The pharmacology of visual hallucinations in synucleinopathies

Visual hallucinations (VH) are commonly found in the course of synucleinopathies like Parkinson's disease and dementia with Lewy bodies. The incidence of VH in these conditions is so high that the absence of VH in the course of the disease should raise questions about the diagnosis. VH may take the form of early and simple phenomena or appear with late and complex presentations that include hallucinatory production and delusions. VH are an unmet treatment need. The review analyzes the past and recent hypotheses that are related to the underlying mechanisms of VH and then discusses their pharmacological modulation. Recent models for VH have been centered on the role played by the decoupling of the default mode network (DMN) when is released from the control of the fronto-parietal and salience networks. According to the proposed model, the process results in the perception of priors that are stored in the unconscious memory and the uncontrolled emergence of intrinsic narrative produced by the DMN. This DMN activity is triggered by the altered functioning of the thalamus and involves the dysregulated activity of the brain neurotransmitters. Historically, dopamine has been indicated as a major driver for the production of VH in synucleinopathies. In that context, nigrostriatal dysfunctions have been associated with the VH onset. The efficacy of antipsychotic compounds in VH treatment has further supported the notion of major involvement of dopamine in the production of the hallucinatory phenomena. However, more recent studies and growing evidence are also pointing toward an important role played by serotonergic and cholinergic dysfunctions. In that respect, in vivo and post-mortem studies have now proved that serotonergic impairment is often an early event in synucleinopathies. The prominent cholinergic impairment in DLB is also well established. Finally, glutamatergic and gamma aminobutyric acid (GABA)ergic modulations and changes in the overall balance between excitatory and inhibitory signaling are also contributing factors. The review provides an extensive overview of the pharmacology of VH and offers an up to date analysis of treatment options

Monoaminergic Neuropathology in Alzheimer's disease

Acknowledgments This work was supported by The Croatian Science Foundation grant. no. IP-2014-09-9730 (“Tau protein hyperphosphorylation, aggregation, and trans-synaptic transfer in Alzheimer’s disease: cerebrospinal fluid analysis and assessment of potential neuroprotective compounds”) and European Cooperation in Science and Technology (COST) Action CM1103 (“Stucture-based drug design for diagnosis and treatment of neurological diseases: dissecting and modulating complex function in the monoaminergic systems of the brain”). PRH is supported in part by NIH grant P50 AG005138.Peer reviewedPostprin

RAPID-ACTING ANTIDEPRESSANT DRUGS: AN EMERGING APPROACH FOR THE TREATMENT OF MAJOR DEPRESSIVE DISORDER

In questa tesi viene proposta ed elaborata l'evoluzione terapeutica contro la depressione resistente ai trattamenti convenzionali, con un'attenzione maggiore a una nuova e promettente classe di farmaci denominata Rapid-Acting-Antidepressant. Inizialmente, viene offerta una presentazione in cui vengono definiti i vari tipi di depressione diagnosticabili, con le rispettive caratterizzazioni e sintomi, per poi delineare le terapie attualmente prescritte contro questa condizione. In seguito, viene introdotta una nuova ipotesi chiamata ipotesi glutammatergica, in quanto si ritiene che la presenza di un'aumentata concentrazione del neurotrasmettitore glutammato sia coinvolta nella manifestazione dei sintomi nei pazienti depressi. Questo neurotrasmettitore eccitatorio è il più abbondante nel sistema nervoso centrale dei mammiferi adulti e possiede un ruolo importante nell'neuroplasticità. In base alla neurotrasmissione, i recettori glutammatergici possono essere suddivisi in: metabotropici (mGluR), che sono recettori accoppiati a proteine G implicati nella plasticità sinaptica, nell'eccitabilità e nella connettività neuronale; e ionotropici (iGluR), che sono canali cationici dipendenti dal ligando. I recettori ionotropici sono proteine di membrana composte da quattro subunità che costituiscono il canale ionico che consente l'afflusso di cationi calcio in seguito al legame con il glutammato. Le subunità sono essenziali per la sinaptogenesi, il rimodellamento sinaptico che dipende dalle variazioni della potenza sinaptica. Nella depressione, vi è una sovrastimolazione di questi recettori causata da alte concentrazioni di glutammato che porta a una condizione di eccitotossicità. Le terapie farmacologiche basate su questa teoria mirano all'inibizione dei recettori N-metil-D-aspartato (NMDA). Il principale capostipite dal punto di vista farmacologico è la ketamina, diffusa come anestetico locale, che ha dimostrato un'attività antidepressiva rapida e prolungata. Tuttavia, la ketamina non può essere considerata un farmaco sicuro perché la sua somministrazione richiede un trattamento ambulatoriale del paziente, a causa della comparsa di effetti collaterali dissociativi e del potenziale di abuso. Per questo motivo, la ricerca si è concentrata sullo sviluppo di altri composti attivi. Oltre alla ketamina, altri antagonisti dei recettori NMDA sono: la memantina, un farmaco prescritto per la malattia di Alzheimer; la norketamina, un derivato della ketamina; l'MK-801, il destrometorfano, il destrometadone e la lanicemina. Tuttavia, esistono anche altri farmaci con un diverso meccanismo d'azione, come il rapastinel, un agonista parziale dei recettori NMDA. Oltre al sistema glutammatergico, negli ultimi anni è stato dimostrato il coinvolgimento di altri sistemi, tra cui il sistema serotoninergico, il sistema colinergico e l'asse ipotalamo-ipofisi-surrene. Ognuno di questi sistemi ha almeno un candidato farmaco in fase di sperimentazione clinica per il trattamento del disturbo depressivo maggiore. In conclusione, questo lavoro di tesi propone un confronto tra le terapie attualmente prescritte e i nuovi approcci terapeutici per la depressione, confrontandone le caratteristiche principali.In this thesis, therapeutic evolution against depression resistant to conventional treatment is proposed and elaborated with a greater focus on a new and promising class of drugs called Rapid-Acting-Antidepressant. Initially, a presentation is offered in which the various types of diagnosable depression are defined along with their respective characterizations and symptoms, and then the currently prescribed therapies against this condition are outlined. Continuing, a new hypothesis called the glutamatergic hypothesis is introduced as it is believed that the presence of increased concentration of the neurotransmitter glutamate is involved in the manifestation of symptoms in depressed patients. This excitatory neurotransmitter is the most abundant in the adult mammalian central nervous system and possesses an important role inneuroplasticity. Based on neurotransmission, glutamatergic receptors can be divided into: metabotropic (mGluR) which are G-protein-coupled receptors implicated in synaptic plasticity, excitability and neuronal connectivity; and ionotropic (iGluR) which are ligand-dependent cation channels. Ionotropic receptors are membrane proteins composed of four subunits that constitute the ion channel which allows the influx of calcium cations following glutamate binding. The subunits are essential for synaptogenesis, the synaptic remodeling dependent on changes in synaptic potency. In depression, there is overstimulation of these receptors caused by high concentrations of glutamate leading to an excitotoxic condition. Phamacological therapies based on this theory target N-methyl-D-aspartate (NMDA) receptor inhibition. The main progenitor from the pharmacological point of view is ketamine, widespread as a local anesthetic, which has shown rapid and sustained antidepressant activity. However, ketamine cannot be regarded as a safe drug because its administration requires ambulatory treatment of the patient, due to the occurrence of dissociative side effects and the potential for abuse. For this reason, research has focused on the development of other active compounds. In addition to ketamine, other NMDA receptor antagonists include: memantine, a drug prescribed for Alzheimer's disease; norketamine, a ketamine derivative; MK-801, dextromethorphan, dextromethadone, and lanicemine. However, there are also other drugs having different mechanism of action such as rapastinel, an NMDA receptor partial agonist. In addition to the glutamatergic system, the involvement of other systems including the serotonergic system, the cholinergic system, and the hypothalamic-pituitary-adrenal axis has been demonstrated in recent years. Each of these systems has at least one drug candidate in clinical trials for the treatment of major depressive disorder. In conclusion, this thesis work proposes a comparison of currently prescribed therapies and new therapeutic approaches for depression by comparing their main characteristics

Reorganisation of brain networks in frontotemporal dementia and progressive supranuclear palsy.

The disruption of large-scale brain networks is increasingly recognised as a consequence of neurodegenerative dementias. We assessed adults with behavioural variant frontotemporal dementia and progressive supranuclear palsy using magnetoencephalography during an auditory oddball paradigm. Network connectivity among bilateral temporal, frontal and parietal sources was examined using dynamic causal modelling. We found evidence for a systematic change in effective connectivity in both diseases. Compared with healthy subjects, who had focal modulation of intrahemispheric frontal-temporal connections, the patient groups showed abnormally extensive and inefficient networks. The changes in connectivity were accompanied by impaired responses of the auditory cortex to unexpected deviant tones (MMNm), despite normal responses to standard stimuli. Together, these results suggest that neurodegeneration in two distinct clinical syndromes with overlapping profiles of prefrontal atrophy, causes a similar pattern of reorganisation of large-scale networks. We discuss this network reorganisation in the context of other focal brain disorders and the specific vulnerability of functional brain networks to neurodegenerative disease

Multi-modal Imaging and Cognitive Profiles in de novo Parkinson’s Disease

The overall aim of my PhD was to study the correlations between cognitive functions, neurodegeneration and functional alterations in diffuse projection systems. To this aim we plan to combine formal neuropsychological testing, structural and functional imaging and in-vivo quantitative assessments of the dopaminergic, serotonergic and cholinergic systems. Through a multi-modal imaging approach, we had the chance to deeply understand neuroanatomical and neurochemical basis of cognition in its whole, in a large cohort of de novo Parkinson’s Disease (PD) patients. Our study cohort ranges from 30 to 96 of de novo PD patients, who underwent 18F- fluorodeoxyglucose Positron Emission Tomography ([18F]FDG-PET), used as a marker of regional neurodegeneration; [123I]Ioflupane Single Photon Emission Computed Tomography ([123I]FP-CIT-SPECT, as a marker of dopaminergic impairment in the basal ganglia and in the cortex as well as a proxy marker of serotonergic deafferentation in the thalamus; and quantitative electroencephalography (qEEG) recordings, used instead as a marker of cholinergic deafferentation. We combined these imaging methods with formal neuropsychological testing, a social cognition test and multiple clinical variables. In this work we aim to answer to three main scientific questions: i) Does social cognition in de novo PD patients have a specific cortical and neurochemical signature? ii) Is there a mediated effect between diffuse projection systems degeneration and cortical metabolism as well as on regional expression of monoaminergic transmission in the deep grey matter? iii) Are specific cognitive domains impaired in de novo PD patients and are they differently affected by regional metabolism and diffuse projection systems degeneration? In Chapter 3 we investigated the topographical and neurochemical bases of Theory of Mind (ToM), which refers to the ability to attribute mental states to others and to predict, describe, and explain behaviour based on such mental states, using multi-tracer molecular imaging and quantitative electroencephalography in a group of 30 drug-naïve, de novo PD patients. ToM was assessed using the “Reading the Mind in the Eyes Task” (RMET), while general cognition with the Mini Menta State examination (MMSE). We found that PD patients performed significantly worse at RMET compared to 60 healthy controls, as well as a significant positive correlation between RMET performance and regional metabolism in the superior temporal gyrus and the insula, and an inverse correlation with [123I]FP-CIT thalamic specific binding ratio values, as expression of serotonin deafferentation. On the other hand, MMSE correlated with qEEG posterior Theta/Alpha power, confirming its independency from social cognition. In Chapter 4, using multi-tracer molecular imaging, we assessed in a cohort of 96 drug-naïve, de novo PD patients the association between cortical metabolism and dopaminergic and serotonergic systems deafferentation of either striatum or thalamus, and whether this association was mediated by either striatum or thalamus metabolism. We found that the impact of deep grey matter monoaminergic deafferentation on cortical function is mediated by striatal and thalamic metabolism in this population. We showed a significant direct correlation between bilateral temporo-parietal metabolism and caudate dopaminergic innervation, as well as a significant correlation between prefrontal metabolism and thalamus serotonergic innervation, which were, respectively, mediated by striatal and thalamic metabolism. In Chapter 5, we evaluate the association between neurotransmitter impairment, brain metabolism and cognition in a cohort of 95 drug-naïve, de novo PD patients, using [18F]FDG-PET images as a marker of brain glucose metabolism and proxy measure of neurodegeneration, [123I]FP-CIT-SPECT for dopaminergic deafferentation in the striatum and frontal cortex, as well as a marker of serotonergic deafferentation in the thalamus, and quantitative electroencephalography (qEEG) as an indirect measure of cholinergic deafferentation. Patients also underwent a complete neuropsychological tests battery. We found positive correlations between (i) executive functions and left cerebellar cortex metabolism, (ii) prefrontal dopaminergic expression and working memory, (iii) qEEG slowing in the posterior leads and both memory and visuo-spatial functions

The role of the cingulate cortex in depression in dementia with Lewy bodies

PhD ThesisDementia with Lewy bodies (DLB) is a significant cause of dementia in the older population with a core set of clinical symptoms that help to distinguish DLB from other forms of dementia such as Alzheimer’s disease (AD). The core symptoms of DLB include fluctuating cognition, recurrent complex visual hallucinations and parkinsonism. Additionally, depression is experienced in around half of DLB patients and is associated with faster rate of cognitive decline, higher mortality rates and a poor response to treatment. The subgenual anterior cingulate cortex (sgACC) is integral in mood regulation, displaying structural, functional and metabolic abnormalities in depression, and shows early and extensive pathological changes in DLB. However, little is known about how any pathological or neurochemical changes in sgACC contribute to the aetiology of depression in DLB. Post-mortem tissue from cingulate cortex subregions was used to quantify neuropathological lesions in DLB cases with and without depression, and cognitively normal controls. Neurochemical analysis was performed to assess disease and depression specific changes in the sgACC in GABAergic, glutamatergic and monoaminergic transmission. Synaptic changes were assessed using confocal and stimulated emission depletion (STED) microscopy. Neuropathological burden in cingulate subregions showed disease, but not depression specific changes in DLB. Abnormalities in GABAergic and glutamatergic neurotransmission were observed in DLB cases with depression, showing greater dysregulation compared to DLB cases without depression. Dopaminergic deficits were observed in sgACC in DLB cases, with a greater reduction in DLB cases with depression, whereas no major changes in serotonergic or noradrenergic neurotransmission were observed in DLB. The results demonstrate that neurodegenerative neuropathological changes within the cingulate cortex do not appear to influence the development of depression in DLB. An imbalance in GABAergic/glutamatergic transmission within the sgACC was greater in DLB cases with depression, which may suggest greater dysregulation in excitation and inhibition, possibly contributing to the development of depression in DLB. This work also demonstrates the major role of dopaminergic neurotransmission in the aetiology of depression in DLB. Overall, this work indicates that treatment of depressive symptoms in DLB could benefit from modulation of dopaminergic, glutamatergic, or GABAergic transmission.The Alzheimer’s Societ