten times more frequent in cases with discordant biomarkers, as compared to csf-/pet- cases (χ = 18.86; p < 0.001). Compared to the CSF+/pet- group, the csf-/PET+ group had lower APOE-ε4ε4 prevalence (χ = 197; p < 0.001; n = 867) and slower rate of brain amyloid-β accumulation (F = 12.76; p < 0.001; n = 608). These results demonstrate that biomarker discordance is a typical stage in the natural history of amyloid-β accumulation, with CSF or PET becoming abnormal first and not concurrently. Therefore, biomarker discordance allows for identification of individuals with elevated risk of progression toward fully abnormal amyloid-β biomarkers, with subsequent risk of neurodegeneration and cognitive decline. Our results also suggest that there are two alternative pathways ("CSF-first" vs. "PET-first") toward established amyloid-β pathology, characterized by different genetic profiles and rates of amyloid-β accumulation. In conclusion, CSF and PET amyloid-β biomarkers provide distinct information, with potential implications for their use as biomarkers in clinical trials.
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http://dx.doi.org/10.1038/s41380-020-00950-wDOI Listing
December 2020

Impaired metabolic brain networks associated with neurotransmission systems in the α-synuclein spectrum.

Parkinsonism Relat Disord 2020 12 21;81:113-122. Epub 2020 Oct 21.

School of Psychology, Vita-Salute San Raffaele University, Milan, Italy; In Vivo Human Molecular and Structural Neuroimaging Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; Nuclear Medicine Unit, San Raffaele Hospital, Milan, Italy. Electronic address:

Introduction: While the involvement of multiple neurotransmitter systems in α-synucleinopathies is reported, a comprehensive study on their metabolic connectivity reconfiguration in the preclinical and clinical disease-spectrum is lacking. We aimed to investigate shared and disease-specific neural vulnerabilities of the nigro-striato-cortical dopaminergic, noradrenergic and cholinergic networks within the α-synuclein-spectrum, by means of metabolic connectivity approach.

Methods: We collected 34 polysomnography-confirmed isolated REM sleep behaviour disorder (iRBD) subjects, 29 idiopathic Parkinson's disease (PD) patients without dementia, 30 patients with probable dementia with Lewy bodies (DLB), and 50 healthy controls for comparisons. Neurotransmission networks' analyses were performed through multivariate partial correlations based on FDG-PET brain metabolic data.

Results: We found: a) the nigro-striato-cortical dopaminergic network with a limited reconfiguration in individuals with iRBD, but moderate-to-severe alterations in patients with DLB and PD; b) an extended connectivity alteration of the noradrenergic network in all groups; c) changes within the cholinergic networks connectivity in the whole disease-spectrum, with some differences: PD with only moderate connectivity reconfiguration and DLB with the most severe alterations, some of these shared with iRBD.

Conclusions: Synucleinopathies can be considered multisystem disorders, with common and disease-specific neurotransmission networks reconfigurations. The present findings indicate dopaminergic connectivity alterations only when associated with parkinsonism, a very early involvement of noradrenergic networks, occurring in both the iRBD and in symptomatic PD/DLB patients and cholinergic alterations with disease-specific vulnerabilities shared by iRBD and DLB. The latter finding may represent an early biomarker of disease progression to dementia.
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http://dx.doi.org/10.1016/j.parkreldis.2020.10.036DOI Listing
December 2020

Perinuclear Anti-Neutrophil Cytoplasmic Antibodies (pANCA) Impair Neutrophil Candidacidal Activity and Are Increased in the Cellular Fraction of Vaginal Samples from Women with Vulvovaginal Candidiasis.

J Fungi (Basel) 2020 Oct 16;6(4). Epub 2020 Oct 16.

Department of Surgical, Medical, Dental and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio, 41125 Emilia, Modena, Italy.

Vulvovaginal candidiasis (VVC) is primarily caused by and affects 75% of childbearing age women. Although can colonize asymptomatically, disease is associated with an increased burden, a loss of epithelial tolerance and a breakdown in vaginal microbiota homeostasis. VVC symptoms have been ascribed to a powerful inflammatory response associated with the infiltration of non-protective neutrophils (PMN). Here, we compared the immunological characteristics of vaginal fluids and cellular protein extracts obtained from 28 VVC women and from 23 healthy women colonized by spp. We measured the levels of antibodies against fungal antigens and human autoantigens (anti- antibodies (ASCA), germ tube antibodies (CAGTAs) and perinuclear anti-neutrophil cytoplasmic antibodies (pANCA)), in addition to other immunological markers. Our results show that the pANCA levels detected in the cellular protein extracts from the vaginal fluids of symptomatic women were significantly higher than those obtained from healthy colonized women. Consistent with a potential physiologically relevant role for this pANCA, we found that specific anti-myeloperoxidase antibodies could completely neutralize the killing capacity of polymorphonuclear cells. Collectively, this preliminary study suggests for the first time that pANCA are found in the pathogenic vaginal environment and can promptly impair neutrophil function against , potentially preventing a protective response.
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http://dx.doi.org/10.3390/jof6040225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712103PMC
October 2020

Neural correlates of naming errors across different neurodegenerative diseases: An FDG-PET study.

Neurology 2020 11 1;95(20):e2816-e2830. Epub 2020 Oct 1.

From the Faculty of Psychology (E.C., F.C., C.G., S.F.C.), Institute for Advanced Studies, IUSS, Pavia; Nuclear Medicine Unit (C.P., V.B., A.P.), Department of Experimental and Clinical Biomedical Sciences, and NEUROFARBA, Department of Neuroscience, Psychology, Drug Research and Child Health (S.S.), University of Florence; Nuclear Medicine Unit (L.P., A.S., D.P.), IRCCS San Raffaele Hospital, Milan; Faculty of Psychology (V.E., A.S., D.P.), Vita-Salute San Raffaele University, Milan; Department of Neurology and INSPE (M.F., G.M.), San Raffaele Scientific Institute, Milan; Clinical Neuroscience Department (S.I.), San Raffaele Turro Hospital, Milan; IRCCS Fondazione Don Carlo Gnocchi (S.S.), Florence, and IRCCS Fondazione Istituto Neurologico Casimiro Mondino (S.F.C.), Pavia, Italy.

Objective: To investigate the types of errors produced in a picture naming task by patients with neurodegenerative dementia due to different etiologies and their neural correlates.

Methods: The same standardized picture naming test was administered to a consecutive sample of patients (n = 148) who had been studied with [F] FDG-PET. The errors were analyzed in 3 categories (visual, semantic, and phonologic). The PET data were analyzed using an optimized single-subject procedure, and the statistical parametric mapping multiple regression design was used to explore the correlation between each type of error and brain hypometabolism in the whole group. Metabolic connectivity analyses were run at the group level on 7 left hemisphere cortical areas corresponding to an a priori defined naming network.

Results: Semantic errors were predominant in most patients, independent of clinical diagnosis. In the whole group analysis, visual errors correlated with hypometabolism in the right inferior occipital lobe and in the left middle occipital lobe. Semantic errors correlated with hypometabolism in the left fusiform gyrus, the inferior and middle temporal gyri, and the temporal pole. Phonologic errors were associated with hypometabolism in the left superior and middle temporal gyri. Both positive (occipital-posterior fusiform) and negative (anterior fusiform gyrus and the superior anterior temporal lobe) connectivity changes were associated with semantic errors.

Conclusions: Naming errors reflect the dysfunction of separate stages of the naming process and are specific markers for different patterns of brain involvement. These correlations are not limited to primary progressive aphasia but extend to other neurodegenerative dementias.
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http://dx.doi.org/10.1212/WNL.0000000000010967DOI Listing
November 2020

Clinical impact of F-FDG-PET among memory clinic patients with uncertain diagnosis.

Eur J Nucl Med Mol Imaging 2021 02 31;48(2):612-622. Epub 2020 Jul 31.

Department of Neurobiology, Care Sciences and Society, Division of Clinical Geriatrics, Center for Alzheimer Research, Karolinska Institutet, 141 52, Stockholm, Sweden.

Purpose: To assess the clinical impact and incremental diagnostic value of F-fluorodeoxyglucose (FDG-PET) among memory clinic patients with uncertain diagnosis.

Methods: The study population consisted of 277 patients who, despite extensive baseline cognitive assessment, MRI, and CSF analyses, had an uncertain diagnosis of mild cognitive impairment (MCI) (n = 177) or dementia (n = 100). After baseline diagnosis, each patient underwent an FDG-PET, followed by a post-FDG-PET diagnosis formulation. We evaluated (i) the change in diagnosis (baseline vs. post-FDG-PET), (ii) the change in diagnostic accuracy when comparing each baseline and post-FDG-PET diagnosis to a long-term follow-up (3.6 ± 1.8 years) diagnosis used as reference, and (iii) comparative FDG-PET performance testing in MCI and dementia conditions.

Results: FDG-PET led to a change in diagnosis in 86 of 277 (31%) patients, in particular in 57 of 177 (32%) MCI and in 29 of 100 (29%) dementia patients. Diagnostic change was greater than two-fold in the sub-sample of cases with dementia "of unclear etiology" (change in diagnosis in 20 of 32 (63%) patients). In the dementia group, after results of FDG-PET, diagnostic accuracy improved from 77 to 90% in Alzheimer's disease (AD) and from 85 to 94% in frontotemporal lobar degeneration (FTLD) patients (p < 0.01). FDG-PET performed better in dementia than in MCI (positive likelihood ratios >5 and < 5, respectively).

Conclusion: Within a selected clinical population, FDG-PET has a significant clinical impact, both in early and differential diagnosis of uncertain dementia. FDG-PET provides significant incremental value to detect AD and FTLD over a clinical diagnosis of uncertain dementia.
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http://dx.doi.org/10.1007/s00259-020-04969-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835147PMC
February 2021

CSF p-tau/Aβ ratio and brain FDG-PET may reliably detect MCI "imminent" converters to AD.

Eur J Nucl Med Mol Imaging 2020 12 15;47(13):3152-3164. Epub 2020 May 15.

Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Purpose: To know whether mild cognitive impairment (MCI) patients will develop Alzheimer's disease (AD) dementia in very short time or remain stable is of crucial importance, also considering new experimental drugs usually tested within very short time frames. Here we combined cerebrospinal fluid (CSF) AD biomarkers and a neurodegeneration marker such as brain FDG-PET to define an objective algorithm, suitable not only to reliably detect MCI converters to AD dementia but also to predict timing of conversion.

Methods: We included 77 consecutive MCI patients with neurological/neuropsychological assessment, brain 18F-FDG-PET and CSF analysis available at diagnosis and a neuropsychological/neurological evaluation every 6 months for a medium- to a long-term follow-up (at least 2 and up to 8 years). Binomial logistic regression models and Kaplan-Meier survival analyses were performed to determine the best biomarker (or combination of biomarkers) in detecting MCI converters to AD dementia and then, among the converters, those who converted in short time frames.

Results: Thirty-five out of 77 MCI patients (45%) converted to AD dementia, with an average conversion time since MCI diagnosis of 26.07 months. CSF p-tau/Aβ42 was the most accurate predictor of conversion from MCI to AD dementia (82.9% sensitivity; 90% specificity). CSF p-tau/Aβ42 and FDG-PET-positive MCIs converted to AD dementia significantly earlier than the CSF-positive-only MCIs (median conversion time, 17.1 vs 31.3 months).

Conclusions: CSF p-tau/Aβ42 ratio and brain FDG-PET may predict both occurrence and timing of MCI conversion to full-blown AD dementia. MCI patients with both biomarkers suggestive for AD will likely develop an AD dementia shortly, thus representing the ideal target for any new experimental drug requiring short periods to be tested for.
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http://dx.doi.org/10.1007/s00259-020-04853-4DOI Listing
December 2020

In vivo MRI Structural and PET Metabolic Connectivity Study of Dopamine Pathways in Alzheimer's Disease.

J Alzheimers Dis 2020 ;75(3):1003-1016

Vita-Salute San Raffaele University, Milan, Italy.

Background: Alzheimer's disease (AD) is characterized by an involvement of brain dopamine (DA) circuitry, the presence of which has been associated with emergence of both neuropsychiatric symptoms and cognitive deficits.

Objective: In order to investigate whether and how the DA pathways are involved in the pathophysiology of AD, we assessed by in vivo neuroimaging the structural and metabolic alterations of subcortical and cortical DA pathways and targets.

Methods: We included 54 healthy control participants, 53 amyloid-positive subjects with mild cognitive impairment due to AD (MCI-AD), and 60 amyloid-positive patients with probable dementia due to AD (ADD), all with structural 3T MRI and 18F-FDG-PET scans. We assessed MRI-based gray matter reductions in the MCI-AD and ADD groups within an anatomical a priori-defined Nigrostriatal and Mesocorticolimbic DA pathways, followed by 18F-FDG-PET metabolic connectivity analyses to evaluate network-level metabolic connectivity changes.

Results: We found significant tissue loss in the Mesocorticolimbic over the Nigrostriatal pathway. Atrophy was evident in the ventral striatum, orbitofrontal cortex, and medial temporal lobe structures, and already plateaued in the MCI-AD stage. Degree of atrophy in Mesocorticolimbic regions positively correlated with the severity of depression, anxiety, and apathy in MCI-AD and ADD subgroups. Additionally, we observed significant alterations of metabolic connectivity between the ventral striatum and fronto-cingulate regions in ADD, but not in MCI-AD. There were no metabolic connectivity changes within the Nigrostriatal pathway.

Conclusion: Our cross-sectional data support a clinically-meaningful, yet stage-dependent, involvement of the Mesocorticolimbic system in AD. Longitudinal and clinical correlation studies are needed to further establish the relevance of DA system involvement in AD.
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http://dx.doi.org/10.3233/JAD-190954DOI Listing
May 2021

Brain metabolic signatures across the Alzheimer's disease spectrum.

Eur J Nucl Med Mol Imaging 2020 02 7;47(2):256-269. Epub 2019 Dec 7.

Vita-Salute San Raffaele University, Milan, Italy.

Purpose: Given the challenges posed by the clinical diagnosis of atypical Alzheimer's disease (AD) variants and the limited imaging evidence available in the prodromal phases of atypical AD, we assessed brain hypometabolism patterns at the single-subject level in the AD variants spectrum. Specifically, we tested the accuracy of [F]FDG-PET brain hypometabolism, as a biomarker of neurodegeneration, in supporting the differential diagnosis of atypical AD variants in individuals with dementia and mild cognitive impairment (MCI).

Methods: We retrospectively collected N = 67 patients with a diagnosis of typical AD and AD variants according to the IWG-2 criteria (22 typical-AD, 15 frontal variant-AD, 14 logopenic variant-AD and 16 posterior variant-AD). Further, we included N = 11 MCI subjects, who subsequently received a clinical diagnosis of atypical AD dementia at follow-up (21 ± 11 months). We assessed brain hypometabolism patterns at group- and single-subject level, using W-score maps, measuring their accuracy in supporting differential diagnosis. In addition, the regional prevalence of cerebral hypometabolism was computed to identify the most vulnerable core regions.

Results: W-score maps pointed at distinct, specific patterns of hypometabolism in typical and atypical AD variants, confirmed by the assessment of core hypometabolism regions, showing that each variant was characterized by specific regional vulnerabilities, namely in occipital, left-sided, or frontal brain regions. ROC curves allowed discrimination among AD variants and also non-AD dementia (i.e., dementia with Lewy bodies and behavioral variant of frontotemporal dementia), with high sensitivity and specificity. Notably, we provide preliminary evidence that, even in AD prodromal phases, these specific [F]FDG-PET patterns are already detectable and predictive of clinical progression to atypical AD variants at follow-up.

Conclusions: The AD variant-specific patterns of brain hypometabolism, highly consistent at single-subject level and already evident in the prodromal stages, represent relevant markers of disease neurodegeneration, with highly supportive diagnostic and prognostic role.
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http://dx.doi.org/10.1007/s00259-019-04559-2DOI Listing
February 2020

High body mass index, brain metabolism and connectivity: an unfavorable effect in elderly females.

Aging (Albany NY) 2019 10 9;11(19):8573-8586. Epub 2019 Oct 9.

Vita-Salute San Raffaele University, Milan, Italy.

There are reported gender differences in brain connectivity associated with obesity. In the elderlies, the neural endophenotypes of obesity are yet to be elucidated. We aim at exploring the brain metabolic and connectivity correlates to different BMI levels in elderly individuals, taking into account gender as variable of interest.We evaluated the association between BMI, brain metabolism and connectivity, in elderly females and males, by retrospectively collecting a large cohort of healthy elderly subjects (N=222; age=74.03±5.88 [61.2-85.9] years; M/F=115/107; BMI=27.00±4.02 [19.21-38.79] kg/m). Subjects underwent positron emission tomography with [18F]FDG. We found that, in females, high BMI was associated with increased brain metabolism in the orbitofrontal cortex (R=0.44; p<0.001). A significant BMI-by-gender interaction was present (F=7.024, p=0.009). We also revealed an altered connectivity seeding from these orbitofrontal regions, namely expressing as a decreased connectivity in crucial control/decision making circuits, and as an abnormally elevated connectivity in reward circuits, only in females. Our findings support a link between high BMI and altered brain metabolism and neural connectivity, only in elderly females. These findings indicate a strong gender effect of high BMI and obesity that brings to considerations for medical practice and health policy.
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http://dx.doi.org/10.18632/aging.102347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814611PMC
October 2019

Variant-specific vulnerability in metabolic connectivity and resting-state networks in behavioural variant of frontotemporal dementia.

Cortex 2019 11 10;120:483-497. Epub 2019 Aug 10.

Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy; Nuclear Medicine Unit, San Raffaele Hospital, Milan, Italy. Electronic address:

Brain connectivity measures represent candidate biomarkers of neuronal dysfunction in neurodegenerative diseases. Previous findings suggest that the behavioural variant of frontotemporal dementia (bvFTD) and its variants (i.e., frontal and temporo-limbic) may be related to the vulnerability of distinct functional connectivity networks. In this study, 82 bvFTD patients were included, and two patient groups were identified as frontal and temporo-limbic bvFTD variants. Two advanced multivariate analytical approaches were applied to FDG-PET data, i.e., sparse inverse covariance estimation (SICE) method and seed-based interregional correlation analysis (IRCA). These advanced methods allowed the assessment of (i) the whole-brain metabolic connectivity, without any a priori assumption, and (ii) the main brain resting-state networks of crucial relevance for cognitive and behavioural functions. In the whole bvFTD group, we found dysfunctional connectivity patterns in frontal and limbic regions and in all major brain resting-state networks as compared to healthy controls (HC N = 82). In the two bvFTD variants, SICE and IRCA analyses identified variant-specific reconfigurations of whole-brain connectivity and resting-state networks. Specifically, the frontal bvFTD variant was characterised by metabolic connectivity alterations in orbitofrontal regions and anterior resting-state networks, while the temporo-limbic bvFTD variant was characterised by connectivity alterations in the limbic and salience networks. These results highlight different neural vulnerabilities in the two bvFTD variants, as shown by the dysfunctional connectivity patterns, with relevance for the different neuropsychological profiles. This new evidence provides further insight in the variability of bvFTD and may contribute to a more accurate classification of these patients.
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http://dx.doi.org/10.1016/j.cortex.2019.07.018DOI Listing
November 2019

The CSF p-tau181/Aβ42 Ratio Offers a Good Accuracy "In Vivo" in the Differential Diagnosis of Alzheimer's Dementia.

Curr Alzheimer Res 2019 ;16(7):587-595

Department of Neurology, INSPE, Vita-Salute University and IRCCS-San Raffaele Hospital, Milan, Italy.

Background: The incoming disease-modifying therapies against Alzheimer's disease (AD) require reliable diagnostic markers to correctly enroll patients all over the world. CSF AD biomarkers, namely amyloid-β 42 (Aβ42), total tau (t-tau), and tau phosphorylated at threonine 181 (p-tau181), showed good diagnostic accuracy in detecting AD pathology, but their real usefulness in daily clinical practice is still a matter of debate. Therefore, further validation in complex clinical settings, that is patients with different types of dementia, is needed to uphold their future worldwide adoption.

Methods: We measured CSF AD biomarkers' concentrations in a sample of 526 patients with a clinical diagnosis of dementia (277 with AD and 249 with Other Type of Dementia, OTD). Brain FDG-PET was also considered in a subsample of 54 patients with a mismatch between the clinical diagnosis and the CSF findings.

Results: A p-tau181/Aβ42 ratio higher than 0.13 showed the best diagnostic performance in differentiating AD from OTD (86% accuracy index, 74% sensitivity, 81% specificity). In cases with a mismatch between clinical diagnosis and CSF findings, brain FDG-PET partially agreed with the p-tau181/Aβ42 ratio, thus determining an increase in CSF accuracy.

Conclusion: The p-tau181/Aβ42 ratio alone might reliably detect AD pathology in heterogeneous samples of patients suffering from different types of dementia. It might constitute a simple, cost-effective and reproducible in vivo proxy of AD suitable to be adopted worldwide not only in daily clinical practice but also in future experimental trials, to avoid the enrolment of misdiagnosed AD patients.
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http://dx.doi.org/10.2174/1567205016666190725150836DOI Listing
September 2020

Vulnerability of multiple large-scale brain networks in dementia with Lewy bodies.

Hum Brain Mapp 2019 10 19;40(15):4537-4550. Epub 2019 Jul 19.

Vita-Salute San Raffaele University, Milan, Italy.

Aberrations of large-scale brain networks are found in the majority of neurodegenerative disorders. The brain connectivity alterations underlying dementia with Lewy bodies (DLB) remain, however, still elusive, with contrasting results possibly due to the pathological and clinical heterogeneity characterizing this disorder. Here, we provide a molecular assessment of brain network alterations, based on cerebral metabolic measurements as proxies of synaptic activity and density, in a large cohort of DLB patients (N = 72). We applied a seed-based interregional correlation analysis approach (p < .01, false discovery rate corrected) to evaluate large-scale resting-state networks' integrity and their interactions. We found both local and long-distance metabolic connectivity alterations, affecting the posterior cortical networks, that is, primary visual and the posterior default mode network, as well as the limbic and attention networks, suggesting a widespread derangement of the brain connectome. Notably, patients with the lowest visual and attention cognitive scores showed the most severe connectivity derangement in regions of the primary visual network. In addition, network-level alterations were differentially associated with the core clinical manifestations, namely, hallucinations with more severe metabolic dysfunction of the attention and visual networks, and rapid eye movement sleep behavior disorder with alterations of connectivity of attention and subcortical networks. These multiple network-level vulnerabilities may modulate the core clinical and cognitive features of DLB and suggest that DLB should be considered as a complex multinetwork disorder.
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http://dx.doi.org/10.1002/hbm.24719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917031PMC
October 2019

Brain Molecular Connectivity in Neurodegenerative Diseases: Recent Advances and New Perspectives Using Positron Emission Tomography.

Front Neurosci 2019 14;13:617. Epub 2019 Jun 14.

Division of Neuroscience, Faculty of Psychology, San Raffaele Scientific Institute (IRCCS), Milan, Italy.

Positron emission tomography (PET) represents a unique molecular tool to get access to a wide spectrum of biological and neuropathological processes, of crucial relevance for neurodegenerative conditions. Although most PET findings are based on massive univariate approaches, in the last decade the increasing interest in multivariate methods has paved the way to the assessment of unexplored cerebral features, spanning from resting state brain networks to whole-brain connectome properties. Currently, the combination of molecular neuroimaging techniques with multivariate connectivity methods represents one of the most powerful, yet still emerging, approach to achieve novel insights into the pathophysiology of neurodegenerative diseases. In this review, we will summarize the available evidence in the field of PET molecular connectivity, with the aim to provide an overview of how these studies may increase the understanding of the pathogenesis of neurodegenerative diseases, over and above "traditional" structural/functional connectivity studies. Considering the available evidence, a major focus will be represented by molecular connectivity studies using [18F]FDG-PET, today applied in the major neuropathological spectra, from amyloidopathies and tauopathies to synucleinopathies and beyond. Pioneering studies using PET tracers targeting brain neuropathology and neurotransmission systems for connectivity studies will be discussed, their strengths and limitations highlighted with reference to both applied methodology and results interpretation. The most common methods for molecular connectivity assessment will be reviewed, with particular emphasis on the available strategies to investigate molecular connectivity at the single-subject level, of potential relevance for not only research but also diagnostic purposes. Finally, we will highlight possible future perspectives in the field, with reference in particular to newly available PET tracers, which will expand the application of molecular connectivity to new, exciting, unforeseen possibilities.
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http://dx.doi.org/10.3389/fnins.2019.00617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587303PMC
June 2019

Antimicrobial and antibiofilm efficacy of a copper/calcium hydroxide-based endodontic paste against Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans.

Dent Mater J 2019 Jul 29;38(4):591-603. Epub 2019 Jun 29.

Department of Surgical, Medical, Dental and Morphological Sciences with interest in Transplant, Oncological and Regenerative Medicine; University of Modena and Reggio Emilia.

Endodontic biofilm is a microbial community, enclosed in a polymeric matrix of polysaccharide origin where are found pathogens, like bacteria and opportunistic fungi responsible for various endodontic pathologies. As clinical importance is the fact, that biofilm is extremely resistant to common intracanal irrigants, antimicrobial drugs and host immune responses. The aim of this study was to evaluate the in vitro efficacy of a Cu/CaOH-based endodontic paste, against bacteria and fungi, such as Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans. We found that such compound significantly reduced microbial replication time and cell growth. Moreover, biofilm formation and persistence were also affected; treated biofilms showed both a reduced number of cells and levels of released pyoverdine. This study provides the first evidence on effectiveness of this endodontic compound against microbial biofilms. Given its wide range of action, its use in prevention and treatment of the main oral biofilm-associated infections will be discussed.
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http://dx.doi.org/10.4012/dmj.2018-252DOI Listing
July 2019

Predicting long-term clinical stability in amyloid-positive subjects by FDG-PET.

Ann Clin Transl Neurol 2019 Jun 24;6(6):1113-1120. Epub 2019 May 24.

Vita-Salute San Raffaele University Milan Italy.

Imaging biomarkers can be used to screen participants for Alzheimer's disease clinical trials. To test the predictive values in clinical progression of neuropathology change (amyloid-PET) or brain metabolism as neurodegeneration biomarker ([18F]FDG-PET), we evaluated data from  = 268 healthy controls and  = 519 mild cognitive impairment subjects. Despite being a significant risk factor, amyloid positivity was not associated with clinical progression in the majority (≥60%) of subjects. Notably, a negative [18F]FDG-PET scan at baseline strongly predicted clinical stability with high negative predictive values (>0.80) for both groups. We suggest [18F]FDG-PET brain metabolism or other neurodegeneration measures should be coupled to amyloid-PET to exclude clinically stable individuals from clinical trials.
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http://dx.doi.org/10.1002/acn3.782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562030PMC
June 2019

Brain glucose metabolism in Lewy body dementia: implications for diagnostic criteria.

Alzheimers Res Ther 2019 02 23;11(1):20. Epub 2019 Feb 23.

Vita-Salute San Raffaele University, Via Olgettina, 60, Segrate, 20132, Milan, Italy.

Background: [18F]FDG-PET hypometabolism patterns are indicative of different neurodegenerative conditions, even from the earliest disease phase. This makes [18F]FDG-PET a valuable tool in the diagnostic workup of neurodegenerative diseases. The utility of [18F]FDG-PET in dementia with Lewy bodies (DLB) needs further validation by considering large samples of patients and disease comparisons and applying state-of-the-art statistical methods. Here, we aimed to provide an extensive validation of the [18F]FDG-PET metabolic signatures in supporting DLB diagnosis near the first clinical assessment, which is characterized by high diagnostic uncertainty, at the single-subject level.

Methods: In this retrospective study, we included N = 72 patients with heterogeneous clinical classification at entry (mild cognitive impairment, atypical parkinsonisms, possible DLB, probable DLB, and other dementias) and an established diagnosis of DLB at a later follow-up. We generated patterns of [18F]FDG-PET hypometabolism in single cases by using a validated voxel-wise analysis (p < 0.05, FWE-corrected). The hypometabolism patterns were independently classified by expert raters blinded to any clinical information. The final clinical diagnosis at follow-up (2.94 ± 1.39 [0.34-6.04] years) was considered as the diagnostic reference and compared with clinical classification at entry and with [18F]FDG-PET classification alone. In addition, we calculated the diagnostic accuracy of [18F]FDG-PET maps in the differential diagnosis of DLB with Alzheimer's disease dementia (ADD) (N = 60) and Parkinson's disease (PD) (N = 36).

Results: The single-subject [18F]FDG-PET hypometabolism pattern, showing temporo-parietal and occipital involvement, was highly consistent across DLB cases. Clinical classification at entry produced several misclassifications with an agreement of only 61.1% with the diagnostic reference. On the contrary, [18F]FDG-PET hypometabolism maps alone accurately predicted diagnosis of DLB at follow-up (88.9%). The high power of the [18F]FDG-PET hypometabolism signature in predicting the final clinical diagnosis allowed a ≈ 50% increase in accuracy compared to the first clinical assessment alone. Finally, [18F]FDG-PET hypometabolism maps yielded extremely high discriminative power, distinguishing DLB from ADD and PD conditions with an accuracy of > 90%.

Conclusion: The present validation of the diagnostic and prognostic accuracy of the disease-specific brain metabolic signature in DLB at the single-subject level argues for the consideration of [18F]FDG-PET in the early phase of the DLB diagnostic flowchart. The assessment of the [18F]FDG-PET hypometabolism pattern at entry may shorten the diagnostic time, resulting in benefits for treatment options and management of patients.
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http://dx.doi.org/10.1186/s13195-019-0473-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387558PMC
February 2019

Antiviral Activity of Synthetic Peptides Derived from Physiological Proteins.

Intervirology 2018 17;61(4):166-173. Epub 2019 Jan 17.

Department of Diagnostic, Clinic and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy,

Background/aims: New antivirals are needed to supplement or replace currently used drugs. The aim of this study was to evaluate the antiviral activity of synthetic peptides derived from physiological proteins.

Methods: Vero cell monolayers were infected with herpes simplex virus 1, vesicular stomatitis virus, adenovirus, and coxsackievirus B5 strains in the presence of different concentrations of the selected peptides and viral yield was determined by plaque reduction assays to evaluate the antiviral activity of the peptides. Virucidal activity was evaluated by determining the residual infectivity of viral suspensions treated for 1 h with the peptides at the same concentrations as in the viral yield assays.

Results: Among the investigated peptides, the killer peptide proved to exert a considerable antiviral activity against herpes simplex virus, attributable to a direct effect on virus particles, while its derivative K10S showed to be effective against the four investigated virus strains only at the highest concentration tested, yet, the inhibitory effects were only partial.

Conclusion: Overall, initial evidence is provided on the antiviral activity of several peptides, as well as of their derivatives. Further investigation is warranted to ascertain the mechanism of action in order to develop new potential antiviral drugs.
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http://dx.doi.org/10.1159/000494354DOI Listing
May 2019

Testing the diagnostic accuracy of [18F]FDG-PET in discriminating spinal- and bulbar-onset amyotrophic lateral sclerosis.

Eur J Nucl Med Mol Imaging 2019 May 7;46(5):1117-1131. Epub 2019 Jan 7.

Vita-Salute San Raffaele University, Milan, Italy.

Purpose: The role for [18F]FDG-PET in supporting amyotrophic lateral sclerosis (ALS) diagnosis is not fully established. In this study, we aim at evaluating [18F]FDG-PET hypo- and hyper-metabolism patterns in spinal- and bulbar-onset ALS cases, at the single-subject level, testing the diagnostic value in discriminating the two conditions, and the correlations with core clinical symptoms severity.

Methods: We included 95 probable-ALS patients with [18F]FDG-PET scan and clinical follow-up. [18F]FDG-PET images were analyzed with an optimized voxel-based-SPM method. The resulting single-subject SPM-t maps were used to: (a) assess brain regional hypo- and hyper-metabolism; (b) evaluate the accuracy of regional hypo- and hyper metabolism in discriminating spinal vs. bulbar-onset ALS; (c) perform correlation analysis with motor symptoms severity, as measured by ALS-FRS-R.

Results: Primary motor cortex showed the most frequent hypo-metabolism in both spinal-onset (∼57%) and bulbar-onset (∼64%) ALS; hyper-metabolism was prevalent in the cerebellum in both spinal-onset (∼56.5%) and bulbar-onset (∼55.7%) ALS, and in the occipital cortex in bulbar-onset (∼62.5%) ALS. Regional hypo- and hyper-metabolism yielded a very low accuracy (AUC < 0.63) in discriminating spinal- vs. bulbar-onset ALS, as obtained from single-subject SPM-t-maps. Severity of motor symptoms correlated with hypo-metabolism in sensorimotor cortex in spinal-onset ALS, and with cerebellar hyper-metabolism in bulbar-onset ALS.

Conclusions: The high variability in regional hypo- and hyper-metabolism patterns, likely reflecting the heterogeneous pathology and clinical phenotypes, limits the diagnostic potential of [18F]FDG-PET in discriminating spinal and bulbar onset patients.
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http://dx.doi.org/10.1007/s00259-018-4246-2DOI Listing
May 2019

Unfavourable gender effect of high body mass index on brain metabolism and connectivity.

Sci Rep 2018 08 22;8(1):12584. Epub 2018 Aug 22.

Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.

The influence of Body Mass Index (BMI) on neurodegeneration in dementia has yet to be elucidated. We aimed at exploring the effects of BMI levels on cerebral resting-state metabolism and brain connectivity, as crucial measures of synaptic function and activity, in a large group of patients with Alzheimer's Dementia (AD) (n = 206), considering gender. We tested the correlation between BMI levels and brain metabolism, as assessed by F-FDG-PET, and the modulation of the resting-state functional networks by BMI. At comparable dementia severity, females with high BMI can withstand a lower degree of brain metabolism dysfunction, as shown by a significant BMI-brain metabolism correlation in the temporal-parietal regions, which are typically vulnerable to AD pathology (R = 0.269, p = 0.009). Of note, high BMI was also associated with reduced connectivity in frontal and limbic brain networks, again only in AD females (p < 0.05 FDR-corrected, k = 100 voxels). This suggests a major vulnerability of neural systems known to be selectively involved in brain compensatory mechanisms in AD females. These findings indicate a strong gender effect of high BMI and obesity in AD, namely reducing the available reserve mechanisms in female patients. This brings to considerations for medical practice and health policy.
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http://dx.doi.org/10.1038/s41598-018-30883-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105632PMC
August 2018

Real-time monitoring of Pseudomonas aeruginosa biofilm formation on endotracheal tubes in vitro.

BMC Microbiol 2018 08 14;18(1):84. Epub 2018 Aug 14.

Department of Surgical, Medical, Dental and Morphological Sciences with interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.

Background: Pseudomonas aeruginosa is an opportunistic bacterial pathogen responsible for both acute and chronic infections in humans. In particular, its ability to form biofilm, on biotic and abiotic surfaces, makes it particularly resistant to host's immune defenses and current antibiotic therapies as well. Innovative antimicrobial materials, like hydrogel, silver salts or nanoparticles have been used to cover new generation catheters with promising results. Nevertheless, biofilm remains a major health problem. For instance, biofilm produced onto endotracheal tubes (ETT) of ventilated patients plays a relevant role in the onset of ventilation-associated pneumonia. Most of our knowledge on Pseudomonas aeruginosa biofilm derives from in vitro studies carried out on abiotic surfaces, such as polystyrene microplates or plastic materials used for ETT manufacturing. However, these approaches often provide underestimated results since other parameters, in addition to bacterial features (i.e. shape and material composition of ETT) might strongly influence biofilm formation.

Results: We used an already established biofilm development assay on medically-relevant foreign devices (CVC catheters) by a stably transformed bioluminescent (BLI)-Pseudomonas aeruginosa strain, in order to follow up biofilm formation on ETT by bioluminescence detection. Our results demonstrated that it is possible: i) to monitor BLI-Pseudomonas aeruginosa biofilm development on ETT pieces in real-time, ii) to evaluate the three-dimensional structure of biofilm directly on ETT, iii) to assess metabolic behavior and the production of microbial virulence traits of bacteria embedded on ETT-biofilm.

Conclusions: Overall, we were able to standardize a rapid and easy-to-perform in vitro model for real-time monitoring Pseudomonas aeruginosa biofilm formation directly onto ETT pieces, taking into account not only microbial factors, but also ETT shape and material. Our study provides a rapid method for future screening and validation of novel antimicrobial drugs as well as for the evaluation of novel biomaterials employed in the production of new classes of ETT.
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http://dx.doi.org/10.1186/s12866-018-1224-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092828PMC
August 2018

The brain metabolic signature of visual hallucinations in dementia with Lewy bodies.

Cortex 2018 11 4;108:13-24. Epub 2018 Jul 4.

Vita-Salute San Raffaele University, Milan, Italy; In Vivo Human Molecular and Structural Neuroimaging Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; Nuclear Medicine Unit, IRCCS San Raffaele Hospital, Milan, Italy. Electronic address:

Visual hallucinations (VH) are a core clinical feature of dementia with Lewy bodies (DLB), but their specific neural substrate remains elusive. We used F-FDG-PET to study the neural dysfunctional signature of VH in a group of 38 DLB patients (mean age±SD 72.9 ± 7.5) with available anamnestic records, cognitive and neurological examination and NeuroPsychiatric Inventory assessing VH. We tested the voxel-wise correlation between F-FDG-PET hypometabolism and VH NPI scores at the whole-group level, then adopting inter-regional correlation analysis to explore the resting-state networks (RSNs) metabolic connectivity in DLB patients with and without visual hallucinations, as compared to N = 38 age-matched healthy controls (HCs) (mean age±SD 71.5 ± 6.9). At the whole-group level, we found a negative correlation between VH NPI scores and F-FDG-PET hypometabolism in the right occipito-temporal cortex (p < .001 uncorrected, p < .05 Family-Wise Error cluster-corrected). Then, splitting the group according to VH presence, we found that DLB non-hallucinators presented a pattern of connectivity seeding from this occipito-temporal cluster and extending to the ventral visual stream. At difference, the DLB hallucinators showed a metabolic connectivity pattern limited to the occipital-dorsal parietal regions. As for RSNs, both the DLB subgroups showed a markedly reduced extent of attention and visual networks compared to HCs, with a variable alteration in the topography. DLB-VH patients showed a more pronounced shrinkage of the primary visual network, which was disconnected from the higher visual hubs, at difference with both HC and DLB non-hallucinators. These findings suggest that an altered brain metabolic connectivity within and beyond visual systems may promote VH in DLB. These results support the most recent neurocognitive models interpreting VH as the result of an inefficient recruitment of the ventral visual stream and of a large-scale multi-network derangement.
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http://dx.doi.org/10.1016/j.cortex.2018.06.014DOI Listing
November 2018

Low-dose CT for the spatial normalization of PET images: A validation procedure for amyloid-PET semi-quantification.

Neuroimage Clin 2018 19;20:153-160. Epub 2018 Jul 19.

Nuclear Medicine Unit, IRCCS San Raffaele Hospital, Milan, Italy.

The reference standard for spatial normalization of brain positron emission tomography (PET) images involves structural Magnetic Resonance Imaging (MRI) data. However, the lack of such structural information is fairly common in clinical settings. This might lead to lack of proper image quantification and to evaluation based only on visual ratings, which does not allow research studies or clinical trials based on quantification. PET/CT systems are widely available and CT normalization procedures need to be explored. Here we describe and validate a procedure for the spatial normalization of PET images based on the low-dose Computed Tomography (CT) images contextually acquired for attenuation correction in PET/CT systems. We included  = 34 subjects, spanning from cognitively normal to mild cognitive impairment and dementia, who underwent amyloid-PET/CT (F-Florbetaben) and structural MRI scans. The proposed pipeline is based on the SPM12 unified segmentation algorithm applied to low-dose CT images. The validation of the normalization pipeline focused on 1) statistical comparisons between regional and global F-Florbetaben-PET/CT standardized uptake value ratios (SUVrs) estimated from both CT-based and MRI-based normalized PET images (SUVr SUVr) and 2) estimation of the degrees of overlap between warped gray matter (GM) segmented maps derived from CT- and MRI-based spatial transformations. We found negligible deviations between regional and global SUVrs in the two CT and MRI-based methods. SUVr and SUVr global uptake scores showed negligible differences (mean ± sd 0.01 ± 0.03). Notably, the CT- and MRI-based warped GM maps showed excellent overlap (90% within 1 mm). The proposed analysis pipeline, based on low-dose CT images, allows accurate spatial normalization and subsequent PET image quantification. A CT-based analytical pipeline could benefit both research and clinical practice, allowing the recruitment of larger samples and favoring clinical routine analysis.
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http://dx.doi.org/10.1016/j.nicl.2018.07.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072675PMC
January 2019

FDG-PET and CSF biomarker accuracy in prediction of conversion to different dementias in a large multicentre MCI cohort.

Neuroimage Clin 2018 28;18:167-177. Epub 2018 Jan 28.

Vita-Salute San Raffaele University, Milan, Italy; Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; Nuclear Medicine Unit, IRCCS San Raffaele Hospital, Milan, Italy. Electronic address:

Background/aims: In this multicentre study in clinical settings, we assessed the accuracy of optimized procedures for FDG-PET brain metabolism and CSF classifications in predicting or excluding the conversion to Alzheimer's disease (AD) dementia and non-AD dementias.

Methods: We included 80 MCI subjects with neurological and neuropsychological assessments, FDG-PET scan and CSF measures at entry, all with clinical follow-up. FDG-PET data were analysed with a validated voxel-based SPM method. Resulting single-subject SPM maps were classified by five imaging experts according to the disease-specific patterns, as "typical-AD", "atypical-AD" (i.e. posterior cortical atrophy, asymmetric logopenic AD variant, frontal-AD variant), "non-AD" (i.e. behavioural variant FTD, corticobasal degeneration, semantic variant FTD; dementia with Lewy bodies) or "negative" patterns. To perform the statistical analyses, the individual patterns were grouped either as "AD dementia vs. non-AD dementia (all diseases)" or as "FTD vs. non-FTD (all diseases)". Aβ42, total and phosphorylated Tau CSF-levels were classified dichotomously, and using the Erlangen Score algorithm. Multivariate logistic models tested the prognostic accuracy of FDG-PET-SPM and CSF dichotomous classifications. Accuracy of Erlangen score and Erlangen Score aided by FDG-PET SPM classification was evaluated.

Results: The multivariate logistic model identified FDG-PET "AD" SPM classification (Expβ = 19.35, 95% C.I. 4.8-77.8, p < 0.001) and CSF Aβ42 (Expβ = 6.5, 95% C.I. 1.64-25.43, p < 0.05) as the best predictors of conversion from MCI to AD dementia. The "FTD" SPM pattern significantly predicted conversion to FTD dementias at follow-up (Expβ = 14, 95% C.I. 3.1-63, p < 0.001). Overall, FDG-PET-SPM classification was the most accurate biomarker, able to correctly differentiate either the MCI subjects who converted to AD or FTD dementias, and those who remained stable or reverted to normal cognition (Expβ = 17.9, 95% C.I. 4.55-70.46, p < 0.001).

Conclusions: Our results support the relevant role of FDG-PET-SPM classification in predicting progression to different dementia conditions in prodromal MCI phase, and in the exclusion of progression, outperforming CSF biomarkers.
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http://dx.doi.org/10.1016/j.nicl.2018.01.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5790816PMC
January 2019

Symptomatic cerebrospinal fluid HIV-1 escape with no resistance-associated mutations following low-level plasma viremia.

J Neurovirol 2018 02 14;24(1):132-136. Epub 2017 Dec 14.

Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Ospedale Amedeo di Savoia, C.so Svizzera 164, 10144, Torino, Italy.

The majority of neurologically symptomatic cerebrospinal fluid HIV-1 escape cases are connected with resistance-associated mutations and potentially explained by low cerebrospinal fluid antiretroviral concentrations. However, there are still significant knowledge gaps regarding the physiopathology and long-term management of neurosymptomatic viral escape. We report a case of Parkinson-like syndrome following cerebrospinal fluid HIV-1 escape in a 40-year-old female patient with an history of persistent low-level plasma viremia under treatment. No resistance-associated mutations, high viral diversity (env deep sequencing), adequate pharmacokinetics, atypical CD3-CD14-CD4+CD5-CD2-/+CD7-/+ lymphocytes, low-level Epstein-Barr virus replication, and white matter autoimmune reactivity were observed in the cerebrospinal fluid. Antiretroviral regimen modification led to rapid clinical and radiological improvements. This case may increase the current uncertain knowledge on the origin of cerebrospinal fluid HIV-1 and illustrates the consequences of uncontrolled compartmental viral replication; it also highlights the relevance and persistence of immune activation and the possibility of various detrimental mechanisms underlying neurosymptomatic viral escape.
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http://dx.doi.org/10.1007/s13365-017-0605-1DOI Listing
February 2018

Herpes simplex virus-1 entrapped in Candida albicans biofilm displays decreased sensitivity to antivirals and UVA1 laser treatment.

Ann Clin Microbiol Antimicrob 2017 Nov 14;16(1):72. Epub 2017 Nov 14.

Department of Diagnostic, Clinic and Public Health Medicine, University of Modena and Reggio Emilia, Via del Pozzo 87, 41125, Modena, Italy.

Background: Recently, we published data suggesting a mutualistic relationship between HSV-1 and Candida. albicans; in particular: (a) HSV-1 infected macrophages are inhibited in their anti-Candida effector function and (b) Candida biofilm protects HSV-1 from inactivation. The present in vitro study is aimed at testing the effects of Candida biofilm on HSV-1 sensitivity to pharmacological and physical stress, such as antiviral drugs (acyclovir and foscarnet) and laser UVA1 irradiation. We also investigated whether fungus growth pattern, either sessile or planktonic, influences HSV-1 sensitivity to antivirals.

Methods: Mature Candida biofilms were exposed to HSV-1 and then irradiated with laser light (UVA1, 355 λ). In another set of experiments, mature Candida biofilm were co-cultured with HSV-1 infected VERO cells in the presence of different concentrations of acyclovir or foscarnet. In both protocols, controls unexposed to laser or drugs were included. The viral yield of treated and untreated samples was evaluated by end-point titration. To evaluate whether this protective effect might occur in relation with a different growth pattern, HSV-1 infected cells were co-cultured with either sessile or planktonic forms of Candida and then assessed for susceptibility to antiviral drugs.

Results: UVA1 irradiation caused a 2 Log reduction of virus yield in the control cultures whereas the reduction was only 1 Log with Candida biofilm, regardless to the laser dose applied to the experimental samples (50 or 100 J/cm). The presence of biofilm increased the IC from 18.4-25.6 J/cm. Acyclovir caused a 2.3 Log reduction of virus yield in the control cultures whereas with Candida biofilm the reduction was only 0.5 Log; foscarnet determined a reduction of 1.4 Log in the controls and 0.2 Log in biofilm cultures. Consequently, the ICs for acyclovir and foscarnet increased by 4- and 12-folds, respectively, compared to controls. When HSV-1 was exposed to either sessile or planktonic fungal cells, the antiviral treatments caused approximately the same weak reduction of virus yield.

Conclusions: These data demonstrate that: (1) HSV-1 encompassed in Candida biofilm is protected from inactivation by physical (laser) and pharmacological (acyclovir or foscarnet) treatments; (2) the drug antiviral activity is reduced at a similar extent for both sessile or planktonic Candida.
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http://dx.doi.org/10.1186/s12941-017-0246-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686830PMC
November 2017

The emerging role of PET imaging in dementia.

F1000Res 2017 12;6:1830. Epub 2017 Oct 12.

Vita-Salute San Raffaele University, Milan, Italy.

A compelling need in the field of neurodegenerative diseases is the development and validation of biomarkers for early identification and differential diagnosis. The availability of positron emission tomography (PET) neuroimaging tools for the assessment of molecular biology and neuropathology has opened new venues in the diagnostic design and the conduction of new clinical trials. PET techniques, allowing the in vivo assessment of brain function and pathology changes, are increasingly showing great potential in supporting clinical diagnosis also in the early and even preclinical phases of dementia. This review will summarize the most recent evidence on fluorine-18 fluorodeoxyglucose-, amyloid -, tau -, and neuroinflammation - PET tools, highlighting strengths and limitations and possible new perspectives in research and clinical applications. Appropriate use of PET tools is crucial for a prompt diagnosis and target evaluation of new developed drugs aimed at slowing or preventing dementia.
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http://dx.doi.org/10.12688/f1000research.11603.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5639932PMC
October 2017

Diagnostics of the neuromyelitis optica spectrum disorders (NMOSD).

Neurol Sci 2017 Oct;38(Suppl 2):231-236

AUO S. Luigi, Orbassano, Italy.

This document presents the guidelines for anti-aquaporin-4 (AQP4) antibody testing that has been developed following a consensus process built on questionnaire-based surveys, internet contacts, and discussions at workshops of the sponsoring Italian Association of Neuroimmunology (AINI) congresses. Essential clinical information on neuromyelitis optica spectrum disorders, indications and limits of anti-AQP4 antibody testing, instructions for result interpretation, and an agreed laboratory protocol (Appendix) are reported for the communicative community of neurologists and clinical pathologists.
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http://dx.doi.org/10.1007/s10072-017-3027-1DOI Listing
October 2017
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