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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 ß-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.
Assuntos
Doença de Alzheimer , Secretases da Proteína Precursora do Amiloide , Ácido Aspártico Endopeptidases , Biomarcadores , Demência Frontotemporal , Proteína Glial Fibrilar Ácida , Humanos , Doença de Alzheimer/sangue , Doença de Alzheimer/diagnóstico , Demência Frontotemporal/sangue , Demência Frontotemporal/diagnóstico , Secretases da Proteína Precursora do Amiloide/sangue , Secretases da Proteína Precursora do Amiloide/metabolismo , Diagnóstico Diferencial , Feminino , Masculino , Biomarcadores/sangue , Idoso , Projetos Piloto , Ácido Aspártico Endopeptidases/sangue , Pessoa de Meia-Idade , Proteína Glial Fibrilar Ácida/sangue , Proteínas de Neurofilamentos/sangue , Estudos de Casos e ControlesRESUMO
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.
Assuntos
Idade de Início , Doença de Alzheimer , Proteína C9orf72 , Degeneração Lobar Frontotemporal , Humanos , Doença de Alzheimer/genética , Proteína C9orf72/genética , Degeneração Lobar Frontotemporal/genética , Feminino , Masculino , Idoso , Pessoa de Meia-Idade , Expansão das Repetições de DNA/genética , Idoso de 80 Anos ou mais , Polimorfismo de Nucleotídeo Único , Transferrina/genética , Transferrina/metabolismo , Predisposição Genética para Doença , Variação GenéticaRESUMO
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.
Assuntos
Doença de Alzheimer , Demência Frontotemporal , Mutação , Proteínas tau , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/epidemiologia , Itália/epidemiologia , Demência Frontotemporal/genética , Demência Frontotemporal/epidemiologia , Demência Frontotemporal/patologia , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Proteínas tau/genética , Idade de Início , Proteína C9orf72/genética , Presenilina-2/genética , Estudos Retrospectivos , Precursor de Proteína beta-Amiloide/genética , Presenilina-1/genética , Progranulinas/genética , Adulto , Idoso de 80 Anos ou mais , Predisposição Genética para DoençaRESUMO
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.
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Changes in lifestyle during the pandemic may have predisposed adolescents to vulnerability to poor mental health. This study aims to evaluate these changes and their association with the course of anxiety. A prospective study was conducted with 153 participants (16 years old, 72% female) who were assessed before the pandemic (T0, November 2019-January 2020) and one year later (T1, April-May 2021). Lifestyle habits (free-time activities, maladaptive behaviors, sleep, screen use) and anxiety were measured. Data concerning experiences related to COVID-19 and family relations during lockdown were collected. A worsening in lifestyle habits and anxiety was found. Of note, the pattern of associations between lifestyle habits and anxiety was quite different in the two time-points, suggesting that the purpose and the impact of some habits may be changed after the pandemic. Regression analyses showed that increases in anxiety were associated with increases in sleep problems, heightened efforts to reduce screen time, and loneliness. Pathway analysis revealed the absence of cross-lagged effects among anxiety, screen use, and sleep, while concurrent associations between variables were found in both the assessments. These results suggest possible long-term effects of the pandemic. Risk-factors associated with the course of anxiety were identified among lifestyle habits, thus contributing to identifying targets for interventions.
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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.
Assuntos
Reserva Cognitiva , Memória Episódica , Estimulação Transcraniana por Corrente Contínua , Córtex Pré-Frontal/fisiologiaRESUMO
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.
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Doença de Alzheimer , Demência Frontotemporal , Doença por Corpos de Lewy , Doença de Pick , Humanos , Autofagia , Proteínas Relacionadas à Autofagia , Proteínas Adaptadoras de Transdução de SinalRESUMO
BACKGROUND: It is well known that the COVID-19 pandemic has caused a global health crisis, especially for young people. However, most studies were conducted during the first waves of the pandemic. Few Italian studies specifically attempted to broadly assess young people's mental health status during the fourth wave of the pandemic. METHODS: This study aimed at evaluating the mental health status among a group of Italian adolescents and young adults during the fourth wave of the COVID-19 pandemic. 11,839 high school students and 15,000 university students (age range 14-25) were asked to complete a multidimensional online survey, of which 7,146 (26,6%) agreed to participate. The survey also included standardized measures for depression, anxiety, anger, somatic symptoms, resilience, loneliness and post-traumatic growth. Two separate clusters were identified through cluster analysis. Random forest, classification tree and logistic regressions analyses were applied to identify factors associated to a good or a poor level of mental health and, thus, to define students' mental health profiles. RESULTS: Overall, the students in our sample showed high levels of psychopathology. The clustering methods performed identified two separate clusters reflecting groups of students with different psychological features, that we further defined as "poor mental health" and "good mental health". The random forest and the logistic regressions found that the most discriminating variables among those two groups were: UCLA Loneliness Scale score, self-harm behaviors, Connor-Davidson Resilience Scale-10 score, satisfaction with family relationships, Fear of COVID-19 Scale score, gender and binge eating behaviors. The classification tree analysis identified students' profiles, showing that, globally, poor mental health was defined by higher scores of loneliness and self-harm, followed by being of female gender, presenting binge eating behaviors and, finally, having unsatisfying family relationships. CONCLUSIONS: The results of this study confirmed the major psychological distress caused by the COVID-19 pandemic in a large sample of Italian students, and provided further insights regarding those factors associated with a good or poor mental health status. Our findings suggest the importance of implementing programs targeting aspects that have been found to be associated to a good mental health.
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PURPOSE: Several [18F]Flortaucipir cutoffs have been proposed for tau PET positivity (T+) in Alzheimer's disease (AD), but none were data-driven. The aim of this study was to establish and validate unsupervised T+ cutoffs by applying Gaussian mixture models (GMM). METHODS: Amyloid negative (A-) cognitively normal (CN) and amyloid positive (A+) AD-related dementia (ADRD) subjects from ADNI (n=269) were included. ADNI (n=475) and Geneva Memory Clinic (GMC) cohorts (n=98) were used for validation. GMM-based cutoffs were extracted for the temporal meta-ROI, and validated against previously published cutoffs and visual rating. RESULTS: GMM-based cutoffs classified less subjects as T+, mainly in the A- CN (<3.4% vs >28.5%) and A+ CN (<14.5% vs >42.9%) groups and showed higher agreement with visual rating (ICC=0.91 vs ICC<0.62) than published cutoffs. CONCLUSION: We provided reliable data-driven [18F]Flortaucipir cutoffs for in vivo T+ detection in AD. These cutoffs might be useful to select participants in clinical and research studies.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Doença de Alzheimer/diagnóstico por imagem , Proteínas tau , Peptídeos beta-Amiloides , Tomografia por Emissão de Pósitrons , AmiloideRESUMO
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.
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Demência Frontotemporal , Degeneração Lobar Frontotemporal , Humanos , Criança , Proteína C9orf72/genética , Progranulinas/genética , Estudos de Coortes , Degeneração Lobar Frontotemporal/genética , Degeneração Lobar Frontotemporal/metabolismo , Demência Frontotemporal/genética , Mutação , Proteínas Quinases/genéticaRESUMO
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.
Assuntos
Vesículas Extracelulares , Demência Frontotemporal , Degeneração Lobar Frontotemporal , Proteína C9orf72/genética , Catepsina D/genética , Vesículas Extracelulares/metabolismo , Degeneração Lobar Frontotemporal/metabolismo , Humanos , Mutação , Progranulinas/genética , Agregados Proteicos , Estudos RetrospectivosRESUMO
BACKGROUND: Adolescents have been deeply exposed to negative consequences of social distancing imposed by Covid-19. There is a lack of longitudinal studies regarding the impact on adolescents of this unfavorable condition, and their results are controversial. The aim of the present prospective study is to assess psychopathological symptoms in adolescent students over time and to evaluate what type of impact the Covid-19 pandemic had on adolescents. Moreover, the association between mental health indexes, potential risk and resilience factors is explored. METHODS: Psychopathological symptoms (i.e., anxiety, depression, stress, emotional dysregulation, maladaptive behaviours), and potential risk and resilience factors (i.e., childhood trauma, emotional regulation skills, family function, personality traits) were assessed among a sample of 153 students (72% female; mean age 16.1 ± 0.49), living in a medium-size city in the north of Italy, at two time points: before the outbreak of the Covid-19 pandemic (November 2019-January 2020) and 1 year later (April-May 2021). RESULTS: After 1 year, we found an increase in mean scores on anxiety, stress for future uncertainty, and higher frequency of maladaptive behaviours. By contrast, the level of stress related to social domains (i.e., school attendance, romantic relationships, peer pressure) decreased. Dysfunctional emotional regulation skills, childhood trauma, low family functioning, and specific personality traits were associated to higher psychopathological symptoms. Cluster analysis detected three groups of youths based on their change over time in psychopathological symptoms: those who worsened (N = 23; 15%), improved (N = 55; 34%), or remained stable (N = 75; 46%). After controlling for baseline mental health status, those adolescents reporting increase in self-harm (OR = 2.61; p < 0.001), binge-drinking (OR = 3.0; p = 0.007), aggressiveness (OR 1.92; p = 0.004), and binge-eating (OR 2.55; p = 0.003) were more likely to present a worsened mental health condition. CONCLUSION: The present results suggest that the Covid-19 pandemic seems to have had a different impact on subgroups of students. Indeed, we found a global worsening of psychological well-being only in a subgroup of adolescents, otherwise other students remained stable or improved. Increased frequency of maladaptive behaviors was found as a predictor of worsened mental health, therefore interventions to strengthen emotional regulation strategies are warranted. Finally, the decrease of stress in social domains could be due to reduction of potential triggering situations, thus indicating only a temporary beneficial effect that requires careful monitoring.