Longitudinal MRI study in schizophrenia patients and their healthy siblings

To investigate whether genetic and/or disease-related factorsare involved in progressive structural brain changes in schizophrenia,magnetic resonance imaging scans with a 5-year scan intervalwere acquired in patients, their same-gender siblings and matchedhealthy controls. Structural equation modelling was appliedto assess disease and familial effects. Whole brain and cerebralgrey matter volumes decreased excessively in patients comparedwith their siblings and the controls, suggesting that the progressivebrain loss in schizophrenia may be related to the disease process.

INTRODUCTION

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INTRODUCTION

Structural brain abnormalities have been reported consistentlyin patients with schizophrenia,¹ with less pronounced abnormalitiesin first-degree relatives of patients.² Thus, the volumetricdifferences may be related in part to the genetic risk of developingthe disease.³ At least part of the morphological brain changesin schizophrenia are progressive over the course of the illness,^4,5 but it is not known for certain whether they are mediated bygenetic or disease-related factors.

Methods

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Methods

Participants were recruited from the sibling-pair cohort andcontrol sample^6,7 at the University Medical Center Utrecht.At baseline, 16 patients with schizophrenia (12 male, 4 female),18 same-gender siblings (14 male, 4 female) and 43 healthycontrols (29 male, 14 female) matched for age, gender and parentaleducation participated. Eleven patients (7 male, 4 female),11 siblings (8 male, 3 female) and 33 controls (22 male, 11female) completed the follow-up after 5 years (mean=5.02 years;s.d.=0.39). Not all sibling-pairs were complete at follow-up;a total of 7 sibling-pairs were scanned twice. At baseline,mean age of the patients, siblings and controls was 40.9 years (s.d.=8.8), 41.2 years (s.d.=8.8) and 40.2 years (s.d.=8.2)respectively. Mean duration of illness in the patients was19.6 years (s.d.=11.5). The follow-up sample was representativeof the baseline sample in that groups did not differ in meanage, handedness, participants' and parental education, and durationof illness.

All individuals underwent extensive psychiatric assessment proceduresusing the Comprehensive Assessment of Symptoms and History⁸at baseline and follow-up. Patients met DSM–IV criteriafor schizophrenia and all siblings were healthy. Siblings wereat least 8 years older than the age the affected sibling developedthe first symptoms of schizophrenia; thus, they would be veryunlikely to develop schizophrenia in the future. Outcome was assessed using the Global Assessment of Functioning,⁹ the Positive and Negative Syndrome Scale¹⁰ and the CamberwellAssessment of Need.¹¹ Participants with a major medical orneurological illness, IQ below 80, previous electroconvulsivetherapy, or history of substance dependence were excluded.

A table from the Dutch National Health Service¹² was used tocalculate the cumulative dosage of antipsychotics during the5-year scan interval and to derive haloperidol equivalents(HAL equiv.). During the scan interval, six patients were exclusivelyon atypical antipsychotics (including clozapine) and two ontypical. Two patients switched between typical and atypicalantipsychotics; for one patient reliable information on medication was absent. Mean cumulative antipsychotic medication duringthe scan interval was 14 345.4 HAL equiv. (s.d. = 7984). Noneof the siblings used antipsychotics. In all, 46% of patients(5 of 11), 18% of siblings (2/11) and 36% of controls (12/33)were smokers. All participants gave written informed consent.The study was approved by the medical ethics committee for research in humans (METC) of the University Medical Center Utrecht.

Magnetic resonance imaging (MRI) brain scans were acquired ona Philips NT (Best, The Netherlands) scanner operating at 1.5T for all participants. A 3D fast field echo and a T₂-weighteddual echo–turbo spin echo were acquired. Protocol detailsand the imaging process are described elsewhere.⁷ Volumes of intracranium, whole brain, cerebral grey and white matter,lateral and third ventricular volumes, and cerebellum weremeasured.

Mixed model analysis was implemented using Structural EquationModeling with Mx software for Windows (www.vcu.edu/mx/mxhomepage.html). Brain volume change was regressed on intracranial volume, gender,age, disease (patients v. siblings and controls) and familialbackground (patients and siblings v. controls). Relatednessin the sibling-pairs was accounted for in the covariance structureby allowing dependencies between the residuals in the regressionanalyses. Effects of disease and familial background were testedby comparing the likelihoods of nested models (–2 log-likelihood),which is chi-squared distributed; ${chi}$ ²>3.84 (1 d.f.) indicatesa significant difference at ${alpha}$ =0.05, and depicts that the discardedeffect (e.g. disease effect) cannot be left out of the model without seriously reducing the goodness of fit. Using the fullmodel, estimates (including 95% CIs) were obtained that indicatedan increase or decrease of the dependent variable (brain volumechange) in patients or in siblings.

Results

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Results

Over time, whole brain volume decreased excessively in patients (–12.6 ml) compared with siblings (+7.3 ml) and controls(–2.3 ml) (Table 1). A greater decrease in cerebralgrey matter volume was observed in patients (–24.9 ml)than in siblings (–9.8 ml) or controls (–16.8 ml).Moreover, patients showed less prominent increases in cerebralwhite matter volume (+5.3 ml) than siblings (+12.9 ml) or controls(+12.5 ml). Changes in grey and white matter volumes do notadd up to changes in total brain volume, because grey/white matter was limited to the cerebrum (i.e. whole brain excludingcerebellum and brain-stem).

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Table 1 Disease and familial effects of schizophrenia on changes in brain volumes^a

No associations were found between clinical variables and brainvolume changes, except that a larger dose of atypical medication(including clozapine) during the scan interval was positivelycorrelated with less progressive decrease in cerebral greymatter volume (r=0.85; P=0.03).

When comparing patients and siblings as a group with the controls,no familial effects were found in any of the brain volume changesover time.

Discussion

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Discussion

The progressive decreases over time in whole brain and cerebralgrey matter volume and less prominent increases in white matterobserved in schizophrenia patients but not in siblings mayrepresent a (disease-related) non-genetic risk factor for thedisease. Our finding of progressive decrease over time is consistentwith those of other longitudinal studies in schizophrenia.^4,5 The findings in siblings are consistent with the normalisationof cortical thickness by the age of 20 in siblings of patientswith childhood-onset schizophrenia.¹³

To our knowledge, this is the first longitudinal MRI study inchronically ill patients with schizophrenia and their healthysiblings. Siblings share on average 50% of their genes. Thesiblings in this study were all healthy and beyond the ageof risk for schizophrenia. Possibly, the disease alleles of schizophrenia-related genes may be underrepresented in thesesiblings.

This study has several limitations. First, the number of participantswas small and genetic factors involved in progressive brainchanges in schizophrenia may not have been elucidated owingto a limited statistical power. Second, it is likely that atleast some of the disease alleles of schizophrenia-relatedgenes are not present in this sample of healthy siblings ofpatients. Our findings have to be considered preliminary andmore final conclusions await follow-up studies in monozygoticand dizygotic twin-pairs discordant for schizophrenia thatare currently underway.

ACKNOWLEDGMENTS

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ACKNOWLEDGMENTS

This research was supported in part by Grant No. 908-02-123(HEHP) from the Netherlands Organization for Health Researchand Development ZonMw.

REFERENCES

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