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Relationships between white matter metabolite abnormalities, cognitive and social functioning in elderly schizophrenic subjects
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Schizophrenia Research 100 (2008) 356 – 358 www.elsevier.com/locate/schres
Letter to the Editors Relationships between white matter metabolite abnormalities, cognitive and social functioning in elderly schizophrenic subjects Dear Editors, White matter brain regions have demonstrated significant pathophysiologic changes in patients with schizophrenia. Proton magnetic resonance spectroscopy (1H-MRS) has demonstrated metabolite abnormalities in white matter regions while diffusion tensor imaging indicated reduced axonal fiber coherence (Tang et al., 2007). However, only two 1H-MRS studies have correlated white matter metabolite concentrations with clinical variables, including one with total BPRS scores (Auer et al., 2001) and one with positive and general psychopathology severity and social functioning (Sigmundsson et al., 2003). The most profound pathological changes in white matter are observed in elderly schizophrenic patients (Hof et al., 2003), a group in whom some report progressive cognitive and functional deterioration (Friedman et al., 2001). Therefore, we evaluated a group of geriatric schizophrenic patients using localized 1H-MRS on a 4 T MR system, in whom we have found lower neuronal marker N-acetyl compounds (NA), lower glial marker myo-inositol (MI) and higher glutamate + glutamine (GLX) concentrations in several white matter brain regions compared with elderly healthy subjects (Chang et al., 2007). The current report extends these MRS findings by evaluating the relationships between these metabolite abnormalities and clinical symptoms, cognitive and functional status, in the same group of schizophrenic patients. Methods: Twenty-three elderly (N 60 years) subjects with a DSM-IV diagnosis of schizophrenia, based on the Comprehensive Assessment of Symptoms and History (CASH) were studied in addition to 17 healthy comparison subjects. Subjects were carefully evaluated to ensure they fulfilled study criteria (Chang et al., 2007). The severity of psychotic and negative symptoms was assessed using the Positive and Negative Syndrome 0920-9964/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2007.10.006
Scale (PANSS; Kay, 1991), and their cognitive functions were evaluated in several key domains, including global functioning (Mini-Mental State examination), attention, concentration and working memory (digit span forward and backwards, letter number sequencing, Trail making test A & B), episodic and procedural memory (Rey-auditory verbal learning test), and executive function (Trail making B & verbal fluency). Functional abilities were measured with the Specific Level of Function scale (SLOF; Schneider and Streuening, 1983) which is an instrument used to assess living skills and behavior problems. Metabolite concentrations were measured in five white matter regions (right and left dorsal lateral prefrontal white matter, right and left medial temporal lobe white matter, and right or left occipital white matter) on a 4 T Varian MR system, and quantified using LC Model with a correction for CSF partial volume. Metabolite concentrations that were found to be abnormal (NAA, MI and Glx) were correlated with symptom severity, cognitive performance and functional capacity of these subjects. Results: The two subject groups had similar gender proportion and ethnicity; however, the schizophrenic subjects were less educated (11.9 ± 1.89 vs. 15.8 ± 3.47 years, t = 4.48, p b .001) and tended to be younger (66 ± 7.24 vs. 70.2 ± 5.81 years, t = 1.9, p = .07). Moreover, the schizophrenic subjects performed worse in every cognitive domain (all p b .05) and all functional domains on the SLOF (personal care skills, p = .006; interpersonal relationship, p = .001; social acceptability, p = .03; activities, p b .001) except work skills (p = .17). The schizophrenic subjects demonstrated moderate positive (16.5 ± 5.9), negative (20 ± 5.5) and general (39 ± 23.8) psychopathology symptoms. The PANSS negative symptom scores also inversely correlated with right and left prefrontal white matter Glx concentrations (Table 1). Furthermore, time to complete the Trails B task (executive function) correlated with Glx concentrations in left and right temporal and left prefrontal white matter (Table 1). Finally, there was a significant correlation between total score on the “Activities”
Letter to the Editors
357
Table 1 Correlations between cerebral white matter metabolites and clinical measures Metabolite
Right prefrontal Glx Left prefrontal Glx Right temporal Glx Left temporal Glx Right prefrontal NAA Left prefrontal NAA Right occipital NAA Left occipital MI
Clinical measure PANSS negative
Trails B time
Schiz
Schiz
HC
r = .50 p = .02 r = .70 p = .03 r = .71 p = .003
r = −.41 p = .19 r = .12 p = .84 r = −.41 p = .49
r = − .48 p = .03 r = − .53 p = .01
r = −.49 p = .03
SLOF activities
r = .40 p = .74
SLOF work skills
Schiz
HC
Schiz
HC
r = .74 p b .001 r = .47 p = .04 r = .91 p = .03 r = − .91 p = .01
NA NA NA NA
r = .63 p = .009
NA NA NA NA
r = .89 p = .02 r = − .83 p = .04
PANSS = Positive and Negative Syndrome Scale. SLOF = Specific Level of Function Scale. Schiz = Schizophrenia patients. HC = Healthy control subjects. Glx = glutamate + glutamine. NAA = N-acetyl aspartate. MI = myo-inositol.
(community living skills) subsection of the SLOF and NAA in right and left prefrontal white matter and right inferior occipital white matter. In addition, there was a significant positive correlation between SLOF “Work Skills” (vocational functioning) and NAA in right prefrontal white matter and right inferior occipital white matter. In the healthy comparison subjects, regional brain metabolites or cognitive performance did not correlate with SLOF scores, probably due to a lack of variance in SLOF scores. Discussion: To our knowledge, this is the first study to demonstrate correlations between symptom, cognitive and functional variables and brain metabolite concentrations in schizophrenic patients. The results of this study suggest that higher levels of glutamate + glutamine in the white matter of older schizophrenic patients may be associated with fewer negative symptoms but greater deficits in executive function, while lower axonal integrity/number (NAA concentration) may lead to impairments in functional capacity (community living and working skills) of elderly schizophrenic patients. These findings are consistent with more contemporary complex views of co-existing hypo- and hyper-glutamatergic states in the schizophrenic brain. Indeed, results of clinical trials conducted with NMDA receptor agonists indicate some dissociation between negative symptoms and cognitive response to these treatments (Javitt et al., 2001; Heresco-Levy et al., 2002). Future clinical trials coupled with serial MRS measurements could determine if improved functional capacity and cognitive functioning are
associated with changes in NAA and Glx concentrations in white matter.
References Auer, D.P., Wilke, M., Grabner, A., Heidenreich, J.O., Bronisch, T., Wetter, T.C., 2001. Reduced NAA in the thalamus and altered membrane and glial metabolism in schizophrenic patients detected by 1H-MRS and tissue segmentation. Schizophr. Res. 52 (1–2), 87–99. Chang, L., Friedman, J., Ernst, T., Zhong, K., Tsopelas, N.D., Davis, K., 2007. Brain metabolite abnormalities in the white matter of elderly schizophrenic subjects: implication for glial dysfunction. Biol. Psychiatry [Aug 10; Epub ahead of print]. Friedman, J.I., Harvey, P.D., Coleman, T., Moriarty, P.J., Bowie, C., Parrella, M., White, L., Adler, D., Davis, K.L., 2001. Six-year follow-up study of cognitive and functional status across the lifespan in schizophrenia: a comparison with Alzheimer's disease and normal aging. Am. J. Psychiatry 158, 1441–1448. Kay, S.R., 1991. Positive and Negative Syndromes in Schizophrenia. Brunner/Mazel, New York. Heresco-Levy, U., Ermilov, M., Shimoni, J., Shapira, B., Silipo, G., Javitt, D.C., 2002. Placebo-controlled trial of D-cycloserine added to conventional neuroleptics, olanzapine, or risperidone in schizophrenia. Am. J. Psychiatry 159 (3), 480–482. Hof, P.R., Haroutunian, V., Friedrich Jr., V.L., Byne, W., Buitron, C., Perl, D.P., Davis, K.L., 2003. Loss and altered spatial distribution of oligodendrocytes in the superior frontal gyrus in schizophrenia. Biol. Psychiatry 53 (12), 1075–1085. Javitt, D.C., Silipo, G., Cienfuegos, A., Shelley, A.M., Bark, N., Park, M., Lindenmayer, J.P., Suckow, R., Zukin, S.R., 2001. Adjunctive high-dose glycine in the treatment of schizophrenia. Int. J. Neuropsychopharmacol 4 (4), 385–391. Schneider, L.C., Streuening, E.L., 1983. SLOF: a behavioral rating scale for assessing the mentally ill. Soc. Work Res. Abstr. 6, 9–21.
358
Letter to the Editors
Sigmundsson, T., Maier, M., Toone, B.K., Williams, S.C., Simmons, A., Greenwood, K., Ron, M.A., 2003. Frontal lobe N-acetylaspartate correlates with psychopathology in schizophrenia: a proton magnetic resonance spectroscopy study. Schizophr. Res. 64 (1), 63–71. Tang, C.Y., Friedman, J., Shungu, D., Chang, L., Ernst, T., Stewart, D., Hajianpour, A., Carpenter, D., Ng, J., Mao, X., Hof, P.R., Buchsbaum, M.S., Davis, K., Gorman, J.M., 2007. Correlations between Diffusion Tensor Imaging (DTI) and Magnetic Resonance Spectroscopy (1H MRS) in schizophrenic patients and normal controls. BMC Psychiatry 7, 25 [Jun 19].
Joseph I. Friedman* Kenneth L. Davis Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, United States ⁎Corresponding author. Tel.: +1 808 586 7467; fax: +1 808 586 8613. Joseph I. Friedman Pilgrim Psychiatric Center, Brentwood, NY, United States
Linda Chang Thomas Ernst Department of Medicine, John A. Burns School of Medicine, University of Hawaii, The Queen's Medical Center, Honolulu, HI, United States E-mail address: [email protected] (L. Chang). Nicholas D. Tsopelas Department of Psychiatry, University of Pittsburgh Medical Center, Pittsburgh, PA, United States Kai Zhong Department of Radiology and Medical Physics, University of Magdeburg, Magdeburg, Germany 10 May 2007
Schizophrenia Research 100 (2008) 356 – 358 www.elsevier.com/locate/schres
Letter to the Editors Relationships between white matter metabolite abnormalities, cognitive and social functioning in elderly schizophrenic subjects Dear Editors, White matter brain regions have demonstrated significant pathophysiologic changes in patients with schizophrenia. Proton magnetic resonance spectroscopy (1H-MRS) has demonstrated metabolite abnormalities in white matter regions while diffusion tensor imaging indicated reduced axonal fiber coherence (Tang et al., 2007). However, only two 1H-MRS studies have correlated white matter metabolite concentrations with clinical variables, including one with total BPRS scores (Auer et al., 2001) and one with positive and general psychopathology severity and social functioning (Sigmundsson et al., 2003). The most profound pathological changes in white matter are observed in elderly schizophrenic patients (Hof et al., 2003), a group in whom some report progressive cognitive and functional deterioration (Friedman et al., 2001). Therefore, we evaluated a group of geriatric schizophrenic patients using localized 1H-MRS on a 4 T MR system, in whom we have found lower neuronal marker N-acetyl compounds (NA), lower glial marker myo-inositol (MI) and higher glutamate + glutamine (GLX) concentrations in several white matter brain regions compared with elderly healthy subjects (Chang et al., 2007). The current report extends these MRS findings by evaluating the relationships between these metabolite abnormalities and clinical symptoms, cognitive and functional status, in the same group of schizophrenic patients. Methods: Twenty-three elderly (N 60 years) subjects with a DSM-IV diagnosis of schizophrenia, based on the Comprehensive Assessment of Symptoms and History (CASH) were studied in addition to 17 healthy comparison subjects. Subjects were carefully evaluated to ensure they fulfilled study criteria (Chang et al., 2007). The severity of psychotic and negative symptoms was assessed using the Positive and Negative Syndrome 0920-9964/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2007.10.006
Scale (PANSS; Kay, 1991), and their cognitive functions were evaluated in several key domains, including global functioning (Mini-Mental State examination), attention, concentration and working memory (digit span forward and backwards, letter number sequencing, Trail making test A & B), episodic and procedural memory (Rey-auditory verbal learning test), and executive function (Trail making B & verbal fluency). Functional abilities were measured with the Specific Level of Function scale (SLOF; Schneider and Streuening, 1983) which is an instrument used to assess living skills and behavior problems. Metabolite concentrations were measured in five white matter regions (right and left dorsal lateral prefrontal white matter, right and left medial temporal lobe white matter, and right or left occipital white matter) on a 4 T Varian MR system, and quantified using LC Model with a correction for CSF partial volume. Metabolite concentrations that were found to be abnormal (NAA, MI and Glx) were correlated with symptom severity, cognitive performance and functional capacity of these subjects. Results: The two subject groups had similar gender proportion and ethnicity; however, the schizophrenic subjects were less educated (11.9 ± 1.89 vs. 15.8 ± 3.47 years, t = 4.48, p b .001) and tended to be younger (66 ± 7.24 vs. 70.2 ± 5.81 years, t = 1.9, p = .07). Moreover, the schizophrenic subjects performed worse in every cognitive domain (all p b .05) and all functional domains on the SLOF (personal care skills, p = .006; interpersonal relationship, p = .001; social acceptability, p = .03; activities, p b .001) except work skills (p = .17). The schizophrenic subjects demonstrated moderate positive (16.5 ± 5.9), negative (20 ± 5.5) and general (39 ± 23.8) psychopathology symptoms. The PANSS negative symptom scores also inversely correlated with right and left prefrontal white matter Glx concentrations (Table 1). Furthermore, time to complete the Trails B task (executive function) correlated with Glx concentrations in left and right temporal and left prefrontal white matter (Table 1). Finally, there was a significant correlation between total score on the “Activities”
Letter to the Editors
357
Table 1 Correlations between cerebral white matter metabolites and clinical measures Metabolite
Right prefrontal Glx Left prefrontal Glx Right temporal Glx Left temporal Glx Right prefrontal NAA Left prefrontal NAA Right occipital NAA Left occipital MI
Clinical measure PANSS negative
Trails B time
Schiz
Schiz
HC
r = .50 p = .02 r = .70 p = .03 r = .71 p = .003
r = −.41 p = .19 r = .12 p = .84 r = −.41 p = .49
r = − .48 p = .03 r = − .53 p = .01
r = −.49 p = .03
SLOF activities
r = .40 p = .74
SLOF work skills
Schiz
HC
Schiz
HC
r = .74 p b .001 r = .47 p = .04 r = .91 p = .03 r = − .91 p = .01
NA NA NA NA
r = .63 p = .009
NA NA NA NA
r = .89 p = .02 r = − .83 p = .04
PANSS = Positive and Negative Syndrome Scale. SLOF = Specific Level of Function Scale. Schiz = Schizophrenia patients. HC = Healthy control subjects. Glx = glutamate + glutamine. NAA = N-acetyl aspartate. MI = myo-inositol.
(community living skills) subsection of the SLOF and NAA in right and left prefrontal white matter and right inferior occipital white matter. In addition, there was a significant positive correlation between SLOF “Work Skills” (vocational functioning) and NAA in right prefrontal white matter and right inferior occipital white matter. In the healthy comparison subjects, regional brain metabolites or cognitive performance did not correlate with SLOF scores, probably due to a lack of variance in SLOF scores. Discussion: To our knowledge, this is the first study to demonstrate correlations between symptom, cognitive and functional variables and brain metabolite concentrations in schizophrenic patients. The results of this study suggest that higher levels of glutamate + glutamine in the white matter of older schizophrenic patients may be associated with fewer negative symptoms but greater deficits in executive function, while lower axonal integrity/number (NAA concentration) may lead to impairments in functional capacity (community living and working skills) of elderly schizophrenic patients. These findings are consistent with more contemporary complex views of co-existing hypo- and hyper-glutamatergic states in the schizophrenic brain. Indeed, results of clinical trials conducted with NMDA receptor agonists indicate some dissociation between negative symptoms and cognitive response to these treatments (Javitt et al., 2001; Heresco-Levy et al., 2002). Future clinical trials coupled with serial MRS measurements could determine if improved functional capacity and cognitive functioning are
associated with changes in NAA and Glx concentrations in white matter.
References Auer, D.P., Wilke, M., Grabner, A., Heidenreich, J.O., Bronisch, T., Wetter, T.C., 2001. Reduced NAA in the thalamus and altered membrane and glial metabolism in schizophrenic patients detected by 1H-MRS and tissue segmentation. Schizophr. Res. 52 (1–2), 87–99. Chang, L., Friedman, J., Ernst, T., Zhong, K., Tsopelas, N.D., Davis, K., 2007. Brain metabolite abnormalities in the white matter of elderly schizophrenic subjects: implication for glial dysfunction. Biol. Psychiatry [Aug 10; Epub ahead of print]. Friedman, J.I., Harvey, P.D., Coleman, T., Moriarty, P.J., Bowie, C., Parrella, M., White, L., Adler, D., Davis, K.L., 2001. Six-year follow-up study of cognitive and functional status across the lifespan in schizophrenia: a comparison with Alzheimer's disease and normal aging. Am. J. Psychiatry 158, 1441–1448. Kay, S.R., 1991. Positive and Negative Syndromes in Schizophrenia. Brunner/Mazel, New York. Heresco-Levy, U., Ermilov, M., Shimoni, J., Shapira, B., Silipo, G., Javitt, D.C., 2002. Placebo-controlled trial of D-cycloserine added to conventional neuroleptics, olanzapine, or risperidone in schizophrenia. Am. J. Psychiatry 159 (3), 480–482. Hof, P.R., Haroutunian, V., Friedrich Jr., V.L., Byne, W., Buitron, C., Perl, D.P., Davis, K.L., 2003. Loss and altered spatial distribution of oligodendrocytes in the superior frontal gyrus in schizophrenia. Biol. Psychiatry 53 (12), 1075–1085. Javitt, D.C., Silipo, G., Cienfuegos, A., Shelley, A.M., Bark, N., Park, M., Lindenmayer, J.P., Suckow, R., Zukin, S.R., 2001. Adjunctive high-dose glycine in the treatment of schizophrenia. Int. J. Neuropsychopharmacol 4 (4), 385–391. Schneider, L.C., Streuening, E.L., 1983. SLOF: a behavioral rating scale for assessing the mentally ill. Soc. Work Res. Abstr. 6, 9–21.
358
Letter to the Editors
Sigmundsson, T., Maier, M., Toone, B.K., Williams, S.C., Simmons, A., Greenwood, K., Ron, M.A., 2003. Frontal lobe N-acetylaspartate correlates with psychopathology in schizophrenia: a proton magnetic resonance spectroscopy study. Schizophr. Res. 64 (1), 63–71. Tang, C.Y., Friedman, J., Shungu, D., Chang, L., Ernst, T., Stewart, D., Hajianpour, A., Carpenter, D., Ng, J., Mao, X., Hof, P.R., Buchsbaum, M.S., Davis, K., Gorman, J.M., 2007. Correlations between Diffusion Tensor Imaging (DTI) and Magnetic Resonance Spectroscopy (1H MRS) in schizophrenic patients and normal controls. BMC Psychiatry 7, 25 [Jun 19].
Joseph I. Friedman* Kenneth L. Davis Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, United States ⁎Corresponding author. Tel.: +1 808 586 7467; fax: +1 808 586 8613. Joseph I. Friedman Pilgrim Psychiatric Center, Brentwood, NY, United States
Linda Chang Thomas Ernst Department of Medicine, John A. Burns School of Medicine, University of Hawaii, The Queen's Medical Center, Honolulu, HI, United States E-mail address: [email protected] (L. Chang). Nicholas D. Tsopelas Department of Psychiatry, University of Pittsburgh Medical Center, Pittsburgh, PA, United States Kai Zhong Department of Radiology and Medical Physics, University of Magdeburg, Magdeburg, Germany 10 May 2007