The neuropsychology of healthy aging: the positive context of the University of the Third Age during the COVID-19 pandemic.

Older adults have been reported to have increased susceptibility to the adverse effects of SARS-CoV-2 infection, such as fatal outcomes, cognitive decline, and changes in physical and/or mental health. However, few studies have examined neuropsychological changes by comparing measurements before and during the pandemic in healthy older people. In addition, no longitudinal studies have examined whether older adults may have responded positively to the pandemic. We examined these issues through a 2-year neuropsychological study before and during the pandemic period. Results showed that scores before and during the pandemic were the same in memory and attention, whereas global cognitive, executive, and language functions improved. Participants also showed no longitudinal changes in depression, hypomania, and disinhibition, while apathy and, to a lesser extent, anxiety increased significantly. To examine possible signs of pandemic-related emotional (dys)regulation, subjects were shown images at follow-up that recalled the most dramatic lockdown phase while heart rate variability was recorded. Higher apathy was predicted by poorer global cognitive performance, increased anxiety, and emotional dysregulation as measured by a higher ratio of low-to-high frequency heart rate variability. Thus, preserved global cognition appears to play a protective role against the effects of pandemic-related anxiety and emotional dysregulation on apathy.

Adverse events of active and placebo groups in SARS-CoV-2 vaccine randomized trials: A systematic review.

BACKGROUND: For safety assessment in clinical trials, adverse events (AEs) are reported for the drug under evaluation and compared with AEs in the placebo group. Little is known about the nature of the AEs associated with clinical trials of SARS-CoV-2 vaccines and the extent to which these can be traced to nocebo effects, where negative treatment-related expectations favor their occurrence. METHODS: In our systematic review, we compared the rates of solicited AEs in the active and placebo groups of SARS-CoV-2 vaccines approved by the Western pharmaceutical regulatory agencies.We implemented a search strategy to identify trial-III studies of SARS-CoV-2 vaccines through the PubMed database. We adopted the PRISMA Statement to perform the study selection and the data collection and identified three trial: two mRNA-based (38403 participants) and one adenovirus type (6736 participants). FINDINGS: Relative risks showed that the occurrence of AEs reported in the vaccine groups was higher compared with the placebo groups. The most frequently AEs in both groups were fatigue, headache, local pain, as injection site reactions, and myalgia. In particular, for first doses in placebo recipients, fatigue was reported in 29% and 27% in BNT162b2 and mRNA-1273 groups, respectively, and in 21% of Ad26.COV2.S participants. Headache was reported in 27% in both mRNA groups and in 24% of Ad26.COV2.S recipients. Myalgia was reported in 10% and 14% in mRNA groups (BNT162b2 and mRNA-1273, respectively) and in 13% of Ad26.COV2.S participants. Local pain was reported in 12% and 17% in mRNA groups (BNT162b2 and mRNA-1273, respectively), and in 17% of Ad26.COV2.S recipients. These AEs are more common in the younger population and in the first dose of placebo recipients of the mRNA vaccines. INTERPRETATION: Our results are in agreement with the expectancy theory of nocebo effects and suggest that the AEs associated with COVID-19 vaccines may be related to the nocebo effect. FUNDING: Fondazione CRT - Cassa di Risparmio di Torino, IT (grant number 66346, "GAIA-MENTE" 2019).

Are Sleep Problems Related to Psychological Distress in Healthy Aging during the COVID-19 Pandemic? A Review.

The SARS-CoV-2 pandemic, characterized by home confinement and other restrictive measures to reduce the spread of the infection, led to significant changes in people's habits and lifestyle. One of the most common problems is the worsening of sleep quality or quantity, which could have negative effects on psychological wellbeing, particularly in older adults. The purposes of the present literature review considering healthy aging subjects are (a) to examine the existing research on sleep alterations during the current pandemic and (b) to highlight possible relationships between sleep problems and psychological distress. A systematic search strategy was implemented according to PRISMA guidelines in the international literature online databases, up to 1 July 2021. After identification and screening phases, 11 articles were included in this review. The studies found possible associations between sleep problems and mood changes-particularly in terms of depression and anxiety. In addition, altered sleep patterns seemed to be related to changes in individual aspects, lifestyle, and attitudes adopted by older adults during the COVID-19 lockdown. Thus, the pandemic could affect the sleep and psychological wellbeing of the older population, even in healthy aging.

The Role of Neuropsychological Factors in Perceived Threat of SARS-CoV-2 in Healthy Ageing.

The COVID-19 pandemic is known to increase older adults' vulnerability to adverse outcomes. Alongside increased physical frailty, anxiety symptoms associated with the risk of SARS-CoV-2 contagion appear to represent its most prominent 'sequelae'. The attentional and linguistic resources required for decoding virus-related information may also influence the perceived threat of contagion. However, the possible role of neuropsychogeriatric factors on the latter dimension has never been assessed in a longitudinal study on the older population. To fill this gap, 50 healthy cognitively preserved older adults underwent a neuropsychological and physical frailty assessment before the pandemic (T0). Subsequently, they agreed to be interviewed and re-assessed during the lockdown (T1) and immediately after it (T2) through a longitudinal one-year study. Perceived threat of SARS-CoV-2 at T2 was predicted both by baseline anxiety and frailty scores, and by decreased performance in information processing speed and language comprehension tests. While confirming the joint role of frailty and anxiety, a moderation/interaction model showed that each of them was sufficient, at its highest level, to support the maximum degree of perceived threat of contagion. The contribution of neuropsychological factors to perceived threat of SARS-CoV-2 highlights their importance of tailoring information campaigns addressed to older people.

Lockdown Effects on Healthy Cognitive Aging During the COVID-19 Pandemic: A Longitudinal Study.

The COVID-19 pandemic is a health issue leading older adults to an increased vulnerability to unfavorable outcomes. Indeed, the presence of physical frailty has recently led to higher mortality due to SARS-CoV-2 infection. However, no longitudinal studies have investigated the role of neuropsychogeriatric factors associated with lockdown fatigue in healthy cognitive aging. Eighty-one healthy older adults were evaluated for their neuropsychological characteristics, including physical frailty, before the pandemic (T0). Subsequently, 50 of them agreed to be interviewed and neuropsychologically re-assessed during the lockdown (T1) and immediately after it (T2). Moreover, during another home confinement, they performed a psychological screening (T3) to evaluate possible mood changes and fatigue. According to Fried's frailty criteria, at T0, 63% of the sample was robust, 34.5% pre-frail, and only 2.5% frail. Significantly, these subjects presented a decrease in handgrip strength and walking speed (29.6 and 6.1%, respectively). Results from Principal Component Analyses and multiple regression models highlighted the contribution of "cognitive" and "psychological" factors (i.e., attentive-executive performance and mood deflections) in explaining handgrip strength and gait speed. At T3, lockdown fatigue was explained by higher scores on the Beck Depression Inventory and lower scores on the Trail Making Test part A. Results from a moderated-mediation model showed that the effect of psychomotor speed on lockdown fatigue was mediated by depression, with a moderating effect of gait speed. Our findings highlight the complex interrelationship between cognitive, psychological, and physical factors in the emergence of pandemic fatigue in a carefully selected older population.

Investigating Neuroimaging Correlates of Early Frailty in Patients With Behavioral Variant Frontotemporal Dementia: A MRI and FDG-PET Study.

Frailty is a dynamic clinical condition characterized by the reduction of interconnections among different psychobiological domains, which leads to a homeostatic vulnerability. The association between physical frailty and cognitive dysfunctions is a possible predictor of poor prognosis in patients with neurodegenerative disorders. However, this construct has not been fully analyzed by a multidimensional neuropsychogeriatric assessment matched with multimodal neuroimaging methods in patients with behavioral variant frontotemporal dementia (bvFTD). We have investigated cognitive dysfunctions and frailty status, assessed by both a neuropsychological evaluation and the Multidimensional Prognostic Index (MPI), in a sample of 18 bvFTD patients and compared to matched healthy controls. Gray matter (GM) volume (as assessed by voxel-based morphometry) and metabolism (on 18fluorodeoxyglucose positron emission tomography) were first separately compared between groups, then voxelwise compared and correlated to each other within patients. Linear regression of the MPI was performed on those voxels presenting a significant correlation between altered GM volume and metabolism. The neuropsychological assessment reflected the diagnoses and the functional-anatomical alterations documented by neuroimaging analyses. In particular, the majority of patients presented significant executive dysfunction and mood changes in terms of apathy, depression, and anxiety. In the overall MPI score, the patients fell in the lower range (indicating an early frailty status). On imaging, they exhibited a bilateral decrease of GM density and hypometabolism involving the frontal pole, the anterior opercular region, and the anterior cingulate cortex. Greater atrophy than hypometabolism was observed in the bilateral orbitofrontal cortex, the triangular part of the inferior frontal gyrus, and the ventral striatum, whereas the contrary was detected in the bilateral dorsal anterior cingulate cortex and pre-supplementary motor area. MPI scores significantly correlated only with the co-occurrence of a decrease of GM density and hypometabolism in the right anterior insular cortex, but not with the separate pathological phenomena. Our results show a correlation between a specific pattern of co-occurring GM atrophy and hypometabolism with early frailty in bvFTD patients. These aspects, combined with executive dysfunction and mood changes, may lead to an increased risk of poor prognosis, highlighting a potentially critical and precocious role of the insula in the pathogenesis of frailty.

How do nocebo effects in placebo groups of randomized controlled trials provide a possible explicative framework for the COVID-19 pandemic?

Introduction: Randomized clinical trials (RCTs) are useful to study the role of individual and contextual factors in which therapies vs placebos are administered and to provide an important perspective for understanding the phenomenon of nocebo-related risks.Areas covered: The results of nocebo effects in RCT placebo groups, measured in terms of adverse events (AEs) and dropouts, will be presented as an explicative framework for the COVID-19 pandemic. Currently, SARS-CoV-2 vaccines are the only RCTs routinely conducted during the pandemic. Information about efficacy and safety of different vaccines represents a fertile ground for nocebo phenomena. Individual and contextual factors will be emphasized in order to understand the presence of a refusal of immunization associated with a specific vaccine considered less effective and safe. Critical aspects and some guidelines will be presented in order to counteract the nocebo effects and to improve adherence to drug treatments and the vaccination campaign.Expert opinion: The nocebo effect could explain the presence of strong resistance in European countries to immunization with a vaccine perceived as less effective, compared to others. Increased awareness of the nocebo effect would be relevant as it could lead to a greater participation in the vaccination campaign and in protecting individuals against SARS-CoV-2 infection.

A Possible Association Between Executive Dysfunction and Frailty in Patients With Neurocognitive Disorders.

Frailty is an age-related dynamic status, characterized by a reduced resistance to stressors due to the cumulative decline of multiple physiological systems. Several researches have highlighted a relationship between physical frailty and cognitive decline; however, the role of specific cognitive domains has not been deeply clarified yet. Current studies have hypothesized that physical frailty and neuropsychological deficits may share systemic inflammation and increased oxidative stress in different neurodegenerative disorders, such as Alzheimer's and Parkinson's disease. However, the role of the executive dysfunction should be investigated in a more detailed way using a multidimensional approach. With this aim, we conducted a review of the literature on the few experimental articles published to discuss the existence of a relationship between frailty and cognitive impairment in neurocognitive disorders, particularly focusing on the domain of executive dysfunction. The data suggest that physical frailty and cognitive decline, especially executive dysfunction, are two aspects strongly linked in mild and major neurocognitive disorders due to Alzheimer's and Parkinson's disease. In light of this, a new framework linking aging, cognitive decline, and neurodegenerative diseases is needed. In order to analyze the effects that aging processes have on neural decline and neurocognitive disease, and to identify relevant groups of users and patients, future longitudinal studies should adopt a multidimensional approach, in the field of primary prevention and in the continuum from mild to major neurocognitive disorder.

How Do Nocebo Phenomena Provide a Theoretical Framework for the COVID-19 Pandemic?

The COVID-19 pandemic is a major health issue, which leads to psychological and behavioural changes. In particular, among various negative feelings, fear seems to be one of the main emotional reactions that can be as contagious as the virus itself. The actual pandemic is likely to function as an important stressor, especially in terms of chronic anxiety and lack of control over the succession of unforeseeable environmental events. In this direction, the psychological impact of previous quarantine measures showed important negative psychological effects, including post-traumatic stress symptoms (PTTS) with long-lasting effects. The presence of psychological discomfort and disturbances due to negative contextual factors can be studied using the nocebo phenomenon as a possible theoretical explanatory framework. Although in the absence of studies linking nocebo to Covid-19 and data-driven evidence, the context of the actual pandemic may be seen as a fertile ground for amplified discomfort and anxiety. The media provide dramatic and negative descriptions and often present conflicting sources of information, which can lead to physical and mental health problems, diminishing response to treatment. This can be worse when supported by conspiracy theories or misinformation. The aim of this perspective review is to propose a new theoretical framework for the COVID-19 pandemic, which should be supported by future empirical studies. In particular, the negative contextual factors, which can predispose individuals to psychological distress and the onset of the nocebo phenomena will be presented here, in order to suggest possible guidelines to mitigate the devastating effects of COVID-19.

Reduced Self-Awareness Following a Combined Polar and Paramedian Bilateral Thalamic Infarction. A Possible Relationship With SARS-CoV-2 Risk of Contagion?

Reduced self-awareness is a well-known phenomenon investigated in patients with vascular disease; however, its impact on neuropsychological functions remains to be clarified. Importantly, selective vascular lesions provide an opportunity to investigate the key neuropsychological features of reduced self-awareness in neurocognitive disorders. Because of its rarity, we present an unusual case of a woman affected by a combined polar and paramedian bilateral thalamic infarction. The patient underwent an extensive neuropsychological evaluation to assess cognitive, behavioral, and functional domains, with a focus on executive functions. She was assessed clinically in the acute phase and after 6 months from the stroke, both clinically and by magnetic resonance imaging. The patient developed a cognitive impairment, characterised by prevalent executive dysfunction associated with reduced self-awareness and mood changes, in terms of apathy and depression. Such condition persisted after 6 months. In May 2020, the patient underwent the serology test in chemiluminescence to detect IgG antibodies against SARS-CoV-2. The result of the quantitative test highlighted a high probability of previous contact with the virus. We suggest that reduced self-awareness related to executive dysfunction and behavioral changes may be due to combined polar and paramedian bilateral thalamic lesion. Metacognitive-executive dysfunction affecting the instrumental abilities of everyday life might make people less able to take appropriate precautions, facilitating the risk of SARS-CoV-2 contagion.

Executive Dysfunction and Reduced Self-Awareness in Patients With Neurological Disorders. A Mini-Review.

Awareness of deficits in patients with neurological disorders may be described as a theoretical unitary phenomenon, which has been analysed reaching interesting results in the last decades. Awareness of deficits manifests itself in a continuum ranging from full awareness to total absence. In line with a neurocognitive approach, a reduction in self-awareness could be explained considering executive dysfunction associated with prefrontal cortex anatomo-functional changes. Our mini-review will focus on reduced self-awareness in neurological disorders, such as Alzheimer's disease, behavioural Frontotemporal Dementia and Acquired Brain Injuries. Results achieved thanks to an explanatory investigative approach combined with a theoretical reference model will be presented. Data suggest the key role of executive functions in supporting adequate self-awareness towards patients' cognitive-behavioural profile and instrumental activity autonomy. The Cognitive Awareness Model seems to be one of the best theoretical model to better approach this phenomenon.

Are Patients With Schizophrenia Spectrum Disorders More Prone to Manifest Nocebo-Like-Effects? A Meta-Analysis of Adverse Events in Placebo Groups of Double-Blind Antipsychotic Trials.

Background: Antipsychotic clinical trials use to present adverse events (AEs) for the drug under evaluation to treat schizophrenia. Interestingly, patients who receive the placebo during antipsychotic trials often report several AEs, but little is known about the essence of these negative effects in patients with schizophrenia spectrum disorders (SCD). In the present meta-analysis, we evaluated the relationship between the level of psychiatric symptomatology expressed as Positive and Negative Syndrome Scale (PANSS) scores and the rates of AEs reported in the placebo arms of double-blind clinical trials, for commonly prescribed atypical antipsychotic medications. Methods: We selected 58 clinical trials describing AEs in SCD placebo groups, which compared atypical antipsychotic medications with placebo. A total of 6,301 placebo-treated patients were considered. AE profiles of the class were clusterized using MedDRA classification and analysed using a meta-regression approach. Results: In the placebo arms the proportions of patients with any AE was 66.3% (95% CI: 62.7-69.8%). The proportion of withdrawal of patients treated with placebo because of AEs was 7.2% (95% CI: 5.9-8.4%). Interestingly, the AEs in the placebo arms corresponded to those of the antipsychotic-atypical-medication-class against which the placebo was compared. Namely, using meta-regression analysis we found an association between the level of psychiatric symptomatology measured with PANSS scores and higher AEs reported as nervous system (p = 0.020) and gastrintestinal disorders (p = 0.004). Moreover, the level of a higher psychiatric symptomatology expressed with PANSS scores was also related with higher AEs associated with psychiatric symptoms (p = 0.017). Conclusion: These findings emphasise that the AEs in placebo arms of clinical trials of antipsychotic medications were substantial. Importantly, a higher level of psychiatric symptomatology makes SCD patients more prone to express AEs, thus contributing to possible drop-outs and to a lower adherence to treatments. These results are consistent with the expectation theory of placebo and nocebo effects.

Neuropsychological correlates of instrumental activities of daily living in neurocognitive disorders: a possible role for executive dysfunction and mood changes.

ABSTRACTSince baseline executive dysfunction predicts worsening Instrumental Activities of Daily Living (i-ADL) over time and progression to Alzheimer's Disease (AD), we aimed to analyze the role of neuropsychological variables to outline which factors can contribute to functional impairment. Specific attention to executive functions (EFs) has been given.A total of 144 subjects complaining of different cognitive deficits - ranging from "MCI likely due to AD" to "mild AD patients" - underwent an overall neuropsychological assessment. The Behavioral Assessment of the Dysexecutive Syndrome was used to analyze EFs. We conducted multiple linear regression analyses to study whether the level of independent living skills - assessed with the Lawton-scale - could be associated with cognitive and behavioral measurements.We found a significant association between i-ADL and specific EFs measured by Rule Shift Cards (p = 0.04) and Modified Six Elements (p = 0.02). Moreover, considering i-ADL scores, we observed an involvement of mood changes and a reduced awareness of deficits in terms of Hamilton Depression Rating Scale (p = 0.02) and Awareness of Deficit Questionnaire - Dementia scale (p < 0.0001), respectively.Our results suggest the importance of considering the association between a reduction in i-ADL and executive dysfunction in patients who have AD etiopathology, for which the ability to inhibit a response, self-monitoring, set-shifting and mood deflection play a key role. Besides, no straightforward associations between i-ADL scores and global cognition, memory, language comprehension, attention, and perspective taking abilities were found.

Neuropsychological Correlates of Pre-Frailty in Neurocognitive Disorders: A Possible Role for Metacognitive Dysfunction and Mood Changes.

BACKGROUND: Recent studies have suggested that cognitive functions in patients with neurocognitive disorders have a significant role in the pathogenic mechanisms of frailty. Although pre-frailty is considered an intermediate, preclinical state, epidemiological research has begun to dislodge cognition and frailty into their specific subcomponents to understand the relationship among them. We aim to analyse the possible association between pre-frailty and neuropsychological variables to outline which factors can contribute to minor and major neurocognitive disorders. METHODS: 60 subjects complaining of different cognitive deficits underwent a deep-in-wide frailty and neuropsychological assessment. We conducted three multiple linear regression analyses adjusted for a combination of demographic measures and involving several neuropsychological-behavioural parameters selected by the literature on physical frailty. RESULTS: We found a significant association between frailty-as measured by the multidimensional prognostic index (MPI)-and action monitoring and monetary gain (cognitive domain), depression and disinhibition (behavioural domain). Moreover, an association between MPI and impaired awareness for instrumental activities disabilities exists. CONCLUSION: We propose a novel framework for understanding frailty associated with metacognitive-executive dysfunction.