Simone Migliore

GSTO1*E155del polymorphism associated with increased risk for late-onset Alzheimer's disease: association hypothesis for an uncommon genetic variant

Glutathione S-transferases are multifunctional enzymes involved in cellular detoxification. A genetic linkage was found between Alzheimers Disease (AD) and the chromosome 10q, where the GSTO1 and GSTO2 genes are located, leading to the hypothesis that GST Omega class (GSTO) genes may be an AD risk factor. Since it is still controversial, we decided to explore GSTO polymorphisms in Italian cohorts. We analyzed 119 AD patients and 114 healthy controls for the GSTO gene polymorphisms. In particular we investigated two common polymorphisms (GSTO1*A140D, GSTO2*N142D) and two uncommon variants (GSTO1*E155del, GSTO1*E208K) to find loci associated with AD risk. Detection of GSTO1*A140D and GSTO2*N142D was performed by PCR-RFLP, while GSTO1*E155del and GSTO1*E208K were detected using confronting two-pair primer and allele specific PCR, respectively. While GSTO1*A140D, GSTO1*E208K and GSTO2*N142D polymorphisms did not show significant outcomes, the GSTO1*E155del polymorphism is associated with AD [P=0.003; adjusted OR=3.70 (1.57-8.75)]. Our results suggest that GSTO1-1 plays a role in AD since the GSTO1*del155 variant is involved in changes in GSTO1-1 activities decreasing in enzyme stability. Specifically, three hypotheses may explain the role of GSTO1-1 in the pathophysiology of AD: the antioxidant activity of GSTO1-1 may protect brain tissue against oxidative stress; GSTO1-1 activity regulate interleukin-1β activation and its genetic variation may act to modulate inflammation in AD; GSTO1-1 is involved in the arsenic biotransformation pathway and gene polymorphisms may be implicated in the modulation of arsenic neurotoxicity. In conclusion, we hypothesized that GSTO1*E155del is an uncommon genetic variant associated with AD risk.

Association between the c. 2495 A>G ATP7B Polymorphism and Sporadic Alzheimer's Disease

Nonceruloplasmin-bound copper (“free”) is reported to be elevated in Alzheimers disease (AD). In Wilsons disease (WD) Cu-ATPase 7B protein tightly controls free copper body levels. To explore whether the ATP7B gene harbours susceptibility loci for AD, we screened 180 AD chromosomes for sequence changes in exons 2, 5, 8, 10, 14, and 16, where most of the Mediterranean WD-causing mutations lie. No WD mutation, but sequence changes corresponding to c.1216 T>G Single-Nucleotide Polymorphism (SNP) and c.2495 A>G SNP were found. Thereafter, we genotyped 190 AD patients and 164 controls for these SNPs frequencies estimation. Logistic regression analyses revealed either a trend for the c.1216 SNP (P = .074) or a higher frequency for c.2495 SNP of the GG genotype in patients, increasing the probability of AD by 74% (P = .028). Presence of the GG genotype in ATP7B c.2495 could account for copper dysfunction in AD which has been shown to raise the probability of the disease.

Counterfactual thinking in moral judgment: An experimental study

Counterfactual thinking is thinking about a past that did not happen. This is often the case in “if only…” situations, where we wish something had or had not happened. To make a choice in a moral decision-making situation is particularly hard and, therefore, may be often associated with the imagination of a different outcome. The main aim of the present study is to investigate counterfactual thinking in the context of moral reasoning. We used a modified version of Greenes moral dilemmas test, studying both the time needed to provide a counterfactual in the first and third person and the type of given response (in context-out of context) in a sample of 90 healthy subjects. We found a longer response time for personal vs. impersonal moral dilemmas. This effect was enhanced in the first person perspective, while in the elderly there was an overall slowing of response time. Out of context/omissive responses were more frequent in the case of personal moral dilemmas presented in the first person version, with females showing a marked increase in this kind of response. These findings suggest that gender and perspective have a critical role in counterfactual thinking in the context of moral reasoning, and may have implications for the understanding of gender-related inclinations as well as differences in moral judgment.

Brain Plasticity Effects of Neuromodulation Against Multiple Sclerosis Fatigue

Rationale We recently reported on the efficacy of a personalized transcranial direct current stimulation (tDCS) treatment in reducing multiple sclerosis (MS) fatigue. The result supports the notion that interventions targeted at modifying abnormal excitability within the sensorimotor network could represent valid non-pharmacological treatments. Objective The present work aimed at assessing whether the mentioned intervention also induces changes in the excitability of sensorimotor cortical areas. Method Two separate groups of fatigued MS patients were given a 5-day tDCS treatments targeting, respectively, the whole body somatosensory areas (S1wb) and the hand sensorimotor areas (SM1hand). The study had a double blind, sham-controlled, randomized, cross-over (Real vs. Sham) design. Before and after each treatment, we measured fatigue levels (by the modified fatigue impact scale, mFIS), motor evoked potentials (MEPs) in response to transcranial magnetic stimulation and somatosensory evoked potentials (SEPs) in response to median nerve stimulation. We took MEPs and SEPs as measures of the excitability of the primary motor area (M1) and the primary somatosensory area (S1), respectively. Results The Real S1wb treatment produced a 27% reduction of the mFIS baseline level, while the SM1hand treatment showed no difference between Real and Sham stimulations. M1 excitability increased on average 6% of the baseline in the S1wb group and 40% in the SM1hand group. Observed SEP changes were not significant and we found no association between M1 excitability changes and mFIS decrease. Conclusion The tDCS treatment was more effective against MS fatigue when the electrode was focused on the bilateral whole body somatosensory area. Changes in S1 and M1 excitability did not correlate with symptoms amelioration. Significance The neuromodulation treatment that proved effective against MS fatigue induced only minor variations of the motor cortex excitability, not enough to explain the beneficial effects of the intervention.

Personalized, bilateral whole-body somatosensory cortex stimulation to relieve fatigue in multiple sclerosis:

Background: The patients suffering from multiple sclerosis (MS) often consider fatigue the most debilitating symptom they experience, but conventional medicine currently offers poorly efficacious therapies. Objective: We executed a replication study of an innovative approach for relieving MS fatigue. Methods: According to the sample size estimate, we recruited 10 fatigued MS patients who received 5-day transcranial direct current stimulation (tDCS) in a randomized, double-blind, Sham-controlled, crossover study, with modified Fatigue Impact Scale (mFIS) score reduction at the end of the treatment as primary outcome. A personalized anodal electrode, shaped on the magnetic resonance imaging (MRI)-derived individual cortical folding, targeted the bilateral whole-body primary somatosensory cortex (S1) with an occipital cathode. Results: The amelioration of fatigue symptoms after Real stimulation (40% of baseline) was significantly larger than after Sham stimulation (14%, p = 0.012). Anodal whole body S1 induced a significant fatigue reduction in mildly disabled MS patients when the fatigue-related symptoms severely hampered their quality of life. Conclusion: This second result in an independent group of patients supports the idea that neuromodulation interventions that properly select a personalized target might be a suitable non-pharmacological treatment for MS fatigue.

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.

Biological and clinical manifestations of juvenile Huntington's disease: a retrospective analysis

BACKGROUND Huntingtons disease is a rare, neurodegenerative disease caused by an expanded CAG repeat mutation in the huntingtin gene. Compared with adult-onset Huntingtons disease, juvenile Huntingtons disease (onset ≤20 years) is even rarer and has not been studied extensively. We aimed to further characterise juvenile Huntingtons disease by examining the effect of CAG repeat size on disease presentation, progression, and survival. METHODS We did a retrospective analysis of patients with juvenile Huntingtons disease aged 20 years or younger, according to the length of their CAG repeat and who had disabling psychiatric symptoms (with motor symptoms) or motor symptoms alone, and of patients with adult-onset Huntingtons disease manifesting aged 30-60 years with 40 or more CAG repeats, from the REGISTRY and ENROLL-HD platforms and from two institutional databases (Lega Italiana Ricerca Huntington Foundation and the Instituto Neurociencias de Buenos Aires and the Sanatorio de la Trinidad Mitre). Patients with psychiatric but no motor symptoms were excluded. We compared symptoms at onset and longitudinally in patients with juvenile Huntingtons disease with highly expanded (HE subgroup) or low expansion (LE subgroup) mutations, grouped by hierarchical clustering analysis. We also compared disease progression (longitudinal change in Unified Huntingtons Disease Rating Scale-Total Motor Score) and survival of patients with juvenile and adult-onset Huntingtons disease. FINDINGS We extracted medical records from 580 patients entered into the studies or databases between June 23, 2004, and March 31, 2018, of whom 36 patients met our definition of juvenile Huntingtons disease and 197 for adult-onset Huntingtons disease. According to caregiver reports, gait disturbance was more often a first presenting symptom in the HE subgroup (eight [80%] of 10 patients) than in the LE subgroup (seven [27%] of 26 patients; p=0·0071), whereas loss of hand dexterity was more common in the LE subgroup (11 [42%] of 26 patients) than in the HE subgroup (0 [0%] of 10 patients; p=0·0160). Compared with the LE subgroup, development delay (0 [0%] in the LE subgroup vs nine [90%] in the HE subgroup; p<0·0001), severe gait impairment (nine [35%] in the LE subgroup vs nine [90%] in the HE subgroup; p=0·0072), and seizures (three [11%] in the LE subgroup vs eight [80%] in the HE subgroup; p<0·0001) prevailed over time in the HE subgroup. Disease progression was more rapid in juvenile Huntingtons disease (n=14) than in adult-onset Huntingtons disease (n=52; generalised estimating equation model, p=0·0003). Of 121 deceased patients, median survival was shorter in the juvenile Huntingtons disease (n=17) cohort than in adult-onset Huntingtons disease (n=104) cohort (hazard ratio 2·18 [95% CI 1·08-4·40]; p=0·002). INTERPRETATION Patients with HE juvenile Huntingtons disease differ clinically from patients with LE juvenile Huntingtons disease or adult-onset Huntingtons disease, suggesting reclassification of this particularly aggressive form of Huntingtons disease might be required. FUNDING Lega Italiana Ricerca Huntington Foundation and IRCCS Ospedale Casa Sollievo della Sofferenza.

Resting‐state connectivity and modulated somatomotor and default‐mode networks in Huntington disease

To analyze brain functional connectivity in the somatomotor and default‐mode networks (DMNs) of patients with Huntington disease (HD), its relationship with gray matter (GM) volume loss, and functional changes after pridopidine treatment.

Generation of the induced pluripotent stem cell line CSSi006-A (3681) from a patient affected by advanced-stage Juvenile Onset Huntington's Disease

Juvenile Onset Huntingtons Disease (JOHD) is a rare variant of HD withage of onset ≤20 years, accounting for 3-10% of all HD patients. The rarity occurrence of JOHD cases, who severely progress towards mental and physical disability with atypical clinical manifestations compared to classical HD, are responsible of general lack of knowledge about this variant. We obtained a fully reprogrammed iPS cell line from fibroblasts of a JOHD patient carrying 65 CAG repeats and age at onset at age 15. At the biopsy time, the patient showed an advanced stage after 10 years of disease.

Moral Judgment and Empathic/Deontological Guilt:

Background People often make complicated decisions to help or to punish perfect strangers. Harming someone or breaking some moral imperative is usually linked to feeling guilt, and several researches suggested the existence of two different kinds of guilt: altruistic/empathic and deontological. Aim Our study aimed to investigate the decision-making processes in moral and nonmoral judgments and assess how specific situations in which the subject is close to the victim or flanked by an authority can influence his decisions. Methods We used three different moral conditions: Empathic Moral (the decision has made while physically close to the potential victims), Deontological Moral (the decision has made while flanked by an “authority”), and Standard Moral (without any influence); a fourth condition is represented by Nonmoral dilemmas (the subject must make a choice between two different things and this does not cause any harm or victims). Previously, a pilot study was carried out for validating the experimental stories to be used in the main study. Results We observed a higher number of utilitarian/positive responses when individuals had to respond to Empathic Moral condition, with respect to Deontological Moral and Nonmoral dilemmas. Moreover, looking at the time needed to read the dilemma, under empathic guilt condition, people tended to be slower in reading the dilemmas than in other conditions and this both in case of positive and negative responses. No significant differences in time needed to effectively respond emerged. Conclusions These findings suggested that be physically close to potential victims or be flanked by an “authority” differentially influence the decision-making processes in moral judgment, inducing slower decisions and more utilitarian answers, particularly in the scenario of physical proximity.