Brain functional connectivity differences between responders and non-responders to sleeve gastrectomy.

PURPOSE: To compare resting-state functional connectivity (RSFC) of obese patients responders or non-responders to sleeve gastrectomy (SG) with a group of obese patients with no past medical history of metabolic or bariatric surgery. METHODS: MR images were acquired at 1.5 Tesla. Resting-state fMRI data were analyzed with statistical significance threshold set at p < 0.05, family-wise error (FWE) corrected. RESULTS: Sixty-two subjects were enrolled: 20 controls (age range 25-64; 14 females), 24 responders (excess weight loss > 50%; age range 23-68; 17 females), and 18 non-responders to sleeve gastrectomy (SG) (excess weight loss < 50%; age range 23-67; 13 females). About within-network RSFC, responders showed significantly lower RSFC with respect to both controls and non-responders in the default mode and frontoparietal networks, positively correlating with psychological scores. Non-responders showed significantly higher (p < 0.05, family-wise error (few) corrected) RSFC in regions of the lateral visual network as compared to controls. Regarding between-network RSFC, responders showed significantly higher anti-correlation between executive control and salience networks (p < 0.05, FWE corrected) with respect to both controls and non-responders. Significant positive correlation (Spearman rho = 0.48, p = 0.0012) was found between % of excess weight loss and executive control-salience network RSFC. CONCLUSION: There are differences in brain functional connectivity in either responders or non-responders patients to SG. The present results offer new insights into the neural correlates of outcome in patients who undergo SG and expand knowledge about neural mechanisms which may be related to surgical response.

Resilience and psychological impact on Italian university students during COVID-19 pandemic. Distance learning and health.

COVID-19 epidemic has been spreading in the world causing strong psychological pressure for the global population. Quarantine has huge impact and can cause considerable psychological stress. The study aims to identify psychological stress, emotional changes, approach to studies, resilience skills related to the experience of the COVID-19 pandemic in a sample of university students. A sample of university students from the Campus Bio Medico University of Rome was studied. The participants responded to an online questionnaire packet that included socio-demographic information, COVID-19 impact on emotions and on university life, perceived stress (PSS-10) and resilience skills (RS-14). We received 955 responses. The respondents experienced an increase in perceived stress in 89.4% of cases (66% stress moderate and 23.4% high). Moreover, 54.4% of students reported decrease in attention span and difficulty in studying with consequent concern about the exam outcomes (55%). Resilience skills positively affect stressful events and in particular the COVID-19 impact on study and interpersonal relationships. The study shows a psychological impact of the Covid-19 emergency on college students. Stress significantly decreases learning and negatively affects psychological well-being of students. Resilience skills were a protective factor to overcome difficulties learning.

Epilepsy and quality of life: what does really matter?

PURPOSE: To assess quality of life (QoL) in adult people with epilepsy (PWE) and identify the main factors affecting it. METHODS: We enrolled consecutively 122 PWE. They were interviewed for a careful collection of demographic and clinical data. Patients completed dedicated questionnaires for the assessment of the quality of life (Quality of Life in Epilepsy Scale-31) (Q31) as well as psychosocial features: depressive symptoms (DS) (Beck Depression Inventory-II/BDI-II), difficulties of emotion regulation (Difficulties of Emotion Regulation Scale/DERS), and stigma related to epilepsy (Stigma Scale of Epilepsy/SSE and Jacoby's Stigma Scale/JSS). The results of Q31 and their subscales were correlated with clinical details of PWE, as well as the other scores. A stepwise multiple regression analysis was applied to identify the main factors affecting QoL. RESULTS: Quality of life is inversely correlated mostly with psychosocial features, as DS, emotion dysregulation, and stigma perception, as well as with epilepsy-related factors, as the seizure frequency and number of antiseizure medications (ASMs). The combination of DS, perceived stigma, and number of ASMs best explained the QoL. Worse features of QoL were detected in females and in patients with age of epilepsy onset in adulthood. CONCLUSION: Quality of life in adult PWE is predominantly affected by psychosocial factors more than epilepsy-related ones. These findings suggest that effective epilepsy management requires more than seizure control, and early detection of psychological dysfunction and tailored interventions to improve the QoL should be considered.

The psychological impact of COVID-19 pandemic on patients included in a bariatric surgery program.

PURPOSE: The COVID-19 pandemic has radically impacted the world lifestyle. Epidemics are well-known to cause mental distress, and patients with a current or past history of obesity are at increased risk for the common presence of psychological comorbidities. This study investigates the psychological impact of the current pandemic in patients participating in a bariatric surgery program. METHODS: Patients were consecutively enrolled during the Italian lockdown among those waiting for bariatric surgery or attending a post-bariatric follow-up, and were asked to complete through an online platform the Depression Anxiety Stress Scales-21 and a self-assessment questionnaire of 22 items evaluating the resilience, change in eating behavior and emotional responses referring to the ongoing pandemic. RESULTS: 59% of the 434 enrolled subjects reported of being worried about the pandemic, and 63% specifically reported of being worried about their or their relatives' health. 37% and 56% felt lonelier and more bored, respectively. 66% was hungrier with increased frequency of snacking (55%) and 39% reported more impulse to eat. Noteworthy, 49% felt unable to follow a recommended diet. No difference in terms of psychological profile was recorded among pre and post-bariatric subjects. Logistic regression analysis on post-bariatric patients showed a relationship between snacking, hunger, eating impulsivity, and anxiety, stress, and/or depression symptoms. CONCLUSION: The pandemic led to increased psychological distress in patients with a current or past history of obesity, reducing quality of life and affecting dietary compliance. Targeted psychological support is warranted in times of increased stress for fragile subjects such as pre- and post-bariatric patients. LEVEL OF EVIDENCE: Level V: cross-sectional descriptive study.

Alexithymia and emotion dysregulation in adult patients with epilepsy.

OBJECTIVE: The concept of alexithymia refers to difficulty perceiving, identifying, and describing emotions. We aimed at evaluating the prevalence of alexithymia in a sample of adult people with epilepsy (PWE) with and without psychogenic nonepileptic seizures (PNES) and healthy control subjects (HC) and identifying major factors able to affect it. MATERIALS AND METHODS: We enrolled consecutively 91 PWE (12 of which with PNES in addition to seizures) and 146 HC age- and gender-matched. Both groups' subjects completed the following questionnaires: TAS-20, Beck Depression Inventory-II (BDI-II), Difficulties in Emotion Regulation Scale (DERS) and the Italian translation of Stigma Scale of Epilepsy (SSE), able to evaluate stigma related to epilepsy both in epileptic and nonepileptic subjects. Moreover, PWE completed the well-known Jacoby's Stigma Scale (JSS), dedicated to the evaluation of stigma only by patients with epilepsy and QOLIE-31 (Q31) for evaluating the quality of life. We analyzed correlations between alexithymia and several epilepsy-related (seizure frequency, antiseizure medications-ASMs) and psychosocial factors. Finally, a stepwise multiple regression analysis was performed to identify major factor affecting alexithymia in both groups. RESULTS: Alexithymia was prevalent in PWE compared to controls (17.6% of alexithymic subjects in PWE vs 11% in HC), without discriminating epileptic subjects with and without PNES. This predominance disappeared when depressive symptoms (DS) were controlled for. The difficulties of identifying feelings and emotions resulted to be clearly higher in PWE, even when DS are controlled for, and significantly correlated with stigma perception. Alexithymia in PWE was also strongly associated with lower quality of life and education and greater number of ASMs and difficulties in emotion regulation (ER), that turned out to be the main factor affecting alexithymia in both groups (PWE and HC). CONCLUSIONS: Alexithymia is prevalent in PWE, mostly influenced by DS and significantly associated with worse quality of life and higher emotion dysregulation and stigma perception. The latter finding could be explained by difficulty identifying emotions (DIE) that selectively characterizes PWE.

Depressive symptoms and difficulties in emotion regulation in adult patients with epilepsy: Association with quality of life and stigma.

OBJECTIVE: The objective of the study was to assess depressive symptoms (DS) and difficulties in emotion regulation (ER) in adult people with epilepsy (PWE) and their correlation with quality of life and stigmatization feelings of patients. MATERIALS AND METHODS: We enrolled consecutively 110 PWE who completed the Beck Depression Inventory-II (BDI-II) questionnaire and, for the first time, the Italian translation of Difficulties in Emotion Regulation Scale (DERS) to evaluate DS and ER. They also fulfilled the Italian version of the Stigma Scale of Epilepsy (SSE), which allowed the quantification of the stigma perception by our cohort of patients and a 3-item Jacoby's Stigma Scale (JSS) and QOLIE-31 (Q31) for the evaluation of stigma and the quality of life. The results of BDI-II and DERS were correlated with clinical details of PWE, as well as the Q31 and SSE scores. Finally, a multiple stepwise regression analysis was applied to identify the main factors affecting DS and ER difficulties in these patients. RESULTS: About 30% of PWE evidenced DS, of which 17.3% showed a BDI-II score higher than 19, suggestive of moderate to severe DS. Several factors related to epilepsy (seizure frequency, number of antiepileptic drugs (AEDs)) as well as ER and quality of life/stigmatization perception resulted significantly correlated with DS. As a new finding, the main factors affecting DS in PWE turned out to be the difficulties in ER and quality of life and stigma perception (as evaluated through Q31 and JSS scores). CONCLUSIONS: Our findings evidenced that DS in PWE are highly prevalent and strongly correlated with ER difficulties that mostly influence DS together with quality of life and stigma perception. Depressive symptoms and emotion dysregulation are linked by a bidirectional relationship and are significantly associated with worse quality of life and higher stigmatization feelings.

Within-network brain connectivity in Crohn's disease patients with gadolinium deposition in the cerebellum.

PURPOSE: Patients with Crohn's disease (CD) undergo multiple gadolinium-based contrast agent injections across their lifespan to enhance signal intensity of the intestinal wall and differentiate active from quiescent inflammatory disease. Thus, CD patients are prone to gadolinium accumulation in the brain and represent a non-neurological population to explore gadolinium-related brain toxicity. Possible effects are expected to be greater on the cerebellar network due to the high propensity of the dentate nucleus to accumulate gadolinium. Herein, we provide a whole-brain network analysis of resting-state fMRI dynamics in long-term quiescent CD patients with normal renal function and MRI evidence of gadolinium deposition in the brain. METHODS: Fifteen patients with CD and 16 healthy age- and gender-matched controls were enrolled in this study. Relevant resting-state networks (RSNs) were identified using independent component analysis (ICA) from functional magnetic resonance imaging data. An unpaired two-sample t test (with age and sex as nuisance variables) was used to investigate between different RSNs. Clusters were determined by using threshold-free cluster enhancement and a family-wise error corrected cluster significance threshold of p < 0.05. RESULTS: Patients showed significantly decreased resting-state functional connectivity (p < 0.05, FWE corrected) of several regions of the right frontoparietal (FPR) and the dorsal attention (DAN) RSNs. No differences between the two groups were found in the functional connectivity maps of all the other RSNs, including the cerebellar network. CONCLUSION: Our findings suggest a non-significant impact of gadolinium deposition on within-network cerebellar functional connectivity of long-term quiescent CD patients.

Absence of dentate nucleus resting-state functional connectivity changes in nonneurological patients with gadolinium-related hyperintensity on T1 -weighted images.

BACKGROUND: The dentate nuclei of the cerebellum are the areas where gadolinium predominantly accumulates. It is not yet known whether gadolinium deposition affects brain functions. PURPOSE/HYPOTHESIS: To assess whether gadolinium-dependent high signal intensity of the cerebellum on T1 -weighted images of nonneurological adult patients with Crohn's disease is associated with modifications of resting-state functional connectivity (RSFC) of the cerebellum and dentate nucleus. STUDY TYPE: Observational, cross-sectional. POPULATION: Fifteen patients affected by Crohn's disease were compared with 16 healthy age- and gender-matched control subjects. All participants underwent neurological, neurocognitive-psychological assessment, and blood sampling. FIELD STRENGTH/SEQUENCE: 1.5-T magnet blood oxygenation level-dependent (BOLD) functional MRI. ASSESSMENT: High signal intensity on T1 -weighted images, cerebellum functional connectivity, neurocognitive performance, and blood circulating gadolinium levels. STATISTICAL TESTS: An unpaired two-sample t-test (age and sex were nuisance variables) was used to investigate between-group differences in cerebellar and dentate nucleus functional connectivity. Z-statistical images were set using clusters determined by Z > 2.3 and a familywise error (FWE)-corrected cluster significance threshold of P = 0.05. RESULTS: Dentate nuclei RSFC was not different (P = n.s.) between patients with gadolinium-dependent high signal intensity on T1 -weighted images and controls. Pre- and postcentral gyrus bilaterally and the right supplementary motor cortex showed a decrease of RSFC with the cerebellum hemispheres (P < 0.05 FWE-corrected) and was related to disease duration but not to gadodiamide cumulative doses (P = n.s.). DATA CONCLUSION: Crohn's disease patients with gadolinium-dependent hyperintense dentate nuclei on unenhanced T1 -weighted images do not show dentate nucleus RSFC changes. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 5 J. Magn. Reson. Imaging 2019;50:445-455.

Epilepsy-associated stigma from the perspective of people with epilepsy and the community in Italy.

OBJECTIVE: The objective of this study was to assess the stigma related to epilepsy from the perspective of people with epilepsy (PWE) and from the Italian community (Rome and central Italy); moreover, the impact of the perceived stigma on the mood and quality of life of patients was also evaluated. MATERIALS AND METHODS: We consecutively enrolled 100 PWE and 202 nonepileptic subjects (NES). Both PWE and NES completed an Italian version of the Stigma Scale of Epilepsy (SSE), a 24-items questionnaire that has been demonstrated to allow the quantification of the stigma perception by patients and people from the community. Moreover, the PWE fulfilled a 3-item Jacoby's Stigma Scale, the Quality of Life in Epilepsy-31 (QOLIE-31 [Q3])), and Beck Depression Inventory II (BDI-II) questionnaires for the evaluation of the quality of life and depressive symptoms. The results of the SSE were correlated with clinical and demographic details of PWE and NES, as well as the Q31 and BDI-II scores in PWE. RESULTS: The SSE scores were significantly higher in NES with respect to PWE (respectively 47.1 vs 39.5, p < .001). Forty-two percent of PWE reported feeling stigmatized, with 5% reporting feeling highly stigmatized. In PWE, the perceived stigma was not correlated with seizure frequency but was significantly associated with worse quality of life, more severe depressive symptoms, and higher number of AEDs. The multiple regression analysis showed that the quality-of-life overall score and Q31 subscale exploring "social function" are the most significant predictors of stigma. CONCLUSIONS: By using an Italian translation of the SSE questionnaire, even if we cannot consider our sample representative of the whole Italian community our study evidenced higher rates of stigma related to epilepsy in NES than in PWE. The PWE still experience feelings of stigmatization strongly correlated with higher depressive symptoms and worse quality of life that has proven to be the most significant predictor of stigma. Finally, seizure frequency does not affect the perceived stigma, which is instead significantly influenced by antiepileptic therapy.

Executive functioning in relapsing-remitting multiple sclerosis patients without cognitive impairment: A task-switching protocol.

BACKGROUND: Cognitive dysfunction affects 40%-65% of multiple sclerosis (MS) patients, most often affecting information processing speed and working memory, mediated by the pre-frontal cortex (PFC). OBJECTIVE: Our study aimed to investigate PFC functioning through a task-switching protocol in relapsing-remitting multiple sclerosis (RRMS) patients without cognitive impairment. METHODS: A total of 24 RRMS patients and 25 controls were enrolled. Two different tasks were performed in rapid and random succession, so that the task was either changed from one trial to the next one (switch trials) or repeated (repetition trials). Switch trials are usually slower than repetitions, causing a so-called switch cost (SC). RESULTS: Patients had worse performance than controls only in the switch trials, as indicated by increased SC and reaction times. Moreover, patients showed a reduced ability to reconfigure the task-set for the execution of a new task and to disengage from the previous one. CONCLUSION: Our results showed a primary deficit in executive control processes involved in the task-switching performance in RRMS patients without cognitive impairment. This deficit may depend on the functional impairment of the PFC, which is essential to adjust behaviour rapidly and flexibly in response to environmental changes, representing one of the most sophisticated human abilities.

Altered metal metabolism in patients with HCV-related cirrhosis and hepatic encephalopathy.

Dysfunctional metal homeostasis contributes to oxidative stress and neuronal damage. These have been implicated in hepatic encephalopathy pathogenesis. To investigate whether altered metal metabolism is associated with hepatic encephalopathy. Twenty-one controls and 34 HCV-cirrhotic patients (ENC/NEC patients according to presence/absence of previous overt episodes of hepatic encephalopathy) and a control group were studied. Serum iron, copper, ceruloplasmin, ceruloplasmin activity, transferrin, and ceruloplasmin/transferrin ratio were determined. Neuropsychological tests were performed by the repeatable battery of neuropsychological status. Magnetic resonance assessed basal ganglia volumes and metal deposition (pallidal index and T2*). Cirrhotic patients performed worse than controls at cognitive tests, especially ENC patients,. At biochemical analysis copper concentrations, ceruloplasmin activity and transferrin levels were lower in ENC than in NEC patients and controls (p < 0.05 and p < 0.01, respectively). Ceruloplasmin/transferrin ratio was higher in ENC compared to NEC patients (p < 0.05), and controls (p < 0.01). By brain magnetic resonance, ENC patients showed reduced caudate and globus pallidus volumes compared to controls (p < 0.05), and ENC and NEC patients an increased pallidal index compared to controls (p < 0.01). In ENC patients, ceruloplasmin activity correlated with caudate volume and pallidal index (ρ = 0.773 and ρ = -0.683, p < 0.05). Altered metal metabolism likely contributes to cirrhotic hepatic encephalopathy.

The psychological impact of the covid-19 pandemic on radiotherapy cancer patients.

In March 2020, the World Health Organization (WHO) characterized the outbreak of the coronavirus disease 2019 (COVID-19) as a pandemic. The aim of this study was to evaluate the psychological impact of the COVID-19 pandemic on cancer patients undergoing radiotherapy. Were enrolled 210 patients in treatment and in follow-up who had access to the Radiation Oncology Department of the Campus Bio-Medico University Hospital Foundation between April and May 2020. The sample was subjected to structured interview and validated questionnaires. 37% of patients showed significant levels of distress; depressive symptoms were reported by 22.4% of patients and 99% of sample had clinically significant anxiety symptoms. All patients anxiety worsened during the COVID-19 pandemic (p=< 0.001). Patients on active treatment had higher levels of distress (3.5 vs 2.6; p = 0.04) and anxiety (3.5 vs 2.6; p = 0.04). Lung cancer patients appeared to be more afraid of COVID-19 than other patients (24.2 vs 22.2). This study highlights the presence of clinically significant anxiety in 99% of sample. This conclusion reflects the condition of emotional distress present during the pandemic which makes it necessary to treat patients in a multidisciplinary perspective that includes psychological support in the care plan.

Psychopathological Comorbidities and Clinical Variables in Patients With Medication Overuse Headache.

The psychopathological profile of patients with medication overuse headache (MOH) appears to be particularly complex. To better define it, we evaluated their performance on a targeted psychological profile assessment. We designed a case-control study comparing MOH patients and matched healthy controls (HC). Headache frequency, drug consumption, HIT-6, and MIDAS scores were recorded. All participants filled in the following questionnaires: Beck Depression Inventory-II Edition (BDI-2), trait subtest of State-Trait Anxiety Inventory (STAI-Y), Difficulties in Emotion Regulation Scale (DERS), Barratt Impulsiveness Scale (BIS-11), Toronto Alexithymia Scale (TAS-20). The primary endpoint was to establish if MOH patients have an altered psychopathological profile. The secondary endpoint was to establish whether the worst profile correlates with the worsening of headache and disability measures. We enrolled 48 consecutive MOH patients and 48 HC. MOH patients showed greater difficulty in recognition/regulation of emotions (DERS, TAS-20), depression (BDI-2), anxiety (STAI-Y), and impulsiveness (BIS-11). We found a positive correlation among DERS, BDI-2, STAI-Y, and BIS scores and MIDAS and HIT-6 scores and among DERS and headache frequency and drug consumption. MOH patients showed a high rate of emotion regulation difficulties, depression, and anxiety, which may negatively affect their headaches. The ability to regulate/recognize emotions may play a central role in sustaining medication overuse.

Epicentral disruption of structural connectivity in Alzheimer's disease.

AIMS: Neurodegenerative changes observed in Alzheimer's disease (AD) have been suggested to begin at the entorhinal cortex and hippocampus and then to propagate in a stereotypical fashion. Using diffusion-weighted imaging, we test whether disruption of structural connectivity in AD is centered on these "epicenters of disease". METHODS: Fifteen healthy controls, 14 amnestic mild cognitive impairment (aMCI), 13 mild, and 15 moderate patients with AD were enrolled. The percentages of affected connections directly linking to the epicenter (named first ring) and to nodes with topological distance 2 from the epicenter (named second ring) were calculated. RESULTS: For the group of aMCI patients, just 5.3% of the first ring (n.s.) and 2.9% of the second ring (n.s.) connections were affected. However, for mild AD there was disruption involving 20% of the first ring (P < 0.0001) and 10.3% of the second ring (P < 0.0001) connections. In the moderate AD group, a stronger effect was observed, with 38.0% of the first ring (P < 0.0001) connections and 17.9% of the second ring (P < 0.0001) connections affected. CONCLUSION: Our results favor an epicentral disruption of structural connectivity in aMCI and AD around entorhinal and hippocampal regions, consistent with the transneuronal spread hypothesis.

Relationship among diffusion tensor imaging, EEG activity, and cognitive status in mild cognitive impairment and Alzheimer's disease patients.

Magnetic resonance (MR) diffusion tensor imaging (DTI) can detect microstructural alterations by means of fractional anisotropy (FA) in patients with dementia, also in relation to cognitive status. The present study aimed at investigating the possible relation among white matter damage in DTI, quantitative electroencephalography (EEG) spectral power, and cognitive status in Alzheimer's disease (AD) and mild cognitive impairment (MCI) patients. Forty-seven subjects (8 moderate AD, 18 mild AD, 12 MCI, and 9 healthy controls) underwent brain MR, neuropsychological evaluation, and resting EEG recording. A progressive increase of EEG delta and theta spectral power was observed from controls to patients, mainly in more anterior areas, with a parallel widespread decrease of beta power. Moreover, a progressive decrease of FA from controls to patients in frontal areas and in the corpus callosum (genu) was observed. Correlation analyses indicated convergence among EEG rhythms changes, DTI values, and cognitive status mainly over anterior areas. The decrease of FA values and EEG spectral power changes might represent markers of neurodegenerative dysfunction, possibly preceding macrostructural atrophy.

Diffusion-weighted lesions after carotid artery stenting are associated with cognitive impairment.

The effect of carotid artery stenting (CAS) on cognitive function is still debated. Cerebral microembolism, detectable by post-procedural diffusion-weighted imaging (DWI) lesions, has been suggested to predispose to cognitive decline. Our study aimed at evaluating the effect of CAS on cognitive profile focusing on the potential role of cerebral microembolic lesions, taking into consideration the impact of factors potentially influencing cognitive status (demographic features, vascular risk profile, neuropsychological evaluation at baseline and magnetic resonance (MR) markers of brain structural damage). Thirty-seven patients with severe carotid artery stenosis were enrolled. Neurological assessment, neuropsychological evaluation and brain MR were performed the day before CAS (E0). Brain MR with DWI was repeated the day after CAS (E1), while neuropsychological evaluation was done after a 14-month median period (E2). Volumes of both white matter hyperintensities and whole brain were estimated at E0 on axial MR FLAIR and T1w-SE sequences, respectively. Unadjusted ANOVA analysis showed a significant CAS*DWI interaction for MMSE (F=7.154(32), p=.012). After adjusting for factors potentially influencing cognitive status CAS*DWI interaction was confirmed for MMSE (F=7.092(13), p=.020). Patients with DWI lesions showed a mean E2-E0 MMSE reduction of -3.1, while group without DWI lesions showed a mean E2-E0 MMSE of +1.1. Our study showed that peri-procedural brain microembolic load impacts negatively on cognitive functions, independently from the influence of patients-related variables.

Is cognitive function linked to serum free copper levels? A cohort study in a normal population.

OBJECTIVE: Much research on copper-dependent neurodegeneration has focused on the study of total copper levels in the organism. However, recent evidence suggests that the portion of copper that does not bind to ceruloplasmin and is loosely transported by micronutrients (free copper) may play a more significant role than copper as a whole. In this paper, we measured markers of copper metabolism in the sera of a group of cognitively normal women to test whether abnormal amounts of free copper have detectable effects on the mental state of clinically normal people. METHODS: We measured serum levels of free and ceruloplasmin-bound copper in 64 women whose normal mental state had been assessed via a battery of neuropsychological tests representing the major cognitive domains. RESULTS: Results show a significant inverse correlation of the serum levels of free copper with both Mini-Mental State Examination (MMSE) and attention-related neuropsychological tests scores. Bound copper, instead, did not correlate with either MMSE scores or any cognitive domain. CONCLUSIONS: Free copper appears to be a player in cognitive decline. SIGNIFICANCE: This evidence suggests the need for a shift of focus from total to free copper levels in the study of mental decline and sustains the notion that free copper may be a risk factor in the development of impaired cognition.