Nonmotor symptoms in Parkinson's disease: Investigating early-phase onset of behavioral dysfunction in the 6-hydroxydopamine-lesioned rat model

To investigate the psychiatric symptoms accompanying the early phases of Parkinson's disease (PD), we injected adult rats with 10.5 μg 6-hydroxydopamine (6-OHDA) bilaterally into the dorsal striatum. The resulting neurodegeneration led, 12 weeks after injection, to a mild (36%) reduction of striatal dopamine. We tested the behavioral response of sham and 6-OHDA-lesioned animals at different time points after injection to evaluate the onset and progression of behavioral abnormalities. The results showed that such a mild reduction of dopamine levels was associated with a decrease in anxiety-like behavior, an increase in "depression"-like behavior, and a marked change in social behavior. Learning and memory abilities were not affected. Overall, the PD rat model used here displays behavioral alterations having face validity with psychiatric symptoms of the pathology and thus appears to be a valuable tool for investigating the neural bases of the early phases of PD. © 2008 Wiley-Liss, Inc

Adenosine receptor heteromers and their integrative role in striatal function

By analyzing the functional role of adenosine receptor heteromers, we review a series of new concepts that should modify our classical views of neurotransmission in the central nervous system (CNS). Neurotransmitter receptors cannot be considered as single functional units anymore. Heteromerization of neurotransmitter receptors confers functional entities that possess different biochemical characteristics with respect to the individual components of the heteromer. Some of these characteristics can be used as a 'biochemical fingerprint' to identify neurotransmitter receptor heteromers in the CNS. This is exemplified by changes in binding characteristics that are dependent on coactivation of the receptor units of different adenosine receptor heteromers. Neurotransmitter receptor heteromers can act as 'processors' of computations that modulate cell signaling, sometimes critically involved in the control of pre- and postsynaptic neurotransmission. For instance, the adenosine A1-A2A receptor heteromer acts as a concentration-dependent switch that controls striatal glutamatergic neurotransmission. Neurotransmitter receptor heteromers play a particularly important integrative role in the 'local module' (the minimal portion of one or more neurons and/or one or more glial cells that operates as an independent integrative unit), where they act as processors mediating computations that convey information from diverse volume-transmitted signals. For instance, the adenosine A2A-dopamine D2 receptor heteromers work as integrators of two different neurotransmitters in the striatal spine module

The α2-adrenergic receptor pathway modulating depression influences the risk of arterial thrombosis associated with BDNFVal66Met polymorphism

Depression is associated with thrombotic risk and arterial events, its proper management is strongly recommended in coronary artery disease (CAD) patients. We have previously shown that the Brain-Derived Neurotrophic Factor (BDNF)Val66Met polymorphism, related to depression, is associated with arterial thrombosis in mice, and with an increased risk of acute myocardial infarction in humans. Herein, expanding the previous findings on BDNFVal66Met polymorphism, we show that desipramine, a norepinephrine reuptake-inhibitor, rescues behavioral impairments, reduces the arterial thrombosis risk, abolishes pathological coagulation and platelet hyper-reactivity, normalizes leukocyte, platelet, and bone marrow megakaryocyte number and restores physiological norepinephrine levels in homozygous knock-in BDNF Val66Met (BDNFMet/Met) mice. The in vitro data confirm the enhanced procoagulant activity and the alpha(2A)-adrenergic receptor (alpha(2A)-ADR) overexpression found in BDNFMet/Met mice and we provide evidence that, in presence of Met variant, norepinephrine is crucial to up-regulate procoagulant activity and to enhance platelet generation. The alpha(2)-ADR antagonist rauwolscine rescues the prothrombotic phenotype in BDNFMet/Met mice and reduces procoagulant activity and platelet generation in cells transfected with BDNFMet plasmid or exposed to pro-BDNFMet peptide. Finally, we show that homozygous BDNFMet/Met CAD patients have hyper-reactive platelets overexpressing abundant alpha(2A)-ADR. The great proplatelet release from their megakaryocytes well reflects their higher circulating platelet number compared to BDNFval/val patients. These data reveal an unprecedented described role of Met allele in the dysregulation of norepinephrine/alpha(2A)-ADR pathway that may explain the predisposition to arterial thrombosis. Overall, the development of alpha(2A)-ADR inhibitors might represent a pharmacological treatment for depression-associated thrombotic conditions in this specific subgroup of CAD patients

Relative effectiveness of a 2nd booster dose of COVID-19 mRNA vaccine up to four months post administration in individuals aged 80 years or more in Italy. A retrospective matched cohort study

Several countries started a 2nd booster COVID-19 vaccination campaign targeting the elderly population, but evidence around its effectiveness is still scarce. This study aims to estimate the relative effectiveness of a 2nd booster dose of COVID-19 mRNA vaccine in the population aged >= 80 years in Italy, during predominant circulation of the Omicron BA.2 and BA.5 subvariants. We linked routine data from the national vaccination registry and the COVID-19 surveillance system. On each day between 11 April and 6 August 2022, we matched 1:1, according to several demographic and clinical characteristics, individuals who received the 2nd booster vaccine dose with individuals who received the 1st booster vaccine dose at least 120 days earlier. We used the Kaplan-Meier method to compare the risks of SARS-CoV-2 infection and severe COVID-19 (hospitalisation or death) between the two groups, calculating the relative vaccine effectiveness (RVE) as (1 - risk ratio)X100. Based on the analysis of 831,555 matched pairs, we found that a 2nd booster dose of mRNA vaccine, 14-118 days post administration, was moderately effective in preventing SARS-CoV-2 infection compared to a 1st booster dose administered at least 120 days earlier [14.3 %, 95 % confidence interval (CI): 2.2-20.2]. RVE decreased from 28.5 % (95 % CI: 24.7-32.1) in the time-interval 14-28 days to 7.6 % (95 % CI: -14.1 to 18.3) in the time-interval 56-118 days. However, RVE against severe COVID19 was higher (34.0 %, 95 % CI: 23.4-42.7), decreasing from 43.2 % (95 % CI: 30.6-54.9) to 27.2 % (95 % CI: 8.3-42.9) over the same time span. Although RVE against SARS-CoV-2 infection was much reduced 2-4 months after a 2nd booster dose, RVE against severe COVID-19 was about 30 %, even during prevalent circulation of the Omicron BA.5 subvariant. The cost-benefit of a 3rd booster dose for the elderly people who received the 2nd booster dose at least four months earlier should be carefully evaluated

Adenosine Receptor Heteromers and their Integrative Role in Striatal Function

By analyzing the functional role of adenosine receptor heteromers, we review a series of new concepts that should modify our classical views of neurotransmission in the central nervous system (CNS). Neurotransmitter receptors cannot be considered as single functional units anymore. Heteromerization of neurotransmitter receptors confers functional entities that possess different biochemical characteristics with respect to the individual components of the heteromer. Some of these characteristics can be used as a “biochemical fingerprint” to identify neurotransmitter receptor heteromers in the CNS. This is exemplified by changes in binding characteristics that are dependent on coactivation of the receptor units of different adenosine receptor heteromers. Neurotransmitter receptor heteromers can act as “processors” of computations that modulate cell signaling, sometimes critically involved in the control of pre- and postsynaptic neurotransmission. For instance, the adenosine A1-A2A receptor heteromer acts as a concentration-dependent switch that controls striatal glutamatergic neurotransmission. Neurotransmitter receptor heteromers play a particularly important integrative role in the “local module” (the minimal portion of one or more neurons and/or one or more glial cells that operates as an independent integrative unit), where they act as processors mediating computations that convey information from diverse volume-transmitted signals. For instance, the adenosine A2A-dopamine D2 receptor heteromers work as integrators of two different neurotransmitters in the striatal spine module

NMDA receptor dysfunction contributes to impaired brain-derived neurotrophic factor-induced facilitation of hippocampal synaptic transmission in a Tau transgenic model.

While the spatiotemporal development of Tau pathology has been correlated with occurrence of cognitive deficits in Alzheimer's patients, mechanisms underlying these deficits remain unclear. Both brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor TrkB play a critical role in hippocampus-dependent synaptic plasticity and memory. When applied on hippocampal slices, BDNF is able to enhance AMPA receptor-dependent hippocampal basal synaptic transmission through a mechanism involving TrkB and N-methyl-d-Aspartate receptors (NMDAR). Using THY-Tau22 transgenic mice, we demonstrated that hippocampal Tau pathology is associated with loss of synaptic enhancement normally induced by exogenous BDNF. This defective response was concomitant to significant memory impairments. We show here that loss of BDNF response was due to impaired NMDAR function. Indeed, we observed a significant reduction of NMDA-induced field excitatory postsynaptic potential depression in the hippocampus of Tau mice together with a reduced phosphorylation of NR2B at the Y1472, known to be critical for NMDAR function. Interestingly, we found that both NR2B and Src, one of the NR2B main kinases, interact with Tau and are mislocalized to the insoluble protein fraction rich in pathological Tau species. Defective response to BDNF was thus likely related to abnormal interaction of Src and NR2B with Tau in THY-Tau22 animals. These are the first data demonstrating a relationship between Tau pathology and synaptic effects of BDNF and supporting a contribution of defective BDNF response and impaired NMDAR function to the cognitive deficits associated with Tauopathies

Sudden Unexpected Deaths and Vaccinations during the First Two Years of Life in Italy: A Case Series Study

Background The signal of an association between vaccination in the second year of life with a hexavalent vaccine and sudden unexpected deaths (SUD) in the two days following vaccination was reported in Germany in 2003. A study to establish whether the immunisation with hexavalent vaccines increased the short term risk of SUD in infants was conducted in Italy. Methodology/Principal Findings The reference population comprises around 3 million infants vaccinated in Italy in the study period 1999–2004 (1.5 million received hexavalent vaccines). Events of SUD in infants aged 1–23 months were identified through the death certificates. Vaccination history was retrieved from immunisation registries. Association between immunisation and death was assessed adopting a case series design focusing on the risk periods 0–1, 0–7, and 0–14 days after immunisation. Among the 604 infants who died of SUD, 244 (40%) had received at least one vaccination. Four deaths occurred within two days from vaccination with the hexavalent vaccines (RR = 1.5; 95% CI 0.6 to 4.2). The RRs for the risk periods 0–7 and 0–14 were 2.0 (95% CI 1.2 to 3.5) and 1.5 (95% CI 0.9 to 2.4). The increased risk was limited to the first dose (RR = 2.2; 95% CI 1.1 to 4.4), whereas no increase was observed for the second and third doses combined. Conclusions The RRs of SUD for any vaccines and any risk periods, even when greater than 1, were almost an order of magnitude lower than the estimates in Germany. The limited increase in RRs found in Italy appears confined to the first dose and may be partly explained by a residual uncontrolled confounding effect of age

Role of Adenosine A2A Receptors in Modulating Synaptic Functions and Brain Levels of BDNF: a Possible Key Mechanism in the Pathophysiology of Huntington's Disease

In the last few years, accumulating evidence has shown the existence of an important cross-talk between adenosine A2A receptors (A2ARs) and brain-derived neurotrophic factor (BDNF). Not only are A2ARs involved in the mechanism of transactivation of BDNF receptor TrkB, they also modulate the effect of BDNF on synaptic transmission, playing a facilitatory and permissive role. The cAMP-PKA pathway, the main transduction system operated by A2ARs, is involved in such effects. Furthermore, a basal tonus of A2ARs is required to allow the regulation of BDNF physiological levels in the brain, as demonstrated by the reduced protein levels measured in A2ARs KO mice. The crucial role of adenosine A2ARs in the maintenance of synaptic functions and BDNF levels will be reviewed here and discussed in the light of possible implications for Huntington's disease therapy, in which a joint impairment of BDNF and A2ARs seems to play a pathogenetic role