Role of ASIC1a in Aß-induced synaptic alterations in the hippocampus.

Acid-sensing ion channels (ASICs) are widely expressed in the mammalian central nervous system where they play a key role in synaptic transmission and in specific forms of memory. On the other hand, ASICs can be persistently active under pathological conditions contributing to neuronal damage in ischemic stroke, brain trauma, epilepsy and Parkinson's disease. However, to date no experimental evidence has linked ASICs to Alzheimer's disease (AD). Aim of the present work was to investigate, in CA1 pyramidal neurons, the possible involvement of ASIC1a in the Aß-mediated effect on metabotropic glutamate (mGlu) receptor dependent transmission. We found that, in slices pretreated with Aß, the pharmacological blockade of ASIC1a restored the increased intrinsic excitability following group I mGlu receptor activation. This suggests that, under certain conditions, ASIC1a might further contribute to the Aß-related depolarizing response. We have recently demonstrated that ASIC1a is also involved long-term depression (LTD) induced either by low-frequency stimulation or by application of the group I mGlu receptor agonist DHPG. Here, we have shown that psalmotoxin-1, a selective blocker of ASIC1a, rescued the DHPG-LTD facilitation associated with genetic and non-genetic models of AD. Overall, these results suggest that a functional coupling between ASIC1a and mGlu receptors occurs and might contribute to the synaptic alterations associated with AD.

Acid-sensing ion channel 1a is required for mGlu receptor dependent long-term depression in the hippocampus.

Acid-sensing ion channels (ASICs), members of the degenerin/epithelial Na+ channel superfamily, are widely distributed in the mammalian nervous system. ASIC1a is highly permeable to Ca2+ and are thought to be important in a variety of physiological processes, including synaptic plasticity, learning and memory. To further understand the role of ASIC1a in synaptic transmission and plasticity, we investigated metabotropic glutamate (mGlu) receptor-dependent long-term depression (LTD) in the hippocampus. We found that ASIC1a channels mediate a component of LTD in P30-40 animals, since the ASIC1a selective blocker psalmotoxin-1 (PcTx1) reduced the magnitude of LTD induced by application of the group I mGlu receptor agonist (S)-3,5-Dihydroxyphenylglycine (DHPG) or induced by paired-pulse low frequency stimulation (PP-LFS). Conversely, PcTx1 did not affect LTD in P13-18 animals. We also provide evidence that ASIC1a is involved in group I mGlu receptor-induced increase in action potential firing. However, blockade of ASIC1a did not affect DHPG-induced polyphosphoinositide hydrolysis, suggesting the involvement of some other molecular partners in the functional crosstalk between ASIC1a and group I mGlu receptors. Notably, PcTx1 was able to prevent the increase in GluA1 S845 phosphorylation at the post-synaptic membrane induced by group I mGlu receptor activation. These findings suggest a novel function of ASIC1a channels in the regulation of group I mGlu receptor synaptic plasticity and intrinsic excitability.

Characterizing structural neural networks in de novo Parkinson disease patients using diffusion tensor imaging.

Parkinson disease (PD) can be considered as a brain multisystemic disease arising from dysfunction in several neural networks. The principal aim of this study was to assess whether large-scale structural topological network changes are detectable in PD patients who have not been exposed yet to dopaminergic therapy (de novo patients). Twenty-one drug-naïve PD patients and thirty healthy controls underwent a 3T structural MRI. Next, Diffusion Tensor Imaging (DTI) and graph theoretic analyses to compute individual structural white-matter (WM) networks were combined. Centrality (degree, eigenvector centrality), segregation (clustering coefficient), and integration measures (efficiency, path length) were assessed in subject-specific structural networks. Moreover, Network-based statistic (NBS) was used to identify whether and which subnetworks were significantly different between PD and control participants. De novo PD patients showed decreased clustering coefficient and strength in specific brain regions such as putamen, pallidum, amygdala, and olfactory cortex compared with healthy controls. Moreover, NBS analyses demonstrated that two specific subnetworks of reduced connectivity characterized the WM structural organization of PD patients. In particular, several key pathways in the limbic system, basal ganglia, and sensorimotor circuits showed reduced patterns of communications when comparing PD patients to controls. This study shows that PD is characterized by a disruption in the structural connectivity of several motor and non-motor regions. These findings provide support to the presence of disconnectivity mechanisms in motor (basal ganglia) as well as in non-motor (e.g., limbic, olfactory) circuits at an early disease stage of PD. Hum Brain Mapp 37:4500-4510, 2016. © 2016 Wiley Periodicals, Inc.

Regional specificity of synaptic plasticity deficits in a knock-in mouse model of DYT1 dystonia.

DYT1 dystonia is a movement disorder caused by a deletion in the C-terminal of the protein torsinA. It is unclear how torsinA mutation might disrupt cellular processes encoding motor activity, and whether this impairment occurs in specific brain regions. Here, we report a selective impairment of corticostriatal synaptic plasticity in knock-in mice heterozygous for Δ-torsinA (Tor1a(+/Δgag) mice) as compared to controls (Tor1a(+/+) mice). In striatal spiny neurons from Tor1a(+/Δgag) mice, high-frequency stimulation failed to induce long-term depression (LTD), whereas long-term potentiation (LTP) exhibited increased amplitude. Of interest, blockade of D2 dopamine receptors (D2Rs) increased LTP in Tor1a(+/+) mice to a level comparable to that measured in Tor1a(+/Δgag) mice and normalized the levels of potentiation across mouse groups. A low-frequency stimulation (LFS) protocol was unable to depotentiate corticostriatal synapses in Tor1a(+/Δgag) mice. Muscarinic M1 acetylcholine receptor (mAChR) blockade rescued plasticity deficits. Additionally, we found an abnormal responsiveness of cholinergic interneurons to D2R activation, consisting in an excitatory response rather than the expected inhibition, further confirming an imbalance between dopaminergic and cholinergic signaling in the striatum. Conversely, synaptic activity and plasticity in the CA1 hippocampal region were unaltered in Tor1a(+/Δgag) mice. Importantly, the M1 mAChR-dependent enhancement of hippocampal LTP was unaffected in both genotypes. Similarly, both basic properties of dopaminergic nigral neurons and their responses to D2R activation were normal. These results provide evidence for a regional specificity of the electrophysiological abnormalities observed and demonstrate the reproducibility of such alterations in distinct models of DYT1 dystonia.

Electrophysiological and metabolic effects of CHF5074 in the hippocampus: protection against in vitro ischemia.

CHF5074 is a non-steroidal anti-inflammatory derivative holding disease-modifying potential for the treatment of Alzheimer's disease. The aim of the present study was to characterize the electrophysiological and metabolic profile of CHF5074 in the hippocampus. Electrophysiological recordings show that CHF5074 inhibits in a dose-dependent manner the current-evoked repetitive firing discharge in CA1 pyramidal neurons. This result is paralleled by a dose-dependent reduction of field excitatory post-synaptic potentials with no effect on the paired-pulse ratio. The effects of CHF5074 were not mediated by AMPA or NMDA receptors, since the inward currents induced by local applications of AMPA and NMDA remained constant in the presence of this compound. We also suggest a possible activity of CHF5074 on ASIC1a receptor since ASIC1a-mediated current, evoked by application of a pH 5.5 solution, is reduced by pretreatment with this compound. Moreover, we demonstrate that CHF5074 treatment is able to counteract in hippocampal slices the OGD-induced increase in alanine, lactate and acetate levels. Finally, CHF5074 significantly reduced the apoptosis in hippocampal neurons exposed to OGD, as revealed by cleaved-caspase-3 immunoreactivity and TUNEL staining. Overall, the present work identifies novel mechanisms for CHF5074 in reducing metabolic acidosis, rendering this compound potentially useful also in conditions of brain ischemia.

Potential neurodegenerative effect of anabolic androgenic steroid abuse.

Anabolic androgenic steroids (AASs) are synthetic androgen-like compounds which are abused in sport communities despite their side effects. AAS abuse has been coupled with several medical complications, such as sterility, gynecomastia, and increased risk of cardiovascular and hepatic diseases. More recently, it has been observed that non-medical use of these steroids is frequently associated with changes in mood as well as cognitive deficits. Although the nature of this association is still largely unexplored, recent animal studies have shown the neurodegenerative potential of these compounds ranging from neurotrophin unbalance to increased neuronal susceptibility to apoptotic stimuli. Hence, exposure to AASs may result in a compromised brain, more susceptible, later in life, to the onset or progression of diseases not usually linked to drug abuse, especially neurodegenerative diseases.

Pharmacological modulation of long-term potentiation in animal models of Alzheimer'’s disease.

The discovery of long-term potentiation (LTP) of hippocampal synaptic transmission, which represents a classical model for learning and memory at the cellular level, has stimulated over the past years substantial progress in the understanding of pathogenic mechanisms underlying cognitive disorders, such as Alzheimer’s disease (AD). Multiple lines of evidence indicate synaptic dysfunction not only as a core feature but also a leading cause of AD. Multiple pathways may play a significant role in the execution of synaptic dysfunction and neuronal death triggered by beta-amyloid (Abeta) in AD. Following intensive investigations into LTP in AD models, a variety of compounds have been found to rescue LTP impairment via numerous molecular mechanisms. Yet very few of these findings have been successfully translated into disease-modifying compounds in humans. This review recapitulates the emerging disease-modifying strategies utilized to modulate hippocampal synaptic plasticity with particular attention to approaches targeting ligand-gated ion channels, G-protein-coupled receptors (GPCRs), Receptor Tyrosine Kinases (RTKs) and epigenetic mechanisms. It is hoped that novel multi-targeted drugs capable of regulating spine plasticity might be effective to counteract the progression of AD and related cognitive syndromes.

Paraquat- and rotenone-induced models of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder mainly characterized by a loss of dopaminergic (DA) neurons in the substantia nigra pars compacta. In recent years, several new genes and environmental factors have been implicated in PD, and their impact on DA neuronal cell death is slowly emerging. However, PD etiology remains unknown, whereas its pathogenesis begins to be clarified as a multifactorial cascade of deleterious factors. Recent epidemiological studies have linked exposure to environmental agents, including pesticides, with an increased risk of developing the disease. As a result, over the last two decades the "environmental hypothesis" of PD has gained considerable interest. This speculates that agricultural chemicals in the environment, by producing selective dopaminergic cell death, can contribute to the development of the disease. However, a causal role for pesticides in the etiology of PD has yet to be definitively established. Importantly, most insights into PD pathogenesis came from investigations performed in experimental models of PD, especially those produced by neurotoxins. This review presents data obtained in our laboratories along with current views on the neurotoxic actions induced by the two most popular parkinsonian pesticide neurotoxins, namely paraquat and rotenone. Although confined to these two chemicals, mechanistic studies underlying dopaminergic cell death are of the utmost importance to identify new drug targets for the treatment of PD.

The protective role of catalase against cerebral ischemia in vitro and in vivo.

The present study aims to assess the protective role of the antioxidant enzyme catalase (CAT) with relation to hydrogen peroxide (H(2)O(2)) degradation in oxygen plus water on electrophysiological and fluorescence changes induced by in vitro ischemia and on brain damage produced by transient in vivo ischemia. Neuroprotective effects of CAT were determined by means of electrophysiological recordings and confocal fluorescence microscopy in the hippocampal slice preparation. Ischemia was simulated in vitro by oxygen/glucose deprivation (OGD). In vivo ischemia was produced by transient middle cerebral artery occlusion (MCAo). A protection of the rat CA1 field excitatory postsynaptic potential (fEPSP) loss caused by a prolonged OGD (40 min) was observed after exogenous CAT (500 U/mL) bath-applied before a combined exposure to OGD and H(2)O(2) (3 mM). Of note, neither H(2)O(2) nor exogenous CAT alone had a protective action when OGD lasted for 40 min. The CAT-induced neuroprotection was confirmed in a transgenic mouse model over-expressing human CAT [Tg(CAT)]. In the presence of H(2)O(2), the hippocampus of Tg(CAT) showed an increased resistance against OGD compared to that of wild-type (WT) animals. Moreover, CAT treatment reduced for about 50 min fEPSP depression evoked by repeated applications of H(2)O(2) in normoxia. A lower sensitivity to H(2)O(2)-induced depression of fEPSPs was also indicated by the rightward shift of concentration-response curve in Tg(CAT) compared to WT mice. Noteworthy, Tg(CAT) mice had a reduced infarct size after MCAo. Our data suggest new strategies to reduce neuronal damage produced by transient brain ischemia through the manipulation of CAT enzyme.

Acid-Sensing Ion Channel 1a Is Involved in N-Methyl D-Aspartate Receptor-Dependent Long-Term Depression in the Hippocampus.

Acid-sensing ion channels (ASICs), members of the degenerin/epithelial Na+ channel superfamily, are largely expressed in the mammalian nervous system. ASIC1a is highly permeable to Ca2+ and are involved in many physiological processes, including synaptic plasticity, learning, and memory. To clarify the role of ASIC1a in synaptic transmission and plasticity, we investigated N-methyl D-aspartate (NMDA) receptor-dependent long-term depression (LTD) in the CA1 region of the hippocampus. We found that: (1) ASIC1a mediates a component of ASIC1a excitatory postsynaptic currents (EPSCs); (2) ASIC1a plays a role in electrical LTD induced by LFS protocol both in P13-18 and P30-40 animals; (3) ASIC1a is involved in chemical LTD induced by brief bath application of NMDA both in P13-18 and P30-40 animals; and finally (4) a functional interaction between ASIC1a and NMDA receptors occurs during LTD. These findings suggest a new role for ASIC1a in specific forms of synaptic plasticity in the mouse hippocampus.

Neuroprotective effect of hydrogen peroxide on an in vitro model of brain ischaemia.

BACKGROUND AND PURPOSE: Reactive oxygen species (ROS) have been postulated to play a crucial role in the pathogenesis of ischaemia-reperfusion injury. Among these, hydrogen peroxide (H(2)O(2)) is known to be a toxic compound responsible for free-radical-dependent neuronal damage. In recent years, however, the 'bad reputation' of H(2)O(2) and other ROS molecules has changed. The aim of this study was to assess the protective role of H(2)O(2) and modification in its endogenous production on the electrophysiological and morphological changes induced by oxygen/glucose deprivation (OGD) on CA1 hippocampal neurons. EXPERIMENTAL APPROACH: Neuroprotective effects of exogenous and endogenous H(2)O(2) were determined using extracellular electrophysiological recordings of field excitatory post synaptic potentials (fEPSPs) and morphological studies in a hippocampal slice preparation. In vitro OGD was delivered by switching to an artificial cerebrospinal fluid solution with no glucose and with oxygen replaced by nitrogen. KEY RESULTS: Neuroprotection against in vitro OGD was observed in slices treated with H(2)O(2) (3 mM). The rescuing action of H(2)O(2) was mediated by catalase as pre-treatment with the catalase inhibitor 3-amino-1,2,4-triazole blocked this effect. More interestingly, we showed that an increase of the endogenous levels of H(2)O(2), due to a combination of an inhibitor of the glutathione peroxidase enzyme and addition of Cu,Zn-superoxide dismutase in the tissue bath, prevented the OGD-induced irreversible depression of fEPSPs. CONCLUSIONS AND IMPLICATIONS: Taken together, our results suggest new possible strategies to lessen the damage produced by a transient brain ischaemia by increasing the endogenous tissue level of H(2)O(2).

AD-Related N-Terminal Truncated Tau Is Sufficient to Recapitulate In Vivo the Early Perturbations of Human Neuropathology: Implications for Immunotherapy.

The NH2tau 26-44 aa (i.e., NH2htau) is the minimal biologically active moiety of longer 20-22-kDa NH2-truncated form of human tau-a neurotoxic fragment mapping between 26 and 230 amino acids of full-length protein (htau40)-which is detectable in presynaptic terminals and peripheral CSF from patients suffering from AD and other non-AD neurodegenerative diseases. Nevertheless, whether its exogenous administration in healthy nontransgenic mice is able to elicit a neuropathological phenotype resembling human tauopathies has not been yet investigated. We explored the in vivo effects evoked by subchronic intracerebroventricular (i.c.v.) infusion of NH2htau or its reverse counterpart into two lines of young (2-month-old) wild-type mice (C57BL/6 and B6SJL). Six days after its accumulation into hippocampal parenchyma, significant impairment in memory/learning performance was detected in NH2htau-treated group in association with reduced synaptic connectivity and neuroinflammatory response. Compromised short-term plasticity in paired-pulse facilitation paradigm (PPF) was detected in the CA3/CA1 synapses from NH2htau-impaired animals along with downregulation in calcineurin (CaN)-stimulated pCREB/c-Fos pathway(s). Importantly, these behavioral, synaptotoxic, and neuropathological effects were independent from the genetic background, occurred prior to frank neuronal loss, and were specific because no alterations were detected in the control group infused with its reverse counterpart. Finally, a 2.0-kDa peptide which biochemically and immunologically resembles the injected NH2htau was endogenously detected in vivo, being present in hippocampal synaptosomal preparations from AD subjects. Given that the identification of the neurotoxic tau species is mandatory to develop a more effective tau-based immunological approach, our evidence can have important translational implications for cure of human tauopathies.

Investigating the role of brain-derived neurotrophic factor in relapsing-remitting multiple sclerosis.

Multiple sclerosis (MS) is a common, heterogeneous disorder of the central nervous system with a complex trait composed of both genetic and environmental factors. Recently, scientific interest has increased in defining factors that possibly contribute to brain functional plasticity; the results might be useful to assess the relationship between MS lesion burden and clinical events, as well as explaining the well-known phenotypic heterogeneity of the disease. In this study, we explored the effect of the Val66Met brain-derived neurotrophic factor (BDNF) functional polymorphism on cognitive performances and volumetric measurements obtained by magnetic resonance imaging of the brain in a selected population of relapsing-remitting MS (RRMS) patients, with relatively short disease duration and minimal clinical disability, compared to gender, age and educational-level matched healthy subjects. We found that in the RRMS group, the BDNF Met-allele was significantly associated with the lower volume of cerebral grey matter (GM) (P = 0.005). Furthermore, a significant (P = 0.013) interaction effect between 'MS-status' and the BDNF genotype was found for GM volumes, with the result that patients carrying the BDNF Met-allele showed a higher risk of developing global GM atrophy than the homozygous Val/Val. No BDNF-related impact on global neuropsychological functions resulted in either RRMS patients or controls. Our data seem to be consistent with the reported influence of BDNF in neuronal plasticity, thus suggesting that the Met-allele might have a negative prognostic effect on cortical morphometry in RRMS patients.

The role of VLA4 polymorphisms in multiple sclerosis: an association study.

Lymphocyte and monocyte brain infiltration determines inflammation in multiple sclerosis. The trafficking of these cells into the CNS results from the VLA-4 binding with its ligand on brain endothelial cells. MS patients treated with an antibody against the alpha-4 subunit, which inhibits this interaction, prevents brain lesion development. We investigated the association between VLA-4 gene polymorphisms and MS in a study on 275 patients and 255 controls. No differences were detected, thus suggesting that these polymorphisms are not a significant genetic risk factor for susceptibility to MS in Italy.

Urban biowaste-derived sensitizing materials for caffeine photodegradation.

Caffeine-photosensitized degradation has been studied in the presence of bio-based materials derived from urban biowaste after aerobic aging. A peculiar fraction (namely bio-based substances (BBSs)), soluble in all the pH range, has been used as photosensitizing agent. Several caffeine photodegradation tests have been performed, and positive results have been obtained in the presence of BBSs and H2O2, without and with additional Fe(II) (photo-Fenton-like process). Moreover, hybrid magnetite-BBS nanoparticles have been synthesized and characterized, in order to improve the sensitizer recovery and reuse after the caffeine degradation. In the presence of such nanoparticles and H2O2 and Fe(II), the complete caffeine degradation has been attained in very short time. Both homogeneous and heterogeneous processes were run at pH = 5, milder condition compared to the classic photo-Fenton process.

Home infusion program with enzyme replacement therapy for Fabry disease: The experience of a large Italian collaborative group.

Fabry disease (FD) [OMIM 301500] is an X-linked lysosomal storage disorder caused by a deficiency of the lysosomal enzyme alpha-galactosidase A, resulting in progressive multisystem accumulation of globotriaosylceramide (Gb3). Although the introduction of Enzyme Replacement Therapy (ERT) resulted in a variety of clinical benefits, life-long intravenous (IV) treatment with ERT with an every other week schedule, may interfere with daily life activities and impact on QoL. We report here a multicentric, observational, longitudinal data analysis on a large cohort of 85 Italian FD patients (45 males, 40 females) from 11 out of 20 Italian regions, who received a cumulative number of 4269 home infusions of agalsidase alfa. For the whole cohort, the average duration of home therapy was 1 year and 11 months (range 3 months-4 years and 6 months), and during this period, compliance to treatment (number of infusions performed vs scheduled) reached 100%. The EQ-5 VAS scale was administered to patients to evaluate the self-reported QoL, 58% of patients showing an increase of EQ-5 VAS score at follow up compared to baseline (home treatment start) or remaining stable. A mild increase of average disease severity, measured through Mainz Severity Score Index (MSSI), was found during hospital treatment (p < 0,007), while it remained stable between the first home therapy infusion and last follow up. Interestingly, 4 out of 7 (57%) patients, showing an improvement in FD-related clinical status after starting home therapy, had previously a sub-optimal compliance to treatment during the period of hospital treatment management. Only 4 adverse non serious reactions (0,093%) were reported totally in 2 patients during home treatment. We conclude that home infusions in eligible patients with FD are safe, contribute to improve treatment compliance and therapeutic clinical outcomes, and may have a positive impact on self-perceived QoL.

Genetic variation in the myeloperoxidase gene and cognitive impairment in multiple sclerosis.

There is evidence that multiple sclerosis (MS) may associated with cognitive impairment in 25 to 40% of cases. The gene encoding myeloperoxidase (MPO) is involved in molecular pathways leading to beta-amyloid deposition. We investigated a functional biallelic (G/A) polymorphism in the promoter region (-463) of the MPO gene in 465 patients affected by MS, divided into 204 cognitively normal and 261 impaired. We did not find significant differences in allele or genotype distributions between impaired and preserved MS patients. Our findings suggest that MPO polymorphism is not a risk factor for cognitive impairment in MS.

PRECISION MEDICINE - The Golden Gate for Detection, Treatment and Prevention of Alzheimer's Disease.

During this decade, breakthrough conceptual shifts have commenced to emerge in the field of Alzheimer's disease (AD) recognizing risk factors and the non-linear dynamic continuum of complex pathophysiologies amongst a wide dimensional spectrum of multi-factorial brain proteinopathies/neurodegenerative diseases. As is the case in most fields of medicine, substantial advancements in detecting, treating and preventing AD will likely evolve from the generation and implementation of a systematic precision medicine strategy. This approach will likely be based on the success found from more advanced research fields, such as oncology. Precision medicine will require integration and transfertilization across fragmented specialities of medicine and direct reintegration of Neuroscience, Neurology and Psychiatry into a continuum of medical sciences away from the silo approach. Precision medicine is biomarker-guided medicine on systems-levels that takes into account methodological advancements and discoveries of the comprehensive pathophysiological profiles of complex multi-factorial neurodegenerative diseases, such as late-onset sporadic AD. This will allow identifying and characterizing the disease processes at the asymptomatic preclinical stage, where pathophysiological and topographical abnormalities precede overt clinical symptoms by many years to decades. In this respect, the uncharted territory of the AD preclinical stage has become a major research challenge as the field postulates that early biomarker guided customized interventions may offer the best chance of therapeutic success. Clarification and practical operationalization is needed for comprehensive dissection and classification of interacting and converging disease mechanisms, description of genomic and epigenetic drivers, natural history trajectories through space and time, surrogate biomarkers and indicators of risk and progression, as well as considerations about the regulatory, ethical, political and societal consequences of early detection at asymptomatic stages. In this scenario, the integrated roles of genome sequencing, investigations of comprehensive fluid-based biomarkers and multimodal neuroimaging will be of key importance for the identification of distinct molecular mechanisms and signaling pathways in subsets of asymptomatic people at greatest risk for progression to clinical milestones due to those specific pathways. The precision medicine strategy facilitates a paradigm shift in Neuroscience and AD research and development away from the classical "one-size-fits-all" approach in drug discovery towards biomarker guided "molecularly" tailored therapy for truly effective treatment and prevention options. After the long and winding decade of failed therapy trials progress towards the holistic systems-based strategy of precision medicine may finally turn into the new age of scientific and medical success curbing the global AD epidemic.

Tremor pattern differentiates drug-induced resting tremor from Parkinson disease.

OBJECTIVE: DAT-SPECT, is a well-established procedure for distinguishing drug-induced parkinsonism from Parkinson's disease (PD). We investigated the usefulness of blink reflex recovery cycle (BRrc) and of electromyographic parameters of resting tremor for the differentiation of patients with drug-induced parkinsonism with resting tremor (rDIP) from those with resting tremor due to PD. METHODS: This was a cross-sectional study. In 16 patients with rDIP and 18 patients with PD we analysed electrophysiological parameters (amplitude, duration, burst and pattern) of resting tremor. BRrc at interstimulus intervals (ISI) of 100, 150, 200, 300, 400, 500 and 750 msec was also analysed in patients with rDIP, patients with PD and healthy controls. All patients and controls underwent DAT-SPECT. RESULTS: Rest tremor amplitude was higher in PD patients than in rDIP patients (p < 0.001), while frequency and burst duration were higher in rDIP than in PD (p < 0.001, p < 0.003, respectively). Resting tremor showed a synchronous pattern in all patients with rDIP, whereas it had an alternating pattern in all PD patients (p < 0.001). DAT-SPECT was normal in rDIP patients while it was markedly abnormal in patients with PD. CONCLUSIONS: In the absence of DAT-SPECT, the pattern of resting tremor can be considered a useful investigation for differentiating rDIP from PD.

Involvement of interleukin-1beta in the mechanism of human immunodeficiency virus type 1 (HIV-1) recombinant protein gp120-induced apoptosis in the neocortex of rat.

The effect of subchronic intracerebroventricular injection of the human immunodeficiency virus type 1 (HIV-1) recombinant protein gp120 (100 ng, given daily for up to seven consecutive days) on interleukin-1beta expression was studied by immunohistochemistry in the brain of adult rats. In comparison to control, bovine serum albumin (300 ng, given intracerebroventricularly for up to seven days) -treated animals (n=6), interleukin-1beta immunoreactivity increased in the brain cortex and hippocampus of rats (n=6) receiving a single injection of the viral protein 24 h before analysis with more substantial increases being observed in these regions of the brain (n=6) after seven days treatment. Double-labelling immunofluorescence experiments support a neuronal and, possibly, a microglial cell origin for gp120-enhanced interleukin-1beta expression. Transmission electron microscopy analysis of brain tissue sections revealed that combination treatments (given intracerebroventricularly daily for seven days) with gp120 (100 ng) and interleukin-1 receptor antagonist (80 ng) or with the interleukin converting enzyme inhibitor II (100 pmol), but not with leupeptin (100 pmol), prevented apoptotic death of rat (n=6/group) brain cortical cells typically elicited by the viral protein. These data demonstrate that gp120 enhances interleukin-1beta expression in the brain and this may be involved in the mechanism underlying apoptosis induced by gp120 in the brain cortex of rat. Further support to this hypothesis comes from the evidence that intracerebroventricular injection of murine recombinant interleukin-1beta (200 U, given daily for seven consecutive days) produces DNA fragmentation in the brain cortex of rat (n=6). Interestingly, the latter treatment enhanced nerve growth factor level in the hippocampus but not in the cerebral cortex and this coincides with a similar effect recently reported in identical brain areas of rats treated likewise with gp120. In conclusion, the present data demonstrate that treatment with gp120 enhances interleukin-1beta expression and this participates in the mechanism of apoptotic cell death in the brain cortex of rat. By contrast, in the hippocampus, gp120-enhanced interleukin-1beta expression elevates nerve growth factor that may prevent or delay apoptosis in this plastic region of the rat brain.