Original Paper Neuropsychobiology 2014;69:202–209 DOI: 10.1159/000358840
Received: August 8, 2013 Accepted after revision: February 25, 2014 Published online: May 23, 2014
The Effects of Aging on Changes in Regional Cerebral Blood Flow in Schizophrenia Kazunori Kawakami Rei Wake Tsuyoshi Miyaoka Motohide Furuya Kristian Liaury Jun Horiguchi Department of Psychiatry, Shimane University Faculty of Medicine, Izumo, Japan
Key Words Schizophrenia · 99mTc-ethyl cysteinate dimer single-photon emission computed tomography · Aging · Cerebral blood flow · Temporal lobe
Abstract Aims: Although there have been no conclusive pathophysiological findings in support of the degeneration theory in the etiology of schizophrenia to date, results of our neuroimaging studies suggest functional changes in the brains of schizophrenics. We evaluated age-related changes of brain perfusion in medicated patients with schizophrenia. Method: In this study, we evaluated age-related changes in brain perfusion in medicated schizophrenia patients (n = 44) and control subjects (n = 37) undergoing 99mTc-ethyl cysteinate dimer single-photon emission computed tomography. Result: Although the regional cerebral blood flow (rCBF) was found to be reduced in bilateral frontal lobes by analysis with age in the patients with schizophrenia, significant differences compared to controls in age effects on perfusion were found in the patients with schizophrenia in bilateral temporal lobes. Moreover, in multiple regression analysis including age, total time of treatment and overall neuroleptic dose, rCBF was found to be reduced in bilateral frontal and parietal
© 2014 S. Karger AG, Basel 0302–282X/14/0694–0202$39.50/0 E-Mail [email protected] www.karger.com/nps
lobes. As a result, cerebral perfusion in temporal lobes with schizophrenia might be related to age rather than medication. Conclusion: In this study, the patients with schizophrenia appeared to have significant bilateral temporal hypoperfusion related to age compared with controls. And bilateral temporal rCBF is decreased in patients with schizophrenia and even more in older schizophrenia patients. These changes might be consistent with degenerative changes observed in patients with schizophrenia and be a promising method for the efficient development of a treatment strategy by measuring temporal perfusion in patients with schizophrenia. © 2014 S. Karger AG, Basel
Introduction
Although schizophrenia has increasingly been conceptualized as a neurodevelopmental disorder [1], there is mounting evidence on progression not only of cognitive, but also of brain structural and functional pathology [2, 3]. Even though this progression might not be related to classical neuropathological markers of neurodegeneration such as astrogliosis, it has significant relevance for our understanding of the disease course, especially with Rei Wake , MD, PhD Department of Psychiatry, Shimane University School of Medicine 89-1 Enyacho Izumo 693-8501 (Japan) E-Mail rei @ med.shimane-u.ac.jp
respect to cognitive deterioration and general clinical outcomes [4, 5]. Alterations in brain structure have been observed in patients with schizophrenia at different stages of the disorder, including prodromal, first-episode and chronic stages, and recent meta-analysis comparing the differences in the cross-sectional patterns of patients with healthy subjects suggest that there might be an increase in structural pathology over the course of the disease [6]. In addition, both structural and functional imaging studies suggest changes at later disease stages that are suggestive of accelerated aging compared with healthy individuals [2]. Thus, the present cross-sectional imaging studies of schizophrenia patients as well as the longitudinal MRI studies with follow-up periods of up to 10 years are suggestive of progressive changes exceeding those seen in healthy subjects [7]. These changes seem to occur at different stages of the disease, including the transition to psychosis, the early course of schizophrenia and the senescence process. In a previous study [8], we revealed that the schizophrenia patients had hypoperfusion of the bilateral temporal lobes and the right frontal lobe compared to control subjects. Moreover, we evaluated age-related changes of brain perfusion in medicated patients with schizophrenia. In this study, we focused on cerebral blood flow and compared age-related changes in patients with schizophrenia with those in healthy controls. Methods Subjects Schizophrenia patients (n = 44) were diagnosed according to DSM-IV criteria [9]. Subjects were outpatients or inpatients of the Department of Psychiatry, Shimane University School of Medicine Hospital, without acute psychiatric symptoms. Psychiatric symptoms were rated on the same day as the single-photon emission computed tomography (SPECT) examination by a senior psychiatrist (T.M.) who was unaware of the SPECT findings and diagnosis using the Brief Psychiatric Rating Scale [10] and the Positive and Negative Syndrome Scale [11]. Diagnoses were determined by the consensus of 3 senior psychiatrists (J.H., T.M. and R.W.) based on extended interviews and reviews of the Structured Clinical Interviews for DSM-IV (SCID) in the medical chart. Patients with alcohol and substance abuse or dependence (other than nicotine) or the presence of a severe organic condition were eliminated from this study. Forty patients were taking second-generation antipsychotics (risperidone, n = 14; olanzapine, n = 10; quetiapine, n = 8; aripiprazole, n = 5; blonanserin, n = 3). Patients were matched for age and sex with healthy controls (n = 37; table 1). None of the control subjects had any history of psychiatric disorders as based on the SCID nonpatient edition, organic disease (diabetes mellitus, hypertension, hyperlipidemia, cerebral infarction or cerebral hem-
Aging Effects of rCBF in Schizophrenia
Table 1. Patient and control data
Subjects, n Men:women Age, years Smokers, n Subtype Paranoid Hebephrenic Catatonic BPRS PANSS Duration of illness, years Duration of neuroleptic therapy, years Users of atypical drugs, n Dose of neurolepticsa, mg/day
Schizophrenia
Controls
44 24:20 40.0 ± 10.5 28
37 22:15 37.5 ± 6.3 7
18 20 6 40.0 ± 6.2 42.3 ± 11.3 5.3 ± 3.5 4.5 ± 3.0 40 319.82 ± 2.1
p value
n.s. n.s.
Received: August 8, 2013 Accepted after revision: February 25, 2014 Published online: May 23, 2014
The Effects of Aging on Changes in Regional Cerebral Blood Flow in Schizophrenia Kazunori Kawakami Rei Wake Tsuyoshi Miyaoka Motohide Furuya Kristian Liaury Jun Horiguchi Department of Psychiatry, Shimane University Faculty of Medicine, Izumo, Japan
Key Words Schizophrenia · 99mTc-ethyl cysteinate dimer single-photon emission computed tomography · Aging · Cerebral blood flow · Temporal lobe
Abstract Aims: Although there have been no conclusive pathophysiological findings in support of the degeneration theory in the etiology of schizophrenia to date, results of our neuroimaging studies suggest functional changes in the brains of schizophrenics. We evaluated age-related changes of brain perfusion in medicated patients with schizophrenia. Method: In this study, we evaluated age-related changes in brain perfusion in medicated schizophrenia patients (n = 44) and control subjects (n = 37) undergoing 99mTc-ethyl cysteinate dimer single-photon emission computed tomography. Result: Although the regional cerebral blood flow (rCBF) was found to be reduced in bilateral frontal lobes by analysis with age in the patients with schizophrenia, significant differences compared to controls in age effects on perfusion were found in the patients with schizophrenia in bilateral temporal lobes. Moreover, in multiple regression analysis including age, total time of treatment and overall neuroleptic dose, rCBF was found to be reduced in bilateral frontal and parietal
© 2014 S. Karger AG, Basel 0302–282X/14/0694–0202$39.50/0 E-Mail [email protected] www.karger.com/nps
lobes. As a result, cerebral perfusion in temporal lobes with schizophrenia might be related to age rather than medication. Conclusion: In this study, the patients with schizophrenia appeared to have significant bilateral temporal hypoperfusion related to age compared with controls. And bilateral temporal rCBF is decreased in patients with schizophrenia and even more in older schizophrenia patients. These changes might be consistent with degenerative changes observed in patients with schizophrenia and be a promising method for the efficient development of a treatment strategy by measuring temporal perfusion in patients with schizophrenia. © 2014 S. Karger AG, Basel
Introduction
Although schizophrenia has increasingly been conceptualized as a neurodevelopmental disorder [1], there is mounting evidence on progression not only of cognitive, but also of brain structural and functional pathology [2, 3]. Even though this progression might not be related to classical neuropathological markers of neurodegeneration such as astrogliosis, it has significant relevance for our understanding of the disease course, especially with Rei Wake , MD, PhD Department of Psychiatry, Shimane University School of Medicine 89-1 Enyacho Izumo 693-8501 (Japan) E-Mail rei @ med.shimane-u.ac.jp
respect to cognitive deterioration and general clinical outcomes [4, 5]. Alterations in brain structure have been observed in patients with schizophrenia at different stages of the disorder, including prodromal, first-episode and chronic stages, and recent meta-analysis comparing the differences in the cross-sectional patterns of patients with healthy subjects suggest that there might be an increase in structural pathology over the course of the disease [6]. In addition, both structural and functional imaging studies suggest changes at later disease stages that are suggestive of accelerated aging compared with healthy individuals [2]. Thus, the present cross-sectional imaging studies of schizophrenia patients as well as the longitudinal MRI studies with follow-up periods of up to 10 years are suggestive of progressive changes exceeding those seen in healthy subjects [7]. These changes seem to occur at different stages of the disease, including the transition to psychosis, the early course of schizophrenia and the senescence process. In a previous study [8], we revealed that the schizophrenia patients had hypoperfusion of the bilateral temporal lobes and the right frontal lobe compared to control subjects. Moreover, we evaluated age-related changes of brain perfusion in medicated patients with schizophrenia. In this study, we focused on cerebral blood flow and compared age-related changes in patients with schizophrenia with those in healthy controls. Methods Subjects Schizophrenia patients (n = 44) were diagnosed according to DSM-IV criteria [9]. Subjects were outpatients or inpatients of the Department of Psychiatry, Shimane University School of Medicine Hospital, without acute psychiatric symptoms. Psychiatric symptoms were rated on the same day as the single-photon emission computed tomography (SPECT) examination by a senior psychiatrist (T.M.) who was unaware of the SPECT findings and diagnosis using the Brief Psychiatric Rating Scale [10] and the Positive and Negative Syndrome Scale [11]. Diagnoses were determined by the consensus of 3 senior psychiatrists (J.H., T.M. and R.W.) based on extended interviews and reviews of the Structured Clinical Interviews for DSM-IV (SCID) in the medical chart. Patients with alcohol and substance abuse or dependence (other than nicotine) or the presence of a severe organic condition were eliminated from this study. Forty patients were taking second-generation antipsychotics (risperidone, n = 14; olanzapine, n = 10; quetiapine, n = 8; aripiprazole, n = 5; blonanserin, n = 3). Patients were matched for age and sex with healthy controls (n = 37; table 1). None of the control subjects had any history of psychiatric disorders as based on the SCID nonpatient edition, organic disease (diabetes mellitus, hypertension, hyperlipidemia, cerebral infarction or cerebral hem-
Aging Effects of rCBF in Schizophrenia
Table 1. Patient and control data
Subjects, n Men:women Age, years Smokers, n Subtype Paranoid Hebephrenic Catatonic BPRS PANSS Duration of illness, years Duration of neuroleptic therapy, years Users of atypical drugs, n Dose of neurolepticsa, mg/day
Schizophrenia
Controls
44 24:20 40.0 ± 10.5 28
37 22:15 37.5 ± 6.3 7
18 20 6 40.0 ± 6.2 42.3 ± 11.3 5.3 ± 3.5 4.5 ± 3.0 40 319.82 ± 2.1
p value
n.s. n.s.
