Publications by authors named "Patrizia Mecocci"

220 Publications

Senotherapeutics: Targeting senescent cells for the main age-related diseases.

Mech Ageing Dev 2021 07 21;197:111526. Epub 2021 Jun 21.

Santa Maria della Misericordia Hospital, Section of Gerontology and Geriatrics, Department of Medicine and Surgery, University of Perugia, Italy.

The review aims to summarize and discuss the current knowledge on targeting senescent cells to reduce the risk of age-related diseases in animal models and human studies. The role of cellular senescence in aging and the major age-related diseases -including Alzheimer's disease, atherosclerosis, and type 2 diabetes- as well as the use of senotherapeutic strategies in both experimental and preclinical studies, will be described. A large number of molecules, including synthetic agents and natural compounds, have been proposed for anti-senescence activities. Research on senotherapeutics, which includes senolytic and senomorphic, has a growing interest, and their safety and reliability as anti-aging drugs have been tested in clinical trials. Initial findings suggest that the senotherapeutic approach may be translatable to humans. Due to the lack of evidence, caution must be used against senolytic agents due to their potential side-effects. In this context, natural senolytic compounds should have the advantage of low toxicity and potentially more useful in humans, although the mechanisms of action need to be defined.
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http://dx.doi.org/10.1016/j.mad.2021.111526DOI Listing
July 2021

Genome-wide association identifies the first risk loci for psychosis in Alzheimer disease.

Mol Psychiatry 2021 Jun 10. Epub 2021 Jun 10.

Neuroscience Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD + P). AD + P affects ~50% of individuals with AD, identifies a subgroup with poor outcomes, and is associated with a greater degree of cognitive impairment and depressive symptoms, compared to subjects without psychosis (AD - P). Although the estimated heritability of AD + P is 61%, genetic sources of risk are unknown. We report a genome-wide meta-analysis of 12,317 AD subjects, 5445 AD + P. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in ENPP6 (rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p = 1.26 × 10) and one spanning the 3'-UTR of an alternatively spliced transcript of SUMF1 (rs201109606, O.R. 0.65 (0.56-0.76), p = 3.24 × 10), had genome-wide significant associations with AD + P. Gene-based analysis identified a significant association with APOE, due to the APOE risk haplotype ε4. AD + P demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We previously observed a negative genetic correlation with schizophrenia; instead, we now found a stronger negative correlation with the related phenotype of bipolar disorder. Analysis of polygenic risk scores supported this genetic correlation and documented a positive genetic correlation with risk variation for AD, beyond the effect of ε4. We also document a small set of SNPs likely to affect risk for AD + P and AD or schizophrenia. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture.
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http://dx.doi.org/10.1038/s41380-021-01152-8DOI Listing
June 2021

Harmonizing neuropsychological assessment for mild neurocognitive disorders in Europe.

Alzheimers Dement 2021 May 13. Epub 2021 May 13.

Department of Medicine and Surgery, Institute of Gerontology and Geriatrics, University of Perugia, Perugia, Italy.

Introduction: Harmonized neuropsychological assessment for neurocognitive disorders, an international priority for valid and reliable diagnostic procedures, has been achieved only in specific countries or research contexts.

Methods: To harmonize the assessment of mild cognitive impairment in Europe, a workshop (Geneva, May 2018) convened stakeholders, methodologists, academic, and non-academic clinicians and experts from European, US, and Australian harmonization initiatives.

Results: With formal presentations and thematic working-groups we defined a standard battery consistent with the U.S. Uniform DataSet, version 3, and homogeneous methodology to obtain consistent normative data across tests and languages. Adaptations consist of including two tests specific to typical Alzheimer's disease and behavioral variant frontotemporal dementia. The methodology for harmonized normative data includes consensus definition of cognitively normal controls, classification of confounding factors (age, sex, and education), and calculation of minimum sample sizes.

Discussion: This expert consensus allows harmonizing the diagnosis of neurocognitive disorders across European countries and possibly beyond.
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http://dx.doi.org/10.1002/alz.12365DOI Listing
May 2021

Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders.

Genome Biol 2021 03 26;22(1):90. Epub 2021 Mar 26.

Centre for Clinical Research, The University of Queensland, Brisbane, QLD, 4019, Australia.

Background: People with neurodegenerative disorders show diverse clinical syndromes, genetic heterogeneity, and distinct brain pathological changes, but studies report overlap between these features. DNA methylation (DNAm) provides a way to explore this overlap and heterogeneity as it is determined by the combined effects of genetic variation and the environment. In this study, we aim to identify shared blood DNAm differences between controls and people with Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease.

Results: We use a mixed-linear model method (MOMENT) that accounts for the effect of (un)known confounders, to test for the association of each DNAm site with each disorder. While only three probes are found to be genome-wide significant in each MOMENT association analysis of amyotrophic lateral sclerosis and Parkinson's disease (and none with Alzheimer's disease), a fixed-effects meta-analysis of the three disorders results in 12 genome-wide significant differentially methylated positions. Predicted immune cell-type proportions are disrupted across all neurodegenerative disorders. Protein inflammatory markers are correlated with profile sum-scores derived from disease-associated immune cell-type proportions in a healthy aging cohort. In contrast, they are not correlated with MOMENT DNAm-derived profile sum-scores, calculated using effect sizes of the 12 differentially methylated positions as weights.

Conclusions: We identify shared differentially methylated positions in whole blood between neurodegenerative disorders that point to shared pathogenic mechanisms. These shared differentially methylated positions may reflect causes or consequences of disease, but they are unlikely to reflect cell-type proportion differences.
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http://dx.doi.org/10.1186/s13059-021-02275-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004462PMC
March 2021

The diagnostic and prognostic capabilities of plasma biomarkers in Alzheimer's disease.

Alzheimers Dement 2021 07 25;17(7):1145-1156. Epub 2021 Jan 25.

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

Introduction: This study investigated the diagnostic and disease-monitoring potential of plasma biomarkers in mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia and cognitively unimpaired (CU) individuals.

Methods: Plasma was analyzed using Simoa assays from 99 CU, 107 MCI, and 103 AD dementia participants.

Results: Phosphorylated-tau181 (P-tau181), neurofilament light, amyloid-β (Aβ42/40), Total-tau and Glial fibrillary acidic protein were altered in AD dementia but P-tau181 significantly outperformed all biomarkers in differentiating AD dementia from CU (area under the curve [AUC] = 0.91). P-tau181 was increased in MCI converters compared to non-converters. Higher P-tau181 was associated with steeper cognitive decline and gray matter loss in temporal regions. Longitudinal change of P-tau181 was strongly associated with gray matter loss in the full sample and with Aβ measures in CU individuals.

Discussion: P-tau181 detected AD at MCI and dementia stages and was strongly associated with cognitive decline and gray matter loss. These findings highlight the potential value of plasma P-tau181 as a non-invasive and cost-effective diagnostic and prognostic biomarker in AD.
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http://dx.doi.org/10.1002/alz.12283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359457PMC
July 2021

Metabolic phenotyping reveals a reduction in the bioavailability of serotonin and kynurenine pathway metabolites in both the urine and serum of individuals living with Alzheimer's disease.

Alzheimers Res Ther 2021 01 9;13(1):20. Epub 2021 Jan 9.

UK Dementia Research Institute, Imperial College London, Hammersmith Hospital, London, W12 0NN, UK.

Background: Both serotonergic signalling disruption and systemic inflammation have been associated with the pathogenesis of Alzheimer's disease (AD). The common denominator linking the two is the catabolism of the essential amino acid, tryptophan. Metabolism via tryptophan hydroxylase results in serotonin synthesis, whilst metabolism via indoleamine 2,3-dioxygenase (IDO) results in kynurenine and its downstream derivatives. IDO is reported to be activated in times of host systemic inflammation and therefore is thought to influence both pathways. To investigate metabolic alterations in AD, a large-scale metabolic phenotyping study was conducted on both urine and serum samples collected from a multi-centre clinical cohort, consisting of individuals clinically diagnosed with AD, mild cognitive impairment (MCI) and age-matched controls.

Methods: Metabolic phenotyping was applied to both urine (n = 560) and serum (n = 354) from the European-wide AddNeuroMed/Dementia Case Register (DCR) biobank repositories. Metabolite data were subsequently interrogated for inter-group differences; influence of gender and age; comparisons between two subgroups of MCI - versus those who remained cognitively stable at follow-up visits (sMCI); and those who underwent further cognitive decline (cMCI); and the impact of selective serotonin reuptake inhibitor (SSRI) medication on metabolite concentrations.

Results: Results revealed significantly lower metabolite concentrations of tryptophan pathway metabolites in the AD group: serotonin (urine, serum), 5-hydroxyindoleacetic acid (urine), kynurenine (serum), kynurenic acid (urine), tryptophan (urine, serum), xanthurenic acid (urine, serum), and kynurenine/tryptophan ratio (urine). For each listed metabolite, a decreasing trend in concentrations was observed in-line with clinical diagnosis: control > MCI > AD. There were no significant differences in the two MCI subgroups whilst SSRI medication status influenced observations in serum, but not urine.

Conclusions: Urine and serum serotonin concentrations were found to be significantly lower in AD compared with controls, suggesting the bioavailability of the neurotransmitter may be altered in the disease. A significant increase in the kynurenine/tryptophan ratio suggests that this may be a result of a shift to the kynurenine metabolic route due to increased IDO activity, potentially as a result of systemic inflammation. Modulation of the pathways could help improve serotonin bioavailability and signalling in AD patients.
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http://dx.doi.org/10.1186/s13195-020-00741-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797094PMC
January 2021

Urinary metabolic phenotyping for Alzheimer's disease.

Sci Rep 2020 12 10;10(1):21745. Epub 2020 Dec 10.

Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, UK.

Finding early disease markers using non-invasive and widely available methods is essential to develop a successful therapy for Alzheimer's Disease. Few studies to date have examined urine, the most readily available biofluid. Here we report the largest study to date using comprehensive metabolic phenotyping platforms (NMR spectroscopy and UHPLC-MS) to probe the urinary metabolome in-depth in people with Alzheimer's Disease and Mild Cognitive Impairment. Feature reduction was performed using metabolomic Quantitative Trait Loci, resulting in the list of metabolites associated with the genetic variants. This approach helps accuracy in identification of disease states and provides a route to a plausible mechanistic link to pathological processes. Using these mQTLs we built a Random Forests model, which not only correctly discriminates between people with Alzheimer's Disease and age-matched controls, but also between individuals with Mild Cognitive Impairment who were later diagnosed with Alzheimer's Disease and those who were not. Further annotation of top-ranking metabolic features nominated by the trained model revealed the involvement of cholesterol-derived metabolites and small-molecules that were linked to Alzheimer's pathology in previous studies.
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http://dx.doi.org/10.1038/s41598-020-78031-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730184PMC
December 2020

The impact of aging in dementia: It is time to refocus attention on the main risk factor of dementia.

Ageing Res Rev 2021 01 10;65:101210. Epub 2020 Nov 10.

Institute of Gerontology and Geriatrics, Department of Medicine and Surgery, University of Perugia-Santa Maria della Misericordia Hospital, Perugia, Italy.

Alzheimer's disease (AD) represents the most common form of dementia among old age subjects, and despite decades of studies, the underlying etiopathogenetic mechanisms remain unsolved, and no cure is available. The amyloid hypothesis has been recently questioned due to the failure of amyloid-centered treatments. The fact that cognitively normal old age subjects have substantial amyloid deposition in the brain comparable to the levels observed in AD patients suggests that amyloid accumulation may enter into the normal process of aging and what really triggers neuronal death and clinical manifestation is the loss of function due to an energetic failure. With this viewpoint article, we aim to challenge the traditional view of amyloid as the leading cause of AD. Conversely, we propose the core feature of aging, that is the progressive brain energy decline, as the main risk factor for dementia in older persons. Thus, a bioenergetic deficit secondary to mitochondrial dysfunction may lead to progressive neuronal death and clinical expression of dementia. The optimization of brain energetics should become a key component in future strategies for preventing and treating dementia.
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http://dx.doi.org/10.1016/j.arr.2020.101210DOI Listing
January 2021

The reliability of a deep learning model in clinical out-of-distribution MRI data: A multicohort study.

Med Image Anal 2020 12 1;66:101714. Epub 2020 May 1.

Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden; Department of Neuroimaging, Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Deep learning (DL) methods have in recent years yielded impressive results in medical imaging, with the potential to function as clinical aid to radiologists. However, DL models in medical imaging are often trained on public research cohorts with images acquired with a single scanner or with strict protocol harmonization, which is not representative of a clinical setting. The aim of this study was to investigate how well a DL model performs in unseen clinical datasets-collected with different scanners, protocols and disease populations-and whether more heterogeneous training data improves generalization. In total, 3117 MRI scans of brains from multiple dementia research cohorts and memory clinics, that had been visually rated by a neuroradiologist according to Scheltens' scale of medial temporal atrophy (MTA), were included in this study. By training multiple versions of a convolutional neural network on different subsets of this data to predict MTA ratings, we assessed the impact of including images from a wider distribution during training had on performance in external memory clinic data. Our results showed that our model generalized well to datasets acquired with similar protocols as the training data, but substantially worse in clinical cohorts with visibly different tissue contrasts in the images. This implies that future DL studies investigating performance in out-of-distribution (OOD) MRI data need to assess multiple external cohorts for reliable results. Further, by including data from a wider range of scanners and protocols the performance improved in OOD data, which suggests that more heterogeneous training data makes the model generalize better. To conclude, this is the most comprehensive study to date investigating the domain shift in deep learning on MRI data, and we advocate rigorous evaluation of DL models on clinical data prior to being certified for deployment.
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http://dx.doi.org/10.1016/j.media.2020.101714DOI Listing
December 2020

cCOG: A web-based cognitive test tool for detecting neurodegenerative disorders.

Alzheimers Dement (Amst) 2020 25;12(1):e12083. Epub 2020 Aug 25.

Combinostics Ltd Tampere Finland.

Introduction: Web-based cognitive tests have potential for standardized screening in neurodegenerative disorders. We examined accuracy and consistency of cCOG, a computerized cognitive tool, in detecting mild cognitive impairment (MCI) and dementia.

Methods: Clinical data of 306 cognitively normal, 120 mild cognitive impairment (MCI), and 69 dementia subjects from three European cohorts were analyzed. Global cognitive score was defined from standard neuropsychological tests and compared to the corresponding estimated score from the cCOG tool containing seven subtasks. The consistency of cCOG was assessed comparing measurements administered in clinical settings and in the home environment.

Results: cCOG produced accuracies (receiver operating characteristic-area under the curve [ROC-AUC]) between 0.71 and 0.84 in detecting MCI and 0.86 and 0.94 in detecting dementia when administered at the clinic and at home. The accuracy was comparable to the results of standard neuropsychological tests (AUC 0.69-0.77 MCI/0.91-0.92 dementia).

Discussion: cCOG provides a promising tool for detecting MCI and dementia with potential for a cost-effective approach including home-based cognitive assessments.
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http://dx.doi.org/10.1002/dad2.12083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446945PMC
August 2020

MicroRNAs Modulate the Pathogenesis of Alzheimer's Disease: An In Silico Analysis in the Human Brain.

Genes (Basel) 2020 08 24;11(9). Epub 2020 Aug 24.

IRCCS Centro Neurolesi "Bonino Pulejo", Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy.

MicroRNAs (miRNAs) are small RNAs involved in the post-transcriptional regulation of their target genes, causing a decrease in protein translation from the mRNA. Different miRNAs are found in the nervous system, where they are involved in its physiological functions, but altered miRNAs expression was also reported in neurodegenerative disorders, including Alzheimer's disease (AD). AD is characterized by memory loss, cognitive function abnormalities, and various neuropsychiatric disturbances. AD hallmarks are amyloid β (Aβ) aggregates, called senile plaques, and neurofibrillary tangles (NFTs) formed by hyperphosphorylated Tau protein. In this study, we performed an analysis to evaluate altered patterns of miRNAs expression in the brains of AD patients compared to healthy subjects. We found 12 miRNAs that were differentially expressed in AD compared to healthy individuals. These miRNAs have target genes involved in AD pathogenesis. In particular, some miRNAs influence Aβ production, having as target secretase and amyloid precursor protein (APP). Some miRNAs were reported to be involved in nervous system functions, and their alteration can cause neuronal dysfunction.
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http://dx.doi.org/10.3390/genes11090983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564652PMC
August 2020

Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology.

J Alzheimers Dis 2020 ;77(3):1353-1368

University of Geneva, Geneva, Switzerland.

Background: Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer's disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown.

Objective: We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes.

Methods: We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677).

Results: We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E ɛ4 genotype distinguished amyloid pathology (A + T-N-, A+T+N-, A+T-N+, and A+T+N+) from no AD pathology (A-T-N-) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts.

Conclusions: Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo.
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http://dx.doi.org/10.3233/JAD-200208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683080PMC
September 2021

The genetic architecture of human brainstem structures and their involvement in common brain disorders.

Nat Commun 2020 08 11;11(1):4016. Epub 2020 Aug 11.

Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway.

Brainstem regions support vital bodily functions, yet their genetic architectures and involvement in common brain disorders remain understudied. Here, using imaging-genetics data from a discovery sample of 27,034 individuals, we identify 45 brainstem-associated genetic loci, including the first linked to midbrain, pons, and medulla oblongata volumes, and map them to 305 genes. In a replication sample of 7432 participants most of the loci show the same effect direction and are significant at a nominal threshold. We detect genetic overlap between brainstem volumes and eight psychiatric and neurological disorders. In additional clinical data from 5062 individuals with common brain disorders and 11,257 healthy controls, we observe differential volume alterations in schizophrenia, bipolar disorder, multiple sclerosis, mild cognitive impairment, dementia, and Parkinson's disease, supporting the relevance of brainstem regions and their genetic architectures in common brain disorders.
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http://dx.doi.org/10.1038/s41467-020-17376-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7421944PMC
August 2020

An epigenome-wide association study of Alzheimer's disease blood highlights robust DNA hypermethylation in the HOXB6 gene.

Neurobiol Aging 2020 11 3;95:26-45. Epub 2020 Jul 3.

College of Medicine and Health, University of Exeter, Exeter, UK. Electronic address:

A growing number of epigenome-wide association studies have demonstrated a role for DNA methylation in the brain in Alzheimer's disease. With the aim of exploring peripheral biomarker potential, we have examined DNA methylation patterns in whole blood collected from 284 individuals in the AddNeuroMed study, which included 89 nondemented controls, 86 patients with Alzheimer's disease, and 109 individuals with mild cognitive impairment, including 38 individuals who progressed to Alzheimer's disease within 1 year. We identified significant differentially methylated regions, including 12 adjacent hypermethylated probes in the HOXB6 gene in Alzheimer's disease, which we validated using pyrosequencing. Using weighted gene correlation network analysis, we identified comethylated modules of genes that were associated with key variables such as APOE genotype and diagnosis. In summary, this study represents the first large-scale epigenome-wide association study of Alzheimer's disease and mild cognitive impairment using blood. We highlight the differences in various loci and pathways in early disease, suggesting that these patterns relate to cognitive decline at an early stage.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.06.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649340PMC
November 2020

Medico-legal assessment of personal damage in older people: report from a multidisciplinary consensus conference.

Int J Legal Med 2020 Nov 17;134(6):2319-2334. Epub 2020 Jul 17.

, Verona, Italy.

Ageing of the global population represents a challenge for national healthcare systems and healthcare professionals, including medico-legal experts, who assess personal damage in an increasing number of older people. Personal damage evaluation in older people is complex, and the scarcity of evidence is hindering the development of formal guidelines on the subject. The main objectives of the first multidisciplinary Consensus Conference on Medico-Legal Assessment of Personal Damage in Older People were to increase knowledge on the subject and establish standard procedures in this field. The conference, organized according to the guidelines issued by the Italian National Institute of Health (ISS), was held in Bologna (Italy) on June 8, 2019 with the support of national scientific societies, professional organizations, and stakeholders. The Scientific Technical Committee prepared 16 questions on 4 thematic areas: (1) differences in injury outcomes in older people compared to younger people and their relevance in personal damage assessment; (2) pre-existing status reconstruction and evaluation; (3) medico-legal examination procedures; (4) multidimensional assessment and scales. The Scientific Secretariat reviewed relevant literature and documents, rated their quality, and summarized evidence. During conference plenary public sessions, 4 pairs of experts reported on each thematic area. After the last session, a multidisciplinary Jury Panel (15 members) drafted the consensus statements. The present report describes Conference methods and results, including a summary of evidence supporting each statement, and areas requiring further investigation. The methodological recommendations issued during the Conference may be useful in several contexts of damage assessment, or to other medico-legal evaluation fields.
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http://dx.doi.org/10.1007/s00414-020-02368-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578136PMC
November 2020

Association of Peripheral Insulin Resistance and Other Markers of Type 2 Diabetes Mellitus with Brain Amyloid Deposition in Healthy Individuals at Risk of Dementia.

J Alzheimers Dis 2020 ;76(4):1243-1248

Institute of Clinical Medicine/Neurology, University of Eastern Finland, Kuopio, Finland.

We explored the association of type 2 diabetes related blood markers with brain amyloid accumulation on PiB-PET scans in 41 participants from the FINGER PET sub-study. We built logistic regression models for brain amyloid status with12 plasma markers of glucose and lipid metabolism, controlled for diabetes and APOEɛ4 carrier status. Lower levels of insulin, insulin resistance index (HOMA-IR), C-peptide, and plasminogen activator (PAI-1) were associated with amyloid positive status, although the results were not significant after adjusting for multiple testing. None of the models found evidence for associations between amyloid status and fasting glucose or HbA1c.
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http://dx.doi.org/10.3233/JAD-200145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504982PMC
June 2021

Evaluating 2-[F]FDG-PET in differential diagnosis of dementia using a data-driven decision model.

Neuroimage Clin 2020 24;27:102267. Epub 2020 Apr 24.

Department of Neurology, Danish Dementia Research Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. Electronic address:

2-[F]fluoro-2-deoxy-d-glucose positron emission tomography (2-[F]FDG-PET) has an emerging supportive role in dementia diagnostic as distinctive metabolic patterns are specific for Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). Previous studies have demonstrated that a data-driven decision model based on the disease state index (DSI) classifier supports clinicians in the differential diagnosis of dementia by using different combinations of diagnostic tests and biomarkers. Until now, this model has not included 2-[F]FDG-PET data. The objective of the study was to evaluate 2-[F]FDG-PET biomarkers combined with commonly used diagnostic tests in the differential diagnosis of dementia using the DSI classifier. We included data from 259 subjects diagnosed with AD, DLB, FTD, vascular dementia (VaD), and subjective cognitive decline from two independent study cohorts. We also evaluated three 2-[F]FDG-PET biomarkers (anterior vs. posterior index (API-PET), occipital vs. temporal index, and cingulate island sign) to improve the classification accuracy for both FTD and DLB. We found that the addition of 2-[F]FDG-PET biomarkers to cognitive tests, CSF and MRI biomarkers considerably improved the classification accuracy for all pairwise comparisons of DLB (balanced accuracies: DLB vs. AD from 64% to 77%; DLB vs. FTD from 71% to 92%; and DLB vs. VaD from 71% to 84%). The two 2-[F]FDG-PET biomarkers, API-PET and occipital vs. temporal index, improved the accuracy for FTD and DLB, especially as compared to AD. Moreover, different combinations of diagnostic tests were valuable to differentiate specific subtypes of dementia. In conclusion, this study demonstrated that the addition of 2-[F]FDG-PET to commonly used diagnostic tests provided complementary information that may help clinicians in diagnosing patients, particularly for differentiating between patients with FTD, DLB, and AD.
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http://dx.doi.org/10.1016/j.nicl.2020.102267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229490PMC
March 2021

Serum alkaline phosphatase is elevated and inversely correlated with cognitive functions in subjective cognitive decline: results from the ReGAl 2.0 project.

Aging Clin Exp Res 2021 Mar 3;33(3):603-609. Epub 2020 May 3.

Institute of Gerontology and Geriatrics, Department of Medicine, University of Perugia, Snta Maria Della Misericordia Hospital, Piazzale Gambuli 1, 06132, Perugia, Italy.

Background: Alkaline phosphatase has been found on neuronal membranes and plasma alkaline phosphatase (ALP) activity increases during brain injury and cerebrovascular diseases, suggesting that its levels may reflect the neuronal loss. It is known that ALP is higher in subjects affected by Alzheimer's dementia and inversely correlated with cognitive functions. No study has investigated the relationship between ALP and cognitive functions in old-age subject with pre-clinical cognitive impairment.

Methods: This is a cross-sectional study with data gathered from the ReGAl 2.0 project (Rete Geriatrica Alzheimer-Geriatric Network on Alzheimer's disease), a large Italian multicentric clinical-based study. A cohort of 209 old-age subjects healthy controls (HC), Subjective cognitive decline (SCD), and Mild Cognitive Impairment (MCI) was included in the study. Cognitive performances were assessed with a large neuropsychological battery. The same day, serum alkaline phosphatase activity was measured in all subjects.

Results: We found that the SCD group had significantly higher ALP levels as compared with HC (p = 0.001). Among all neuropsychological tests, in all population ALP levels negatively correlated with scores at attentional matrices (r =  - 0.243, p = 0.002), Digit Span Forward (r =  - 0.241, p = 0.003) and Letter Fluency Test (r =  - 0.196, p = 0.044). Attentional Matrices (r =  - 0.208, p = 0.014) and Letter Fluency Test (r =  - 0.229, p = 0.019) remained significantly correlated with ALP even after controlling for gender. In the SCD group, only the Attentional Matrices significantly and negatively correlated with ALP (r =  - 0.344 p = 0.035), while no significant correlations were found in HC or MCI.

Conclusions: Results indicate that serum alkaline phosphatase activity is increased in SCD and inversely correlates with cognitive functions. Further studies are needed to investigate the role of ALP in the progression to AD.
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http://dx.doi.org/10.1007/s40520-020-01572-6DOI Listing
March 2021

COVID-19: A Geriatric Emergency.

Geriatrics (Basel) 2020 Apr 26;5(2). Epub 2020 Apr 26.

Section of Gerontology and Geriatrics, Department of Medicine, University of Perugia, Santa Maria della Misericordia Hospital, 06132 Perugia, Italy.

The older Italian population is posing a challenge in the number of deaths for coronavirus disease 2019 (COVID-19). According to previous data from China, pre-existing health conditions dramatically increase the risk of dying from COVID-19. The presence of multiple diseases in older patients may be considered as a mark of frailty, which increases the person's vulnerability to stress and impairs the multisystemic compensatory effort to restore homeostasis. The clinical complexity associated with the management of frailty may increase the risk of complications during infection as well as the lack of the early recognition of atypical symptoms. There is an urgent need to share expertise and clinical management skills with geriatricians as well as the need for early diagnosis to start treatment at the earliest convenience in the community, with the aim to avoid the collapse of intensive care units.
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http://dx.doi.org/10.3390/geriatrics5020024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7345675PMC
April 2020

Uric acid and late-onset Alzheimer's disease: results from the ReGAl 2.0 project.

Aging Clin Exp Res 2021 Feb 10;33(2):361-366. Epub 2020 Apr 10.

Institute of Gerontology and Geriatrics, Department of Medicine, Santa Maria Della Misericordia Hospital, University of Perugia, Piazzale Gambuli 1, 06132, Perugia, Italy.

Background: It has been suggested that oxidative stress may have a role in the pathogenesis of Alzheimer's disease (AD). Serum uric acid (UA) could exert neuroprotective effects via its antioxidant capacities. Many studies investigated serum UA levels in subjects with AD, but to date, results are conflicting and evidence in old age subjects is weak.

Aims: In this study, we assess whether serum UA levels would be altered in the AD old age subjects compared to those of initial cognitive impairment and healthy controls.

Methods: This is a retrospective study with data gathered from the ReGAl 2.0 project (Rete Geriatrica Alzheimer-Geriatric Network on Alzheimer's disease), a large Italian multicentric clinical-based study. A cohort of 232 subjects, including 65 (healthy controls HC), 95 mild cognitive impairment (MCI), and 72 AD, were included in the study. Serum UA was measured in all subjects by routine laboratory method.

Results: The sample population includes 232 subjects, mostly women with a mean age of 79.16 ± 5.64 (range 66-93) years. No significant difference was found in gender distribution between groups. No significant correlation was found in all populations between age and uric acid levels. AD group had significantly lower UA levels as compared with HC. The association of uric acid with AD presence after adjusting for age, gender, body mass index (BMI) and creatinine levels showed that uric acid level was independently associated with the diagnosis of AD.

Conclusions: These data indicate that serum UA is reduced in AD, supporting that UA may have a potential protective role against AD in old age.
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http://dx.doi.org/10.1007/s40520-020-01541-zDOI Listing
February 2021

The Importance of Cellular Senescence in Frailty and Cardiovascular Diseases.

Adv Exp Med Biol 2020 ;1216:79-86

Department of Medicine, Santa Maria della Misericordia Hospital, Section of Gerontology and Geriatrics, University of Perugia, Piazzale Gambuli 1, 06132, Perugia, Italy.

Frailty is a complex clinical syndrome, progressively described in the last thirty years, resulting from multiple impairments across many organs and systems and characterized by a reduction in physiological reserves and increased vulnerability to stressors, as well. Cardiovascular diseases (CVDs) are a common health problem in very old populations. Age-related changes occur throughout the body and in all organs, including the cardiovascular system. Cellular senescence links age-related CVDs and frailty by many mechanisms of particular interest in the aging biology and geriatric syndromes. Cellular senescence may represent the pivotal factor with its senescence-associated secretory phenotype (SASP) leading to systemic inflammation. In this context, SASP may represent the key element in the association between aging, frailty and the development of age-related CVDs.
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http://dx.doi.org/10.1007/978-3-030-33330-0_9DOI Listing
February 2020

Effects of Weekly Supplementation of Cholecalciferol and Calcifediol Among the Oldest-Old People: Findings From a Randomized Pragmatic Clinical Trial.

Nutrients 2019 Nov 15;11(11). Epub 2019 Nov 15.

Gerontology and Geriatrics Institute, Department of Medicine, University of Perugia, Santa Maria della Misericordia Hospital, 1 06123 P.le Menghini, Italy.

Vitamin D inadequacy is pervasive in the oldest-old. Many vitamin D metabolites are available for supplementation, their effects on the recovery of adequate serum levels remain unknown. We investigate the effects of supplementation with cholecalciferol (D3) and calcifediol (25D3) on serum levels of 25(OH)D, 1-25(OH)D, bone and inflammatory markers, ultimately identifying clinical predictors of successful treatment. Sixty-seven oldest-old individuals were randomized to weekly administration of 150 mcg of 25D3 or D3, from hospital admission to 7 months after discharge. Supplementation of 25D3 and D3 were associated with increasing serum levels of 25(OH)D ( < 0.001) and 1-25(OH)D ( = 0.01). Participants on 25D3 experienced a steeper rise than those on D3 (group*time interaction = 0.01), after adjustment for intact parathyroid hormone (iPTH) levels the differences disappeared (intervention*iPTH interaction = 0.04). Vitamin D supplementation was associated with a decreasing trend of iPTH and C-reactive protein (CRP) ( < 0.001). Polypharmacy and low handgrip strength were predictors of failure of intervention, independent of vitamin D metabolites. In conclusion, D3 and 25D3 supplementation significantly increase vitamin D serum levels in the oldest-old individuals, with a tendency of 25D3 to show a faster recovery of acceptable iPTH levels than D3. Polypharmacy and low muscle strength weaken the recovery of adequate vitamin D serum levels.
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http://dx.doi.org/10.3390/nu11112778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893743PMC
November 2019

Cognitive Decline and Alzheimer's Disease in Old Age: A Sex-Specific Cytokinome Signature.

J Alzheimers Dis 2019 ;72(3):911-918

Institute of Gerontology and Geriatrics, Department of Medicine, University of Perugia, Perugia, Italy.

Background: Elevated peripheral levels of different cytokines and chemokines in subjects with Alzheimer's disease (AD), as compared with healthy controls (HC), have emphasized the role of inflammation in such a disease. Considering the cross-talking between the central nervous system and the periphery, the inflammatory analytes may provide utility as biomarkers to identify AD at earlier stages.

Objective: Using an advanced statistical approach, we can discriminate the interactive network of cytokines/chemokines and propose a useful tool to follow the progression and evolution of AD, also in light of sex differences.

Methods: A cohort of 289 old-age subjects was screened for cytokine and chemokine profiling, measured in plasma, after a thorough clinical and neuropsychological evaluation. A custom algorithm based on Fisher linear discriminant analysis was applied to ascertain a classification signature able to discriminate HC from mild cognitive impairment (MCI) and AD.

Results: We observed that a joint expression of three proteins (a "signature" composed by IFN-α2, IL-1α, TNFα) can discriminate HC from AD with an accuracy of 65.24%. Using this signature on MCI samples, 84.93% of them were classified as "non-HC". Stratifying MCI samples by sex, we observed that 87.23% of women were classified as "non-HC", and only 57.69% of males. Indeed, in a scatter plot of IFN-α2 and IL-1α, the HC group was better separated from MCI and AD in women as compared with men.

Conclusion: These findings suggest that AD is accompanied by a peripheral inflammatory response that can already be present in MCI subjects, thus providing a mean for detecting this at-risk status and allow an anticipated intervention.
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http://dx.doi.org/10.3233/JAD-190480DOI Listing
November 2020

Genetic architecture of subcortical brain structures in 38,851 individuals.

Nat Genet 2019 11 21;51(11):1624-1636. Epub 2019 Oct 21.

Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
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http://dx.doi.org/10.1038/s41588-019-0511-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055269PMC
November 2019

Common brain disorders are associated with heritable patterns of apparent aging of the brain.

Nat Neurosci 2019 10 24;22(10):1617-1623. Epub 2019 Sep 24.

Centre for Psychiatry Research, Department of Clinical Neuroscience Karolinska Institutet & Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.

Common risk factors for psychiatric and other brain disorders are likely to converge on biological pathways influencing the development and maintenance of brain structure and function across life. Using structural MRI data from 45,615 individuals aged 3-96 years, we demonstrate distinct patterns of apparent brain aging in several brain disorders and reveal genetic pleiotropy between apparent brain aging in healthy individuals and common brain disorders.
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http://dx.doi.org/10.1038/s41593-019-0471-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823048PMC
October 2019

Biomarker-based prognosis for people with mild cognitive impairment (ABIDE): a modelling study.

Lancet Neurol 2019 11 13;18(11):1034-1044. Epub 2019 Sep 13.

Center for Neuroscience and Cell Biology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Department of Neurology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.

Background: Biomarker-based risk predictions of dementia in people with mild cognitive impairment are highly relevant for care planning and to select patients for treatment when disease-modifying drugs become available. We aimed to establish robust prediction models of disease progression in people at risk of dementia.

Methods: In this modelling study, we included people with mild cognitive impairment (MCI) from single-centre and multicentre cohorts in Europe and North America: the European Medical Information Framework for Alzheimer's Disease (EMIF-AD; n=883), Alzheimer's Disease Neuroimaging Initiative (ADNI; n=829), Amsterdam Dementia Cohort (ADC; n=666), and the Swedish BioFINDER study (n=233). Inclusion criteria were a baseline diagnosis of MCI, at least 6 months of follow-up, and availability of a baseline Mini-Mental State Examination (MMSE) and MRI or CSF biomarker assessment. The primary endpoint was clinical progression to any type of dementia. We evaluated performance of previously developed risk prediction models-a demographics model, a hippocampal volume model, and a CSF biomarkers model-by evaluating them across cohorts, incorporating different biomarker measurement methods, and determining prognostic performance with Harrell's C statistic. We then updated the models by re-estimating parameters with and without centre-specific effects and evaluated model calibration by comparing observed and expected survival. Finally, we constructed a model combining markers for amyloid deposition, tauopathy, and neurodegeneration (ATN), in accordance with the National Institute on Aging and Alzheimer's Association research framework.

Findings: We included all 2611 individuals with MCI in the four cohorts, 1007 (39%) of whom progressed to dementia. The validated demographics model (Harrell's C 0·62, 95% CI 0·59-0·65), validated hippocampal volume model (0·67, 0·62-0·72), and updated CSF biomarkers model (0·72, 0·68-0·74) had adequate prognostic performance across cohorts and were well calibrated. The newly constructed ATN model had the highest performance (0·74, 0·71-0·76).

Interpretation: We generated risk models that are robust across cohorts, which adds to their potential clinical applicability. The models could aid clinicians in the interpretation of CSF biomarker and hippocampal volume results in individuals with MCI, and help research and clinical settings to prepare for a future of precision medicine in Alzheimer's disease. Future research should focus on the clinical utility of the models, particularly if their use affects participants' understanding, emotional wellbeing, and behaviour.

Funding: ZonMW-Memorabel.
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http://dx.doi.org/10.1016/S1474-4422(19)30283-2DOI Listing
November 2019

Lower serum levels of IL-13 is associated with increased carotid intima-media thickness in old age subjects.

Aging Clin Exp Res 2020 Jul 29;32(7):1289-1294. Epub 2019 Aug 29.

Department of Medicine, Institute of Gerontology and Geriatrics, Santa Maria Della Misericordia Hospital, University of Perugia, Piazzale Gambuli 1, 06132, Perugia, Italy.

Background: Cardiovascular diseases due to atherosclerosis represent the major cause of disability and mortality in old age subjects. The atherosclerotic process is linked to a low grade of systemic inflammation with the involvement of many cytokines and inflammatory proteins. Among them, evidence from animal studies suggests that IL-13 has a protective property. However, the role of IL-13 in the pathogenesis of atherosclerosis in humans is still unknown.

Aims: With this study, we aim to investigate a potential association between IL-13 and carotid intima-media thickness (IMT) in old age subjects.

Methods: This is a retrospective study conducted among 79 old age subjects (over 75 years old). All subjects underwent IMT assessment by high-resolution B-mode ultrasonography and IL-13 measurement in serum by ELISA.

Results: Subjects (41 M/38F) had a mean age of 81.0 ± 4.5 years and were mostly overweight. Stratifying the whole cohort by IMT thickness (IMT ≤ 0.9, n = 17; IMT ≥ 1 and ≤ 1.3, n = 50; IMT ≥ 1.4, n = 12) among the main variables explored, only BMI and triglycerides differed among groups, having subjects with higher IMT significantly higher BMI and lower triglycerides. Serum IL-13 levels significantly differed among groups having subjects with IMT ≥ 1.4 lower levels as compared to other groups (p < 0.0001). In all sample population, IMT values significantly correlate with IL-13 levels (r = - 0.454, p < 0.0001). Indeed, a linear regression analysis showed that independent of age, gender, body mass index, triglycerides, systolic blood pressure, statin use and smoking habit, lower IL-13 serum levels were associated with higher IMT values.

Conclusions: IL-13, an anti-inflammatory cytokine, may have a protective role in the human atherosclerotic process. It could be used as an effective and promising novel therapeutic target development.
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http://dx.doi.org/10.1007/s40520-019-01313-4DOI Listing
July 2020
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