The Associations between Lifestyle Habits and Anxiety: A Prospective Study on Adolescents One Year after the Outbreak of the COVID-19 Pandemic.

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.

Cognitive reserve predicts episodic memory enhancement induced by transcranial direct current stimulation in healthy older adults.

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.

Autophagy Markers Are Altered in Alzheimer's Disease, Dementia with Lewy Bodies and Frontotemporal Dementia.

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.

Unsupervised [18F]Flortaucipir cutoffs for tau positivity and staging in Alzheimer's disease.

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.

Risk and protective factors associated with mental health status in an Italian sample of students during the fourth wave of COVID-19 pandemic.

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.

The PINK1 p.Asn521Thr Variant Is Associated with Earlier Disease Onset in GRN/C9orf72 Frontotemporal Lobar Degeneration.

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.

Plasma Small Extracellular Vesicle Cathepsin D Dysregulation in GRN/C9orf72 and Sporadic Frontotemporal Lobar Degeneration.

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.

Adolescents' mental health and maladaptive behaviors before the Covid-19 pandemic and 1-year after: analysis of trajectories over time and associated factors.

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.