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We evaluated the association between hippocampal atrophy and increase of the EEG markers alpha3/alpha2 relative power ratio in mild cognitive impairment (MCI) and Alzheimer's disease patients. Seventy-nine subjects with MCI and 11 patients with AD underwent EEG recording and MRI scan. The MCI group was subdivided in three subgroups according to growing hippocampal atrophy. The groups were characterized by alpha3/alpha2 relative power ratio. In AD patients group mapped hippocampal regions were computed and related with alpha3/alpha2 power ratio. Results show that the increase of alpha3/alpha2 power ratio is correlated with atrophy of hippocampus both in MCI and in Alzheimer's disease patients. This finding confirms the possible diagnostic role of EEG markers as diagnostic and prognostic factors in patient with prodromal and declared Alzheimer's disease.

We evaluated the relationship between brain rhythmicity and both the cerebrovascular damage (CVD) and amygdalohippocampal complex (AHC) atrophy, as revealed by scalp electroencephalography (EEG) in a cohort of subjects with mild cognitive impairment (MCI). All MCI subjects underwent EEG recording and magnetic resonance imaging. EEGs were recorded at rest. Relative power was separately computed for delta, theta, alpha1, alpha2, and alpha3 frequency bands. In the spectral band power the severity of CVD was associated with increased delta power and decreased alpha2 power. No association of vascular damage was observed with alpha3 power. Moreover, the theta/alpha1 ratio could be a reliable index for the estimation of the individual extent of CV damage. On the other side, the group with moderate hippocampal atrophy showed the highest increase of alpha2 and alpha3 power. Moreover, when the amygdalar and hippocampal volumes are separately considered, within amygdalohippocampal complex (AHC), the increase of theta/gamma ratio is best associated with amygdalar atrophy whereas alpha3/alpha2 ratio is best associated with hippocampal atrophy. CVD and AHC damages are associated with specific EEG markers. So far, these EEG markers could have a prospective value in differential diagnosis between vascular and degenerative MCI.

Objective. The increase of high alpha relative to low alpha power has been recently demonstrated as a reliable EEG marker of hippocampal atrophy conversion of patients with mild cognitive impairment (MCI) in Alzheimer's disease (AD). In the present study we test the reliability of this EEG index in subjects with AD. Methods. Correlation between EEG markers and volumetric differences in mapped hippocampal regions was estimated in AD patients. Results. Results show that the increase of alpha3/alpha2 power ratio is correlated with atrophy of mapped hippocampal regions in Alzheimer's disease. Conclusions. The findings confirm the possible diagnostic role of EEG markers.

Limosilactobacillus fermentum Lf2 (Lf2) is an autochthonous strain that produces high levels of exopolysaccharides (EPS). The objective of this work was to evaluate the probiotic potential of Lf2 and its relationship with these metabolites in a mouse model of TNBS (trinitrobenzene sulfonic acid)-induced chronic colitis. Mice were treated intrarectally with increasing doses of TNBS resuspended in 50% ethanol for 14 days. In parallel, they received different treatments by gavage (lactose 10% as the matrix): freeze-dried Lf2 (L); purified EPS (E); and lactose 10% (T). A healthy control group (H) was treated with 50% alcohol without TNBS (intrarectally) and 10% lactose (by gavage). In the small intestine, there was a significant increase in IgA levels for the group that received EPS and a decrease in IFN-γ for mice treated with the strain compared to the other groups. In the large intestine, IL-2 and IFN-γ presented the lowest levels in the groups treated with EPS and the strain. The concentrations of acetic and propionic acids in mice that received Lf2 were the highest, while the levels of butyric acid were comparable to the healthy control group. An increase in the abundance of SCFA-producing bacteria was observed for mice treated with EPS and the strain in comparison with the colitis control group. The enzyme activity of catalase was higher in all the treatments compared to the TNBS-induced colitis control mice. To summarize the results obtained, a principal component analysis (PCA) was performed, clearly grouping the treatments in different clusters according to the variables studied. This is one of the first studies to address the role of a potential probiotic strain in a chronic colitis mouse model, trying to elucidate the relationship between its properties and the EPS synthesized.

Elderly people are an important part of the global population who suffer from the natural processes of senescence, which lead to changes in the gut microbiota composition. These modifications have a great impact on their quality of life, bringing a general putrefactive and inflammatory status as a consequence. Some of the most frequent conditions related to this status are constipation, undernutrition, neurodegenerative diseases, susceptibility to opportunistic pathogens, and metabolic disbalance, among others. For these reasons, there is an increasing interest in improving their quality of life by non-invasive treatments such as the consumption of probiotics, prebiotics, and synbiotics. The aim of the present mini-review is to describe the benefits of these functional supplements/food according to the most recent clinical and pre-clinical studies published during the last decade. In addition, insights into several aspects we consider relevant to improve the quality of future studies are provided.

The advent of computerized medical recording systems in healthcare facilities has made data retrieval tasks easier, compared to manual recording. Nevertheless, the potential of the information contained within medical records remains largely untapped, mostly due to the time and effort required to extract data from unstructured documents. Natural Language Processing (NLP) represents a promising solution to this challenge, as it enables the use of automated text-mining tools for clinical practitioners. In this work, we present the architecture of the Virtual Dementia Institute (IVD), a consortium of sixteen Italian hospitals, using the NLP Extraction and Management Tool (NEMT), a (semi-) automated end-to-end pipeline that extracts relevant information from clinical documents and stores it in a centralized REDCap database. After defining a common Case Report Form (CRF) across the IVD hospitals, we implemented NEMT, the core of which is a Question Answering Bot (QABot) based on a modern NLP model. This QABot is fine-tuned on thousands of examples from IVD centers. Detailed descriptions of the process to define a common minimum dataset, Inter-Annotator Agreement calculated on clinical documents, and NEMT results are provided. The best QABot performance show an Exact Match score (EM) of 78.1%, a F1-score of 84.7%, a Lenient Accuracy (LAcc) of 0.834, and a Mean Reciprocal Rank (MRR) of 0.810. EM and F1 scores outperform the same metrics obtained with ChatGPTv3.5 (68.9% and 52.5%, respectively). With NEMT the IVD has been able to populate a database that will contain data from thousands of Italian patients, all screened with the same procedure. NEMT represents an efficient tool that paves the way for medical information extraction and exploitation for new research studies.

Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the two major neurodegenerative diseases causing dementia. Due to similar clinical phenotypes, differential diagnosis is challenging without specific biomarkers. Beta-site Amyloid Precursor Protein cleaving enzyme 1 (BACE1) is a β-secretase pivotal in AD pathogenesis. In AD and mild cognitive impairment subjects, BACE1 activity is increased in brain/cerebrospinal fluid, and plasma levels appear to reflect those in the brain. In this study, we aim to evaluate serum BACE1 activity in FTD, since, to date, there is no evidence about its role. The serum of 30 FTD patients and 30 controls was analyzed to evaluate (i) BACE1 activity, using a fluorescent assay, and (ii) Glial Fibrillary Acid Protein (GFAP) and Neurofilament Light chain (NfL) levels, using a Simoa kit. As expected, a significant increase in GFAP and NfL levels was observed in FTD patients compared to controls. Serum BACE1 activity was not altered in FTD patients. A significant increase in serum BACE1 activity was shown in AD vs. FTD and controls. Our results support the hypothesis that serum BACE1 activity is a potential biomarker for the differential diagnosis between AD and FTD.

Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10 -12 , OR = 1.27) and APOE (rs6857; p = 1.31 × 10 -12 , OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10 -8 , OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex., Competing Interests: Declaration of interests O.A.A. has received speakers’ honoraria from Janssen, Lundbeck, and Sunovion and is a consultant to Cortechs.ai. C.C. received research support from GSK and EISAI. The funders of the study had no role in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. C.C. is a member of the advisory board of Vivid Genomics and Circular Genomics. M.A.N. and H.L.L. hold part of a competitive contract awarded to Data Tecnica International LLC by the National Institutes of Health to support open science research. M.A.N. currently serves on the scientific advisory board for Character Bio Inc. and Neuron23 Inc. I.R.M. receives license royalties for patent related to PGRN therapy and is a member of the scientific advisory committee for Prevail Therapeutics. H.R.M. is employed by UCL. In the last 12 months he reports paid consultancy from Roche, Aprinoia, AI Therapeutics, and Amylyx; lecture fees/honoraria from BMJ, Kyowa Kirin, and Movement Disorders Society; and research grants from Parkinson’s UK, Cure Parkinson’s Trust, PSP Association, Medical Research Council, and the Michael J. Fox Foundation. H.R.M. is a co-applicant on a patent application related to C9ORF72—Method for diagnosing a neurodegenerative disease (PCT/GB2012/052140). R.P. has received honoraria for advisory boards and speaker engagements from Roche, EISAI, Eli Lilly, Biogen, Janssen-Cilag, Astra Zeneca, Schwabe, Grifols, Novo Nordisk, and Tabuk. R.S.-V. served in advisory board meetings for Wave Life Sciences, Ionis, and Novo Nordisk; has received personal fees for participating in educational activities from Janssen, Roche Diagnostics, and Neuraxpharm; and has received funding to her institution for research projects from Biogen and Sage Pharmaceuticals. S.W.S. received research support from Cerevel Therapeutics and is a member of the scientific advisory board of the Lewy Body Dementia Association and the Multiple System Atrophy Coalition. J.S.Y. serves on the scientific advisory board for the Epstein Family Alzheimer’s Research Collaboration. J.H. does consulting and gives talks for Eli-Lilly, Roche, and Eisai and is on the Ceracuity advisory board., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) and Frontotemporal lobar degeneration (FTLD) represent the most common forms of neurodegenerative dementias with a highly phenotypic variability. Herein, we investigated the role of genetic variants related to the immune system and inflammation as genetic modulators in AD and related dementias. In patients with sporadic AD/FTLD (n = 300) and GRN / C9orf72 mutation carriers (n = 80), we performed a targeted sequencing of 50 genes belonging to the immune system and inflammation, selected based on their high expression in brain regions and low tolerance to genetic variation. The linear regression analyses revealed two genetic variants: (i) the rs1049296 in the transferrin ( TF ) gene, shown to be significantly associated with age at onset in the sporadic AD group, anticipating the disease onset of 4 years for each SNP allele with respect to the wild-type allele, and (ii) the rs7550295 in the calsyntenin-1 ( CLSTN1 ) gene, which was significantly associated with age at onset in the C9orf72 group, delaying the disease onset of 17 years in patients carrying the SNP allele. In conclusion, our data support the role of genetic variants in iron metabolism ( TF ) and in the modulation of the calcium signalling/axonal anterograde transport of vesicles ( CLSTN1 ) as genetic modulators in AD and FTLD due to C9orf72 expansions.

Alzheimer's Disease (AD) and Frontotemporal Dementia (FTD) are the two major neurodegenerative diseases with distinct clinical and neuropathological profiles. The aim of this report is to conduct a population-based investigation in well-characterized APP , PSEN1 , PSEN2 , MAPT , GRN , and C9orf72 mutation carriers/pedigrees from the north, the center, and the south of Italy. We retrospectively analyzed the data of 467 Italian individuals. We identified 21 different GRN mutations, 20 PSEN1 , 11 MAPT , 9 PSEN2 , and 4 APP . Moreover, we observed geographical variability in mutation frequencies by looking at each cohort of participants, and we observed a significant difference in age at onset among the genetic groups. Our study provides evidence that age at onset is influenced by the genetic group. Further work in identifying both genetic and environmental factors that modify the phenotypes in all groups is needed. Our study reveals Italian regional differences among the most relevant AD/FTD causative genes and emphasizes how the collaborative studies in rare diseases can provide new insights to expand knowledge on genetic/epigenetic modulators of age at onset.

Background: In recent years, an increasing number of studies have examined the potential efficacy of cognitive training procedures in individuals with normal ageing and mild cognitive impairment (MCI)., Objective: The aims of this study were to (i) evaluate the efficacy of the cognitive Virtual Reality Rehabilitation System (VRRS) combined with anodal transcranial direct current stimulation (tDCS) applied to the left dorsolateral prefrontal cortex compared to placebo tDCS stimulation combined with VRRS and (ii) to determine how to prolong the beneficial effects of the treatment. A total of 109 subjects with MCI were assigned to 1 of 5 study groups in a randomized controlled trial design: (a) face-to-face (FTF) VRRS during anodal tDCS followed by cognitive telerehabilitation (TR) (clinic-atDCS-VRRS+Tele@H-VRRS); (b) FTF VRRS during placebo tDCS followed by TR (clinic-ptDCS-VRRS+Tele@H-VRRS); (c) FTF VRRS followed by cognitive TR (clinic-VRRS+Tele@H-VRRS); (d) FTF VRRS followed by at-home unstructured cognitive stimulation (clinic-VRRS+@H-UCS); and (e) FTF cognitive treatment as usual (clinic-TAU)., Results: An improvement in episodic memory was observed after the end of clinic-atDCS-VRRS ( p  < 0.001). We found no enhancement in episodic memory after clinic-ptDCS-VRRS or after clinic-TAU.Moreover, the combined treatment led to prolonged beneficial effects (clinic-atDCS-VRRS+Tele@H-VRRS vs. clinic-ptDCS-VRRS+Tele@H-VRRS: p  = 0.047; clinic-atDCS-VRRS+Tele@H-VRRS vs. clinic-VRRS+Tele@H-VRRS: p  = 0.06)., Discussion: The present study provides preliminary evidence supporting the use of individualized VRRS combined with anodal tDCS and cognitive telerehabilitation for cognitive rehabilitation., Clinical Trial Registration: https://clinicaltrials.gov/study/NCT03486704?term=NCT03486704&rank=1, NCT03486704., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Manenti, Baglio, Pagnoni, Gobbi, Campana, Alaimo, Rossetto, Di Tella, Pagliari, Geviti, Bonfiglio, Calabrò, Cimino, Binetti, Quartarone, Bramanti, Cappa, Rossini and Cotelli.)

Background: Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations., Methods: Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data., Results: We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p = 0.007) with a trend in non-carriers (p = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers., Conclusions: These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD., (© 2024. The Author(s).)

Introduction: The goal of the present work was to assess the incidence of dementia with onset before the age of 65 years (i.e., young-onset dementia [YOD]) and define the frequencies of young-onset Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD), and dementia with Lewy bodies (DLB) in the general population., Methods: The study was conducted from January 1, 2019 to December 31, 2019 in Brescia province (population: 1,268,455). During the study period, all new YOD cases (incident YOD) were counted, and all patients' records reviewed. The incidence was standardized to the Italian general population in 2019., Results: A total of 29 YOD patients were diagnosed. The age-sex standardized incidence rate was 4.58 (95% confidence interval, 3.07-6.58) per 100,000 person-years. No difference in incidence rate between YOD due to AD or FTLD ( P  = 0.83) and between sexes ( P  = 0.81) was observed. YOD incidence increased with age, reaching its peak after 60 years., Discussion: Presenting neurodegenerative YOD phenotypes encompasses both AD and FTLD. Improved knowledge on YOD epidemiology is essential to adequately plan and organize health services., Competing Interests: The authors declare no conflicts of interest. Author disclosures are available in the supporting information., (© 2024 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Episodic memory shows the largest degree of age-related decline. Anodal transcranial Direct Current Stimulation (tDCS) can enhance episodic memory in aging but there is also evidence of response variability even when using identical stimulation parameters. To explore which inter-individual factors (i.e. age, education, encoding performance, cognitive reserve, tDCS group and timing of tDCS application) may directly and/or indirectly modulate verbal memory recall, we used data from our previous tDCS studies that showed enhanced episodic memory recall in 80 healthy older adults. In these studies we used the same paradigm and stimulation parameters but tDCS was applied during different memory stages. Memory recall was tested 48 hours and 30 days after encoding. Univariate regression models showed that tDCS group (Anodal vs. Sham) predicted memory recall, indicating higher scores in the Anodal group than in the Sham group. Encoding performance predicted memory recall in both tDCS groups. Multiple regression models revealed that cognitive reserve, measured with a life experience questionnaire, predicted memory recall only for the Anodal group. Higher cognitive reserve was linked to better memory recall. Accounting for individual differences in cognitive reserve at baseline helps to explain tDCS responsiveness. This knowledge may contribute to optimize its use in older adults., (© 2024. The Author(s).)

The accumulation of protein aggregates defines distinct, yet overlapping pathologies such as Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). In this study, we investigated ATG5, UBQLN2, ULK1, and LC3 concentrations in 66 brain specimens and 120 plasma samples from AD, DLB, FTD, and control subjects (CTRL). Protein concentration was measured with ELISA kits in temporal, frontal, and occipital cortex specimens of 32 AD, 10 DLB, 10 FTD, and 14 CTRL, and in plasma samples of 30 AD, 30 DLB, 30 FTD, and 30 CTRL. We found alterations in ATG5, UBQLN2, ULK1, and LC3 levels in patients; ATG5 and UBQLN2 levels were decreased in both brain specimens and plasma samples of patients compared to those of the CTRL, while LC3 levels were increased in the frontal cortex of DLB and FTD patients. In this study, we demonstrate alterations in different steps related to ATG5, UBQLN2, and LC3 autophagy pathways in DLB and FTD patients. Molecular alterations in the autophagic processes could play a role in a shared pathway involved in the pathogenesis of neurodegeneration, supporting the hypothesis of a common molecular mechanism underlying major neurodegenerative dementias and suggesting different potential therapeutic targets in the autophagy pathway for these disorders.

Introduction: As the chemokine receptor5 (CCR5) may play a role in ischemia, we studied the links between CCR5 deficiency, the sensitivity of neurons to oxidative stress, and the development of dementia., Methods: Logistic regression models with CCR5/apolipoprotein E (ApoE) polymorphisms were applied on a sample of 205 cognitively normal individuals and 189 dementia patients from Geneva. The impact of oxidative stress on Ccr5 expression and cell death was assessed in mice neurons., Results: CCR5-Δ32 allele synergized with ApoEε4 as risk factor for dementia and specifically for dementia with a vascular component. We confirmed these results in an independent cohort from Italy (157 cognitively normal and 620 dementia). Carriers of the ApoEε4/CCR5-Δ32 genotype aged ≥80 years have an 11-fold greater risk of vascular-and-mixed dementia. Oxidative stress-induced cell death in Ccr5 -/- mice neurons., Discussion: We propose the vulnerability of CCR5-deficient neurons in response to oxidative stress as possible mechanisms contributing to dementia., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The introduction of computerized medical records in hospitals has reduced burdensome activities like manual writing and information fetching. However, the data contained in medical records are still far underutilized, primarily because extracting data from unstructured textual medical records takes time and effort. Information Extraction, a subfield of Natural Language Processing, can help clinical practitioners overcome this limitation by using automated text-mining pipelines. In this work, we created the first Italian neuropsychiatric Named Entity Recognition dataset, PsyNIT, and used it to develop a Transformers-based model. Moreover, we collected and leveraged three external independent datasets to implement an effective multicenter model, with overall F1-score 84.77 %, Precision 83.16 %, Recall 86.44 %. The lessons learned are: (i) the crucial role of a consistent annotation process and (ii) a fine-tuning strategy that combines classical methods with a "low-resource" approach. This allowed us to establish methodological guidelines that pave the way for Natural Language Processing studies in less-resourced languages., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Primary Progressive Aphasia (PPA) is a syndrome due to different neurodegenerative disorders selectively disrupting language functions. PPA specialist care is underdeveloped. There are very few specialists (neurologists, psychiatrists, neuropsychologists, and speech therapists) and few hospital- or community-based services dedicated to the diagnosis and continuing care of people with PPA. Currently, healthcare systems struggle to provide adequate coverage of care that is too often fragmented, uncoordinated, and unresponsive to the needs of people with PPA and their families. Recently, attention has been gained by non-invasive brain stimulation techniques that allow a personalized treatment approach, such as transcranial Direct Current Stimulation (tDCS). The MAINSTREAM trial looks forward to introducing and evaluating therapeutic innovations such as tDCS coupled with language therapy in rehabilitation settings. A Multimodal Approach for Clinical Diagnosis and Treatment of Primary Progressive Aphasia, MAINSTREAM (ID: 3430931) was registered in the clinicaltrials.gov database (identifier: NCT05730023) on 15 February 2023.

Objectives: There is increasing evidence for a protective role of nutritional factors on cognitive decline. Many studies have reported a preventive effect of specific dietary patterns, in particular of the Mediterranean diet (MD), on the risk of cognitive decline, but only limited evidence is available about its effects on neuropsychological performance. The aim of this work is to evaluate the relationship between nutrition and cognitive performance in a frail elderly population living in Northern Italy. Methods: In this study we have investigated the impact of the Mediterranean dietary pattern on cognitive performance in a frail elderly population (n = 140). Structural equation modeling was applied to highlight the interrelationship between three cognitive domains: i) Verbal Fluency ; ii) Attention/executive function ; iii) Memory, and two MD factors: i) Nutrition ; ii) Anthropometric/physical activity. In addition, the Multiple Correspondence Analysis was performed to detect the food and nutrients with the highest association with MD and nutritional status. Results: In our sample, 54% of subjects have a medium-high adherence to MD and only 4% have a risk of malnutrition. The variable Nutrition was significantly associated (p < 0.001) with the cognitive domain Attention/executive function, with an increase in Nutrition directly associated with a better performance in Attention/executive function . Conclusions: This study provides preliminary evidence of an association between good nutritional status, related to a high adherence to the MD, and cognitive performance in a non-clinical elderly population living in Northern Italy.

Primary progressive aphasias (PPAs) are a group of neurodegenerative diseases mainly characterized by language impairment, and with variably presence of dysexecutive syndrome, behavioural disturbances and parkinsonism. Detailed knowledge of neurotransmitters impairment and its association with clinical features hold the potential to develop new tailored therapeutic approaches. In the present study, we applied JuSpace toolbox, which allowed for cross-modal correlation of magnetic resonance imaging (MRI)-based measures with nuclear imaging derived estimates covering various neurotransmitter systems including dopaminergic, serotonergic, noradrenergic, GABAergic and glutamatergic neurotransmission. We included 103 PPA patients and 80 age-matched healthy controls (HC). We tested if the spatial patterns of grey matter volume (GMV) alterations in PPA patients (relative to HC) are correlated with specific neurotransmitter systems. As compared to HC, voxel-based brain changes in PPA were significantly associated with spatial distribution of serotonin, dopamine, and glutamatergic pathways (p < .05, False Discovery Rate corrected-corrected). Disease severity was negatively correlated with the strength of GMV colocalization of D1 receptors (p = .035) and serotonin transporter (p = .020). Moreover, we observed a significant negative correlation between positive behavioural symptoms, as measured with Frontal Behavioural Inventory, and GMV colocalization of D1 receptors (p = .007) and serotonin transporter (p < .001). This pilot study suggests that JuSpace is a helpful tool to indirectly assess neurotransmitter deficits in neurodegenerative dementias and may provide novel insight into disease mechanisms and associated clinical features., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: Non-fluent/agrammatic variant of Primary Progressive Aphasia (avPPA) is primarily characterized by language impairment due to atrophy of the inferior frontal gyrus and the insula cortex in the dominant hemisphere. The Screening for Aphasia in NeuroDegeneration (SAND) battery has been recently proposed as a screening tool for PPA, with several tasks designed to be specific for different language features. Applying multivariate approaches to neuroimaging data and verbal fluency tasks, Aachener Aphasie Test (AAT) naming subtest and SAND data may help in elucidating the neuroanatomical correlates of language deficits in avPPA., Objective: To investigate the neuroanatomical correlates of language deficits in avPPA using verbal fluency tasks, AAT naming subtest and SAND scores as proxies of brain structural imaging abnormalities., Methods: Thirty-one avPPA patients were consecutively enrolled and underwent extensive neuropsychological assessment and MRI scan. Raw scores of verbal fluency tasks, AAT naming subtest, and SAND subtests, namely living and non-living picture naming, auditory sentence comprehension, single-word comprehension, words and non-words repetition and sentence repetition, were used as proxies to explore structural (gray matter volume) neuroanatomical correlates. We assessed univariate (voxel-based morphometry, VBM) as well as multivariate (source-based morphometry, SBM) approaches. Age, gender, educational level, and disease severity were considered nuisance variables., Results: SAND picture naming (total, living and non-living scores) and AAT naming scores showed a direct correlation with the left temporal network derived from SBM. At univariate analysis, the left middle temporal gyrus was directly correlated with SAND picture naming (total and non-living scores) and AAT naming score. When words and non-words repetition (total score) was considered, a direct correlation with the left temporal network (SBM) and with the left fusiform gyrus (VBM) was also evident., Conclusion: Naming impairments that characterize avPPA are related to specific network-based involvement of the left temporal network, potentially expanding our knowledge on the neuroanatomical basis of this neurodegenerative condition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Premi, Cotelli, Gobbi, Pagnoni, Binetti, Gadola, Libri, Mattioli, Pengo, Iraji, Calhoun, Alberici, Borroni and Manenti.)

Genetic frontotemporal lobar degeneration (FTLD) is characterized by heterogeneous phenotypic expression, with a disease onset highly variable even in patients carrying the same mutation. Herein we investigated if variants in lysosomal genes modulate the age of onset both in FTLD due to GRN null mutations and C9orf72 expansion. In a total of 127 subjects ( n = 74 GRN mutations and n = 53 C9orf72 expansion carriers), we performed targeted sequencing of the top 98 genes belonging to the lysosomal pathway, selected based on their high expression in multiple brain regions. We described an earlier disease onset in GRN/C9orf72 pedigrees in subjects carrying the p.Asn521Thr variant (rs1043424) in PTEN-induced kinase 1 ( PINK1 ), a gene that is already known to be involved in neurodegenerative diseases. We found that: (i) the PINK1 rs1043424 C allele is significantly associated with the age of onset; (ii) every risk C allele increases hazard by 2.11%; (iii) the estimated median age of onset in homozygous risk allele carriers is 10-12 years earlier than heterozygous/wild type homozygous subjects. A replication study in GRN/C9orf72 negative FTLD patients confirmed that the rs1043424 C allele was associated with earlier disease onset (-5.5 years in CC versus A carriers). Understanding the potential mechanisms behind the observed modulating effect of the PINK1 gene in FTLD might prove critical for identifying biomarkers and/or designing drugs to modify the age of onset, especially in GRN/C9orf72 -driven disease.

Emerging data suggest the roles of endo-lysosomal dysfunctions in frontotemporal lobar degeneration (FTLD) and in other dementias. Cathepsin D is one of the major lysosomal proteases, mediating the degradation of unfolded protein aggregates. In this retrospective study, we investigated cathepsin D levels in human plasma and in the plasma small extracellular vesicles (sEVs) of 161 subjects (40 sporadic FTLD, 33 intermediate/pathological C9orf72 expansion carriers, 45 heterozygous/homozygous GRN mutation carriers, and 43 controls). Cathepsin D was quantified by ELISA, and nanoparticle tracking analysis data (sEV concentration for the cathepsin D level normalization) were extracted from our previously published dataset or were newly generated. First, we revealed a positive correlation of the cathepsin D levels with the age of the patients and controls. Even if no significant differences were found in the cathepsin D plasma levels, we observed a progressive reduction in plasma cathepsin D moving from the intermediate to C9orf72 pathological expansion carriers. Observing the sEVs nano-compartment, we observed increased cathepsin D sEV cargo (ng/sEV) levels in genetic/sporadic FTLD. The diagnostic performance of this biomarker was fairly high (AUC = 0.85). Moreover, sEV and plasma cathepsin D levels were positively correlated with age at onset. In conclusion, our study further emphasizes the common occurrence of endo-lysosomal dysregulation in GRN/C9orf72 and sporadic FTLD.

Many physiological processes in the human body follow a 24-h circadian rhythm controlled by the circadian clock system. Light, sensed by retina, is the predominant "zeitgeber" able to synchronize the circadian rhythms to the light-dark cycles. Circadian rhythm dysfunction and sleep disorders have been associated with aging and neurodegenerative diseases including mild cognitive impairment (MCI) and Alzheimer's disease (AD). In the present study, we aimed at investigating the genetic variability of clock genes in AD patients compared to healthy controls from Italy. We also included a group of Italian centenarians, considered as super-controls in association studies given their extreme phenotype of successful aging. We analyzed the exon sequences of eighty-four genes related to circadian rhythms, and the most significant variants identified in this first discovery phase were further assessed in a larger independent cohort of AD patients by matrix assisted laser desorption/ionization-time of flight mass spectrometry. The results identified a significant association between the rs3027178 polymorphism in the PER1 circadian gene with AD, the G allele being protective for AD. Interestingly, rs3027178 showed similar genotypic frequencies among AD patients and centenarians. These results collectively underline the relevance of circadian dysfunction in the predisposition to AD and contribute to the discussion on the role of the relationship between the genetics of age-related diseases and of longevity., (© 2021. The Author(s).)

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele., (© 2022. The Author(s).)

Background: Memory impairment is among one of the greatest cognitive complaints in midlife and in old age. Considering the importance of good memory functioning in everyday life, it is crucial to study interventions that can reduce the natural decline in this cognitive function. Transcranial Magnetic Stimulation (TMS) studies have demonstrated that the lateral prefrontal cortex (PFC) plays a causal role in enhancing episodic memory recall through reconsolidation. Using a similar paradigm with transcranial direct current stimulation (tDCS) over the left lateral PFC, facilitation effects were observed in delayed memory retrieval in older adults with subjective memory complaints (SMCs) and amnestic Mild Cognitive Impairment (aMCI). However, it remains unclear which potential factors (i.e., tDCS group, cognitive reserve, education level, diagnosis and encoding performance) directly and/or indirectly modulate the tDCS-induced memory reconsolidation effects., Methods: We reanalyzed data acquired in our previous tDCS studies with 22 SMC and 18 aMCI participants from the perspective of predicting delayed memory retrieval performance. These studies included a learning session on Day 1, a reactivation by a contextual reminder followed by 15 min of tDCS session on Day 2 (24 h after Day 1), and two retrieval sessions (free recall and recognition) tested on Days 3 and 30 (48 h and 30 Days after Day 1)., Results: Univariate models showed that tDCS group (sham vs. active) significantly predicted memory recognition (but not free recall), evidenced by higher scores in the active tDCS group than in sham group, confirming our previous results. Encoding performance and diagnosis (SMC vs. aMCI) significantly predicted memory retrieval, suggesting higher performances in individuals with SMC than in those with aMCI. Regarding cognitive reserve, higher leisure time activity subscores significantly predicted better memory recognition. Finally, multiple models did not show any tDCS group × predictor interaction effects, indicating that the effects of the predictors on retrieval occurred irrespective of tDCS group., Conclusion: Our results shed light on predicting factors of episodic memory retrieval in this reconsolidation paradigm in individuals with SMC and aMCI. The findings suggest that multifactorial interventions program may be most promising to slow cognitive decline and delay the onset of dementia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cotelli, Ferrari, Gobbi, Binetti, Manenti and Sandrini.)

Cutting-edge research suggests endosomal/immune dysregulation in GRN / C9orf72 -associated frontotemporal lobar degeneration (FTLD). In this retrospective study, we investigated plasma small extracellular vesicles (sEVs) and complement proteins in 172 subjects (40 Sporadic FTLD, 40 Intermediate/Pathological C9orf72 expansion carriers, and 49 Heterozygous/Homozygous GRN mutation carriers, 43 controls). Plasma sEVs (concentration, size) were analyzed by nanoparticle tracking analysis; plasma and sEVs C1q, C4, C3 proteins were quantified by multiplex assay. We demonstrated that genetic/sporadic FTLD share lower sEV concentrations and higher sEV sizes. The diagnostic performance of the two most predictive variables (sEV concentration/size ratio) was high (AUC = 0.91, sensitivity 85.3%, specificity 81.4%). C1q, C4, and C3 cargo per sEV is increased in genetic and sporadic FTLD. C4 (cargo per sEV, total sEV concentration) is increased in Sporadic FTLD and reduced in GRN + Homozygous, suggesting its specific unbalance compared with Heterozygous cases. C3 plasma level was increased in genetic vs. sporadic FTLD. Looking at complement protein compartmentalization, in control subjects, the C3 and C4 sEV concentrations were roughly half that in respect to those measured in plasma; interestingly, this compartmentalization was altered in different ways in patients. These results suggest sEVs and complement proteins as potential therapeutic targets to mitigate neurodegeneration in FTLD.

Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD) represent the three major neurodegenerative dementias characterized by abnormal brain protein accumulation. In this study, we investigated extracellular vesicles (EVs) and neurotrophic factors in the cerebrospinal fluid (CSF) of 120 subjects: 36 with AD, 30 with DLB, 34 with FTD and 20 controls. Specifically, CSF EVs were analyzed by Nanoparticle Tracking Analysis and neurotrophic factors were measured with ELISA. We found higher EV concentration and lower EV size in AD and DLB groups compared to the controls. Classification tree analysis demonstrated EV size as the best parameter able to discriminate the patients from the controls (96.7% vs. 3.3%, respectively). The diagnostic performance of the EV concentration/size ratio resulted in a fair discrimination level with an area under the curve of 0.74. Moreover, the EV concentration/size ratio was associated with the p-Tau181/Aβ42 ratio in AD patients. In addition, we described altered levels of cystatin C and progranulin in the DLB and AD groups. We did not find any correlation between neurotrophic factors and EV parameters. In conclusion, the results of this study suggest a common involvement of the endosomal pathway in neurodegenerative dementias, giving important insight into the molecular mechanisms underlying these pathologies.

Background: Beta-site APP cleaving enzyme 1 (BACE1) is the rate-limiting enzyme in amyloid-β (Aβ) plaques formation. BACE1 activity is increased in brains of patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) and plasma levels of BACE1 appears to reflect those in the brains., Objective: In this work, we investigated the role of serum BACE1 activity as biomarker for AD, estimating the diagnostic accuracy of the assay and assessing the correlation of BACE1 activity with levels of Aβ1 - 40, Aβ1 - 42, and Aβ40/42 ratio in serum, known biomarkers of brain amyloidosis., Methods: Serum BACE1 activity and levels of Aβ1 - 40, Aβ1 - 42, were assessed in 31 AD, 28 MCI, diagnosed as AD at follow-up (MCI-AD), and 30 controls. The BACE1 analysis was performed with a luciferase assay, where interpolation of relative fluorescence units with a standard curve of concentration reveals BACE1 activity. Serum levels of Aβ1 - 40, Aβ1 - 42 were measured with the ultrasensitive Single Molecule Array technology., Results: BACE1 was increased (higher than 60%) in AD and MCI-AD: a cut-off of 11.04 kU/L discriminated patients with high sensitivity (98.31%) and specificity (100%). Diagnostic accuracy was higher for BACE1 than Aβ40/42 ratio. High BACE1 levels were associated with worse cognitive performance and earlier disease onset, which was anticipated by 8 years in patients with BACE1 values above the median value (> 16.67 kU/L)., Conclusion: Our results provide new evidence supporting serum/plasma BACE1 activity as an early biomarker of AD.

Dysfunctions in the endo-lysosomal system have been hypothesized to underlie neurodegeneration in major neurocognitive disorders due to Alzheimer's disease (AD), Frontotemporal Lobar Degeneration (FTLD), and Lewy body disease (DLB). The aim of this study is to investigate whether these diseases share genetic variability in the endo-lysosomal pathway. In AD, DLB, and FTLD patients and in controls (948 subjects), we performed a targeted sequencing of the top 50 genes belonging to the endo-lysosomal pathway. Genetic analyses revealed (i) four previously reported disease-associated variants in the SORL1 (p.N1246K, p.N371T, p.D2065V) and DNAJC6 genes (p.M133L) in AD, FTLD, and DLB, extending the previous knowledge attesting SORL1 and DNAJC6 as AD- and PD-related genes, respectively; (ii) three predicted null variants in AD patients in the SORL1 (p.R985X in early onset familial AD, p.R1207X) and PPT1 (p.R48X in early onset familial AD) genes, where loss of function is a known disease mechanism. A single variant and gene burden analysis revealed some nominally significant results of potential interest for SORL1 and DNAJC6 genes. Our data highlight that genes controlling key endo-lysosomal processes (i.e., protein sorting/transport, clathrin-coated vesicle uncoating, lysosomal enzymatic activity regulation) might be involved in AD, FTLD and DLB pathogenesis, thus suggesting an etiological link behind these diseases.

Alzheimer's disease (AD) is a pathology characterized by the accumulation in the brain of intracellular and extracellular amyloid-β (Aβ) aggregates, especially of Aβ1-40 and Aβ1-42 peptides. It is known that N-terminally truncated or modified Aβ forms also exist in AD brains and cerebrospinal fluid (CSF), and they play a key role in the pathogenesis of the disease. Herein, we developed an antibody-free method based on Solid-Phase Extraction and Electrospray Ionization Liquid Chromatography Mass Spectrometry for the identification and quantitation in human CSF of Aβ isoforms. In human CSF, we could detect and quantify a panel of 19 Aβ isoforms, including N-terminally truncated and pyroglutamate-modified forms, never quantified before in CSF. Among these, we identified novel N-terminally truncated Aβ species: four bound to copper and two phosphorylated forms, which were found to be the most common proteoforms in human CSF along with Aβ1-40, Aβ3-40, and AβpE11-42. We tested the newly developed and validated method in a pilot study on CSF from elderly individuals with subjective memory complaints (SMCs, n = 9), mild cognitive impairment (MCI, n = 18), and AD ( n = 15); along with Aβ1-42, five N-terminally truncated forms (Aβ11-40, Aβ3-42, AβpE11-42, AβpE3-40, and Aβ4-40 Cu 2+ ) are altered in AD/MCI. Thus, we demonstrated that N-terminally truncated and pyroglutamate-modified Aβ can be quantified in human CSF, and five of them, along with Aβ1-42, are potential markers of AD progression. The described method could represent a useful tool for patients' stratification and monitoring. Moreover, the newly identified Aβ CSF species might represent new potential therapeutic targets., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Domingo, Benussi, Saraceno, Bertuzzi, Nicsanu, Longobardi, Bellini, Cagnotto, Salmona, Binetti and Ghidoni.)

Background: Primary progressive aphasia (PPA) is a neurodegenerative disorder characterized by a gradual, insidious and progressive loss of language abilities, with naming difficulties being an early and persistent impairment common to all three variants. In the absence of effective pharmacological treatments and given the progressive nature of the disorder, in the past few decades, many studies have investigated the effectiveness of language training to minimize the functional impact of word-finding difficulties in daily life., Main Body: We review language treatments most commonly used in clinical practice among patients with different variants of PPA, with a focus on the enhancement of spoken and written naming abilities. Generalization of gains to the ability to name untrained stimuli or to other language abilities and the maintenance of these results over time are also discussed. Forty-eight studies were included in this literature review, identifying four main types of language treatment: a) lexical retrieval treatment, b) phonological and/or orthographic treatment, c) semantic treatment, and d) a multimodality approach treatment. Overall, language training is able to induce immediate improvements of naming abilities in all variants of PPA. Moreover, despite the large variability among results, generalization and long-term effects can be recorded after the training. The reviewed studies also suggest that one factor that determines the choice of a particular approach is the compromised components of the lexical/semantic processing system., Conclusion: The majority of studies have demonstrated improvements of naming abilities following language treatments. Given the progressive nature of PPA, it is essential to apply language treatment in the early stages of the disease., (© 2021. The Author(s).)

Background: In recent years, emphasis has been placed on cognitive enhancement to stimulate cognitive abilities and prevent functional decline. Considering that traditional face-to-face interventions can be very expensive and are not accessible to all individuals, the need to transfer care from the clinic to the patient's home is evident. In this regard, cognitive tele-enhancement interventions have received increased attention. Aim: The aim of this review was to provide an overview of protocols that apply remotely controlled cognitive training with individualized feedback on performance by the therapist in healthy older adults or participants with subjective memory complaints. Methods: Out of 35 articles assessed for eligibility, eight studies were identified. Of the selected studies, five included cognitively healthy older adults, while three included participants with subjective memory complaints. Results: Most of the reviewed studies showed beneficial effects of cognitive tele-enhancement interventions, reporting improvements in memory, sustained attention, working memory, executive functions, and language abilities. Moreover, reductions in anxiety and depression symptomatology levels, as well as in subjective memory difficulties, were described in some of the studies. Conclusions: Cognitive tele-enhancement treatment could be a good alternative to face-to-face intervention. This literature review highlights the importance of applying preventive cognitive interventions to subjects with initial subjective memory complaints. Remote modalities seem to facilitate the application of such interventions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Alaimo, Campana, Stoppelli, Gobbi, Baglio, Rossetto, Binetti, Zanetti, Manenti and Cotelli.)

Evidence indicates that patients with Alzheimer's dementia (AD) show signs of copper (Cu) dyshomeostasis. This study aimed at evaluating the potential of Cu dysregulation as an AD susceptibility factor. We performed a meta-analysis of 56 studies investigating Cu biomarkers in brain specimens (pooled total of 182 AD and 166 healthy controls, HC) and in serum/plasma (pooled total of 2929 AD and 3547 HC). We also completed a replication study of serum Cu biomarkers in 97 AD patients and 70 HC screened for rs732774 and rs1061472 ATP7B , the gene encoding for the Cu transporter ATPase7B. Our meta-analysis showed decreased Cu in AD brain specimens, increased Cu and nonbound ceruloplasmin (Non-Cp) Cu in serum/plasma samples, and unchanged ceruloplasmin. Serum/plasma Cu excess was associated with a three to fourfold increase in the risk of having AD. Our replication study confirmed meta-analysis results and showed that carriers of the ATP7B AG haplotype were significantly more frequent in the AD group. Overall, our study shows that AD patients fail to maintain a Cu metabolic balance and reveals the presence of a percentage of AD patients carrying ATP7B AG haplotype and presenting Non-Cp Cu excess, which suggest that a subset of AD subjects is prone to Cu imbalance. This AD subtype can be the target of precision medicine-based strategies tackling Cu dysregulation.

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

The observation of neurological patients showing selective impairments for specific conceptual categories contributed in the development of semantic memory theories. Here, we studied two patients (P01, P02), affected, respectively, by the semantic variant of Primary Progressive Aphasia (sv-PPA) and Cortico-Basal Syndrome (CBS). An implicit lexical decision task, including concrete (animals, tools) and abstract (emotions, social, quantity) concepts, was administered to patients and healthy controls.P01 and P02 showed an abolished priming effect for social and quantity-related concepts, respectively. This double dissociation suggests a role of different brain areas in representing specific abstract categories, giving insights for current semantic memory theories.

Alzheimer's disease (AD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB) are the three major neurodegenerative dementias. In this study, we provide evidence that an alteration in extracellular vesicles (EVs) release is common across the three most common neurodegenerative dementias, AD, DLB, and FTD. Specifically, we analyzed plasma EVs in three groups of patients affected by AD, DLB, and FTD, and we found a significant reduction in EVs concentration and larger EVs size in all patient groups. We then investigated whether the loss of neurotrophic factors is also a common pathogenic mechanism among FTD, DLB, and AD, and if levels of neurotrophic factors might affect EVs release. Plasma levels of progranulin and cystatin C (CysC) were partially altered; however, taking together all variables significantly associated with the diagnostic groups only EVs size and concentration were able to distinguish patients from controls. The diagnostic performance of these two EVs parameters together (ratio) was high, with a sensitivity of 83.3% and a specificity of 86.7%, able to distinguish patients from controls but not to differentiate the different forms of dementias. Among the candidate neurotrophic factors, only CysC levels were associated with EVs concentration. Our study suggests that an alteration in the intercellular communication mediated by EVs might be a common molecular pathway underlying neurodegenerative dementias. The identification of shared disease mechanisms is of pivotal importance to develop treatments to delay disease progression. To this aim, further studies investigating plasma EVs size and concentration as early biomarkers of dementia are required., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Longobardi, Benussi, Nicsanu, Bellini, Ferrari, Saraceno, Zanardini, Catania, Di Fede, Squitti, Binetti and Ghidoni.)

Frontotemporal dementia (FTD) is a clinical, genetic, and pathologic heterogeneous group of neurodegenerative diseases. In this study, we investigated the role of APOƐ4, rs5848 in GRN, and rs1042522 in TP53 gene as disease risk factors and/or phenotype modifiers in 440 FTD patients, including 175 C9orf72 expansion carriers. We found that the C9orf72 expansion carriers showing an earlier age at onset (p < 0.001). Among the clinical groups, the FTD-MND (motoneuron disease) showed the lowest survival (hazard ratio [HR] = 4.12), and the progressive nonfluent aphasia group showed the highest onset age (p = 0.03). In our cohort, the rs1042522 in TP53 was associated with disease onset (p = 0.02) and survival (HR = 1.73) and rs5848 GRN with a significantly shorter survival in CC homozygous patients (HR = 1.98). The frequency of APOƐ4 carriers was significantly increased in the C9orf72 noncarriers (p = 0.022). Although validation of our findings is necessary, our results suggest that TP53, GRN, and APOE genes may act as phenotype modifiers in FTD and should be considered in future clinical trials., (Copyright © 2020 Elsevier Inc. All rights reserved.)

We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered., Competing Interests: Declaration of Interests S.P.-B., A.B.S., J.A.H., H.R.M., and B.J.T. hold US, EU, and Canadian patents on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9 or f72. S.W.S. serves on the scientific advisory council of the Lewy Body Dementia Association and is an editorial board member for the Journal of Parkinson’s Disease. B.J.T. is an editorial board member for JAMA Neurology, JNNP, and Neurobiology of Aging. V.S. is on the journal editorial boards of Amyotrophic Lateral Sclerosis, European Neurology, American Journal of Neurodegenerative Diseases, and Frontiers in Neurology. He has also received compensation for consulting services and speaking activities from AveXis, Cytokinetics, Italfarmaco, and Zambon. J.B.R. is an editor for Brain and has received compensation for consulting services from Asceneuron, Biogen, UCB, Astex, and SV Health. J.E.L. is a member of the scientific advisory board for Cerevel Therapeutics and a consultant and provides expert testimony for Perkins Coie., (Published by Elsevier Inc.)

Eating behavior can change during aging due to physiological, psychological, and social changes. Modifications can occur at different levels: (1) in food choice, (2) in eating habits, and (3) in dietary intake. A good dietary behavior, like the Mediterranean dietary pattern, can be a protective factor for some aging related pathologies, such as dementia, while a worse eating behavior can lead to pathological conditions such as malnutrition. Changes in eating behavior can also be linked to the onset of dementia: for some types of dementia, such as frontotemporal dementia, dietary changes are one of the key clinical diagnostic feature, for others, like Alzheimer's disease, weight loss is a clinical reported feature. For these reasons, it is important to be able to assess eating behavior in a proper way, considering that there are normal age-related changes. An adequate assessment of dietary behavior can help to plan preventive intervention strategies for heathy aging or can help to identify abnormal behaviors that underline aging related-diseases. In this review, we have analyzed normal age-related and dementia-related changes and the tools that can be used to assess eating behavior. Thus, we make recommendations to screening and monitoring eating behavior in aging and dementia, and to adopt these tools in clinical practice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Fostinelli, De Amicis, Leone, Giustizieri, Binetti, Bertoli, Battezzati and Cappa.)