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Epidemiological data and etiopathogenesis of brain fog are very heterogeneous in the literature, preventing adequate diagnosis and treatment. Our study aimed to explore the relationship between brain fog, neuropsychiatric and cognitive symptoms in the general population. A sample of 441 subjects underwent a web-based survey, including the PANAS, the DASS-21, the IES-R, the Beck Cognitive Insight Scale, and a questionnaire investigating demographic information, brain fog, subjective cognitive impairments (Scc) and sleep disorders. ANOVA, ANCOVA, correlation and multiple stepwise regression analyses were performed. In our sample, 33% of participants were defined as Healthy Subjects (HS; no brain fog, no Scc), 27% as Probable Brain Fog (PBF; brain fog or Scc), and 40% as Functional Brain Fog (FBF; brain fog plus Scc). PBF and FBF showed higher levels of neuropsychiatric symptoms than HS, and FBF showed the worst psychological outcome. Moreover, worse cognitive symptoms were related to the female gender, greater neuropsychiatric symptoms, sleep disorders, and rumination/indecision. Being a woman and more severe neuropsychiatric symptoms were predictors of FBF severity. Our data pointed out a high prevalence and various levels of severity and impairments of brain fog, suggesting a classificatory proposal and a multifaceted etiopathogenic model, thus facilitating adequate diagnostic and therapeutic approaches.

The COVID-19 evolution has forced the massive introduction of homeworking (HW) for most employees in the initial stages of the pandemic and then return to work, mainly due to the vaccination campaign. These multiple abrupt adjustment demands in work may be a source of intense stress for office workers with consequences on wellbeing and the quality of life. This long-term prospective study aimed at investigating the effect of adaptation demands on a broad population of employees of a large Italian banking group in the job-related stress framework. We administered a web-based survey to 1,264 participants in Reopening after the first lockdown, from June to October 2020, at 841 subjects in Second Wave, corresponding to the rise of contagions from November 2020 to January 2021, and to 491 individuals in Vaccination Round, which ranged from February to June 2021. We assessed workaholism by using the Dutch Work Addiction Scale (DUWAS-10), work-family conflicting overlap by using the Work and Family Conflict Scale (WAFCS), and concern for back to work (BW) and for HW by specific questions. Higher WAFCS scores characterized Reopening and Vaccination Round while Second Wave had the highest level of concern for HW. Women and younger individuals showed the highest concern for BW, WAFCS, and DUWAS-10 scores regardless of the pandemic stage. HW days per week were related to more heightened concern for BW and lower concern for HW, DUWAS, and WAFCS scores. The number of children was related to lower Concern for BW and higher WAFCS scores in Reopening and Second Wave. Our data showed that massive adjustment demands in work and family routine represented a significant source of stress for employees, regardless of the different pandemic stages. The highest level of fatigue emerged in women and younger subjects. These results shed light on the need for a road map to promote a gradual and structured adjustment for workers and encourage organizations to consider homeworking as a valid stable alternative.

This study is one of the first aiming at investigating the mental health in the post-lockdown period in an Italian adult population and detecting demographic and psychological predictors for a worse outcome. 1401 participants answered a web-based survey including the Emotional Reaction Questionnaire (ERQ), the Positive Affect and Negative Affect Scale (PANAS), the Impact of Event Scale-Revised (IES-R), the General Health Questionnaire (GHQ), the Depression, Anxiety and Stress Scale (DASS-21), and the Dutch Work Addiction Scale (DUWAS). Simple slope analyses highlighted that women, lower age, and suppression were related to higher scores for the PANAS negative affect scale, the DASS-21, the IES-R, the GHQ, and the DUWAS. In our sample, 1.2% of participants showed depressive symptoms, 0.5% anxiety symptoms, and 2% stress symptoms. Moreover, 5.4% of participants reported post-traumatic symptoms and 15% signs of psychological distress. Compared with data on the lockdown period, our results show lower levels of depressive, anxiety, and stress symptoms, possibly due to the slackening of preventive measures adopted since June. Despite this, post-traumatic symptoms and signs of psychological distress were still present. Our data suggest the necessity to monitor psychological adaption over time in general and at-risk subjects.

Alzheimer's disease (AD) is the most common form of dementia characterized by the prevalent memory impairment. Mild cognitive impairment (MCI) may represent the early stage of AD, in particular when MCI patients show biomarkers consistent with AD pathology (MCI due to AD). Neuropsychiatric symptoms (NPS) frequently affect both MCI and AD patients. Cerebrospinal-fluid (CSF) tau and β-amyloid42 (Aβ42) levels are actually considered the most sensitive and specific biomarkers for AD neurodegeneration. In the present retrospective observational study, we evaluated CSF biomarkers and neuropsychological data (also including NPS measured by the neuropsychiatric inventory-NPI) in a population of patients affected by MCI due to AD compared with mild to moderate AD patients. We documented higher NPI scores in MCI compared with AD patients. In particular, sub-items related to sleep, appetite, irritability, depression, and anxiety were higher in MCI than AD. We also found the significant correlation between NPS and CSF AD biomarkers in the whole population of MCI and AD patients. Consistently, t-tau/Aβ42 ratio correlated with NPS in all the MCI and AD patients. These results suggest the more prevalent occurrence of NPS in MCI patients showing AD pathology and converting to dementia than AD patients. Moreover, a more significant degree of AD neurodegeneration, featured by high t-tau/Aβ42 ratio, correlated with more severe NPS, thus supposing that in MCI and AD patients a more extensive AD neurodegeneration is related to more severe behavioral disturbances.

The frontal alpha asymmetry (FAA) is a neurophysiological measure of motivation and preference. Despite the FAA is associated to commercial pleasantness, conflicting evidence emerged in the literature regarding its relationship with behavior. To study the association between FAA and consumers' decision, we manipulated a commercial script to elicit diverse consumers' attitudes and decisions and to evaluate whether the FAA score is associated to their final investment. A little informative script (S1) was used to polarize consumers' attitudes and investments toward unfavorable scores, while a more personalized message (S2) to elicit in customers a favorable attitude and higher investments. Twenty-one participants listened to the scripts, and their FAA, attitude, and monetary investment were measured. In S1, the FAA did not correlate with neither attitude nor the investment decision, while a robust negative correlation between these variables was found in S2. No other peripheral body and neural measures associated with attitude or final decision. Our data suggest that the FAA correlates with attitude and decision, when a commercial script is customized and provides an adequate information, likely leading the consumer to a more reasoned and planned decision-making process. When facilitating a favorable attitude toward an offer, the negative correlation of FAA and behavior may reflect the involvement of a control system, whose role is to monitor and govern possible conflicts between approach and avoidance motivations. This observation provides additional indication on the value of FAA as a marker of consumer behaviors, and how it could be affected by experimental and contextual bias.

Objective: Interaction between the nervous and immune systems may influence emotions, ultimately affecting human health. Cytokines may play a role in developing emotional dysregulation as in alexithymia, a personality construct characterized by the subclinical inability to identify and describe emotions, often associated with several psychiatric and psychosomatic disorders. The proinflammatory cytokine IL-18, with a recognized role in brain functions, may influence serotonin metabolism and appears to be associated with alexithymia. Healthy individuals carrying the long allele (L) of the serotonin transporter gene polymorphic region (5-HTTLPR), and thus having lower concentrations of serotonin in the synaptic cleft, show a greater tendency toward alexithymia, with some gender differences. To explore a potential physiological interaction between IL-18, serotonin neurotransmission, and alexithymia, we investigated whether IL-18 serum levels and 5-HTTLPR are linked to alexithymic traits in healthy subjects. Methods: We measured IL-18 serum levels in 115 Italian-Caucasian healthy subjects genotyped for 5-HTTLPR allele variants, divided by gender and assessed for alexithymia scores using the 20-item Toronto Alexithymia Scale. Results: IL-18 levels are significantly more elevated in individuals with the LL genotype (n = 25) than in carriers of the short allele (n = 90, p = 0.0073). Specifically, in LL males (n = 11), i.e., the group with the most relevant increase in IL-18, cytokine values positively correlated with difficulty identifying feelings, which is a component of alexithymia (r = 0.634, p = 0.036). Conclusions: These results indicate a possible novel interaction between IL-18 and the serotoninergic system to mediate emotional unawareness, suggesting putative biological predictors of emotional dysregulation, which in turn can act as a risk factor for a variety of medical conditions in susceptible subjects.

Homotaurine supplementation may have a positive effect on early Alzheimer's disease. Here, we investigated its potential neuroprotective effect on the hippocampus structure and episodic memory performances in amnestic mild cognitive impairment (aMCI). Neuropsychological, clinical, and neuroimaging assessment in 11 treated and 22 untreated patients were performed at baseline and after 1 year. Magnetic resonance data were analyzed using voxel-based morphometry to explore significant differences (Family Wise Error corrected) between the two groups over time. Patients treated with homotaurine showed decreased volume loss in the left and right hippocampal tail, left and right fusiform gyrus, and right inferior temporal cortex which was associated with improved short-term episodic memory performance as measured by the recency effect of the Rey 15-word list learning test immediate recall. Thus, homotaurine supplementation in individuals with aMCI has a positive effect on hippocampus atrophy and episodic memory loss. Future studies should further clarify the mechanisms of its effects on brain morphometry.

White matter abnormalities have been shown in the large deep fibers of Alzheimer's disease patients. However, the late myelinating superficial white matter comprised of intracortical myelin and short-range association fibers has not received much attention. To investigate this area, we extracted a surface corresponding to the superficial white matter beneath the cortex and then applied a cortical pattern-matching approach which allowed us to register and subsequently sample diffusivity along thousands of points at the interface between the gray matter and white matter in 44 patients with Alzheimer's disease (Age: 71.02 ± 5.84, 16M/28F) and 47 healthy controls (Age 69.23 ± 4.45, 19M/28F). In patients we found an overall increase in the axial and radial diffusivity across most of the superficial white matter (P

Introduction Anosognosia is a multidimensional phenomenon with detrimental effects on patients' illness course, therapy compliance and quality of life. We aimed at investigating anosognosia for cognitive and behavioral symptoms in Parkinson's Disease (PD) with dementia (PDD) and, for the first time, in PD with Mild Cognitive Impairment (MCI-PD). Methods Community dwelling subjects (47 mild PDD, 136 multidomain MCI-PD (mdMCI-PD), 5 single domain MCI-PD (sdMCI-PD), and 197 PD without cognitive impairment (noCI-PD) were enrolled in a cross-sectional design study. All the subjects were administered the Anosognosia Questionnaire for Dementia, the Mental Deterioration Battery and a number of neuropsychiatric inventories. Results A diagnosis of anosognosia was made in 36% of patients with mild PDD and 16% with mdMCI-PD, whether it was negligible in sdMCI-PD and noCI-PD. Higher severity of anosognosia for cognitive impairment was also found in PDD and in mdMCI-PD. SdMCI-PD had the lower severity of anosognosia for cognitive impairment. Higher anosognosia for cognitive impairment was associated to lower depression in noCI-PD (r = −0.227, p = 0.0013) and mdMCI-PD (r = −0.266, p = 0.0016), and to reduced hedonic tone in noCI-PD (r = −0.191, p = 0.0071). Greater anosognosia was associated to lower executive performances in PDD (r = 0.424, p = 0.0074). Conclusions Anosognosia for non-motor symptoms is frequent in PD patients with mild dementia or mdMCI. Results confirm the role of neuropsychiatric characteristics in anosognosia also in PD, the high prevalence of anosognosia in neurodegenerative illnesses and suggest a common pathogenic path for anosognosia in different neurodegenerative and psychiatric disorders.

Corpus callosum (CC) abnormalities may cause cognitive and neuropsychiatric complications due to reduced hemispheric integration. Over a one-year period, we investigated whether the CC structure of 20 patients with mild Alzheimer's disease (AD) was linked to the evolution of cognitive and neuropsychiatric symptoms. We also investigated whether this anatomical-clinical relationship was localized topographically on the CC by combining voxel-based morphometry and diffusion tensor imaging approaches. We assessed patients' global cognitive deterioration and neuropsychiatric symptoms with the Mini-Mental State Examination and the Neuropsychiatric Inventory. Increased global cognitive deterioration during the early course of AD was significantly related to reduced white matter density (p = 0.004) and fractional anisotropy (FA) (p = 0.012) and increased mean diffusivity (MD) (p = 0.017) at the level of the CC isthmus/splenium. Further, increased depression severity was significantly related to reduced FA (p = 0.008) and increased MD (p = 0.018) at the level of the CC rostrum. These results indicate that changes in early myelinated CC fibers, which subserve the lateral temporal and parietal cortices and are less vulnerable to damage, may be related to cognitive impairment. Furthermore, changes in late myelinated CC fibers, which connect the orbitofrontal cortices and are more vulnerable to damage, may be related to the earliest neuropsychiatric symptoms of AD, such as depression.

Background There is no consensus about which hippocampal subfields become atrophic earliest in the course of Alzheimer's disease (AD). Methods Thirty AD patients, 41 mild cognitive impairment (MCI) patients, and 38 healthy controls (HCs) underwent cerebral magnetic resonance imaging (with an automated segmentation protocol for the volumetric analysis of hippocampal subfields) and a test of immediate and delayed recall of a 15‐word list. Results The volumes of the presubiculum and subiculum presented the most remarkable reduction in the patient's groups. In the MCI group, only the volumes of presubiculum and subiculum predicted performance on the memory tests. In AD patients, the volumes of all hippocampal subfields (with the notable exception of the CA1) predicted memory scores. Conclusions Our data point to a prevalent atrophy of the presubicular‐subicular complex from the early phases of AD. This finding is consistent with neuropathological observations in AD patients and probably reflects the severe degeneration of the perforant pathway while penetrating the hippocampus through the subicular field in its course from the entorhinal cortex to the dentate gyrus.

Background Awareness of cognitive deficits may be reduced in mild cognitive impairment (MCI). This may have a detrimental effect on illness course and may be a predictor of subsequent conversion to AD. Although neuropsychological correlates have been widely investigated, no evidence of a neuroanatomical basis of the phenomenon has been reported yet. This study was aimed at investigating the neuroanatomical correlates of deficit awareness in amnestic MCI to determine whether they constitute risk factors for conversion to AD. Method A sample of 36 first-diagnosis amnestic MCI patients were followed for five years. At the first diagnostic visit they were administered an extensive diagnostic and clinical procedure and the Memory Insight Questionnaire (MIQ), measuring a total index and four sub-indices, to investigate awareness of deficits in dementia; they also underwent a high resolution T1-weighted Magnetic Resonance Imaging (MRI) investigation. Grey matter brain volumes were analysed on a voxel-by-voxel basis using Statistical Parametric Mapping 8. Data of 10 converter patients (CONV) and those of 26 non converter patients (NOCONV) were analysed using multiple regression models. Results At baseline, self-awareness of memory deficits was poorer in CONV compared to NOCONV. Furthermore, reduced awareness of cognitive deficits in CONV correlated with reduced grey matter volume of the anterior cingulate (memory deficit awareness), right pars triangularis of the inferior frontal cortex (memory deficit awareness) and cerebellar vermis (total awareness), whereas in NOCONV it correlated with reduced grey matter volume of left superior (total awareness) and middle (language deficit awareness) temporal areas. Further, at baseline self-awareness of memory deficits were poorer in CONV than in NOCONV. Conclusions Defective awareness of cognitive deficits is underpinned by different mechanisms in CONV and NOCONV amnestic MCI patients. Our data support the hypothesis that poor awareness of cognitive deficit is a predictor of subsequent conversion to AD.

International audience; We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

The study aimed at investigating the role of the hippocampal subfields in cognitive insight and the clinical and neuropsychological underpinnings of the related two sub-dimensions, Self-Reflectiveness (SR), i.e., openness to external feedback, and Self-Certainty (SC), i.e., unrealistic overconfidence in one's opinions. In order to do this, 45 patients with a diagnosis of schizophrenia and 45 age- and gender-matched healthy control subjects (HC) were administered the Beck Cognitive Insight Scale (BCIS), along with neuropsychological, clinical and psychopathological assessment, and underwent an MRI investigation. Hippocampal segmentation was carried out. Regression analyses were performed for BCIS indexes, volumetric parameters of hippocampal subfields and clinical and neuropsychological variables. Results highlighted that in the schizophrenia group, higher levels of SC were related to reduced volume of the left presubiculum, and worse episodic memory. No significant relationship emerged for the SR index. There was no significant relationship between any of the BCIS indexes and volumetric data of the hippocampal subfields in the HC group. Our data support the hypothesis that unrealistic self-overconfidence in schizophrenia is related to the hippocampal presubiculum atrophy, which is involved in episodic memory and cognitive control and is supposed to be underpinned by difficulty in integrating new memories and thus in generating new hypotheses about the self.

Aim: Several neuropsychopharmacological properties have been attributed to the 3α-reduced pregnane steroids, allopregnanolone and pregnanolone, as well as to dehydroepiandrosterone sulfate because of their ability to modulate γ-aminobutyric acid (GABAA) receptors in the CNS. In order to understand better their role in several mechanisms in CNS, a new methodology is proposed to monitor these compounds in human plasma. Methodology & results: The analytes were first derivatized with 2-hydrazinopyridine and extracted from plasma using SPE. Then, the compounds were separated and detected by LC–MS/MS. A mobile phase of formic acid (0.1%) in water and methanol through a gradient of composition and a flow rate of 0.3 ml min-1 resulted in good separations of the analytes. Linear responses in wide range of concentrations and LOQs ranging from 10 (dehydroepiandrosterone 3-sulfate) to 40 pg ml-1 (dehydroepiandrosterone) were obtained in

Lack of insight into illness is a multidimensional phenomenon that has relevant implications on clinical course and therapy compliance. Here, we focused on metacognitive insight in schizophrenia, that is, the ability to monitor one's changes in state of mind and sensations, with the aim of investigating its neuroanatomical, psychopathological, and neuropsychological correlates. Fifty-seven consecutive patients with Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) diagnosis of schizophrenia were administered the Insight Scale, and comprehensive psychopathological and neuropsychological batteries. They underwent a high-resolution T1-weighted magnetic resonance imaging investigation. Gray matter (GM) and white matter (WM) volumes were analyzed on a voxel-by-voxel basis using Statistical Parametric Mapping 8. Reduced metacognitive insight was related to reduced GM volumes in the left ventrolateral prefrontal cortex, right dorsolateral prefrontal cortex and insula, and bilateral premotor area and putamen. Further, it was related to reduced WM volumes of the right superior longitudinal fasciculum, left corona radiata, left forceps minor, and bilateral cingulum. Increased metacognitive insight was related to increased depression severity and attentional control impairment, while the latter was related to increased GM volumes in brain areas linked to metacognitive insight. Results of this study suggest that prefrontal GM and WM bundles, all implied in cognitive control and self-reflection, may be the neuroanatomical correlates of metacognitive insight in schizophrenia. Further, higher metacognitive insight is hypothesized to be a risk factor for depression which may subsequently impair attention. This line of research may provide the basis for the development of cognitive interventions aimed at improving self-monitoring and compliance to treatment.

Polyunsaturated fatty acids (PUFA) of the n-3 series have been linked to brain physiology and cognitive decline, but little is known about the other components of the complex fatty acids category. Here, we compared 30 molecular species pertaining to saturated, monounsaturated, polyunsaturated, and trans fatty acids, measured in plasma by gas chromatography, in 14 patients with a diagnosis of amnestic single domain mild cognitive impairment (aMCI), 30 patients with mild Alzheimer's disease (AD), and 30 healthy controls (HC). As no participants showed neuroimaging evidence of cerebrovascular disease, patients could be considered as purely neurodegenerative. We found differences in specific components of almost all fatty acid classes except n-3-polyunsaturated fatty acids. Compared with HC, aMCI and AD patients had higher levels of arachidic (C20:0), erucic (C22:1, n-9), and vaccenic acid (C18:1, n-9) and lower levels of cerotic (C26:0) and linoleic acid (C18:2, n-6). In particular, level of linoleic acid decreased and level of mead acid increased progressively from HC to aMCI to AD patients, and they were also inversely correlated in AD and aMCI patients. In conclusion, we found a previously unrecognized linoleic acid deficiency in the early phase of neurodegeneration that was strongly supported by an increased, compensatory mead acid level. These findings suggest the importance of creating new dietary manipulation strategies to counteract disease progression. © 2013 - IOS Press and the authors. All rights reserved.

Objective: As the literature on conventional cri- teria for discriminating early-onset (EO) from late-onset (LO) Alzheimer’s disease (AD) is sparse and controversial, the aim of this study was to establish a precise age at onset (AAO) criterion, by using a specific statistical proce- dure, and to describe the clinical characteristics of the two sub-groups. Methods: Admixture analysis was performed to establish the AAO cut-off in a multi-center study including 2000 AD patients consecutively recruited in eight Italian Memory Clinics. None of the patients were tak- ing acetylcholinesterase inhibitors, antipsychotic or anti-depressant drugs. At the first diagnostic visit, they were administered the Mini Mental State Examination, the Basic and Instrumental Activi- ties of Daily Living and the Neuropsychiatric Inventory to assess clinical phenomenology. Results: Using a specific statistical procedure, we established that AAO that discriminated EO- from LO-AD was 66. Compared with the LO-AD group, the EO-AD group showed longer duration of illness and a higher educational level as well as less severe functional impairment and delu- sions. Conclusions: Differences in sociodemo- graphic and clinical characteristics, such as duration of illness, education and delusion se-verity, suggested the involvement of different pathogenic processes. Additional studies are needed to further investigate the mechanisms underlying the disorder in the two sub-groups of AD patients.

Here we quantitatively summarized evidence of impaired awareness in Mild Cognitive Impairment (MCI) and meta-analytically explored the relationship between Subjective Cognitive Complaints (SCC) and actual cognitive impairment. Twenty-three studies were included, 14 comparing awareness measures in MCI and healthy elderly subjects, and 16 also exploring the neuropsychological underpinnings of impaired awareness. Moderator analyses were conducted to determine whether self-awareness varied according to patient group, the particular state in relation to which insight was assessed, or the approach to measuring awareness. The meta-analysis shows that MCI patients have knowledge of their neuropsychological deficits and that level of awareness varies according to cognitive status, language and memory abilities. The assessment technique employed impacted on the insight phenomena. Specifically, MCI patients seem particularly accurate in evaluating the current state of their performance during an ongoing task and this could be essential in regulating their behavior so that compensative strategies are practiced and greater cognitive independence is achieved. Thus, assessment technique and cognitive status are crucial factors that influence level of awareness and should be taken into consideration in awareness evaluation and rehabilitation.

Summary: Cognitive insight is the ability to monitor and correct one’s own erroneous convictions. The Beck Cognitive Insight Scale (BCIS) assesses two sub-dimensions of cognitive insight: self-reflectiveness (SR), which is the attitude of questioning one’s own judgments; and self-certainty (SC), which is the unwillingness to modify and correct one’s own convictions. There is little information about cognitive insight in healthy participants (HP). Here we investigated the socio-demographic and neuropsychological correlates of cognitive insight in 50 HP who were administered the BCIS and a comprehensive neuropsychological battery. The global BCIS R-C index correlated positively with age and WCST perseverative errors. SR correlated positively with age. These data support the hypothesis that a less self-reflective and more self-confident style is cognitively functional in HP. Thus, what has been found malfunctioning in mental illnesses is adaptive in HP. Future studies should consider a wider range of factors that might affect this complex construct. Copyright # 2011 John Wiley & Sons, Ltd.

Introduction In this systematic review, we aimed to evaluate the role of alexithymia in Parkinson's disease (PD) and its relationship to neurological, neuropsychiatric, cognitive, and neuroimaging correlates. Methods The database was selected using PubMed Services, Cochrane, PsycNET and Scopus and a number of key words. Further studies were sought by manually searching for secondary sources, including relevant journals and references in primary articles. The search was restricted to articles written in English between January 1980 and August 2015. Results Ten studies reported that alexithymia prevalence was about double in PD patients compared to control subjects and that specific dimensions of alexithymia might be related to depression, anxiety, apathy and impulsivity. Some studies investigated the relationship between alexithymia and neuropsychological symptoms and found correlations with frontal and parietal lobe functions. Two studies on neurological features reported a link between alexithymia and disease stage or a specific motor subtype of PD; the remaining studies found that alexithymia was independent from neurological symptoms, dopaminergic therapy and laterality of motor symptom onset. Data on neuroimaging correlates and therapeutic intervention on alexithymia in PD patients are still lacking. Conclusion Although results suggest that alexithymia is a primary characteristics of PD, further studies with larger patient samples are needed to definitively clarify the impact of alexithymia on the clinical features of PD patients.

Characteristics associated with life expectancy in Alzheimer's disease (AD) are still far from known. Here we aimed at examining the ability of baseline/longitudinal clinical variables to predict time to death. One-hundred fifty AD outpatients underwent diagnostic, neuropsychiatric, and functional assessment at baseline (when ApoE ɛ4 was also investigated) and at each subsequent annual visit. A random effects joint modeling approach was used to simultaneously model the baseline and longitudinal trajectory of each factor and predict the time to death, adjusting for demographic covariates. An ancillary analysis of ApoE ɛ4 status as a predictor was also conducted. Kaplan-Meier survival curves were constructed to elucidate the relationship between each factor and the estimated probability of death over time. Shorter survival was associated with male gender, higher education, older age, lower cognition, and worse functioning in daily life, but not ApoE ɛ4 status. Longitudinal trajectories increased predictive power over using just baseline levels highlighting apathy, and secondarily aberrant motor behaviors and sleep disorders, as a highly reliable predictor for mortality. Apathy was the strongest neuropsychiatric predictor of time to death, which supports its role in the pathogenesis of the disorder. An increased knowledge of factors modulating survival in AD is a strategic prerequisite to plan therapeutic interventions.

Background Dendritic cells (DCs) are major orchestrators of immune responses and inflammation. They are migratory cells, which may play a role in Alzheimer’s disease (AD), as suggested by prior in vitro studies. With the intent to investigate the clinical relevance of DC modifications in vivo, the present study was aimed to evaluate the levels of blood DCs in AD patients, in relation to the progression of the disease, the severity of its symptoms, and the treatment with acetylcholinesterase inhibitors (AChEIs), a class of drugs used to improve cognitive functioning in people with dementia. Methods The two main subpopulations of immature blood DCs, namely myeloid (mDCs) and plasmacytoid (pDCs) cells, were evaluated by flow cytometry analysis in 106 AD patients, in comparison with the same cells from 65 individuals with mild cognitive impairment (MCI) and 73 healthy control subjects (HC). The relationship between blood DC levels and symptom severity was also assessed in AD patients, and their blood DC frequency was considered both in the absence or presence of treatment with AChEIs. Results A significant depletion in blood mDCs was observed in AD patients, as compared to HC and MCI subjects. At variance, pDC levels were comparable among the three groups of subjects. The mDC decrease was evident only after the emergence of AD clinical symptoms, as confirmed by the follow-up analysis of a subgroup of MCI subjects who exhibited a significant decline in mDCs after their conversion to AD. Notably, the mDC decline was inversely correlated in AD patients with the frequency and severity of depressive symptoms. Eventually, the mDC depletion was not observable in patients treated with AChEIs. Conclusions Our results provide the first evidence that blood mDC levels are dysregulated in AD. This phenomenon appears mainly linked to AD progression, associated with stronger severity of AD-related symptoms, and influenced by AChEI treatment. Taken all together, these data suggest that blood mDCs may serve as a cell source to test disease-induced and treatment-related changes and support the innovative notion that DCs play a role in AD, as ultimate evidence of the immune system participation in disease progression.

In Alzheimer's disease patients (AD), the age at onset (AAO) ranges from 40 to 90. Usually, AD patients who develop symptoms before the age of 65 are classified as early onset (EO). The best known genetic risk factor for AD is the e4 allele of the apolipoprotein E (APOE). In this study, 474 subjects with AD were consecutively recruited in the memory clinic of the Santa Lucia Foundation in Rome. The best fitting model for the discrimination between EO and late onset (LO) was chosen based on lowest value of the Bayesian Information Criterion, which suggests the theoretical model with minimal deviation from the empirical distribution function of AAO in our sample. The FMM was used to compare EO and LO groups with respect to the following demographic and clinical variables: gender, age, education, MMSE and NPI. Furthermore a quantitative assessment of ADL and IADL was performed. Finally, the frequency of the APOE e4 allele was compared in EO and LO groups. Using the admixture analysis, we established that the AAO discriminating EO from LO-AD was 63-64. Higher education was associated with earlier onset in the EO but not in LO, and duration of illness was associated with earlier onset only in LO. The e4 allele was associated with later onset in EO but earlier onset in LO. Finally, increased impairment in ADL, IADL and NPI was associated with later onset only in the LO subgroup. Thus, the e4 allele of the APOE gene was significantly associated with both EO and LO distributions but with opposite effect, suggesting genetic heterogeneity. Additional studies are needed to further clarify the genetic mechanisms differentiating EO- and LO-AD.

Lack of insight into illness is a multidimensional phenomenon that has relevant implications on clinical course and therapy compliance. Here, we focused on metacognitive insight in schizophrenia, that is, the ability to monitor one's changes in state of mind and sensations, with the aim of investigating its neuroanatomical, psychopathological, and neuropsychological correlates. Fifty‐seven consecutive patients with Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) diagnosis of schizophrenia were administered the Insight Scale, and comprehensive psychopathological and neuropsychological batteries. They underwent a high‐resolution T1‐weighted magnetic resonance imaging investigation. Gray matter (GM) and white matter (WM) volumes were analyzed on a voxel‐by‐voxel basis using Statistical Parametric Mapping 8. Reduced metacognitive insight was related to reduced GM volumes in the left ventrolateral prefrontal cortex, right dorsolateral prefrontal cortex and insula, and bilateral premotor area and putamen. Further, it was related to reduced WM volumes of the right superior longitudinal fasciculum, left corona radiata, left forceps minor, and bilateral cingulum. Increased metacognitive insight was related to increased depression severity and attentional control impairment, while the latter was related to increased GM volumes in brain areas linked to metacognitive insight. Results of this study suggest that prefrontal GM and WM bundles, all implied in cognitive control and self‐reflection, may be the neuroanatomical correlates of metacognitive insight in schizophrenia. Further, higher metacognitive insight is hypothesized to be a risk factor for depression which may subsequently impair attention. This line of research may provide the basis for the development of cognitive interventions aimed at improving self‐monitoring and compliance to treatment. Hum Brain Mapp 35:4729–4740, 2014. © 2014 Wiley Periodicals, Inc.

Dendritic cells (DCs), the main actors of immune responses and inflammation, may play a role in Alzheimer's disease (AD). Recent studies demonstrate that monocyte-derived DCs (MDDCs), generated in vitro in the presence of amyloid β1-42 peptide (Aβ1-42), show a functional alteration and an increased production of inflammatory molecules. Accordingly, MDDCs from AD patients show a more pronounced pro-inflammatory profile than DCs obtained from control subjects. In this study, we aimed at further investigating DC role in AD. Thus, we analyzed the in vitro effect of Aβ1-42 treatment on already differentiated DCs from AD patients, as compared to control subjects. We found that Aβ1-42 significantly decreases the expression of brain-derived neurotrophic factor (BDNF) in DCs derived from AD patients but not from control subjects. Thus, possibly due to their Aβ-induced reduction of neurotrophic support to neurons, DCs from AD patients might contribute to brain damage by playing a part in Aβ-dependent neuronal toxicity.

Anosognosia is a multidimensional phenomenon that negatively affects course of illness. This study aimed to explore the association between anosognosia and neuropsychiatric phenomena in mild Alzheimer's disease (AD) and in mild cognitive impairment (MCI). The Anosognosia Questionnaire for Dementia to assess anosognosia, and the Neuropsychiatric Inventory to assess neuropsychiatric symptoms were administered to 209 patients (103 mild AD, 52 amnestic-MCI, and 54 amnestic multidomain-MCI). Categorical diagnoses of apathy, depression, and psychosis were made using specific criteria for dementia. With regard to continuous scores, in mild AD, we found positive correlation between symptoms of anosognosia and apathy, agitation and aberrant motor behaviors, while in MCI, we did not find significant association. At a categorical level, the diagnosis of anosognosia in mild AD was associated with the diagnosis of apathy. In mild AD, the frequent co-occurrence of frontally mediated behavioral disorders and anosognosia, particularly apathy, supports the hypothesis of a shared neuropsychogenic process due to the disruption of frontal brain networks.

Objectives To evaluate severity of anosognosia and to identify its neuropsychological correlates in preclinical and clinical Alzheimer's Disease (AD). Methods The Clinical Insight Rating Scale, the Anosognosia Questionnaire for Dementia (AQ-D), and the Mental Deterioration Battery were used to assess anosognosia and cognitive performances in mild AD (N = 38), amnesic mild cognitive impairment (a-MCI; N=35), and multiple domain MCI (md-MCI; N=38). Results Patients with mild AD were more anosognosic than both MCI groups, which, however, did not differ from one other. A categorical diagnosis of anosognosia was made in 42% of patients with mild AD, 3% of md-MCI, but in no subjects with a-MCI. Reduced verbal episodic memory raw score was associated with decreased awareness of cognitive difficulties (AQ-D total and intellectual functioning scores) only in MCI. In mild AD, anosognosia was linked only to increased age and reduced basic activities of daily living performances. Conclusions The diagnosis of anosognosia is frequent in patients with mild AD but not in those with MCI. In the latter case, the authors cannot speak of true anosognosia but only of decreased awareness of illness. Furthermore, reduced awareness of cognitive difficulties is linked with verbal memory performances in patients with MCI but not in those with AD, suggesting for the latter the involvement of factors other than neuropsychological. Thus, neuropsychiatric dimensions commonly present in patients with AD should be investigated along with anosognosia.

Clinical practice has highlighted a possible discrepancy between patient's verbal assertions, called clinical insight, and the actual convictions about the illness, called emotional insight. The complementary construct of cognitive insight refers to the cognitive processes involved in self-reflection and the ability to modify erroneous beliefs and misinterpretations. The aim of this study was to determine the psychopathological and neuropsychological predictors of cognitive insight in schizophrenia. Sixty outpatients with Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) schizophrenia diagnosis were administered the Beck Cognitive Insight Scale, the Positive and Negative Symptom Scale (PANSS), and a comprehensive neuropsychological battery. Results indicate that poor global cognitive insight in schizophrenia is significantly related to lower visual working memory, while a higher self-overconfidence is significantly related to deficits in verbal and visual memory and to the failure in using external information to correct erroneous convictions. Thus, our study suggests that impaired cognitive insight depends mainly on reduced working memory and executive function performances. These findings highlight the fundamental importance of the development of specific therapeutic strategies to improve the metacognitive components of insight in order to enhance treatment adherence in schizophrenia.

Conflicts of interest may influence medical research. In particular, the study on psychotropic treatment of ageing subjects suffering from neurological disorders and comorbid neuropsychiatric phenomena may be hypothetically considered economically non-advantageous, or even of negative impact on drug reputation, because of the high probability of non-response or side effects. Thus, studies on this issue may be disregarded from industry. We aimed to verify whether the global commitment of medical research reflects the actual relevance of depression in the world ageing population, associated or not with neurological conditions. Here, we: 1) have reviewed the literature on this issue, 2) have examined world published data concerning population by age, burden of disease and frequency of depressive disorders and antidepressant therapies, and 3) have reviewed the frequency of published papers on depression and its treatment associated with three neurological conditions. The overall rate of papers about depressive disorders in ageing people reflects adequately the world population and the prevalence of depression in the elderly. However, the rate of papers concerning medical experimentation for antidepressant treatment in Alzheimer's disease, Parkinson's disease and stroke is quite inadequate with respect to the rate of depressive disorders associated to these conditions. Thus, innovative medical experimentation must be encouraged, also in areas apparently of dubious economical advantage but of undoubted clinical relevance and the adoption of strategies to limit the detrimental effect of conflicts of interest in research must be enhanced.

In this study, we assess white matter microstructural deficit correlates of apathy level in 20 patients with amnestic mild cognitive impairment by means of diffusion tensor imaging. Mean diffusivity correlated positively with apathy level in the right temporal portion of the uncinate, middle longitudinal and inferior longitudinal fasciculi and in the parathalamic white matter, the fornix and the posterior cingulum of the right hemisphere. Fractional anisotropy results confirmed evidence of disconnection associated with apathy in all white matter areas except the middle longitudinal fasciculus. These results support the view that alterations in the neural mechanisms underlying apathy level occur in the early phase of degenerative dementias.