Mario Guazzelli

Tau gene mutation G389R causes a tauopathy with abundant pick body-like inclusions and axonal deposits.

Exonic and intronic mutations in Tau cause familial neurodegenerative syndromes characterized by frontotemporal dementia and dysfunction of multiple cortical and subcortical circuits. Here we describe a G389R mutation in exon 13 of Tau. When 38 years old, the proband presented with progressive aphasia and memory disturbance, followed by apathy, indifference, and hyperphagia. Repeated magnetic resonance imaging showed the dramatic progression of cerebral atrophy. Positron emission tomography revealed marked glucose hypometabolism that was most severe in left frontal, temporal, and parietal cortical regions. Rigidity, pyramidal signs and profound dementia progressed until death at 43 years of age. A paternal uncle, who had died at 43 years of age, had presented with similar symptoms. The probands brain showed numerous tau-immunoreactive Pick body-like inclusions in the neocortex and the fascia dentata of the hippocampus. In addition, large numbers of tau-positive filamentous inclusions were present in axons in the frontal, temporal, and parietal lobes. Immunoblot analysis of sarkosyl-insoluble tau showed 2 major bands of 60 and 64 kDa. Upon dephosphorylation, these bands resolved into 4 bands consisting of three- and four-repeat tau isoforms. Most isolated tau filaments were straight and resembled filaments found in Alzheimer disease and some frontotemporal dementias with tau mutations. A smaller number of twisted filaments was also observed. Biochemically, recombinant tau proteins with the G389R mutation showed a reduced ability to promote microtubule assembly, suggesting that this may be the primary effect of the mutation. Taken together, the present findings indicate that the G389R mutation in Tau can cause a dementing condition that closely resembles Picks disease.

Do We Really Need Vision? How Blind People “See” the Actions of Others

Observing and learning actions and behaviors from others, a mechanism crucial for survival and social interaction, engages the mirror neuron system. To determine whether vision is a necessary prerequisite for the human mirror system to develop and function, we used functional magnetic resonance imaging to compare brain activity in congenitally blind individuals during the auditory presentation of hand-executed actions or environmental sounds, and the motor pantomime of manipulation tasks, with that in sighted volunteers, who additionally performed a visual action recognition task. Congenitally blind individuals activated a premotor–temporoparietal cortical network in response to aurally presented actions that overlapped both with mirror system areas found in sighted subjects in response to visually and aurally presented stimuli, and with the brain response elicited by motor pantomime of the same actions. Furthermore, the mirror system cortex showed a significantly greater response to motor familiar than to unfamiliar action sounds in both sighted and blind individuals. Thus, the mirror system in humans can develop in the absence of sight. The results in blind individuals demonstrate that the sound of an action engages the mirror system for action schemas that have not been learned through the visual modality and that this activity is not mediated by visual imagery. These findings indicate that the mirror system is based on supramodal sensory representations of actions and, furthermore, that these abstract representations allow individuals with no visual experience to interact effectively with others.

Differential modulation of neural activity throughout the distributed neural system for face perception in patients with Social Phobia and healthy subjects

Social Phobia (SP) is a marked and persistent fear of social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others. Faces of others are perceived as threatening by social phobic patients (SPP). To investigate how face processing is altered in the distributed neural system for face perception in Social Phobia, we designed an event-related fMRI study in which Healthy Controls (HC) and SPP were presented with angry, fearful, disgusted, happy and neutral faces and scrambled pictures (visual baseline). As compared to HC, SPP showed increased neural activity not only in regions involved in emotional processing including left amygdala and insula, as expected from previous reports, but also in the bilateral superior temporal sulcus (STS), a part of the core system for face perception that is involved in the evaluation of expression and personal traits. In addition SPP showed a significantly weaker activation in the left fusiform gyrus, left dorsolateral prefrontal cortex, and bilateral intraparietal sulcus as compared to HC. These effects were found not only in response to emotional faces but also to neutral faces as compared to scrambled pictures. Thus, SPP showed enhanced activity in brain areas related to processing of information about emotional expression and personality traits. In contrast, brain activity was decreased in areas for attention and for processing other information from the face, perhaps as a result of a feeling of wariness. These results indicate a differential modulation of neural activity throughout the different parts of the distributed neural system for face perception in SPP as compared to HC.

The neurometabolic landscape of cognitive decline: In vivo studies with positron emission tomography in Alzheimer's disease

Alzheimers disease, the most common form of dementia in the elderly, is characterized by the progressive, global and irreversible deterioration of cognitive abilities. The development of positron emission tomography (PET) methodologies has made it possible to study the in vivo brain metabolic correlates of human cognitive and behavioral functions. Moreover, as PET scan examinations can be repeated, the progression of the neuropathological process and its relation to cognitive dysfunction can be followed over time. In an effort to understand the changes in neural function that precede and accompany onset of dementia and their relation to clinical manifestations, in the last several years, we have conducted clinical, neuropsychological and brain metabolic studies in groups of Alzheimers disease patients at different stages of dementia severity or with distinct clinical pictures and in populations at risk for developing the disease. Here, we discuss the main findings and implications obtained from these studies.

Italian guidelines for primary headaches: 2012 revised version

The first edition of the Italian diagnostic and therapeutic guidelines for primary headaches in adults was published in J Headache Pain 2(Suppl. 1):105–190 (2001). Ten years later, the guideline committee of the Italian Society for the Study of Headaches (SISC) decided it was time to update therapeutic guidelines. A literature search was carried out on Medline database, and all articles on primary headache treatments in English, German, French and Italian published from February 2001 to December 2011 were taken into account. Only randomized controlled trials (RCT) and meta-analyses were analysed for each drug. If RCT were lacking, open studies and case series were also examined. According to the previous edition, four levels of recommendation were defined on the basis of levels of evidence, scientific strength of evidence and clinical effectiveness. Recommendations for symptomatic and prophylactic treatment of migraine and cluster headache were therefore revised with respect to previous 2001 guidelines and a section was dedicated to non-pharmacological treatment. This article reports a summary of the revised version published in extenso in an Italian version.

Is Social Phobia a “Mis-Communication” Disorder? Brain Functional Connectivity during Face Perception Differs between Patients with Social Phobia and Healthy Control Subjects

Recently, a differential recruitment of brain areas throughout the distributed neural system for face perception has been found in social phobic patients as compared to healthy control subjects. These functional abnormalities in social phobic patients extend beyond emotion-related brain areas, such as the amygdala, to include cortical networks that modulate attention and process other facial features, and they are also associated with an alteration of the task-related activation/deactivation trade-off. Functional connectivity is becoming a powerful tool to examine how components of large-scale distributed neural systems are coupled together while performing a specific function. This study was designed to determine whether functional connectivity networks among brain regions within the distributed system for face perception also would differ between social phobic patients and healthy controls. Data were obtained from eight social phobic patients and seven healthy controls by using functional magnetic resonance imaging. Our findings indicated that social phobic patients and healthy controls have different patterns of functional connectivity across brain regions within both the core and the extended systems for face perception and the default mode network. To our knowledge, this is the first study that shows that functional connectivity during brain response to socially relevant stimuli differs between social phobic patients and healthy controls. These results expand our previous findings and indicate that brain functional changes in social phobic patients are not restricted to a single specific brain structure, but rather involve a mis-communication among different sensory and emotional processing brain areas.

How the brain heals emotional wounds: the functional neuroanatomy of forgiveness

In life, everyone goes through hurtful events caused by significant others: a deceiving friend, a betraying partner, or an unjustly blaming parent. In response to painful emotions, individuals may react with anger, hostility, and the desire for revenge. As an alternative, they may decide to forgive the wrongdoer and relinquish resentment. In the present study, we examined the brain correlates of forgiveness using functional Magnetic Resonance Imaging (fMRI). Healthy participants were induced to imagine social scenarios that described emotionally hurtful events followed by the indication to either forgive the imagined offenders, or harbor a grudge toward them. Subjects rated their imaginative skills, levels of anger, frustration, and/or relief when imagining negative events as well as following forgiveness. Forgiveness was associated with positive emotional states as compared to unforgiveness. Granting forgiveness was associated with activations in a brain network involved in theory of mind, empathy, and the regulation of affect through cognition, which comprised the precuneus, right inferior parietal regions, and the dorsolateral prefrontal cortex. Our results uncovered the neuronal basis of reappraisal-driven forgiveness, and extend extant data on emotional regulation to the resolution of anger and resentment following negative interpersonal events.

Stress and chronic headache

Abstract The aims of this study were to assess how stress affects chronic headaches, and in particular to determine whether events play a role in the transformation of an episodic headache into a chronic form. A population of 267 Italian patients with chronic headache (headache present on average more than 15 days per month) was studied. Our results confirm a triggering role of stress on headache. We also found that episodic headache (migraine in most patients, 74.1%) preceded the development of a chronic form in about 90% cases. Among these patients, in 44.8% a stressful event correlated with the transformation. Analysis of these events revealed that minor events played a greater role than major life events, suggesting that patients with transformed headache are characterised by a different way of reacting to stress.

Mental activity after early afternoon nap awakenings in healthy subjects.

Despite the common misconception that rapid eye movement (REM) sleep is a unique correlate of dreaming, reports of mental activity can be elicited after awakenings from any stage of nocturnal sleep. We extended the investigation to naps and tried to explore the relationship between recall length and level of sleep stage and depth preceding the awakening. We hypothesized that dream report length would be related to arousal level. In 10 healthy young adults, sleep EEG and EOG were recorded for four non-consecutive early afternoon naps. Dream recalls were recorded following 10 s, 1 min, and 6 min of NREM Stage 2 and after 5 min of first REM period. We measured mental recall with total word count (TWC) method, sleep stages by using EEG visual scoring and Delta and Beta activity by period amplitude (PAA) and power spectral (PSA) analyses. All awakening conditions were followed by a dream report. TWC was significantly greater after REM than after 10 s and 1 min of NREM, and TWC did not differ among the NREM awakenings. Delta activity after REM was significantly lower compared to the NREM 6 and 1 min while Beta activity did not differ across the conditions. Assuming that arousal level decreased with increased NREM duration and increasing Delta EEG activity, the constant TWC across the three NREM awakenings indicates that arousal level cannot be the only factor affecting dream report length. Some other factor such as memory processing may explain the longer dream reports following REM sleep, or it may be that the EEG is an imperfect indicator of arousal level.

A follow up study on the efficacy of metadoxine in the treatment of alcohol dependence

BackgroundWe carried out a three months follow-up study on the efficacy of metadoxine in a cohort of alcoholics admitted to the Alcohol misuse Long-term Treatment (ALT) Unit – University of Pisa (Italy). We analyzed the clinical data, psychometric tests and blood tests of 160 alcoholics on admission and after 3 months of treatment. We compared 58 pts treated with metadoxine (MET) with 102 pts who did not receive (NULL) any drug as an adjunct to the psycho-educational interventions provided by the ALT Unit.ResultsAt follow-up, the patients in treatment with metadoxine showed a significant improvement in the rate of complete abstinence (44.8% vs. 21.6%; chi square: 8.45, df = 1, p < 0.0037). Furthermore, the number of drop-outs at three months of treatment was also significantly lower in the MET than in the NULL group (17% vs. 57%; chi square of 23.22, df = 1, p < 0.001).ConclusionOur findings support the use of metadoxine in the management of alcohol dependence. However, randomized clinical trials are necessary to confirm and replicate them. This study raises the importance of identifying new pharmacological compounds effective on the outcome of alcoholism in order to help patients to best adhere to treatment programs and to prevent the development of mental and physical complications due to chronic and heavy use of alcohol.