Systemic Oxidative Stress in Subacute Stroke Patients Undergoing Rehabilitation Treatment.

The imbalance in oxidative stress in acute stroke has been extensively studied; on the contrary, its investigation in the subacute phase is limited. The aim of this study was to analyse the variation in the systemic oxidative status in subacute post-stroke patients before (T0) and after a six-week rehabilitation treatment (T1) and to investigate the relationship between systemic oxidative status and rehabilitation outcomes. We enrolled 109 subjects in two different centres, and we analysed their serum hydroperoxide levels (d-ROMs), biological antioxidant power (BAP), thiol antioxidant components (-SHp), and relative antioxidant capacity (OSI and SH-OSI indices). Activity of Daily Living (ADL), hand grip strength, and walking endurance were evaluated using the modified Barthel Index, the Hand Grip test, and the 6-min walk test, respectively. At T0, most of the patients showed very high levels of d-ROMs and suboptimal levels of the BAP, OSI, and SH-OSI indices. Comparing the T1 and T0 data, we observed an improvement in the rehabilitation outcomes and a significant decrease in d-ROMs (549 ± 126 vs. 523 ± 148, p = 0.023), as well as an improvement in the OSI and SH-OSI indices (4.3 ± 1.3 vs. 4.7 ± 1.5, p = 0.001; 11.0 ± 0.4 vs. 1.2 ± 0.4, p < 0.001). In addition, significant correlations were seen between the oxidative stress parameters and the rehabilitation outcomes. These results suggest monitoring the systemic oxidative stress status in post-stroke patients in order to plan a tailored intervention, considering its relationship with functional recovery.

Muscle quality improvement in subacute post-stroke patients after rehabilitation: Usefulness of segmental phase angle from bioelectrical impedance analysis.

BACKGROUND & AIMS: During stroke rehabilitation, the whole-body Phase Angle (PhA) from Bioelectrical Impedance Analysis (BIA) is measured to assess whole-body muscle quality, which reflects cellular integrity and function. The segmental BIA is a valuable method for assessing the body composition of specific body segments, such as the arms, legs, and hemisoma. After a stroke insult, patients frequently experience hemiparesis, and segmental PhA from segmental BIA appears to be an appropriate parameter for examining the muscle quality of affected and unaffected limbs separately. This study aims to investigate whether segmental PhA is more informative than whole-body PhA in (a) assessing the deterioration of muscle quality in post-stroke patients and (b) monitoring its recovery following rehabilitative treatment. METHODS: This longitudinal study recruited subacute post-stroke patients who were admitted to our rehabilitation center. At admission, demographic, anamnestic, and clinical information, such as the presence of comorbidities, were recorded. BIA was used to evaluate the whole-body PhA and segmental PhA of the affected and unaffected hemisoma, arms, and legs at admission (T0) and after a six-week rehabilitation program (T1). The modified Barthel Index (mBI), Fugl-Meyer Assessment for the Upper Extremity (FMA-UE), and Motricity Index of the Upper (MI-UE) and Lower (MI-LE) Extremities were evaluated at T0 and T1 to determine the patient's Activity of Daily Living (ADL) performance, upper limb motor performance, and upper and lower limb muscle strength, respectively. RESULTS: We evaluated segmental and whole-body BIA in 70 subacute post-stroke patients (women n = 34, ischemic n = 56, mean age 70 ± 11) at T0 and T1. Whole-body PhA values of the patients were below the normal range. Considering segmental data, the affected hemisoma, arm, and leg had considerably lower PhA values as compared to the unaffected body segments. Furthermore, at T1, the PhA values of all affected body segments improved, while those of the unaffected ones and whole-body PhA did not. At both T0 and T1, the segmental PhA values of the affected body segments showed to be related with all clinical outcome measures, while whole-body PhA correlated only with mBI. CONCLUSIONS: This study emphasizes the significance of measuring segmental PhA in hemiparetic subacute stroke patients undergoing rehabilitation treatment. Segmental PhA is a more accurate parameter to evaluate rehabilitation treatment in patients with hemiparesis because it can distinguish affected from unaffected body segments, hence facilitating accurate monitoring of muscle quality improvements resulting from a rehabilitation program.

Nutrition in Post-Stroke Subjects during Rehabilitation.

Correct and appropriate nutrition after a stroke insult appears to exert an essential influence on, and play a key role in, the recovery of patients [...].

Relationship between Nutritional Status, Food Consumption and Sarcopenia in Post-Stroke Rehabilitation: Preliminary Data.

After a stroke, patients can suffer from sarcopenia, which can affect recovery. This could be closely related to an impairment in nutritional status. In this preliminary analysis of a longitudinal prospective study, we screened 110 subjects admitted to our rehabilitation center after a stroke. We then enrolled 61 patients, who underwent a 6-week course of rehabilitation treatment. We identified a group of 18 sarcopenic patients (SG), according to the European Working Group on Sarcopenia in Older People 2 (EWGSOP2), by evaluating muscle strength with the handgrip test, and muscle mass with bioelectrical impedance analysis (BIA). With respect to the non-sarcopenic group (NSG), the SG at admission (T0) had worse muscle quality, according to the BIA-derived phase angle, and a lower score of MNA®-SF. In contrast to the NSG, the SG also exhibited lower values for both BMI and the Geriatric Nutritional Risk Index (GNRI) at T0 and T1. Moreover, 33% of the SG had a major risk of nutrition-related complications (GNRI at T0 < 92) and discarded on average more food during the six weeks of rehabilitation (about one-third of the average daily plate waste). Of note is the fact that the Barthel Index's change from baseline indicated that the SG had a worse functional recovery than the NGS. These results suggest that an accurate diagnosis of sarcopenia, along with a proper evaluation of the nutritional status on admission to rehabilitation centers, appears strictly necessary to design individual, targeted physical and nutritional intervention for post-stroke patients, to improve their ability outcomes.

A Remote Assessment of Anxiety on Young People: Towards Their Views and Their Different Pet Interaction.

The lockdown was imposed in Italy on 9 March 2020 due to the COVID-19 outbreak. Restrictions severely limiting individual freedom were indispensable to protect the population and reduce virus diffusion. Italian people had never before experienced similar restrictions that undoubtedly tested psychological health. After 1 week, we developed an electronic survey to collect demographic data and information on the presence of pets and the type of interaction with them and to administer a self-assessment anxiety test. A total of 3905 subjects, pet owners and non pet owners, filled in the electronic survey; 652 (16.7%, mean age 21.6) of them were young subjects, adolescents, and university students. The study first showed the feasibility and success of the technological solution used, capable of providing, at a distance, structured information on the participants and quantitative data on the psychological condition. Second, it reported that 23.1% of the youths showed anxiety above an attention level during the lockdown, in line with other studies. Third, it indicated, based on the outcome of the self-assessment test, that the pet presence could have a positive effect in mitigating the psychological impact and encourage to continue and deepen these investigations. Fourth, it reported positive feedback from the participants on the procedure, found useful during the pandemic and for the post-pandemic future. The study highlights the importance of investing in these solutions based on mobile technology and useful both for mental health and to deepen the investigation of the impact of the pet presence on the human psychology.

Effects of Social Distancing on Quality of Life and Emotional-Affective Sphere of Caregivers and Older Patients Hospitalized in Rehabilitation Departments during COVID-19 Quarantine: An Observational Study.

During the COVID-19 emergency, institutional social distancing conditions were established, preventing family and caregivers' access to rehabilitation departments. Our study goal was to assess inpatients' and caregivers' anxiety, depression, and Quality of Life (QoL) during the Italian lockdown due to the pandemic. We investigated anxiety, depression, and QoL in 53 patients and 51 caregivers, using the Beck Anxiety Inventory (BAI), the Beck Depression Inventory-II (BDI-II), and the Short Form 36 Health Survey (SF36). These questionnaires were given to patients after one (T0) and two months (T1) since the hospitalization. The BAI showed that anxiety was moderate for 7.5% of patients and 23.5% of caregivers, and severe for 35.8% of patients and 17.6% of caregivers. The BDI found moderate depression in 11.3% of patients and 15.7% of caregivers, and severe depression in 34.0% of patients and 9.8% of caregivers. Depression was higher in patients than caregivers, while no differences were detected in anxiety. Compared to normative data, patients' QoL declined in all eight SF36 dimensions, while caregivers' QoL declined only in social, emotional, and mental components. Unexpectedly, patients still hospitalized at T1 showed significant improvements in both anxiety and three QoL subscores. These findings emphasize the importance of psychological support for patients and their families.

Pet Presence Can Reduce Anxiety in the Elderly: The Italian Experience during COVID-19 Lockdown Assessed by an Electronic Survey.

The lockdown imposed in Italy due to the COVID-19 outbreak required restrictions that severely limited individual freedom to protect the population and reduce virus diffusion. This situation psychologically challenged the entire Italian population but mostly the elderly. The "Digital mental health approach" employs digital tools to evaluate and prevent increasing mental health problems. "Anonymous online electronic surveys" are digital tools that assess rates of mental health outcomes (using for example self-assessment/awareness tools). Immediately at the beginning of restrictions, we designed an electronic survey a) to remotely investigate the psychological impact of the lockdown and b) to compare the anxiety between pet owners and not-pet owners. A total of 3905 subjects filled out the survey; we focused our study on 781 (20%) elderly subjects. Dividing elderly patients between pet-owners (n = 405) and not-pet owners (n = 376), the pet owners showed a Zung scale score significantly lower in respect to the not-pet owners. We observed that, during the COVID-19 outbreak, the pet presence could have a positive effect on anxiety in the elderly subject. These results: (A) encourage the use of mobile technologies for the assessment of psychological disorders that can be promptly employed in emergencies such as the COVID-19 outbreak; (B) highlight the positive effect of pet interaction to mitigate the psychological distress in elderly people.

Oxidative Stress Status in Post Stroke Patients: Sex Differences.

After a cerebral stroke insult, there is an overproduction of Reactive Oxygen Species (ROS), which overcome the antioxidant defenses, causing further tissues damage. The status of oxidative stress in stroke patients over time, particularly in those undergoing rehabilitation treatments, has been poorly investigated. We analyzed the oxidative stress status in 61 subacute stroke patients (33 females and 28 males) admitted to our rehabilitation center by measuring, in serum: hydroperoxides levels (d-ROMs), antioxidant activity (BAP test), and the relative antioxidant capacity (OSI index). We also analyzed patients for glucose levels and lipid profile. In addition, we analyzed the correlation between oxidative stress status biomarkers and motor deficits, disability, and pain. Almost all patients showed high or very high levels of d-ROMs, while BAP levels were apparently in the reference range of normality. Females had lower BAP values (females: 2478 ± 379; males: 2765 ± 590; p = 0.034) and lower OSI index (females: 5.7 ± 1.9; males: 6.8 ± 1.9; p = 0.043). Moreover, in the male group, the correlation with motor impairment and disability showed a worsened motor performance when oxidative stress is higher. Female group, on the other hand, had an unexpected different trend of correlation, probably due to an unbalanced systemic oxidative stress. Further research is needed to see if sex differences in oxidative stress status in subacute stroke patients persist after rehabilitation.

Serotonin Levels and Cognitive Recovery in Patients with Subacute Stroke after Rehabilitation Treatment.

Post-stroke depression and cognitive impairment are common conditions affecting patients after stroke. Serotonin is a neurotransmitter involved in modulating, among others, mood, cognition, learning, and memory. Sub-optimal serotonin activity may be in part responsible for cognitive deficits seen in depression. In this pilot study serotonin levels were evaluated in 29 patients with sub-acute stroke before and after a rehabilitation treatment (consisting of a program of upper limb robotic rehabilitation in addition to conventional physical therapy treatment). We employed the Back Depression Inventory scale to evaluate symptoms of depression, and specific tools to evaluate cognitive functions. We found a significant reduction of the serotonin levels after rehabilitation in the whole group (T0: 85.9 ± 92.4 ng/mL; T1: 61.9 ± 58.4 ng/mL; p = 0.0018), as well as in the subgroup of patients untreated with Selective Serotonin Reuptake Inhibitors (SRRI), (mean serotonin at T0: 154.0 ± 102.3 ng/mL; mean serotonin at T1: 92.9. ± 68.7 ng/mL at T1; p = 0.005). We also found a correlation with cognitive assessment: in particular, the change from baseline of the serotonin (ΔSerotonin) was correlated with the changes from baseline of the Rey's Figure (ΔROCF) (r = 0.535; p < 0.05), the Tower of London (ΔToL) (subscore point: r = 0.621; p < 0.005; subscore time: r = -0.619; p < 0.005) meaning that a serotonin levels decrease is associated with a worsening of cognitive functions. Considering patients treated and untreated with SSRIs separately, in patients treated with SSRIs (n = 16) we found only a positive correlation between ∆Serotonin and ∆ToL (subscore point: r= 0.587; p = 0.045), whereas in patients untreated with SSRIs (n = 13) we found a positive correlations between ΔSerotonin and ΔROCF (r = 0.700; p = 0.036), ∆Stroop (subscore time: r = 0.750; p = 0.020) and ∆Tol (subscore point: r = 0.740; p = 0.023) and a negative correlation between ΔSerotonin and ∆Tol (subscore time: r= -0.833; p = 0.005). These results suggest that variation of serotonin levels should be monitored in patients during a rehabilitation program, not only for their relationship with depression symptoms, but also for the correlation with cognitive performance.

Association Study of SLC6A4 (5-HTTLPR) Polymorphism and Its Promoter Methylation with Rehabilitation Outcome in Patients with Subacute Stroke.

Recently it has been suggested that serotonin transporter (SLC6A4) and its 5HTTLPR polymorphism could be involved in post stroke recovery. Here, we characterized the methylation profile of two different CpG islands within the SLC6A4 promoter region in the whole blood of 50 patients with subacute stroke before and after a six-week rehabilitation treatment. These patients were genotyped for 5HTTLPR polymorphism identifying patients on the basis of short (S) and L (L) alleles: 17 patients LL, 22 patients LS and 11 patients SS. At baseline, all CpG sites for both CpG islands displayed a heterogeneous methylation percentage that were not influenced by the different genotypes. After rehabilitation, we found a significant variation in the methylation levels (increase/decrease) in the specific CpG sites of both CpG islands. The statistical analysis showed a significant relationship between the LL, LS and SS alleles and the outcome of the rehabilitation intervention (χ2 (2,50) = 6.395, p = 0.041). Specifically, we found a significant difference between patients with or without a favorable outcome in the LL (11.1% with a favorable outcome) and in the SS (54.4% with a favorable outcome) groups. Our data suggest that 5-HTTLPR polymorphisms and SLC6A4 promoter methylation may be employed as a non-invasive biological marker of recovery in patients with stroke undergoing rehabilitation.

BDNF rs6265 Polymorphism and Its Methylation in Patients with Stroke Undergoing Rehabilitation.

Brain-Derived Neurotrophic Factor (BDNF) and its rs6265 single nucleotide polymorphism (SNP) play an important role in post-stroke recovery. We investigated the correlation between BDNF rs6265 SNP and recovery outcome, measured by the modified Barthel index, in 49 patients with stroke hospitalized in our rehabilitation center at baseline (T0) and after 30 sessions of rehabilitation treatment (T1); moreover, we analyzed the methylation level of the CpG site created or abolished into BDNF rs6265 SNP. In total, 11 patients (22.4%) were heterozygous GA, and 32 (65.3%) and 6 (12.2%) patients were homozygous GG and AA, respectively. The univariate analysis showed a significant relationship between the BDNF rs6265 SNP and the modified Barthel index cut-off (χ2(1, N = 48) = 3.86, p = 0.049), considering patients divided for carrying (A+) or not carrying (A-) the A allele. A higher percentage of A- patients obtained a favorable outcome, as showed by the logistic regression model corrected by age and time since the stroke onset, compared with the A+ patients (OR: 5.59). At baseline (T0), the percentage of BDNF methylation was significantly different between GG (44.6 ± 1.1%), GA (39.5 ± 2.8%) and AA (28.5 ± 1.7%) alleles (p < 0.001). After rehabilitation (T1), only patients A- showed a significant increase in methylation percentages (mean change = 1.3, CI: 0.4-2.2, p = 0.007). This preliminary study deserves more investigation to confirm if BDNF rs6265 SNP and its methylation could be used as a biological marker of recovery in patients with stroke undergoing rehabilitation treatment.

Correction: Single nucleotide polymorphisms in the human ATP7B gene modify the properties of the ATP7B protein.

Correction for 'Single nucleotide polymorphisms in the human ATP7B gene modify the properties of the ATP7B protein' by Courtney J. McCann et al., Metallomics, 2019, 11, 1128-1139.

Single nucleotide polymorphisms in the human ATP7B gene modify the properties of the ATP7B protein.

Single nucleotide polymorphisms (SNPs) are the largest source of sequence variation in the human genome. However, their functional significance is not well understood. We show that SNPs in the Wilson disease gene, ATP7B, that produce amino-acid substitutions K832R and R952K, modulate ATP7B properties in vitro and influence serum copper (Cu) status in vivo. The presence of R832 is associated with a lower ATP7B abundance and a diminished trafficking in response to elevated Cu. The K832R substitution alters surface exposure of amino acid residues in the actuator domain and increases its conformational flexibility. All SNP-related ATP7B variants (R832/R952, R832/K952, K832/K952, and K832/R952) have Cu-transport activity. However, the activity of ATP7B-K832/K952 is lower compared to other variants. In humans, the presence of K952 is associated with a higher fraction of exchangeable Cu in serum. Thus, SNPs may modulate the properties of ATP7B and the organism Cu status.

Oxidative Stress Related to Iron Metabolism in Relapsing Remitting Multiple Sclerosis Patients With Low Disability.

Oxidative status may play a role in chronic inflammation and neurodegeneration which are considered critical etiopathogenetic factors in Multiple Sclerosis (MS), both in the early phase of the disease and in the progressive one. The aim of this study is to explore oxidative status related to iron metabolism in peripheral blood of stable Relapsing-Remitting MS with low disability. We studied 60 Relapsing-Remitting MS patients (age 37.2 ± 9.06, EDSS median 1.0), and 40 healthy controls (age 40.3 ± 10.86). We measured total hydroperoxides (dROMs test) and Total Antioxidant Status (TAS), along with the iron metabolism biomarkers: Iron (Fe), ferritin (Ferr), transferrin (Tf), transferrin saturation (Tfsat), and ceruloplasmin (Cp) panel biomarkers [concentration (iCp) and enzymatic activity (eCp), copper (Cu), ceruloplasmin specific activity (eCp:iCp), copper to ceruloplasmin ratio (Cu:Cp), non-ceruloplasmin copper (nCp-Cu)]. We computed also the Cp:Tf ratio as an index of oxidative stress related to iron metabolism. We found lower TAS levels in MS patients than in healthy controls (CTRL) and normal reference level and higher dROMs and Cp:Tf ratio in MS than in healthy controls. Cp and Cu were higher in MS while biomarkers of iron metabolism were not different between patients and controls. Both in controls and MS, dROMs correlated with iCp (CTRL r = 0.821, p < 0.001; MS r = 0.775 p < 0.001) and eCp (CTRL r = 0.734, p < 0.001; MS r = 0.820 p < 0.001). Moreover, only in MS group iCp correlated negatively with Tfsat (r = -0.257, p = 0.047). Dividing MS patients in "untreated" group and "treated" group, we found a significant difference in Fe values [F(2, 97) = 10.136, p < 0.001]; in particular "MS untreated" showed higher mean values (mean = 114.5, SD = 39.37 µg/dL) than CTRL (mean 78.6, SD = 27.55 µg/dL p = 0.001) and "MS treated" (mean = 72.4, SD = 38.08 µg/dL; p < 0.001). Moreover, "MS untreated" showed significantly higher values of Cp:Tf (mean = 10.19, SD = 1.77∗10-2; p = 0.015), than CTRL (mean = 9.03, SD = 1.46 ∗10-2). These results suggest that chronic oxidative stress is relevant also in the remitting phase of the disease in patients with low disability and short disease duration. Therefore, treatment with antioxidants may be beneficial also in the early stage of the disease to preserve neuronal reserve.

Copper in Glucose Intolerance, Cognitive Decline, and Alzheimer Disease.

Trace metal dyshomeostasis has been linked to loss of cognitive performance. In particular, a disturbance in the regulation of copper (Cu), characterized by an increase in circulating Cu not bound to ceruloplasmin (non-Cp Cu), is thought to play a role in the development of Alzheimer disease (AD) and other neurodegenerative diseases in the aging population. Non-Cp Cu is redox active and its toxicity is thought to result from its ability to accelerate oxidative stress and advanced glycation endproduct (AGE) formation, leading to extracellular matrix damage in tissues including the brain. Cognitive loss is increasingly recognized to be a feature of type 2 diabetes and the increased AGE formation characteristic of diabetes may play a role in the development of this complication. There also is evidence for copper dyshomeostasis in type 2 diabetes, and therefore this could contribute to the cognitive deterioration associated with this disease. Demonstrating that disturbances of copper homeostasis correlate with an increased rate of cognitive decline in type 2 diabetes patients, and that they correlate with an increased rate of conversion from prediabetes to diabetes would bring almost immediate benefits in the clinical community in terms of treatment efficacy, AD prevention, and cost savings.

Copper and Zinc Dysregulation in Alzheimer's Disease.

Alzheimer's disease (AD) is one of the most common forms of dementia. Despite a wealth of knowledge on the molecular mechanisms involved in AD, current treatments have mainly focused on targeting amyloid ß (Aß) production, but have failed to show significant effects and efficacy. Therefore, a critical reconsideration of the multifactorial nature of the disease is needed. AD is a complex multifactorial disorder in which, along with Aß and tau, the convergence of polygenic, epigenetic, environmental, vascular, and metabolic factors increases the global susceptibility to the disease and shapes its course. One of the cofactors converging on AD is the dysregulation of brain metals. In this review, we focus on the role of AD-related neurodegeneration and cognitive decline triggered by the imbalance of two endogenous metals: copper and zinc.

Prognostic Value of Serum Copper for Post-Stroke Clinical Recovery: A Pilot Study.

The clinical course after ischemic stroke can vary considerably despite similar lesions and clinical status at the onset of symptoms, suggesting that individual factors modulate clinical recovery. Here, we sought to test the working hypothesis that elevated copper values provide prognostic information, and specifically predict worse clinical recovery. We further sought to support previous findings regarding metal metabolism in acute stroke. We assessed total antioxidant status, oxidative stress factors (peroxides) and metal metabolism markers (iron, copper, ceruloplasmin concentration and activity, ferritin, and transferrin) in the acute phase (2-10 days from symptom onset) in 30 patients affected by unilateral middle cerebral artery (MCA) stroke. A longitudinal assessment of clinical deficit was performed in the acute and stabilized phases (typically 6 months post-stroke) using the National Institutes of Health Stroke Scale (NIHSS). In identifying recovery-related factors, we considered effective recovery (ER), calculated as the ratio between actual NIHSS recovery and the total potential recovery. This allows an estimation of the actual recovery adjusted for the patient's initial condition. In the acute phase, clinical severity was correlated with increased peroxide concentrations, and lower iron levels. Less successful clinical recovery was correlated with increased acute copper levels, which entered a multiple regression model that explained 24% of ER variance. These pilot data suggest that, in the acute phase of an ischemic stroke, copper may provide useful information about clinical recovery.

Serum Copper is not Altered in Frontotemporal Lobar Degeneration.

Meta-analyses show copper dyshomeostasis in Alzheimer's disease. However, a study evaluating copper changes in other neurodegenerative forms of dementia has not yet been performed. In this study, we assessed copper, ceruloplasmin, copper not bound to ceruloplasmin, and copper to ceruloplasmin ratio in 85 patients affected by frontotemporal lobar degeneration (FTLD) and 55 healthy controls. Data were analyzed through multivariate ANOVA models taking into account age and sex as covariates and the stratification for FTLD variants, after calculating power analysis to ensure the reliability of the conclusions drawn. The study revealed no difference between the groups.

Innovative Biomarkers for Alzheimer's Disease: Focus on the Hidden Disease Biomarkers.

The criteria for the clinical diagnosis of AD include the analysis of biomarkers of the underlying brain disease pathology; a set of cerebrospinal fluid (CSF) tests, amyloid-ß1-42 (Aß42), total-tau (t-tau), and phosphorylated tau (p-tau), are available and their performance in a clinical setting has been assessed in several studies. Thus, in dementia research, great advances have been made in the discovery of putative biomarkers; however, disappointingly, few of them have been translated into clinically applicable assays. To find biomarkers able to reliably detect AD pathology already at prodromal stages and in blood is even more important. Recent technical breakthroughs have provided ultrasensitive methods that allow the detection of brain-specific proteins in blood. In the present review, we will focus on the usefulness of ultrasensitive technologies for biomarker discovery and trace elements detection; moreover, we will review studies on circulating nano-compartments, a promising novel source of material for molecular diagnostics.

Copper dyshomeostasis in Wilson disease and Alzheimer's disease as shown by serum and urine copper indicators.

Abnormal handling of copper is the cause of Wilson disease (WD), a rare disorder typified by increased levels in plasma copper not-bound to ceruloplasmin (nCp-Cu, also known as 'free' copper). In Alzheimer's disease (AD), meta-analyses show that copper decreases in brain but increases in serum, due to the nCp Cu component increase. Despite the similarities, a direct comparison of copper biological status in the two diseases has never been carried out. To fill this gap, we evaluated serum copper, ceruloplasmin, nCp-Cu and Cu:Cp in 385 CE and 336 healthy controls previously investigated that were compared with 9 newly diagnosed WD patients. We then assessed 24h copper urinary excretion in 24 WD patients under D-penicillamine (D-pen) treatment and in 35 healthy controls, and compared results with those of AD patients participating to a D-pen phase II clinical trial previously published. After adjusting for sex and age, serum nCp-Cu and Cu:Cp resulted higher in AD and in WD than in healthy controls (both p<0.001). While nCp-Cu was similar between AD and WD, Cu:Cp was higher in WD (p<0.016). 24h urinary copper excretion in AD patients (12.05µg/day) was higher than in healthy controls (4.82µg/day; p<0.001). 77.8% of the AD patients under D-pen treatment had a 24h urinary excretion higher than 200µg/day, suggestive of a failure of copper control. This study provides new insight into the pathophysiology of copper homeostasis in AD, showing a failure of copper control and the Cu:Cp ratio as an eligible marker.