Neuroimaging strutturale nello studio delle malattie psichiatriche Marina Boccardi LENITEM (Laboratory of Epidemiology, Neuroimaging & Telemedicine)

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1 SIN Corso di Aggiornamento in Neuroimmagini Brescia, 26 Marzo 2009 Neuroimaging strutturale nello studio delle malattie psichiatriche Marina Boccardi LENITEM (Laboratory of Epidemiology, Neuroimaging & Telemedicine)

2 > Translability GERIATRIC SCHIZOPHRENIA PATIENTS CPM - cortical pattern matching ENDOPHENOTYPES MTL in familial mood disorders PSYCHOPATHY RAM - radial atrophy mapping < Translability

3 GERIATRIC SCHIZOPHRENIA PATIENTS CPM - cortical pattern matching ENDOPHENOTYPES MTL in familial mood disorders PSYCHOPATHY RAM - radial atrophy mapping

IRCCS Centro San Giovanni di Dio FBF, Brescia, Italy Schizophrenia Research Institute, Sydney, Australia University of Newcastle, Newcastle, Australia SDN Foundation, Institute of Diagnostic and

4 IRCCS Centro San Giovanni di Dio FBF, Brescia, Italy Schizophrenia Research Institute, Sydney, Australia University of Newcastle, Newcastle, Australia SDN Foundation, Institute of Diagnostic and Nuclear Development, and University of Naples Parthenope, Naples, Italy Service of Neuroradiology, Istituto Clinico Città di Brescia, Brescia, Italy University Hospitals of Geneva, University Hospitals of Lausanne, Switzerland Laboratory of Neuro Imaging, UCLA School of Medicine, Los Angeles, USA

5 Brain morphology in AD and schizophrenia Direct comparison of elderly schizophrenia and AD patients similar functional impairment requiring long term assistance lacking in the available literature

6 Healthy elderly subjects (N=20) Elderly schizophrenia patients (N=20) Alzheimer s disease patients (N=20) Age, years 72.5 ± ± ± 9.1 [range] [58-85] [60-78] [58-81] Sex, female 14 (70%) 10 (50%) 12 (60%) Education, years 8.8 ± ± ± 5.1 Mini Mental State Exam [range] 29.1 ± 0.9 [27-30] 22.8 ± 4.4 [14-30] 22.0 ± 4.3 [13-28] Barthel Index 100 ± 0 89 ± ± 13 Hypertension 4 (20%) 5 (25%) 6 (30%) Diabetes 0 (0%) 4 (20%) 1 (5%) Smoking 2 (10%) 9 (45%) 9 (45%) Alcohol consumption 9 (45%) 4 (20%) 10 (50%)

7 Thompson et al., J Neurosci 2003; Thompson et al., Neuroimage 2004

8 Elderly schizophrenia patients Permutation test: p= p= Alzheimer disease patients p= p= % P

9 Greater atrophy in elderly schizophrenia patients than in AD Permutation test: p=0.01 Greater atrophy in AD than in elderly schizophrenia patients Permutation test: p=0.05

10 GM reduction higher than 13%, significant after correction for multiple comparisons Sc<Ct Sc<AD Sc<Ct & Sc AD

11 Elderly Schizophrenia Patients Alzheimer s Disease Patients PANSS+ Letter fluency permutation test: p=n.s. p=.06 p=.002 p=.007

12 Brain morphology in AD and schizophrenia clinical translability SC patients are not only clinically, but also biologically different from AD These findings should guide therapeutic strategies for rehabilitation and other treatment interventions, included the (creation and) referral to appropriate services

13 GERIATRIC SCHIZOPHRENIA PATIENTS CPM - cortical pattern matching ENDOPHENOTYPES MTL in familial mood disorders PSYCHOPATHY RAM - radial atrophy mapping

14 Brain function dysmodulation of motivated behavior MTL? (Hasler et al., 2006) Endophentypes: medial temporal lobe (MTL) morphology in mood disorders Brain structure larger amygdalar but not hippocampal volumes in bipolar smaller but hyperactive amygdalae in unipolar (Haltshuler et al., 1998,2000; Strakowski et al., 1999,2002; Brambilla et al., 2003)

15 The family: unaffected, UNIPOLAR AND BIPOLAR subjects Major depression Bipolar disorder, type I Bipolar disorder, type II MRI available

16 Clinical evaluation Clinical unstructured and structured (SCID-I/P, version First et al., 1995) interview aimed to evaluate Axis 1 DSM-IV diagnosis 21-item Hamilton Rating Scale for Depression (Hamilton, 1960) Young Mania rating Scale (Young et al., 1978)

17 Psychotropic medications Physical diseases Subj Age Onset Axis I DSM IV diagnosis N. of episodes Status at the time of assessment Past Present Axis III physical comorbidity Medications Affected II Bipolar disorder type I Recurrent Depressive symptoms Venlafaxine, lorazepam, alprazolam, trazodone, paroxetine, lithium Venlaflaxine, lithium carbonate, lamotrigine Thyroidectomy at 71 and 76 hypothyroidism Thyroxin, hormonal replacement therapy, nifedipine ramipril III Major depressive disorder, generalized anxiety disease, breathing-related sleep 2 Remission Clomipramine, paroxetine Zolpidem, lormetazepam, Breast cancer, headache Naproxene sodium, ibuprofen, tamoxifene disorder sleep apnoea syndrome, coffee abuse trimipramine III Major depressive episode 2 Depressive Trimipramine, citalopram, Trimipramine symptoms benzodiazepines III Major depressive disorder 1 Remission Amitriptyline Annual therapy with estradiol valerate II Seasonal major depressive disorder 4 Incomplete remission Venlafaxine Venlafaxine Thyroidectomy at 18 and 58 Estrogen replacement therapy Non affected III III 4 53 IV 1 24 Estrogen replacement therapy III Hyperthyroidism Hyperthyroidism therapy III Amphetamine for overweight at 33 Asymptomatic multinodular goiter III Asymptomatic multinodular goiter III Asymptomatic multinodular goiter II Asymptomatic multinodular goiter III Headache Pizotifen II Hypercholesterolemia Cholesterol lowering agents

18 Sociodemographic features Affected (n=5) Controls for affected (n=5) P Non affected (n=10) Controls for non affected (n=10) Age 58.7 (17) 58.9 (17.3) (14) 45.0 (13.2) 0.94 P Sex (f) 5 (100%) 5 (100%) (60%) 6 (60%) 1.00 Education 6.2 (1.6) 6.2 (1.6) (3.2) 9.4 (3.1) 0.61 MMSE 28.4 (0.5) 29.4 (0.5) (0.8) 29 (0.7) 0.07

19 MRI 1.0 T 3D high resolution MRI Manual tracings of the amygdala and hippocampus

21 Abnormal MTL volumes in both affected and non affected Affected family members (n=5) Controls for affected (n=5) Non affected family members (n=10) Controls for non affected (n=10) Hippocampus Right 2.72±0.06* 2.95± ±0.34* 3.19± Left 2.85± ± ± ± Asymmetry 0.96± ± ±0.08* 1.09± Amygdala Right 1.42± ± ±0.20* 1.18± Left 1.42±0.20* 1.16± ±0.18* 1.15± Asymmetry 1.01± ± ± ± Amy/Hippo Right 0.53± ± ±0.10* 0.52± Left 0.50± ± ±0.07* 0.41± P * significantly different from their matched controls; significantly different at exact test.

22 Abnormal MTL volumes in both affected and non affected Non affected family member Unrelated control subject Abnormal MTL = plausible endophenotype for mood disorder

23 Pathogenesis insights Larger amygdala & affective disorders Shifting from an initiated activation Autoassociative networks (Rolls, 2007) Smaller hippocampus & affective disorders Stress-related vulnerability Memory (Bearden 2006) Context processing, including reward Context processing deficits in bipolar (Brambilla 2007) Anxiety (Gray & McNaughton 2000) Neurogenesis and coping with novelty/complexity neurogenesis is augmented by most antidepressants (Kempermann 2002)

24 Discussion most patients depressed, but morphometry compatible with a bipolar pattern: MTL as a disease marker? Implications for diagnosis and treatment, prognosis and risk evaluation Pathogenesis insights and implications for psychological/rehabilitation treatment

25 GERIATRIC SCHIZOPHRENIA PATIENTS CPM - cortical pattern matching ENDOPHENOTYPES MTL in familial mood disorders PSYCHOPATHY RAM - radial atrophy mapping

26 Methods 26 Finnish offenders; Psychiatric pre-trial evaluation 25 Finnish controls Clinical (including PCL-R psychopathy scale) and neuropsychological evaluation 1T MRI Advanced post-processing

27 Subjects High psychopathy (N=12) Medium psychopathy (N=14) P-value Mean age (in years) 33.0 ± ± Duration of alcohol abuse (in years) 19.6 ± ± Amphetamine use 9 (75%) 6 (43%) Polysubstance* abuse 12 (100%) 8 (57%) Mean global IQ score 94.7 ± ± Current psychotropic medication 8 (67%) 7 (50%) Mean score PCL-R total 34.6 ± ± 2.8 < Arrogant Deceitful Interpersonal Conduct and Deficient Affective Experience (Hare s F1) 14.0± ±1.5 < Impulsive, Irresponsible Behavioral Style (Hare s F2) Arrogant and deceitful interpersonal style (Cooke s F1) 17.2± ± ± ± 1.1 < Deficient affective experience (Cooke s F2) 7.8 ± ± 1.1 < Impulsive, irresponsible behavioral style (Cooke s F3) 9.6 ± ±

29 Hippocampus manual tracing Frisoni et al., Neuroimage 2006

Methods 3D parametric surface mesh models were created using manual tracings of hippocampal boundaries from coronal slices in each subject.

The radial size of each hippocampus at each boundary point was assessed by automatically measuring the radial 3D distance from the surface points to the medial curve defined for

30 Methods 3D parametric surface mesh models were created using manual tracings of hippocampal boundaries from coronal slices in each subject. A medial curve was automatically defined as the 3D curve traced out by the centroid of the hippocampal boundary in each image slice. The radial size of each hippocampus at each boundary point was assessed by automatically measuring the radial 3D distance from the surface points to the medial curve defined for each individual s hippocampal surface model. Different radial distances were used as index of morphological abnormalities and maps of statistical significance and percent change were generated indicating local abnormalities (p<0.05). Thompson et al., Neuroimage 2004

31 Frisoni et al., 2006; Duvernoy et al., 1998

32 Local hippocampal changes in 26 offenders compared with 25 controls (A) percent difference (B) significant difference permutation test: p=0.002 bilaterally

33 Smaller dentate gyrus reduced fear conditioning

34 Psychopathy Clinical translability Pathogenesis insights & implications for treatment < DG, < fear conditioning (Butkevich et al., 2003; Tsetsenis et al., 2007) > lateral CA3, > opioid receptors, < sensitivity to pain (Daumas et al., 2007) An effect of substance abuse to this morphometric pattern has been ruled out Legal fallbacks: How to judge responsibility for crimes? How to manage persons charged for violent behavior?

35 > Translability improved management of patients (elderly schizophrenia and psycopathy pts) help in diagnosis and treatment (unipolar or bipolar?) < Translability pathogenesis insights and new ideas for rehabilitation

36 Acknowledgements IRCCS SAN GIOVANNI DI DIO - FATEBENEFRATELLI LENITEM Psychosocial Psychogeriatrics Mental Disability Rehabilitation Unit Unit Service Giovanni B Frisoni Annapaola Prestia Rossana Ganzola Michela Pievani Samantha Galluzzi Anna Caroli Marco Lorenzi Chiara Barattieri Marco Podavini Cristina Scarpazza Alberto Redolfi Enrica Cavedo Daniela Costardi Donata Paternicò Laura Frassine Giuseppe Rossi Roberta Rossi Genoveffa Borsci Neuroimaging & Brain Mapping Division Dept of Neurology, Los Angeles - CA - USA Paul Thompson Cristina Geroldi Andrea Adorni Dept of Forensic Psychiatry & University of Kuopio Kuopio Finland Jari Tiihonen Eila Repo-Tiihonen Mikko Laakso Hannu Aronen Olli Vaurio Hilkka Soininen Mervi Könönen Sergio Monchieri

37 CENTRO SAN GIOVANNI DI DIO FATEBENEFRATELLI IRCCS - Istituto di Ricovero e Cura a Carattere Scientifico Provincia Lombardo-Veneta Ordine Ospedaliero di San Giovanni di Dio Fatebenefratelli via Pilastroni 4, 25125, Brescia Direzione Scientifica Tel , Fax irccs.fatebenefratelli@fatebenefratelli.it Direzioni Amministrativa e Sanitaria Tel , Fax centro.sangiovanni.di.dio@fatebenefratelli.it

Marina Boccardi Thomson Reuter Researcher ID: B ORCID ID: Update: May 2014

Marina Boccardi Thomson Reuter Researcher ID: B-2733-2010 ORCID ID: 0000-0001-6744-8246 Update: May 2014 Education: Degree in Experimental Psychology Psychobiology, 110/110 cum laude, University of Padua-