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Zonta, Filippo (2013) Hippocampal volumes in patients with bipolar-schizophrenic spectrum disorders and their unaffected first-degree relatives. [Ph.D. thesis]

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Abstract (english)

BACKGROUND: schizophrenic and bipolar disorders are complex and disabling psychiatric diseases whose classical nosography and classification are still under challenging debate aiming to overcome the traditional “Kraepelinian Dichotomy”. For the past hundred years most clinical work and research in psychiatry has proceeded under the assumption that schizophrenia and bipolar disorderaredistinctentities with separate underlying disease processes and treatments. In more recent years there has been increasing evidence for phenomenological, biological and genetic overlap between the two disorders (Potash and Bienvenu 2009). Nowadays, the categorical approach to psychiatric nosography is in contrast with the recent neurobiological, neuropsychological and genetic findings in affective and schizophrenic disorders. Further, symptoms and signs constituting bipolar and schizophrenic disorders are continuously, not dichotomously, distributed; there may be no point of “real cleavage” (Phelps et al. 2008). This recognition has led some clinicians and researchers to call for a diagnostic model that, moving to a “dimensional perspective”, formally recognizes a continuous spectrum from schizophrenic to bipolar (and recurrent depressive) disorders. Kelsoe argued that the existing data coming from various fields of research in bipolar and schizophrenic disorders may best fit a model in which different set of genes predispose to overlapping phenotypes in a continuum. Given the apparent overlap of regions of the genome implicated in bipolar disorder with those for schizophrenia (Kelsoe 1999; Berrettini 2000), the data suggest the possibility that a common polygenic background predisposes to both bipolar disorder and schizophrenia, according to the so-called “multiple threshold model” (Kelsoe 2003). As highlighted by Craddock and Owen, the recent findings are compatible with a model of functional psychosis in which susceptibility to a spectrum of clinical phenotypes is under the influence of overlapping sets of genes, which, together with environmental and epigenetic factors, determine an individual’s expression of illness (Craddock and Owen 2005). A lot of interest is focusing on brain structural abnormalities in patients suffering from schizophrenia and bipolar disorder. A huge amount of neuroimaging studies has been published so far, however the literature is heterogeneous and there is still some degree of uncertainty concerning what key regions are involved in the pathogenesis of such disorders. Schizophrenia and Bipolar Disorder have a number of overlapping symptoms and risk factors, but it is not yet clear if the disorders are characterized by similar deviations in brain morphometry or whether any such deviations reflect the impact of shared susceptibility genes on brain structure. To date there is no consensus about whether, and to what extent, gray matter loss in Schizophrenia is mirrored in Bipolar Disorder and what is the effect of medication or other confounding factors. Studies in family members of patients, who share the risk of the disease but not the confounding factors, may help elucidate whether abnormalities in brain structures are shared by both illnesses.

AIM OF THE STUDY: to investigate hippocampal gray matter volume differences in a group of patients with bipolar-schizophrenic spectrum disorders, a group of their unaffected first-degree relatives, and a group of healthy control subjects.

METHODS: a total of 104 subjects - 36 schizophrenic or schizoaffective (SZ), 27 bipolar (BP), 2 major depression, 8 unaffected relatives (UR), and 31 healthy controls (HC) - underwent 1,5 T MRI scanning, with volumetric T1 3D acquisition protocol, at the Neuroradiology Unit of Conegliano Hospital. We calculate bilateral hippocampal gray matter volume (HV) and total cerebral volume (TCV) in a sample of 31 SZ, 27 BP, 8 UR and 26 HC, with a stereological method using ANALYZE 10.0 software.

RESULTS: we found statistically significant reductions in bilateral HV in the BP-SZ patients compared to HC; the direct comparison between patient groups identified statistically significant reduction in the right HV of SZ, but no significant differences for left HV or TCV (however statistical significance was lost after normalization); statistically significant reduction in the left HV and a trend towards statistical significance for right HV in the UR compared to HC (a trend towards statistically significant reduction in bilateral HV persisted after normalization).

CONCLUSION: it might be speculated that the alterations of the gray matter volume in the hippocampus highlighted in our study could be interpreted as a possible structural “biological marker” in the schizophrenic-bipolar spectrum.

Abstract (italian)

INTRODUZIONE: schizofrenia e disturbo bipolare sono malattie psichiatriche complesse e invalidanti, il cui inquadramento nosografico è oggetto di continuo dibattito nel superamento della classica “dicotomia Kraepeliniana” tra Dementia Praecox e Malattia Maniaco-Depressiva. Negli ultimi cento anni, buona parte della pratica clinica e della ricerca in psichiatria sono state basate sull’assunto che schizofrenia e disturbo bipolare fossero entità categorialmente distinte, separate da distinti meccanismi patologici e trattamenti. In anni più recenti invece, si sono accumulate numerose evidenze a supporto di una parziale sovrapposizione fenomenologica, biologica e genetica tra questi disturbi (Potash e Bienvenu 2009). Attualmente, l’approccio nosografico “categoriale” nei disturbi affettivi e schizofrenici è in contrasto con le più recenti scoperte in ambito neurobiologico, neuropsicologico e genetico. Inoltre è stato evidenziato come, nemmeno dal punto di vista clinico vi sia un reale punto di “separazione” tra i due disturbi, che presentano segni e sintomi comuni e sovrapponibili (Phelps et al. 2008). Tale consapevolezza ha portato clinici e ricercatori a orientarsi verso un modello diagnostico che, spostandosi in una prospettiva “dimensionale”, formalmente riconosce l’esistenza di uno spettro tra disturbi schizofrenici e bipolari. Kelsoe afferma che i dati provenienti dai vari filoni di ricerca nei disturbi bipolari e schizofrenici potrebbero essere meglio spiegati da un modello in cui differenti set di geni predispongono a fenotipi clinici che si sovrappongono in un continuum. Data la documentata sovrapposizione fra regioni genomiche implicate nel disturbo bipolare con quelle della schizofrenia (Kelsoe 1999; Berrettini 2000), le evidenze suggeriscono la possibilità che un substrato poligenico comune possa conferire una predisposizione a entrambi i disturbi, secondo il cosiddetto modello delle “soglie multiple” (Kelsoe 2003). Come sottolineato da Craddock e Owen, le più recenti scoperte in tale ambito sono compatibili con un modello di psicosi funzionale, nel quale la suscettibilità ad uno spettro di fenotipi clinici è sotto l’influenza di un set di geni condivisi, che, insieme a fattori ambientali ed epigenetici, determina l’espressione di malattia in ciascun individuo (Craddock e Owen 2005). Notevole interesse si sta inoltre focalizzando sulle alterazioni strutturali cerebrali in pazienti affetti da schizofrenia e disturbo bipolare. Nonostante l’ingente mole di studi di neuroimaging finora pubblicati, la letteratura sull’argomento è molto eterogenea ed esiste ancora notevole incertezza su quali siano le specifiche regioni cerebrali coinvolte nella patogenesi di tali disturbi. Schizofrenia e Disturbo Bipolare condividono una serie di sintomi e fattori di rischio, ma non è ancora stato chiarito se questi disturbi siano caratterizzati da comuni modificazioni morfometriche cerebrali e se tali alterazioni riflettano l’impatto di geni comuni di suscettibilità sulla morfologia del cervello. Ad oggi, non è stato definitivamente chiarito se, e fino a che punto, la documentata perdita di sostanza grigia nella Schizofrenia si rifletta anche nel Disturbo Bipolare e su quali siano gli effetti della farmacoterapia o di altri fattori di confondimento. Gli studi sui membri non affetti di pazienti schizofrenici e bipolari, che condividono la predisposizione genetica ai disturbi, ma non i fattori di confondimento, posso rivelarsi utili nel verificare se le varie anomalie cerebrali siano condivise nelle due patologie.

SCOPO DELLO STUDIO: analizzare eventuali differenze volumetriche nella sostanza grigia ippocampale in un gruppo di pazienti dello spettro bipolare-schizofrenico, un gruppo di familiari di primo grado non affetti e un gruppo di soggetti sani di controllo.

MATERIALI E METODI: un totale di 104 sogetti - 36 pazienti con disturbo schizofrenico o schizoaffettivo (SZ), 27 pazienti con disturbo bipolare (BP), 2 pazienti affetti da depressione maggiore ricorrente, 8 familiari di primo grado non affetti (UR) e 31 controlli sani (HC) sono stati sottoposti ad una procedura di Risonanza Magnetica cerebrale ad 1,5 Tesla, secondo un protocollo di acquisizione di sequenze T1 3D volumetriche, presso l’Unità Operativa di Neuroradiologia del Presidio Ospedaliero di Conegliano. Mediante l’utilizzo del Software ANALYZE 10.0, sono stati calcolati, con un metodo stereologico, i volumi bilaterali della sostanza grigia ippocampale (HV) ed il volume cerebrale totale (TCV) in un campione di 31 SZ, 27 BP, 8 UR e 26 HC.

RISULTATI: sono state riscontrate riduzioni volumetriche statisticamente significative della sostanza grigia di ippocampo destro e sinistro tra i gruppi di pazienti dello spettro bipolare-schizofrenico rispetto ai controlli; nel confronto diretto tra il gruppo di pazienti schizofrenici e quello dei bipolari è stata identificata una riduzione statisticamente significativa del volume della sostanza grigia dell’ippocampo destro (tale significatività non persiste in seguito a normalizzazione) e nessuna significativa differenza nei volumi della sostanza grigia dell’ippocampo sinistro o nel volume cerebrale totale; nel confronto tra il gruppo di familiari di primo grado non affetti rispetto al gruppo di soggetti sani di controllo è stata evidenziata una significativa riduzione volumetrica della sostanza grigia dell’ippocampo sinistro e un trend verso la significatività statistica per l’ippocampo destro (tali riduzioni volumetriche della grigia ippocampale mantenevano bilateralmente tale trend verso la significatività statistica anche dopo la normalizzazione).

CONCLUSIONE: la alterazione volumetrica della sostanza grigia ippocampale evidenziata nel nostro studio potrebbe essere interpretata come un possibile “marker biologico” strutturale nei disturbi dello spettro schizofrenico-bipolare.

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EPrint type:Ph.D. thesis
Tutor:Perini, Giulia
Ph.D. course:Ciclo 25 > Scuole 25 > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > NEUROSCIENZE
Data di deposito della tesi:29 January 2013
Anno di Pubblicazione:29 January 2013
Key Words:MRI, Hippocampus, Hippocampal Volume, Bipolar Disorder, Schizophrenia, unaffected relatives
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/25 Pschiatria
Area 06 - Scienze mediche > MED/37 Neuroradiologia
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Cardiologiche, Toraciche e Vascolari
Dipartimenti > Dipartimento di Neuroscienze
Codice ID:5695
Depositato il:14 Oct 2013 13:54
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