P Calabresi’s research while affiliated with Università Cattolica del Sacro Cuore and other places

Glutamatergic hyperactivity in the nucleus striatum, the main basal ganglia input, has been involved in the progression of Parkinson's disease (PD) and the onset of L-Dopa-induced dyskinesias (LIDs). Abnormalities in the spiny projection neurons (SPNs) excitability and firing, and in the overactivity of glutamate transmission found in animal models of PD, pointed to the synaptic dysfunctions as a primary target to counteract alterations before overt neurodegeneration, conferring a key role to striatal glutamatergic transmission in the early phases of the disease. The present paper will provide an overview of the evidence that glutamatergic overactivity is a critical mechanism underlying different PD-associated striatal alterations in early and advanced symptomatic stages of the disease. These aberrant changes, under L-Dopa therapy, lead to a more complex synaptopathy that involves other neurotransmitter systems and persistent modifications to generate LIDs. The review will discuss the main changes in glutamatergic functions found in PD preclinical models and clinical studies and an update of the current pharmacological strategies to modulate the glutamatergic systems at the pre- and postsynaptic levels will be provided.

Introduction Brain iron load is an important neuropathological mark in Parkinson’s disease (PD) and it can be quantified by MR susceptibility-weighted imaging (SWI). We estimated the correlation between cerebral iron distribution evaluated by SWI and cognitive pattern in a group of PD patients. Materials and methods 32 patients and 10 healthy subjects comparable for age and gender were enrolled. Patients were examined for motor and cognitive assessment. Cognitive outline was assessed with MoCA for global cognitive abilities and with a battery of neuropsychological tests. Functional daily abilities were tested using ADL and IADL scales. Patients and controls underwent MRI acquisition on a 3.0 T Philips Achieva system. For each emisphere seven ROIs were considered: putamen, globus pallidus, caudate nucleus, red nucleus, substantia nigra, dentate nucleus and frontal white matter. We measured SWI-intensity values for each ROI: lower values correspond to higher iron content. All the collected data were expressed as mean value and standard deviation. Chi-square test was used to verify associations between categorical variables. Results Higher iron deposits were detected in all the ROIs in patients compared to controls. SWI-intensity values of substantia nigra correlates negatively with disease duration and UPDRS-III off and positively with ADL and IADL scores. A positive and significant relationship between MoCA (<26 cut-off) and SWI-intensity values in putamen, globus pallidus and substantia nigra was found. WAIS-IV Similarities shows a significant positive association with SWI-intensity values in all the ROIs, moreover Spatial Span and Gradient Named Test positively correlate with SWI intensity values of substantia nigra. Conclusions According to literature [1], brain iron distribution estimated by SWI seems to be a useful tool for cognitive decline in PD.

Objectives This observational study aimed to investigate the presence of potential vestibular system subclinical dysfunction among migraineurs without a history of vertigo and dizziness compared with healthy controls. Methods Patients diagnosed with episodic migraine with and without aura were enrolled. All patients and healthy controls underwent vestibular examination using the following conventional tests: sitting position, Pagnini‐McClure's, Dix‐Hallpike's, head hanging, video head impulse, subjective visual vertical, Romberg, Fukuda, and caloric vestibular stimulation by Fitzgerald‐Hallpike's tests. Nystagmus and angular velocity of the slow phase during culmination phase was analyzed by video‐nystagmography. Results Overall, 33 patients (76% female, 7 with aura and 26 without aura; mean age (mean ± SD): 29.1 ± 4.3 years) and 22 controls (33% female, mean age: 30.8 ± 9.4 years) were enrolled. There were no statistically significant differences in demographic features between patients and controls. Caloric vestibular stimulation test results were found to differ among patients and controls. In particular, right and left angular velocity (AV) were highly correlated one another (r = 0.88, P < .001). Right AV (53.0 ± 6.7 vs 44.0 ± 9.6) and left AV (54.3 ± 5.3 vs 43.3 ± 9.0) were statistically higher in migraineurs as compared to controls (P < .001). Also right V‐HIT (1.1 ± 0.1 vs 0.8 ± 0.4) and left V‐HIT (1.1 ± 0.1 vs 0.7 ± 0.2) were statistically higher in migraineurs compared to controls (P < .001). Conclusion Our findings suggest a subclinical alteration of vestibular pathway in migraineurs who have never complained vertigo or postural imbalance. This finding supports the hypothesis of a vestibular‐cerebellar dysfunction in migraineurs, particularly among those with aura.

Background and purpose: We assessed the prevalence and magnitude of neuropsychiatric adverse events (NPAEs) associated with antiepileptic drugs (AEDs) among patients with brain tumour-related epilepsy (BTRE). Methods: This observational, prospective, multicentre study enrolled 259 patients with BTRE after neurosurgery. All patients received AED monotherapy. Efficacy was assessed through clinical diaries, whereas NPAEs were collected using the Neuropsychiatric Inventory Test-12 questionnaire at baseline and after 5 months. Results: Tumour localization in the frontal lobe was associated with a higher prevalence of NPAEs (odds ratio, 7.73; P < 0.001). Independent of tumour localization, levetiracetam (LVT) treatment was associated with higher prevalence and magnitude of NPAEs (odds ratio, 7.94; P < 0.01) compared with other AEDs. Patients with oligodendroglioma reported more NPAEs than patients with other tumour types. NPAEs were not influenced by chemotherapy, radiotherapy or steroid treatment. Evaluating non-neurobehavioural adverse events of AEDs, no significant differences were found among AEDs, although patients treated with old AEDs had a higher prevalence of adverse events than those treated with new AEDs. Conclusions: Both tumour localization in the frontal lobe and LVT treatment are associated with a higher risk of NPAEs in patients with BTRE. LVT is regarded as a first-line option in patients with BTRE because of easy titration and few significant drug-to-drug interactions. Thus, as NPAEs lead to poor compliance and a high dropout rate, clinicians need to accurately monitor NPAEs after AED prescription, especially in patients with frontal lobe tumours receiving LVT.

Molecular Psychiatry publishes work aimed at elucidating biological mechanisms underlying psychiatric disorders and their treatment

Objective We performed a systematic review on the comorbidities of familial/sporadic hemiplegic migraine (F/SHM) with seizure/epilepsy in patients with CACNA1A, ATP1A2 or SCN1A mutations, to identify the genotypes associated and investigate for the presence of mutational hot spots. Methods We performed a search in MEDLINE and in the Human Gene Mutation and Leiden Open Variation Databases for mutations in the CACNA1A, ATP1A2 and SCN1A genes. After having examined the clinical characteristics of the patients, we selected those having HM and seizures, febrile seizures or epilepsy. For each gene, we determined both the frequency and the positions at protein levels of these mutations, as well as the penetrance of epilepsy within families. Results Concerning F/SHM-Epilepsy1 (F/SHME1) and F/SHME2 endophenotypes, we observed a prevalent involvement of the transmembrane domains, and a strong correlation in F/SHME1 when the positively charged amino acids were involved. The penetrance of epilepsy within the families was highest for patients carrying mutation in the CACNA1A gene (60%), and lower in those having SCN1A (33.3%) and ATP1A2 (30.9%) mutations. Conclusion Among the HM cases with seizure/epilepsy, we observed mutational hot spots in the transmembrane domains of CACNA1A and ATP1A2 proteins. These findings could lead to a better understanding of the pathological mechanisms underlying migraine and epilepsy, therein guaranteeing the most appropriate therapeutic approach.

In this chapter we describe the basic characteristics of corticostriatal synaptic plasticity in both physiological and pathological conditions. In particular, we analyze the general features of the most important forms of activity-dependent plasticity of striatal glutamatergic transmission such as long-term depression (LTD), long-term potentiation (LTP), and depotentiation (reversal of previously induced LTP) in medium spiny projection neurons. We also report on the role of distinct ionotropic and metabotropic glutamate receptors as well as the modulatory function of dopaminergic, cholinergic, and endocannabinoid systems in the expression of these forms of striatal plasticity. Moreover, we describe some forms of synaptic plasticity induced by repetitive glutamatergic stimulation in striatal interneurons. Finally, we analyze the alterations of synaptic plasticity in toxic and genetic models of the most important neurological disorders involving the striatum such as Parkinson's disease, L-DOPA-induced dyskinesia, Huntington's disease, dystonia, and brain ischemia.

SHANK3 (also called PROSAP2) genetic haploinsufficiency is thought to be the major cause of neuropsychiatric symptoms in Phelan-McDermid syndrome (PMS). PMS is a rare genetic disorder that causes a severe form of intellectual disability (ID), expressive language delays and other autistic features. Furthermore, a significant number of SHANK3 mutations have been identified in patients with autism spectrum disorders (ASD), and SHANK3 truncating mutations are associated with moderate to profound ID. The Shank3 protein is a scaffold protein that is located in the postsynaptic density (PSD) of excitatory synapses and is crucial for synapse development and plasticity. In this study, we investigated the molecular mechanisms associated with the ASD-like behaviors observed in Shank3Δ11 −/− mice, in which exon 11 has been deleted. Our results indicate that Shank3 is essential to mediating metabotropic glutamate receptor 5 (mGlu5)-receptor signaling by recruiting Homer1b/c to the PSD, specifically in the striatum and cortex. Moreover, augmenting mGlu5-receptor activity by administering 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide ameliorated the functional and behavioral defects that were observed in Shank3Δ11 − / − mice, suggesting that pharmaceutical treatments that increase mGlu5 activity may represent a new approach for treating patients that are affected by PMS and SHANK3 mutations.

SHANK3 (also called PROSAP2) genetic haploinsufficiency is thought to be the major cause of neuropsychiatric symptoms in Phelan-McDermid syndrome (PMS). PMS is a rare genetic disorder that causes a severe form of intellectual disability (ID), expressive language delays and other autistic features. Furthermore, a significant number of SHANK3 mutations have been identified in patients with autism spectrum disorders (ASD), and SHANK3 truncating mutations are associated with moderate to profound ID. The Shank3 protein is a scaffold protein that is located in the postsynaptic density (PSD) of excitatory synapses and is crucial for synapse development and plasticity. In this study, we investigated the molecular mechanisms associated with the ASD-like behaviors observed in Shank3Δ11(-/-) mice, in which exon 11 has been deleted. Our results indicate that Shank3 is essential to mediating metabotropic glutamate receptor 5 (mGlu5)-receptor signaling by recruiting Homer1b/c to the PSD, specifically in the striatum and cortex. Moreover, augmenting mGlu5-receptor activity by administering 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide ameliorated the functional and behavioral defects that were observed in Shank3Δ11(-/-) mice, suggesting that pharmaceutical treatments that increase mGlu5 activity may represent a new approach for treating patients that are affected by PMS and SHANK3 mutations.Molecular Psychiatry advance online publication, 29 March 2016; doi:10.1038/mp.2016.30.