Skip to main content Accessibility help
×
Home
Hostname: page-component-5d6d958fb5-9cwrl Total loading time: 1.046 Render date: 2022-11-29T19:14:40.031Z Has data issue: true Feature Flags: { "shouldUseShareProductTool": true, "shouldUseHypothesis": true, "isUnsiloEnabled": true, "useRatesEcommerce": false, "displayNetworkTab": true, "displayNetworkMapGraph": false, "useSa": true } hasContentIssue true

Longitudinal MRI study in schizophrenia patients and their healthy siblings

Published online by Cambridge University Press:  02 January 2018

Rachel G. H. Brans*
Affiliation:
Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, The Netherlands
Neeltje E. M. van Haren
Affiliation:
Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, The Netherlands
G. Caroline M. van Baal
Affiliation:
Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, The Netherlands
Wouter G. Staal
Affiliation:
Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, The Netherlands
Hugo G. Schnack
Affiliation:
Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, The Netherlands
René S. Kahn
Affiliation:
Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, The Netherlands
Hilleke E. Hulshoff Pol
Affiliation:
Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, The Netherlands
*
Rachel G.H. Brans, Rudolf Magnus Institute of Neuroscience, Department of Psychiatry, University Medical Center Utrecht, A01.126, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. Email: R.Brans@azu.nl
Rights & Permissions[Opens in a new window]

Summary

To investigate whether genetic and/or disease-related factors are involved in progressive structural brain changes in schizophrenia, magnetic resonance imaging scans with a 5-year scan interval were acquired in patients, their same-gender siblings and matched healthy controls. Structural equation modelling was applied to assess disease and familial effects. Whole brain and cerebral grey matter volumes decreased excessively in patients compared with their siblings and the controls, suggesting that the progressive brain loss in schizophrenia may be related to the disease process.

Type
Short Reports
Copyright
Copyright © Royal College of Psychiatrists, 2008 

Structural brain abnormalities have been reported consistently in patients with schizophrenia, Reference Wright, Rabe-Hesketh, Woodruff, David, Murray and Bullmore1 with less pronounced abnormalities in first-degree relatives of patients. Reference Boos, Aleman, Cahn, Hulshoff Pol and Kahn2 Thus, the volumetric differences may be related in part to the genetic risk of developing the disease. Reference Hulshoff Pol, Brans, van Haren, Schnack, Langen, Baaré, van Oel and Kahn3 At least part of the morphological brain changes in schizophrenia are progressive over the course of the illness, Reference van Haren, Hulshoff Pol, Schnack, Cahn, Brans, Carati, Rais and Kahn4,Reference Pantelis, Yücel, Wood, Velakoulis, Sun, Berger, Stuart, Yung, Phillips and McGorry5 but it is not known for certain whether they are mediated by genetic or disease-related factors.

Methods

Participants were recruited from the sibling-pair cohort and control sample Reference Staal, Hulshoff Pol, Schnack, Hoogendoorn, Jellema and Kahn6,Reference Hulshoff Pol, Schnack, Bertens, van Haren, van der Tweel, Staal, Baaré and Kahn7 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 healthy controls (29 male, 14 female) matched for age, gender and parental education participated. Eleven patients (7 male, 4 female), 11 siblings (8 male, 3 female) and 33 controls (22 male, 11 female) 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 was 19.6 years (s.d.=11.5). The follow-up sample was representative of the baseline sample in that groups did not differ in mean age, handedness, participants' and parental education, and duration of illness.

All individuals underwent extensive psychiatric assessment procedures using the Comprehensive Assessment of Symptoms and History Reference Andreasen, Flaum and Arndt8 at baseline and follow-up. Patients met DSM–IV criteria for schizophrenia and all siblings were healthy. Siblings were at least 8 years older than the age the affected sibling developed the first symptoms of schizophrenia; thus, they would be very unlikely to develop schizophrenia in the future. Outcome was assessed using the Global Assessment of Functioning, Reference Hall9 the Positive and Negative Syndrome Scale Reference Kay, Fiszbein and Opler10 and the Camberwell Assessment of Need. Reference Phelan, Slade, Thornicroft, Dunn, Holloway, Wykes, Strathdee, Loftus, McCrone and Hayward11 Participants with a major medical or neurological illness, IQ below 80, previous electroconvulsive therapy, or history of substance dependence were excluded.

A table from the Dutch National Health Service 12 was used to calculate the cumulative dosage of antipsychotics during the 5-year scan interval and to derive haloperidol equivalents (HAL equiv.). During the scan interval, six patients were exclusively on atypical antipsychotics (including clozapine) and two on typical. Two patients switched between typical and atypical antipsychotics; for one patient reliable information on medication was absent. Mean cumulative antipsychotic medication during the scan interval was 14 345.4 HAL equiv. (s.d. = 7984). None of 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 on a Philips NT (Best, The Netherlands) scanner operating at 1.5 T for all participants. A 3D fast field echo and a T 2-weighted dual echo–turbo spin echo were acquired. Protocol details and the imaging process are described elsewhere. Reference Hulshoff Pol, Schnack, Bertens, van Haren, van der Tweel, Staal, Baaré and Kahn7 Volumes of intracranium, whole brain, cerebral grey and white matter, lateral and third ventricular volumes, and cerebellum were measured.

Mixed model analysis was implemented using Structural Equation Modeling 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 familial background (patients and siblings v. controls). Relatedness in the sibling-pairs was accounted for in the covariance structure by allowing dependencies between the residuals in the regression analyses. Effects of disease and familial background were tested by comparing the likelihoods of nested models (–2 log-likelihood), which is chi-squared distributed; χ2>3.84 (1 d.f.) indicates a significant difference at α=0.05, and depicts that the discarded effect (e.g. disease effect) cannot be left out of the model without seriously reducing the goodness of fit. Using the full model, estimates (including 95% CIs) were obtained that indicated an increase or decrease of the dependent variable (brain volume change) in patients or in siblings.

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 cerebral grey 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 cerebral white matter volume (+5.3 ml) than siblings (+12.9 ml) or controls (+12.5 ml). Changes in grey and white matter volumes do not add up to changes in total brain volume, because grey/white matter was limited to the cerebrum (i.e. whole brain excluding cerebellum and brain-stem).

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

Brain volumes at baseline, ml: mean (s.d.) Percentage change per year per group, mean (s.d.) Disease effects, % change/year Familial effects, % change/year
Brain area Patients Siblings Controls Patients Siblings Controls Estimates (95% CI) χ2 Estimates (95% CI) χ2
Whole brain 1226.0 1267.9 1264.8 –0.20 0.15 –0.04 –0.33 5.18 * 0.17 1.17
(154.4) (115.1) (109.7) (0.38) (0.40) (0.41) (–0.61 to −0.06) (–0.15 to 0.49)
Cerebral grey matter b 599.8 640.7 636.5 –0.84 –0.18 –0.54 –0.70 3.97 * 0.40 1.39
(78.5) (71.0) (65.1) (1.09) (1.00) (0.65) (–1.35 to −0.02) (–0.29 to 1.11)
Cerebral white matter b 468.7 473.9 474.8 0.30 0.51 0.59 –0.36 3.89 * –0.03 0.02
(79.7) (51.2) (56.0) (1.19) (0.69) (0.90) (–2.54 to −0.00) (–0.50 to 0.44)
Cerebellum 144.2 140.5 140 0.28 0.52 0.19 –0.23 1.34 0.33 2.63
(19.9) (14.6) (10.9) (0.37) (0.54) (0.55) (–0.63 to 0.17) (–0.08 to 0.73)
Lateral ventricles 29.15 14.33 15.57 2.32 1.13 1.80 0.75 0.32 –0.80 3.09
(22.50) (5.73) (7.68) (3.38) (1.67) (2.16) (–2.18 to 3.23) (–1.68 to 0.09)
Third ventricles 1.65 1.15 0.89 2.70 –0.29 0.86 2.56 0.64 –1.38 0.91
(1.13) (0.62) (0.41) (4.35) (5.01) (5.73) (–2.61 to 7.14) (–4.56 to 1.87)

a. Sample: patients with schizophrenia (n=11), siblings (n=11) and healthy controls (n=33). The estimates are corrected for intracranial volume, age and gender. A significant estimate indicates an increase (positive estimate) or decrease (negative estimate) of the dependent variable in patients or in siblings compared with controls

b. Grey matter and white matter volumes of two patients were missing

* Significant differences at χ2>3.84; P<0.05

No associations were found between clinical variables and brain volume changes, except that a larger dose of atypical medication (including clozapine) during the scan interval was positively correlated with less progressive decrease in cerebral grey matter 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 changes over time.

Discussion

The progressive decreases over time in whole brain and cerebral grey matter volume and less prominent increases in white matter observed in schizophrenia patients but not in siblings may represent a (disease-related) non-genetic risk factor for the disease. Our finding of progressive decrease over time is consistent with those of other longitudinal studies in schizophrenia. Reference van Haren, Hulshoff Pol, Schnack, Cahn, Brans, Carati, Rais and Kahn4,Reference Pantelis, Yücel, Wood, Velakoulis, Sun, Berger, Stuart, Yung, Phillips and McGorry5 The findings in siblings are consistent with the normalisation of cortical thickness by the age of 20 in siblings of patients with childhood-onset schizophrenia. Reference Gogtay, Greenstein, Lenane, Clasen, Sharp, Gochman, Butler, Evans and Rapoport13

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

This study has several limitations. First, the number of participants was small and genetic factors involved in progressive brain changes in schizophrenia may not have been elucidated owing to a limited statistical power. Second, it is likely that at least some of the disease alleles of schizophrenia-related genes are not present in this sample of healthy siblings of patients. Our findings have to be considered preliminary and more final conclusions await follow-up studies in monozygotic and dizygotic twin-pairs discordant for schizophrenia that are currently underway.

Acknowledgements

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

Footnotes

Declaration of interest

None. Funding detailed in Acknowledgements.

References

1 Wright, IC, Rabe-Hesketh, S, Woodruff, PW, David, AS, Murray, RM, Bullmore, ET. Meta-analysis of regional brain volumes in schizophrenia. Am J Psychiatry 2000; 157: 1625.CrossRefGoogle Scholar
2 Boos, HB, Aleman, A, Cahn, W, Hulshoff Pol, HE, Kahn, RS. Brain volumes in relatives of patients with schizophrenia: a meta-analysis. Arch Gen Psychiatry 2007; 64: 297304.CrossRefGoogle ScholarPubMed
3 Hulshoff Pol, HE, Brans, RGH, van Haren, NEM, Schnack, HG, Langen, M, Baaré, WF, van Oel, CJ, Kahn, RS. Gray and white matter volume abnormalities in monozygotic and same-gender dizygotic twins discordant for schizophrenia. Biol Psychiatry 2004; 55: 126–30.CrossRefGoogle Scholar
4 van Haren, NEM, Hulshoff Pol, HE, Schnack, HG, Cahn, W, Brans, RGH, Carati, I, Rais, M, Kahn, RS. Progressive brain volume loss in schizophrenia over the course of the illness: evidence of maturational abnormalities in early adulthood. Biol Psychiatry 2008; 26: 106–13.Google Scholar
5 Pantelis, C, Yücel, M, Wood, SJ, Velakoulis, D, Sun, D, Berger, G, Stuart, GW, Yung, A, Phillips, L, McGorry, PD. Structural brain imaging evidence for multiple pathological processes at different stages of brain development in schizophrenia. Schizophr Bull 2005; 31: 672–96.CrossRefGoogle Scholar
6 Staal, WG, Hulshoff Pol, HE, Schnack, HG, Hoogendoorn, ML, Jellema, K, Kahn, RS. Structural brain abnormalities in patients with schizophrenia and their healthy siblings. Am J Psychiatry 2000; 157: 416–21.CrossRefGoogle ScholarPubMed
7 Hulshoff Pol, HE, Schnack, HG, Bertens, MG, van Haren, NEM, van der Tweel, I, Staal, WG, Baaré, WF, Kahn, RS. Volume changes in gray matter in patients with schizophrenia. Am J Psychiatry 2002; 159: 244–50.CrossRefGoogle ScholarPubMed
8 Andreasen, NC, Flaum, M, Arndt, S. The Comprehensive Assessment of Symptoms and History (CASH). An instrument for assessing diagnosis and psychopathology. Arch Gen Psychiatry 1992; 49: 615–23.CrossRefGoogle ScholarPubMed
9 Hall, RC. Global assessment of functioning. A modified scale. Psychosomatics 1995; 36: 267–75.Google ScholarPubMed
10 Kay, SR, Fiszbein, A, Opler, LA. (1987) The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13: 261–7.CrossRefGoogle Scholar
11 Phelan, M, Slade, M, Thornicroft, G, Dunn, G, Holloway, F, Wykes, T, Strathdee, G, Loftus, L, McCrone, P, Hayward, P. The Camberwell Assessment of Need: the validity and reliability of an instrument to assess the needs of people with severe mental illness. Br J Psychiatry 1995; 167: 589–95.CrossRefGoogle ScholarPubMed
12 Commissie Farmaceutische Hulp van het College voor Zorgverzekeringen Farmacotherapeutisch Kompas [in Dutch]. Amstelveen, The Netherlands, 2002.Google Scholar
13 Gogtay, N, Greenstein, D, Lenane, M, Clasen, L, Sharp, W, Gochman, P, Butler, P, Evans, A, Rapoport, J. Cortical brain development in nonpsychotic siblings of patients with childhood-onset schizophrenia. Arch Gen Psychiatry 2007; 64: 772–80.CrossRefGoogle ScholarPubMed
Figure 0

Table 1 Disease and familial effects of schizophrenia on changes in brain volumesa

Submit a response

eLetters

No eLetters have been published for this article.
You have Access
31
Cited by

Save article to Kindle

To save this article to your Kindle, first ensure coreplatform@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Longitudinal MRI study in schizophrenia patients and their healthy siblings
Available formats
×

Save article to Dropbox

To save this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you used this feature, you will be asked to authorise Cambridge Core to connect with your Dropbox account. Find out more about saving content to Dropbox.

Longitudinal MRI study in schizophrenia patients and their healthy siblings
Available formats
×

Save article to Google Drive

To save this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you used this feature, you will be asked to authorise Cambridge Core to connect with your Google Drive account. Find out more about saving content to Google Drive.

Longitudinal MRI study in schizophrenia patients and their healthy siblings
Available formats
×
×

Reply to: Submit a response

Please enter your response.

Your details

Please enter a valid email address.

Conflicting interests

Do you have any conflicting interests? *