Immunità e disturbo bipolare

Transcription

1 Immunità e disturbo bipolare Francesco Benede,, M.D. Ospedale San Raffaele Division of Neuroscience Psychiatry and clinical Psychobiology Milano Italy

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6 Mean diffusivity

7 Radial diffusivity

8 Frac?onal anisotropy

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18 CSF protein analysis of patients with schizophrenic and affective spectrum disorders in Reibergrams. Classified CSF data of protein analysis from paired blood CSF samples of patients with schizophrenic spectrum disorders (squares) and affective spectrum disorders (open circles) in Reibergrams. (a) Subgroup with inflammatory signs in CSF (n = 9), (b) subgroup with isolated blood CSF barrier dysfunction (n = 15) (c) subgroup with normal CSF (n = 33).

19 CSF protein analysis of patients with schizophrenic and affective spectrum disorders in Reibergrams. Classified CSF data of protein analysis from paired blood CSF samples of patients with schizophrenic spectrum disorders (squares) and affective spectrum disorders (open circles) in Reibergrams. (a) Subgroup with inflammatory signs in CSF (n = 9), (b) subgroup with isolated blood CSF barrier dysfunction (n = 15) (c) subgroup with normal CSF (n = 33). Bechter K, Herzog S, Schreiner V, Brinkmeier H, Aulkemeyer P, Weber F, et al. Borna disease virus-related therapy-resistant depression improved after cerebrospinal fluid filtration. Journal of Psychiatric Research 2000;34:393 6.

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21 Increased serum and/or plasma concentra?ons of Interleukin (IL)- 6 IL- 1- b and tumor necrosis factor (TNF)- a C- reac?ve protein and other acute- phase proteins a- 1- acid glycoprotein, a- 1- an?chymotrypsin haptoglobin Increased levels of chemokines and adhesion molecules human macrophage chemoanractant protein- 1 (MCP- 1), soluble intracellular adhesion molecule- 1 (sicam- 1) E- selec?n,

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25 AGP-RC = coefficiente di reattività della alfa-1-glicoproteina acida (Crossed-affinity immunoelectrophoresis with free concanavalin A)

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31 Amytriptiline 6 weeks; plasma levels: responders (112) mg/l nonresponders (133) mg/l)!

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34 Variazione nella gravità osservata della depressione (Scala di Hamilton) Variazione nel tono dell umore percepito (Scala analogica visiva)

35 Baseline Correlazione tra tono dell umore percepito e livello plasmatico di IL-6 After TSD After TSD and SPA

36 Benede% et al. (1999) Ongoing lithium treatment prevents relapse a:er sleep depriva;on. Journal of Clinical Psychopharmacology, 19(3):

37 Rate of response (21- item Hamilton Depression Scale score 50% reduc?on): No drug resistance: 69.7% Resistant: to SSRIs 50.0% to SSRIs and TCAs 41.2%

38 one night of sleep loss triggers a response that includes s?mula?on of both pro- and an?- inflammatory proteins

39 Increased PGE2 in the saliva, the serum and the cerebrospinal fluid of depressed pa?ents IL6?

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41 Kynurenine is broken into 1. a neuroprotec?ve kynurenic acid, NMDA receptor antagonist pathway 2. a neurotoxic 3- hydroxy kynurenine and quinolinic acid, NMDA receptor agonist pathway. In the brain: 1. astrocytes produce mainly protec?ve kynurenic acid 2. macrophages produce mainly neurotoxic metabolites.

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43 In depressed pa?ents: Mean tryptophan breakdown index was higher Mean kynurenic acid concentra?on was lower Mean neuroprotec?ve ra?os were lower In ROC analysis, the kynurenic acid concentra?ons and the neuroprotec?ve ra?o showed clear discrimina?on between depressed pa?ents and controls with area under the curve 79% and 76.3% respec?vely.

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45 and behavioural changes in animal models of depression parallel all this.

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47 Hypothalamic- pituitary- adrenal (HPA) axis disturbances in MDD Major mood disorders are characterized by HPA- axis disturbances,in par?cular by a CRH hyperdrive. A resistance to steroids most likely plays a role in the HPA- axis disturbances.

48 Anno 2004

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51 Nuovi bersagli per la terapia Disturbances in metabolic networks are implicated in the pathophysiology, brain volumetric changes, symptoma?c expression (e.g., neurocogni?ve decline), and medical comorbidity in depressive disorders: insulin- glucose homeostasis, immuno- inflammatory processes, adipokine synthesis and secre?on, intra- cellular signaling cascades, mitochondrial respira?on Depression as a neuropsychiatric syndrome in which altera?ons in metabolic networks are a defining pathophysiological component. Innova?ve treatments for mood disorders, which primarily target aberrant metabolic networks, may cons?tute poten?ally novel, and disease- modifying, treatment avenues.

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54 FA RD MD

55 Disrup?on of white maner integrity in bipolar depression: a state- dependent structural marker of illness? A survey of the literature about DTI in adult bipolar pa?ents shows that in several studies the current state of the pa?ent was not reported the sample included pa?ents with heterogeneous clinical states:these laner studies observed either a reduc?on of FA or mixed abnormali?es depending on the studied brain region. Four studies have been performed on euthymic or rela?vely stable pa?ents, and all but one observed an increased FA in pa?ents with bipolar disorder compared to controls.

56 Disrup?on of white maner integrity in bipolar depression: a state- dependent structural marker of illness? It is then temp?ng to speculate that 1. cri?cal bipolar illness phases could be associated with DTI findings sugges?ng disrupted WM integrity (reduced FA and increased radial and mean diffusivity), 2. with opposite observa?ons in stable euthymia (increased FA, increased connec?vity). In agreement with this hypothesis, in a mixed sample currently depressed pa?ents had lower FA values than remined pa?ents, while among clinically stable pa?ents subsyndromal depression ra?ngs correlated inversely with FA.

57 Disrup?on of white maner integrity in bipolar depression: a state- dependent structural marker of illness? Following this perspec?ve, it should be noted that the increase of FA in euthymic condi?ons could well reflect neuroplas?city, but that several factors may all contribute: increases in myelina?on microscopic deficits of axonal structures decreases in axonal diameter decreases in packing density decreases in fiber branching Increased FA has been associated with neuropsychological deficits in some neurological condi?ons. Persistent WM abormali?es associated with euthymic intervals could then parallel persistent neuropsychological deficits in bipolar disorder.

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59 Conclusioni Citochine e immunità come marcatore sindrome metabolica stress depressione resistente Citochine e immunità come fanore patogene?co specifiche costellazioni di sintomi lesioni neurotrasme,tori Monitoraggio Bersaglio