Background Results obtained from brain imaging studies indicate that serotonin transporter (SERT) and dopamine transporter (DAT) densities are altered in major depression. However, no such studies have been published on current mania or hypomania.
Background
Results obtained from brain imaging studies indicate that serotonin transporter (SERT) and dopamine transporter (DAT) densities are altered in major depression. However, no such studies have been published on current mania or hypomania.Case presentation In this single photon emission computed tomography (SPECT) study with [ 123 I]nor-β-CIT we present a case with simultaneous symptoms of major depression and hypomania. She had an elevated serotonin transporter availability (SERT) in the midbrain and elevated dopamine transporter availability (DAT) in the striatum, which normalised in a one-year follow-up period during which she received eight months of psychodynamic psychotherapy.
Case presentation
In this single photon emission computed tomography (SPECT) study with [ 123 I]nor-β-CIT we present a case with simultaneous symptoms of major depression and hypomania. She had an elevated serotonin transporter availability (SERT) in the midbrain and elevated dopamine transporter availability (DAT) in the striatum, which normalised in a one-year follow-up period during which she received eight months of psychodynamic psychotherapy.Conclusions To our knowledge, this is the first report on SERT and DAT associated with mania. In our case the availability of both SERT in the midbrain and DAT in the striatum were elevated at baseline and declined during psychotherapy, while the SERT and DAT of the depressed controls increased during psychotherapy. Symptoms of hypomania in the case were alleviated during psychotherapy. Clinical recovery was also reflected in the Hamilton Depression Rating Scale (HDRS) scores.
Conclusions
To our knowledge, this is the first report on SERT and DAT associated with mania. In our case the availability of both SERT in the midbrain and DAT in the striatum were elevated at baseline and declined during psychotherapy, while the SERT and DAT of the depressed controls increased during psychotherapy. Symptoms of hypomania in the case were alleviated during psychotherapy. Clinical recovery was also reflected in the Hamilton Depression Rating Scale (HDRS) scores.

Background Decreased serotonin transporter densities (SERT) have been recorded from the brains of depressed patients [ 1 , 2 ], which have also been reported to normalise during psychotherapy [ 3 , 4 ]. A few studies have also revealed altered levels of dopamine transmission in major depression [ 5 , 6 ]. However, in a search of the PubMed database we found no serotonin-specific brain imaging studies on mania or hypomania. In this paper we present a case with simultaneous symptoms of major depression and hypomania. The structural diagnostic classifications DSM-IV and ICD-10 are unable to diagnose this kind of mixed state, even though similar cases have been presented earlier in the literature [ 7 ].
Background
Decreased serotonin transporter densities (SERT) have been recorded from the brains of depressed patients [ 1 , 2 ], which have also been reported to normalise during psychotherapy [ 3 , 4 ]. A few studies have also revealed altered levels of dopamine transmission in major depression [ 5 , 6 ]. However, in a search of the PubMed database we found no serotonin-specific brain imaging studies on mania or hypomania.In this paper we present a case with simultaneous symptoms of major depression and hypomania. The structural diagnostic classifications DSM-IV and ICD-10 are unable to diagnose this kind of mixed state, even though similar cases have been presented earlier in the literature [ 7 ].Materials and methods Case The index subject was a 25-year-old female with a history of two periods of major depression according to the DSM-IV-R criteria. She had also had hypomanic periods that did not completely fulfil the criteria of mania, and at baseline she fulfilled the criteria of hypomania, moderate depression and dysthymia (296.32, 300.40). She was overactive, restless and irritated and coped with a reduced amount of sleep. She had difficulty in concentrating on one thing at a time, and she appeared very lively and talkative. She was therefore diagnosed with bipolar mood disorder type II. In other words, our index patient had a mixed mania without fulfilling the criteria of full-blown mania during the baseline scan. Controls The 6 female depressed controls were diagnosed to have severe or moderate depression (296.22, 296.23, 296.32 or 296.33). Three of them also fulfilled the criteria for dysthymia (300.40) and three had previously suffered periods of major depression. They were participants of our larger study on the effects of psychotherapy on SERT and DAT densities to be reported in full elsewhere. The group of 10 healthy controls consisted mainly of employees of Kuopio University Hospital and medical students. Depression was an exclusion criterion for the control group. Controls had previously received no psychotropic medication or other psychiatric treatment and were physically healthy. Psychiatric evaluation Psychiatric diagnosis was based on clinical assessment and verified for all study subjects by a trained independent psychiatrist using the Structured Clinical Interview for DSM-IV-R (SCID-I) [ 8 ]. The severity of depression was assessed with the 17-item Hamilton Depression Rating Scale (HDRS) [ 9 ]. Setting, therapist and therapy The depressed controls (see Table for sociodemographic characteristics) received psychotherapy for 12 months in an outpatient clinic of the Department of Psychiatry of Kuopio University Hospital. The case discontinued the therapy after eight months because she felt it was no longer useful to her. The case and the depressed controls had received no psychiatric treatment or medication prior the SPECT imaging and they were treated without medication. Psychotherapy sessions occurred twice a week, 80 sessions per year. The psychotherapists had formal postgraduate professional training in psychodynamic psychotherapy. The study design was approved by the ethics committee of Kuopio University Hospital. Table 1 Characteristics of the participants. Values of the controls are means ± SD. Case Depressed controls n = 6 Healthy controls n = 10 Age, y 25 27.2 (5.9) 26.3 (5.9) Duration of depressive episode, months 9 10.6 (6.9) - SERT availability in midbrain at baseline 1.51 1.08 (0.12) 1.28 (0.12) SERT availability in midbrain at 12 months 1.36 1.23 (0.20) - DAT availability in striatum at baseline 2.75 2.48 (0.35) 2.45 (0.25) DAT availability in striatum at 12 months 2.61 2.70 (0.45) - HDRS score at baseline 15 17.67 (3.44) - HDRS score at 12 months 5 12.66 (5.09) - Abbreviations: DAT: Dopamine transporter, HDRS: Hamilton Depression Rating Scale SD: Standard deviation, SERT: Serotonin transporter. Participants of the study were right-handed and all were female. The depressed and the healthy controls were age-matched with the case (Table). The healthy controls were not followed up. Imaging procedure SPECT imaging was performed on the Wednesday after the menstrual bleeding that preceded the psychotherapy and on 12-month follow-up. A dose of 185 MBq of [ 123 I] nor-β-CIT (supplied by MAP Medical Technologies OY, Tikkakoski Finland) was diluted in a volume of 10 ml physiological saline. The specific activity was higher than 1.8 × 10 11  Bq/μmol [ 10 ]. The dose was slowly injected into the right antecubital vein in a dimly lit and quiet room. Serial SPECT scans (5 min, 6 h and 24 h) were performed on a dedicated Siemens MultiSPECT 3 gamma camera with fan-beam collimators (Siemens Medical Systems; Hoffman Estates I11., USA) [ 11 ]. Head positioning was monitored during acquisition by using two position lasers. Data analysis The SPECT scans were decay-corrected and reconstructed with Butterworth-filtered back-projection in a 128 × 128 matrix with a pixel size of 3 × 3 mm, and were attenuation-corrected with Chang's algorithm [ 10 , 11 ]. The imaging resolution was 8–9 mm. The SPECT slices were consecutively summarised to the slice thickness of 6 mm and re-aligned using a Siemens semi-automatic brain quantification program and the Talairach coordinates [ 12 ]. The slices were rotated and re-aligned so that transaxial (x-direction), sagittal (y-direction) and coronal (z-direction) slices were at right angles to each other. Region of interest placement was based on a Siemens semi-automatic brain quantification program. The lower threshold of 60% of the maximum count was used to reduce the volume averaging and partial volume errors. Regions of interest were the cerebellum, striatum and the midbrain. It was assumed that the cerebellum (reference region) corresponds to a two-compartment model (unbound tracer in arterial blood and free plus non-specifically bound tracer in the tissue) [ 13 ]. The specific binding in ml/ml for SERT and DAT was calculated using a graphical plot [ 13 ]. The slope of this plot is equal to the distribution volume ratio: (Region - Cerebellum)/Cerebellum = V D  - 1. The striatal uptake was pooled. Functional neuroanatomy by means of SPECT was confirmed using magnetic resonance imaging (MRI) within two weeks of the SPECT imaging. If any cerebral focal abnormalities or organic brain diseases were detected by MRI scan, the patient was excluded from our study. The participants of our study thus had normal findings. Reproducibility of SPECT The reproducibility of the SPECT scan had been previously studied with eleven healthy subjects (5 males and 6 females; age range 20–39 y). SPECT studies were performed twice with a 12-month interval. The correspondence between the studies was good, with the mean difference being 0.00 ± 0.08 (SD = standard deviation) for SERT (mean and SD: 1.27 ± 0.11 and 1.27 ± 0.14, respectively) and 0.04 ± 0.18 for DAT (mean and SD: 2.49 ± 0.28 and 2.45 ± 0.27, respectively). The intraclass correlation coefficient was 0.82 (p < 0.01) and 0.79 (p < 0.01), respectively (unpublished data). Statistics The Student's t-test was used to compare the depressed controls and the healthy controls and paired samples t-test to compare SERT densities of the depressed controls at baseline and on follow-up. A p-value of less than 0.05 was considered as the criterion for statistical significance.
Materials and methods
Case The index subject was a 25-year-old female with a history of two periods of major depression according to the DSM-IV-R criteria. She had also had hypomanic periods that did not completely fulfil the criteria of mania, and at baseline she fulfilled the criteria of hypomania, moderate depression and dysthymia (296.32, 300.40). She was overactive, restless and irritated and coped with a reduced amount of sleep. She had difficulty in concentrating on one thing at a time, and she appeared very lively and talkative. She was therefore diagnosed with bipolar mood disorder type II. In other words, our index patient had a mixed mania without fulfilling the criteria of full-blown mania during the baseline scan.
Case
The index subject was a 25-year-old female with a history of two periods of major depression according to the DSM-IV-R criteria. She had also had hypomanic periods that did not completely fulfil the criteria of mania, and at baseline she fulfilled the criteria of hypomania, moderate depression and dysthymia (296.32, 300.40). She was overactive, restless and irritated and coped with a reduced amount of sleep. She had difficulty in concentrating on one thing at a time, and she appeared very lively and talkative. She was therefore diagnosed with bipolar mood disorder type II. In other words, our index patient had a mixed mania without fulfilling the criteria of full-blown mania during the baseline scan.Controls The 6 female depressed controls were diagnosed to have severe or moderate depression (296.22, 296.23, 296.32 or 296.33). Three of them also fulfilled the criteria for dysthymia (300.40) and three had previously suffered periods of major depression. They were participants of our larger study on the effects of psychotherapy on SERT and DAT densities to be reported in full elsewhere. The group of 10 healthy controls consisted mainly of employees of Kuopio University Hospital and medical students. Depression was an exclusion criterion for the control group. Controls had previously received no psychotropic medication or other psychiatric treatment and were physically healthy.
Controls
The 6 female depressed controls were diagnosed to have severe or moderate depression (296.22, 296.23, 296.32 or 296.33). Three of them also fulfilled the criteria for dysthymia (300.40) and three had previously suffered periods of major depression. They were participants of our larger study on the effects of psychotherapy on SERT and DAT densities to be reported in full elsewhere.The group of 10 healthy controls consisted mainly of employees of Kuopio University Hospital and medical students. Depression was an exclusion criterion for the control group. Controls had previously received no psychotropic medication or other psychiatric treatment and were physically healthy.Psychiatric evaluation Psychiatric diagnosis was based on clinical assessment and verified for all study subjects by a trained independent psychiatrist using the Structured Clinical Interview for DSM-IV-R (SCID-I) [ 8 ]. The severity of depression was assessed with the 17-item Hamilton Depression Rating Scale (HDRS) [ 9 ].
Psychiatric evaluation
Psychiatric diagnosis was based on clinical assessment and verified for all study subjects by a trained independent psychiatrist using the Structured Clinical Interview for DSM-IV-R (SCID-I) [ 8 ]. The severity of depression was assessed with the 17-item Hamilton Depression Rating Scale (HDRS) [ 9 ].Setting, therapist and therapy The depressed controls (see Table for sociodemographic characteristics) received psychotherapy for 12 months in an outpatient clinic of the Department of Psychiatry of Kuopio University Hospital. The case discontinued the therapy after eight months because she felt it was no longer useful to her. The case and the depressed controls had received no psychiatric treatment or medication prior the SPECT imaging and they were treated without medication. Psychotherapy sessions occurred twice a week, 80 sessions per year. The psychotherapists had formal postgraduate professional training in psychodynamic psychotherapy. The study design was approved by the ethics committee of Kuopio University Hospital. Table 1 Characteristics of the participants. Values of the controls are means ± SD. Case Depressed controls n = 6 Healthy controls n = 10 Age, y 25 27.2 (5.9) 26.3 (5.9) Duration of depressive episode, months 9 10.6 (6.9) - SERT availability in midbrain at baseline 1.51 1.08 (0.12) 1.28 (0.12) SERT availability in midbrain at 12 months 1.36 1.23 (0.20) - DAT availability in striatum at baseline 2.75 2.48 (0.35) 2.45 (0.25) DAT availability in striatum at 12 months 2.61 2.70 (0.45) - HDRS score at baseline 15 17.67 (3.44) - HDRS score at 12 months 5 12.66 (5.09) - Abbreviations: DAT: Dopamine transporter, HDRS: Hamilton Depression Rating Scale SD: Standard deviation, SERT: Serotonin transporter. Participants of the study were right-handed and all were female. The depressed and the healthy controls were age-matched with the case (Table). The healthy controls were not followed up.
Setting, therapist and therapy
The depressed controls (see Table for sociodemographic characteristics) received psychotherapy for 12 months in an outpatient clinic of the Department of Psychiatry of Kuopio University Hospital. The case discontinued the therapy after eight months because she felt it was no longer useful to her. The case and the depressed controls had received no psychiatric treatment or medication prior the SPECT imaging and they were treated without medication. Psychotherapy sessions occurred twice a week, 80 sessions per year. The psychotherapists had formal postgraduate professional training in psychodynamic psychotherapy. The study design was approved by the ethics committee of Kuopio University Hospital.Characteristics of the participants. Values of the controls are means ± SD.Abbreviations: DAT: Dopamine transporter, HDRS: Hamilton Depression Rating Scale SD: Standard deviation, SERT: Serotonin transporter.Participants of the study were right-handed and all were female. The depressed and the healthy controls were age-matched with the case (Table). The healthy controls were not followed up.Imaging procedure SPECT imaging was performed on the Wednesday after the menstrual bleeding that preceded the psychotherapy and on 12-month follow-up. A dose of 185 MBq of [ 123 I] nor-β-CIT (supplied by MAP Medical Technologies OY, Tikkakoski Finland) was diluted in a volume of 10 ml physiological saline. The specific activity was higher than 1.8 × 10 11  Bq/μmol [ 10 ]. The dose was slowly injected into the right antecubital vein in a dimly lit and quiet room. Serial SPECT scans (5 min, 6 h and 24 h) were performed on a dedicated Siemens MultiSPECT 3 gamma camera with fan-beam collimators (Siemens Medical Systems; Hoffman Estates I11., USA) [ 11 ]. Head positioning was monitored during acquisition by using two position lasers.
Imaging procedure
SPECT imaging was performed on the Wednesday after the menstrual bleeding that preceded the psychotherapy and on 12-month follow-up. A dose of 185 MBq of [ 123 I] nor-β-CIT (supplied by MAP Medical Technologies OY, Tikkakoski Finland) was diluted in a volume of 10 ml physiological saline. The specific activity was higher than 1.8 × 10 11  Bq/μmol [ 10 ]. The dose was slowly injected into the right antecubital vein in a dimly lit and quiet room. Serial SPECT scans (5 min, 6 h and 24 h) were performed on a dedicated Siemens MultiSPECT 3 gamma camera with fan-beam collimators (Siemens Medical Systems; Hoffman Estates I11., USA) [ 11 ]. Head positioning was monitored during acquisition by using two position lasers.Data analysis The SPECT scans were decay-corrected and reconstructed with Butterworth-filtered back-projection in a 128 × 128 matrix with a pixel size of 3 × 3 mm, and were attenuation-corrected with Chang's algorithm [ 10 , 11 ]. The imaging resolution was 8–9 mm. The SPECT slices were consecutively summarised to the slice thickness of 6 mm and re-aligned using a Siemens semi-automatic brain quantification program and the Talairach coordinates [ 12 ]. The slices were rotated and re-aligned so that transaxial (x-direction), sagittal (y-direction) and coronal (z-direction) slices were at right angles to each other. Region of interest placement was based on a Siemens semi-automatic brain quantification program. The lower threshold of 60% of the maximum count was used to reduce the volume averaging and partial volume errors. Regions of interest were the cerebellum, striatum and the midbrain. It was assumed that the cerebellum (reference region) corresponds to a two-compartment model (unbound tracer in arterial blood and free plus non-specifically bound tracer in the tissue) [ 13 ]. The specific binding in ml/ml for SERT and DAT was calculated using a graphical plot [ 13 ]. The slope of this plot is equal to the distribution volume ratio: (Region - Cerebellum)/Cerebellum = V D  - 1. The striatal uptake was pooled. Functional neuroanatomy by means of SPECT was confirmed using magnetic resonance imaging (MRI) within two weeks of the SPECT imaging. If any cerebral focal abnormalities or organic brain diseases were detected by MRI scan, the patient was excluded from our study. The participants of our study thus had normal findings.
Data analysis
The SPECT scans were decay-corrected and reconstructed with Butterworth-filtered back-projection in a 128 × 128 matrix with a pixel size of 3 × 3 mm, and were attenuation-corrected with Chang's algorithm [ 10 , 11 ]. The imaging resolution was 8–9 mm. The SPECT slices were consecutively summarised to the slice thickness of 6 mm and re-aligned using a Siemens semi-automatic brain quantification program and the Talairach coordinates [ 12 ]. The slices were rotated and re-aligned so that transaxial (x-direction), sagittal (y-direction) and coronal (z-direction) slices were at right angles to each other.Region of interest placement was based on a Siemens semi-automatic brain quantification program. The lower threshold of 60% of the maximum count was used to reduce the volume averaging and partial volume errors. Regions of interest were the cerebellum, striatum and the midbrain. It was assumed that the cerebellum (reference region) corresponds to a two-compartment model (unbound tracer in arterial blood and free plus non-specifically bound tracer in the tissue) [ 13 ]. The specific binding in ml/ml for SERT and DAT was calculated using a graphical plot [ 13 ]. The slope of this plot is equal to the distribution volume ratio: (Region - Cerebellum)/Cerebellum = V D  - 1. The striatal uptake was pooled.Functional neuroanatomy by means of SPECT was confirmed using magnetic resonance imaging (MRI) within two weeks of the SPECT imaging. If any cerebral focal abnormalities or organic brain diseases were detected by MRI scan, the patient was excluded from our study. The participants of our study thus had normal findings.Reproducibility of SPECT The reproducibility of the SPECT scan had been previously studied with eleven healthy subjects (5 males and 6 females; age range 20–39 y). SPECT studies were performed twice with a 12-month interval. The correspondence between the studies was good, with the mean difference being 0.00 ± 0.08 (SD = standard deviation) for SERT (mean and SD: 1.27 ± 0.11 and 1.27 ± 0.14, respectively) and 0.04 ± 0.18 for DAT (mean and SD: 2.49 ± 0.28 and 2.45 ± 0.27, respectively). The intraclass correlation coefficient was 0.82 (p < 0.01) and 0.79 (p < 0.01), respectively (unpublished data).
Reproducibility of SPECT
The reproducibility of the SPECT scan had been previously studied with eleven healthy subjects (5 males and 6 females; age range 20–39 y). SPECT studies were performed twice with a 12-month interval. The correspondence between the studies was good, with the mean difference being 0.00 ± 0.08 (SD = standard deviation) for SERT (mean and SD: 1.27 ± 0.11 and 1.27 ± 0.14, respectively) and 0.04 ± 0.18 for DAT (mean and SD: 2.49 ± 0.28 and 2.45 ± 0.27, respectively). The intraclass correlation coefficient was 0.82 (p < 0.01) and 0.79 (p < 0.01), respectively (unpublished data).Statistics The Student's t-test was used to compare the depressed controls and the healthy controls and paired samples t-test to compare SERT densities of the depressed controls at baseline and on follow-up. A p-value of less than 0.05 was considered as the criterion for statistical significance.
Statistics
The Student's t-test was used to compare the depressed controls and the healthy controls and paired samples t-test to compare SERT densities of the depressed controls at baseline and on follow-up. A p-value of less than 0.05 was considered as the criterion for statistical significance.Results The background characteristics of the case and the controls are presented in the table. The case and the depressed controls had HDRS scores of 14 or more. The midbrain SERT availability did not correlate with HDRS scores in depressive controls either at baseline or on follow-up. Neither did the change in the HDRS score correlate with changes in SERT or DAT capacities under therapy. The case had an elevated SERT availability in the midbrain at baseline, while the depressed controls had decreased levels compared to the healthy controls (t = 3.17, p < 0.01; Table and Figure  1 ). The SERT availability of the index case was two standard deviations (SD) higher than the mean SERT availability of the depressed controls and almost two SD higher than the mean SERT availability of the healthy controls. The MRI scans of the case and the controls were normal. At the twelve-month follow-up, the HDRS scores of both the case and the depressed controls had decreased. The mean decrease in HDRS scores in depressed patients during the follow-up period was 5 (SD 3.3; t = 3.7, p = 0.02). The SERT availability in the midbrain had decreased in the case by 9.9% (Fig.  2 ) and increased in the depressed controls by 12.5% (t = 3.00, p = 0.03) during the one year of psychotherapy. Figure 1 SERT densities of the healthy controls, depressed controls and of the index subject at baseline. Figure 2 Transaxial slices of [ 123 I]nor-β-CIT scans in the index subject at baseline (A and B) and after 12 months (C and D). A and C indicate midbrain SERT binding and B and D striatal DAT binding. A 10% step colour scale is shown on the right and the cerebellum was used in its normalization. DAT densities in the striatum were elevated in the case (Table, Fig.  2 .) and slightly elevated in the depressed controls at baseline compared to the healthy controls. On 12-month follow-up the DAT availability in the striatum of the case had decreased by 5.1%, while DAT densities in the depressed controls had increased by 8.8%. The increase in DAT binding was not significant (data not shown).
Results
The background characteristics of the case and the controls are presented in the table. The case and the depressed controls had HDRS scores of 14 or more.The midbrain SERT availability did not correlate with HDRS scores in depressive controls either at baseline or on follow-up. Neither did the change in the HDRS score correlate with changes in SERT or DAT capacities under therapy.The case had an elevated SERT availability in the midbrain at baseline, while the depressed controls had decreased levels compared to the healthy controls (t = 3.17, p < 0.01; Table and Figure  1 ). The SERT availability of the index case was two standard deviations (SD) higher than the mean SERT availability of the depressed controls and almost two SD higher than the mean SERT availability of the healthy controls. The MRI scans of the case and the controls were normal. At the twelve-month follow-up, the HDRS scores of both the case and the depressed controls had decreased. The mean decrease in HDRS scores in depressed patients during the follow-up period was 5 (SD 3.3; t = 3.7, p = 0.02). The SERT availability in the midbrain had decreased in the case by 9.9% (Fig.  2 ) and increased in the depressed controls by 12.5% (t = 3.00, p = 0.03) during the one year of psychotherapy.DAT densities in the striatum were elevated in the case (Table, Fig.  2 .) and slightly elevated in the depressed controls at baseline compared to the healthy controls. On 12-month follow-up the DAT availability in the striatum of the case had decreased by 5.1%, while DAT densities in the depressed controls had increased by 8.8%. The increase in DAT binding was not significant (data not shown).Discussion To our knowledge, this is the first report on SERT and DAT associated with a current mania. In our case the densities of both SERT in the midbrain and DAT in the striatum were elevated at baseline and they decreased during psychotherapy, while the SERT and DAT of the depressed controls increased during psychotherapy. Clinical recovery was also reflected in the change in the HDRS score. Furthermore, the index case had no symptoms of hypomania after the psychotherapy. Ichimiya et al. [ 14 ] found increased SERT binding of the radioligand in the thalamus in a sample of patients with either major depression (n = 7) or bipolar disorder (n = 6) compared to healthy controls (n = 21). In their study the bipolar patients were either depressed or euthymic prior to brain imaging. There were no significant differences in binding potentials in the midbrain compared to the mood-disorder patients and the healthy controls. Bipolar patients had slightly higher binding potentials in the midbrain than the healthy controls, while patients with major depression had slightly lower binding potentials than the healthy controls. However, these differences were not significant. The patients of Ichimiya and co-workers were euthymic or depressed, so we cannot compare our results with theirs. It is clinically well known that anti-depressive medication, including serotonin-selective drugs, may aggravate mania [ 15 ]. If the serotonergic functions had already been elevated in mania and had then been further enhanced by anti-depressive medication, it is reasonable that this might further increase the manic symptoms. In animal models, the administration of an amino-acid mixture lacking the cathecolamine precursors tyrosine and phenylalanine decreases the availability of plasma tyrosine to the brain, which further diminishes cathecolamine synthesis [ 16 ]. In a few clinical human studies, decreasing tyrosine availability has had a positive effect on the symptoms of acute mania [ 17 , 18 ]. Tyrosine depletion has also led to decreased dopamine functions in healthy volunteers [ 19 ]. In positron emission tomography, a tyrosine-free amino-acid mixture increased striatal binding of the dopamine receptor ligand in healthy volunteers, which may reflect lowered presynaptic dopamine release [ 20 ]. SPECT studies revealing increased amphetamine-induced dopamine release in bipolar disorder patients have also been published [ 21 ]. The above-mentioned results indicate that acute mania may be associated with elevated dopaminergic functions in the central nervous system. A decrease in the DAT availability of the striatum was associated with clinical recovery in our case, which may support this hypothesis. The DAT densities of the depressed controls were only slightly above the level of the healthy controls. Laasonen-Balk et al. [ 5 ] have previously observed a greater increase in DAT densities in depressed patients. Because of the small sample size of this study there was insufficient statistical power to draw any conclusions in this issue. Our results support previous findings that the SERT densities of depressed patients are lower than in healthy controls [ 1 , 2 , 4 ]. Previous studies on neurotransmitters in association with mania have mostly dealt with dopamine. We cannot completely rule out the bias of nor-β-cit binding to the noradrenergic transporters (NORT). The noradrenergic cell-body rich nucleus ceruleus is close to our target region. This is assumed to contain the nucleus raphe, which is mostly comprised of serotonergic cell-bodies. The dopamine cell-body rich substantia nigra is also located close to our region of interest. However, nor-β-cit is considered to be more serotonin-specific than previous radioligands [ 10 ]. Three studies have been published on the association between SERT availability and the serotonin transporter genotype. Two of these were performed on healthy subjects [ 22 , 23 ], while the third concerned abstinent alcoholics and healthy controls [ 24 ]. In the study of Van Dyck and co-workers the short homozygotes had a significantly greater SERT availability than the long-short heterozygotes, which indicates a complex relationship between the genotype and SERT availability. Furlong et al. [ 25 ] found an association between promoter allele 2 of the SERT gene and bipolar disorder. Studies combining brain imaging and data of genotype are also recommended in the evaluation of bipolar disorder. PET would be a more valid method if adequate radioligands were available [ 14 ], as PET provides absolute rather than relative values for transporter availability.
Discussion
To our knowledge, this is the first report on SERT and DAT associated with a current mania. In our case the densities of both SERT in the midbrain and DAT in the striatum were elevated at baseline and they decreased during psychotherapy, while the SERT and DAT of the depressed controls increased during psychotherapy. Clinical recovery was also reflected in the change in the HDRS score. Furthermore, the index case had no symptoms of hypomania after the psychotherapy.Ichimiya et al. [ 14 ] found increased SERT binding of the radioligand in the thalamus in a sample of patients with either major depression (n = 7) or bipolar disorder (n = 6) compared to healthy controls (n = 21). In their study the bipolar patients were either depressed or euthymic prior to brain imaging. There were no significant differences in binding potentials in the midbrain compared to the mood-disorder patients and the healthy controls. Bipolar patients had slightly higher binding potentials in the midbrain than the healthy controls, while patients with major depression had slightly lower binding potentials than the healthy controls. However, these differences were not significant. The patients of Ichimiya and co-workers were euthymic or depressed, so we cannot compare our results with theirs.It is clinically well known that anti-depressive medication, including serotonin-selective drugs, may aggravate mania [ 15 ]. If the serotonergic functions had already been elevated in mania and had then been further enhanced by anti-depressive medication, it is reasonable that this might further increase the manic symptoms.In animal models, the administration of an amino-acid mixture lacking the cathecolamine precursors tyrosine and phenylalanine decreases the availability of plasma tyrosine to the brain, which further diminishes cathecolamine synthesis [ 16 ]. In a few clinical human studies, decreasing tyrosine availability has had a positive effect on the symptoms of acute mania [ 17 , 18 ]. Tyrosine depletion has also led to decreased dopamine functions in healthy volunteers [ 19 ]. In positron emission tomography, a tyrosine-free amino-acid mixture increased striatal binding of the dopamine receptor ligand in healthy volunteers, which may reflect lowered presynaptic dopamine release [ 20 ]. SPECT studies revealing increased amphetamine-induced dopamine release in bipolar disorder patients have also been published [ 21 ]. The above-mentioned results indicate that acute mania may be associated with elevated dopaminergic functions in the central nervous system. A decrease in the DAT availability of the striatum was associated with clinical recovery in our case, which may support this hypothesis.The DAT densities of the depressed controls were only slightly above the level of the healthy controls. Laasonen-Balk et al. [ 5 ] have previously observed a greater increase in DAT densities in depressed patients. Because of the small sample size of this study there was insufficient statistical power to draw any conclusions in this issue. Our results support previous findings that the SERT densities of depressed patients are lower than in healthy controls [ 1 , 2 , 4 ]. Previous studies on neurotransmitters in association with mania have mostly dealt with dopamine.We cannot completely rule out the bias of nor-β-cit binding to the noradrenergic transporters (NORT). The noradrenergic cell-body rich nucleus ceruleus is close to our target region. This is assumed to contain the nucleus raphe, which is mostly comprised of serotonergic cell-bodies. The dopamine cell-body rich substantia nigra is also located close to our region of interest. However, nor-β-cit is considered to be more serotonin-specific than previous radioligands [ 10 ].Three studies have been published on the association between SERT availability and the serotonin transporter genotype. Two of these were performed on healthy subjects [ 22 , 23 ], while the third concerned abstinent alcoholics and healthy controls [ 24 ]. In the study of Van Dyck and co-workers the short homozygotes had a significantly greater SERT availability than the long-short heterozygotes, which indicates a complex relationship between the genotype and SERT availability. Furlong et al. [ 25 ] found an association between promoter allele 2 of the SERT gene and bipolar disorder. Studies combining brain imaging and data of genotype are also recommended in the evaluation of bipolar disorder. PET would be a more valid method if adequate radioligands were available [ 14 ], as PET provides absolute rather than relative values for transporter availability.Conclusion We have found no previous imaging studies showing that serotonin plays a role in mania. Further research is needed to determine whether our findings could be generalised to all manic states.
Conclusion
We have found no previous imaging studies showing that serotonin plays a role in mania. Further research is needed to determine whether our findings could be generalised to all manic states.Competing interests None declared.
Competing interests
None declared.Authors' contributions TT planned the study and analysed and interpreted the data. MJ also interpreted the data. PIS initiated and planned the study and organised the psychotherapy setting. HM took care of the imaging procedures. PA organised the psychotherapy setting. RV was responsible for the MRI scans and the interpretation of the scans. JK performed SPECT analyses. JT participated in the design of the study. JL initiated and planned the study project. All authors read, critically revised and approved the final manuscript.
Authors' contributions
TT planned the study and analysed and interpreted the data. MJ also interpreted the data. PIS initiated and planned the study and organised the psychotherapy setting. HM took care of the imaging procedures. PA organised the psychotherapy setting. RV was responsible for the MRI scans and the interpretation of the scans. JK performed SPECT analyses. JT participated in the design of the study. JL initiated and planned the study project. All authors read, critically revised and approved the final manuscript.Abbreviations DAT: Dopamine transporter HDRS: Hamilton Depression Rating Scale SD: Standard deviation SERT: Serotonin transporter SPECT: Single photon emission computed tomography
Abbreviations
DAT: Dopamine transporterHDRS: Hamilton Depression Rating ScaleSD: Standard deviationSERT: Serotonin transporterSPECT: Single photon emission computed tomographyPre-publication history The pre-publication history for this paper can be accessed here:
Pre-publication history
The pre-publication history for this paper can be accessed here:


The role of inflammation in Alzheimer's disease (AD) has been controversial since its first consideration. As with most instances of neuroinflammation, the possibility must be considered that activation of glia and cytokine networks in AD arises merely as a reaction to neurodegeneration. Active, healthy neurons produce signals that suppress inflammatory events, and dying neurons activate phagocytic responses in microglia at the very least. But simultaneous with the arrival of a more complex view of microglia, evidence that inflammation plays a causal or exacerbating role in AD etiology has been boosted by genetic, physiological, and epidemiological studies. In the end, it may be that the semantics of "inflammation" and glial "activation" must be regarded as too simplistic for the advancement of our understanding in this regard. It is clear that elaboration of the entire repertoire of activated microglia – a phenomenon that may be termed "malactivation" – must be prevented for healthy brain structure and function. Nevertheless, recent studies have suggested that phagocytosis of Aβ by microglia plays an important role in clearance of amyloid plaques, a process boosted by immunization paradigms. To the extent that this clearance might produce clinical improvements (still an open question), this relationship thus obligates a more nuanced consideration of the factors that indicate and control the various activities of microglia and other components of neuroinflammation.

Introduction Alzheimer's disease (AD) is a progressive degeneration of neural structure and function that arises in the cerebral cortex. Behaviorally, affected individuals usually present with semantic difficulty, followed by a deficiency in episodic memory, spatial disorientation, sleep disturbances, depression, agitation, loss of longer memories, general difficulty with the activities of daily living, and eventually, death. Neuropathological findings include a relatively high number of extracellular deposits of the amyloid β-peptide (Aβ), argyrophillic cytoskeletal aggregates in neurons, accumulation of α-synuclein, loss of synapses, loss of cholinergic and adrenergic fibers, loss of pyramidal neurons, and cerebral amyloid angiopathy (CAA) – deposition of Aβ around blood vessels. Most of the AD correlates above have been connected in some way to inflammation. For instance, the plaques – comprised primarily of aggregated amyloid β-peptide (Aβ) – are inundated with microglia that show profiles of morphology and gene expression consistent with inflammation. Indeed, if one characterizes any activity by microglia as a sign of "neuroinflammation," it can be said that inflammatory responses have been evident in AD for at least 40 years [ 1 ]. But, it was not until the late 1980s that investigators were willing to express the hypothesis that inflammatory events were causal or otherwise contributing to the progression of the disease. Recognition of the powerful impact of a cytokine like interleukin-1 (IL-1), elevated in AD microglia, permitted such speculation [ 2 ]. Similarly, research accrued showing that primary inflammation could lead to many of the aberrations found in AD, fueling the consideration that inflammatory events were seminal [ 3 - 5 ]. Many of the individual molecules produced by activated microglia and astrocytes are conditional neurotoxins: hydrogen peroxide, glutamate and other agonists of glutamate receptors, complement components, prostanoids. (Nitric oxide from inducible nitric oxide synthase, produced abundantly in rodent glia, may be less important in human tissues.) Retrospective epidemiological studies showed protection against AD – either in age of onset or rate of progression – by nonsteroidal antiinflammatory drugs (NSAIDs); such correlations have now been born out in a prospective study [ 6 ]. Perhaps most compelling, polymorphisms in the genes for proinflammatory cytokines are indicative of risk for AD [ 7 ]. Despite these indications, there are reasons to believe that the changes observed in glia and inflammatory cytokines constitute a compensatory response in AD. Indeed, some investigators have been reluctant to apply the term "inflammation" to the constellation of events related to AD pathology. Some of the cytokines and other gene products expressed in peripheral sites of inflammation are present in the AD brain, but there is no apparent vasodilation or extravasation of neutrophils. In general, there seems to be less of the molecular and cellular behavior that is responsible for bystander tissue damage in peripheral inflammation. This journal was founded partially out of recognition that "neuroinflammation" is distinct. In essence, the concept reflects a compromise befitting the difficult line that must be maintained between effective cell-mediated immune responses and damage to the precious components of the CNS. Microglia elevate their expression of neurotrophic factors under many of the same conditions in which they show inflammation-related responses such as phagocytosis, retraction of processes, release of excitotoxins, and production of IL-1β and IL-6 and tumor necrosis factor [ 8 ]; in fact, the latter cytokines can have neurotrophic effects themselves [ 9 , 10 ]. Astrocytes deposit proteoglycans around the Aβ deposits destined to become plaques [ 11 ], perhaps sequestering this neurotoxic peptide from doing its harm. Even the apparent benefits of NSAIDs can be parsed from their presumed mechanism of inhibiting cyclooxygenase-2 [ 12 , 13 ](and references therein).
Introduction
Alzheimer's disease (AD) is a progressive degeneration of neural structure and function that arises in the cerebral cortex. Behaviorally, affected individuals usually present with semantic difficulty, followed by a deficiency in episodic memory, spatial disorientation, sleep disturbances, depression, agitation, loss of longer memories, general difficulty with the activities of daily living, and eventually, death. Neuropathological findings include a relatively high number of extracellular deposits of the amyloid β-peptide (Aβ), argyrophillic cytoskeletal aggregates in neurons, accumulation of α-synuclein, loss of synapses, loss of cholinergic and adrenergic fibers, loss of pyramidal neurons, and cerebral amyloid angiopathy (CAA) – deposition of Aβ around blood vessels.Most of the AD correlates above have been connected in some way to inflammation. For instance, the plaques – comprised primarily of aggregated amyloid β-peptide (Aβ) – are inundated with microglia that show profiles of morphology and gene expression consistent with inflammation. Indeed, if one characterizes any activity by microglia as a sign of "neuroinflammation," it can be said that inflammatory responses have been evident in AD for at least 40 years [ 1 ]. But, it was not until the late 1980s that investigators were willing to express the hypothesis that inflammatory events were causal or otherwise contributing to the progression of the disease. Recognition of the powerful impact of a cytokine like interleukin-1 (IL-1), elevated in AD microglia, permitted such speculation [ 2 ]. Similarly, research accrued showing that primary inflammation could lead to many of the aberrations found in AD, fueling the consideration that inflammatory events were seminal [ 3 - 5 ]. Many of the individual molecules produced by activated microglia and astrocytes are conditional neurotoxins: hydrogen peroxide, glutamate and other agonists of glutamate receptors, complement components, prostanoids. (Nitric oxide from inducible nitric oxide synthase, produced abundantly in rodent glia, may be less important in human tissues.) Retrospective epidemiological studies showed protection against AD – either in age of onset or rate of progression – by nonsteroidal antiinflammatory drugs (NSAIDs); such correlations have now been born out in a prospective study [ 6 ]. Perhaps most compelling, polymorphisms in the genes for proinflammatory cytokines are indicative of risk for AD [ 7 ].Despite these indications, there are reasons to believe that the changes observed in glia and inflammatory cytokines constitute a compensatory response in AD. Indeed, some investigators have been reluctant to apply the term "inflammation" to the constellation of events related to AD pathology. Some of the cytokines and other gene products expressed in peripheral sites of inflammation are present in the AD brain, but there is no apparent vasodilation or extravasation of neutrophils. In general, there seems to be less of the molecular and cellular behavior that is responsible for bystander tissue damage in peripheral inflammation. This journal was founded partially out of recognition that "neuroinflammation" is distinct. In essence, the concept reflects a compromise befitting the difficult line that must be maintained between effective cell-mediated immune responses and damage to the precious components of the CNS. Microglia elevate their expression of neurotrophic factors under many of the same conditions in which they show inflammation-related responses such as phagocytosis, retraction of processes, release of excitotoxins, and production of IL-1β and IL-6 and tumor necrosis factor [ 8 ]; in fact, the latter cytokines can have neurotrophic effects themselves [ 9 , 10 ]. Astrocytes deposit proteoglycans around the Aβ deposits destined to become plaques [ 11 ], perhaps sequestering this neurotoxic peptide from doing its harm. Even the apparent benefits of NSAIDs can be parsed from their presumed mechanism of inhibiting cyclooxygenase-2 [ 12 , 13 ](and references therein).Discussion Recent experiments with anti-Aβ immunization have highlighted another beneficial effect of "activated" microglia: removal of Aβ. It has long been recognized that microglia can efficiently phagocytose and at least partially degrade Aβ both in vitro and in vivo. But the persistence of amyloid plaques suggests that microglia are stymied in this regard during the development of AD or in the deposition of Aβ in mice transgenically engineered to produce large amounts of the peptide. Introduction of antibodies recognizing Aβ, either by active vaccination or by passive immunization (injection of antibodies, typically monoclonal), results in removal of some Aβ deposits and/or prevention of their formation. Although the phenomenon has been studied most rigorously in the transgenic mouse models, similar clearance of parenchymal plaques seems to have occurred in two human subjects that participated in an Aβ-vaccine trial [ 14 , 15 ]. And microglia appear to contribute; Aβ can be readily detected in microglia of immunized mice [ 16 ] and was also abundant in some microglia and related syncitia in the AD trial subjects [ 14 , 15 ]. However, the only reason we are privy to the effects of the vaccination paradigm in humans is because these two individuals died after complications of meningeal encephalitis – rampant cranial inflammation brought on by the immunization. This iatrogenic event occurred in about five percent of the human subjects vaccinated against Aβ, prompting discontinuation. One interesting finding from both autopsies is that while parenchymal Aβ deposits were substantially lower than to be expected in AD victims, both individuals had relatively high levels of vascular deposition. This CAA was accompanied by microhemorrhage in at least one of the subjects [ 15 ], consistent with the majority of advanced cases of CAA [ 17 ]. Wilcock  et al . [ 18 ] have now produced evidence that the appearance of CAA after immunization may represent an actual increase in this parameter triggered by anti-Aβ antibodies. Furthermore, the investigators also found that the CAA was accompanied by an increase in hemorrhages – similar to a previous report [ 19 ] – and a vascular accumulation of CD45 +  cells presumed to be microglia. The experimental paradigm was one of passive immunization of transgenic mice at nearly two years of age, old enough to have accumulated substantial Aβ deposits. Consistent with expectations, injection of anti-Aβ antibody diminished deposits in the parenchyma, even those that were mature enough to stain with Congo red. However, vascular deposition of Congo-red staining was elevated by approximately four-fold in the anti-Aβ-treated animals. Pfeiffer  et al . found similar results in another transgenic line [ 19 ]. Further, Wilcock  et al . now show that the regional accumulation of vascular amyloid was accompanied by an elevated index of hemorrhages and a congregation of CD45 +  cells, presumed to be microglia [ 18 ]. Given that stromal microglia show increased signs of activity and contain Aβ after passive Aβ immunization [ 20 ], one interpretation is that the immunization-induced shift in amyloid from the parenchyma to the vasculature is mediated by phagocytic microglia attempting to discard the Aβ into the bloodstream. Such a phenomenon is tenuously supported by the analogous transport of pyknotic neuronal nuclei to the vasculature by microglia, observed in 3-D time-lapse videos by Dailey and coworkers [ 21 ]. In those images, microglia are occasionally seen to transfer the nuclei to another cell, conceivably a perivascular macrophage or dendritic cell. Thus, it is not clear whether the CD45 +  cells observed by Wilcock and coworkers are microglia or another cell type. It is also unclear whether the accumulation of amyloid and inflammatory cells at the blood vessels represents an arrested state in Aβ clearance or simply a bottleneck in the transport, one that would eventually yield to complete removal of the peptide. However, the appearance of CAA in the human subjects that suffered from acute encephalitis suggests that the vascular accumulation is an untoward event, created or facilitated by inflammation. Another vascular irregularity caused by Aβ has been linked to inflammatory events in both transgenic mice and isolated human blood vessels [ 22 ]. The apparent contributions of inflammatory mechanisms to both Aβ clearance and vascular pathology illustrate a somewhat unique example of microglial ambivalence. While many had argued that microglial "activation" by Aβ was at least partially responsible for AD-associated degeneration, others had pointed to microglial phagocytosis as a desirable consequence of activation. For the purposes of discussion, the term " mal activation" will be applied here to microglial activation which produces neurodegeneration. One obvious question is whether there might be a mode of "activation" that permits phagocytosis while limiting malactivation. In fact, stimulation of Fc receptors – the antibody receptors that initiate a good deal of antibody-triggered phagocytosis – can inhibit cytotoxicity in macrophages [ 23 ]. Similarly, phagocytosis of apoptotic cells inhibits macrophage expression of proinflammatory cytokines like IL-1, IL-8, tumor necrosis factor, and several prostanoids through stimulation of a phosphatidylserine receptor [ 24 ]. Evidence indicates that malactivation involves the production of reactive oxygen species like superoxide and peroxide, nitric oxide, and excitotoxins (glutamate, quinolinate, and D-serine). If these criteria are germane, malactivation certainly can be suppressed by specific cytokines, such as transforming growth factor β (TGFβ) [ 25 ]. Although TGFβ has often been characterized broadly as "anti-inflammatory," it does not inhibit the phagocytic activity of microglia in a setting where another "anti-inflammatory" cytokine (IL-4) does [ 26 ]. Interestingly, TGFβ1 transgenesis promotes the same apparent shift of Aβ from parenchyma to vessel that is observed after Aβ immunization [ 27 ].
Discussion
Recent experiments with anti-Aβ immunization have highlighted another beneficial effect of "activated" microglia: removal of Aβ. It has long been recognized that microglia can efficiently phagocytose and at least partially degrade Aβ both in vitro and in vivo. But the persistence of amyloid plaques suggests that microglia are stymied in this regard during the development of AD or in the deposition of Aβ in mice transgenically engineered to produce large amounts of the peptide. Introduction of antibodies recognizing Aβ, either by active vaccination or by passive immunization (injection of antibodies, typically monoclonal), results in removal of some Aβ deposits and/or prevention of their formation. Although the phenomenon has been studied most rigorously in the transgenic mouse models, similar clearance of parenchymal plaques seems to have occurred in two human subjects that participated in an Aβ-vaccine trial [ 14 , 15 ]. And microglia appear to contribute; Aβ can be readily detected in microglia of immunized mice [ 16 ] and was also abundant in some microglia and related syncitia in the AD trial subjects [ 14 , 15 ]. However, the only reason we are privy to the effects of the vaccination paradigm in humans is because these two individuals died after complications of meningeal encephalitis – rampant cranial inflammation brought on by the immunization. This iatrogenic event occurred in about five percent of the human subjects vaccinated against Aβ, prompting discontinuation. One interesting finding from both autopsies is that while parenchymal Aβ deposits were substantially lower than to be expected in AD victims, both individuals had relatively high levels of vascular deposition. This CAA was accompanied by microhemorrhage in at least one of the subjects [ 15 ], consistent with the majority of advanced cases of CAA [ 17 ].Wilcock  et al . [ 18 ] have now produced evidence that the appearance of CAA after immunization may represent an actual increase in this parameter triggered by anti-Aβ antibodies. Furthermore, the investigators also found that the CAA was accompanied by an increase in hemorrhages – similar to a previous report [ 19 ] – and a vascular accumulation of CD45 +  cells presumed to be microglia. The experimental paradigm was one of passive immunization of transgenic mice at nearly two years of age, old enough to have accumulated substantial Aβ deposits. Consistent with expectations, injection of anti-Aβ antibody diminished deposits in the parenchyma, even those that were mature enough to stain with Congo red. However, vascular deposition of Congo-red staining was elevated by approximately four-fold in the anti-Aβ-treated animals. Pfeiffer  et al . found similar results in another transgenic line [ 19 ]. Further, Wilcock  et al . now show that the regional accumulation of vascular amyloid was accompanied by an elevated index of hemorrhages and a congregation of CD45 +  cells, presumed to be microglia [ 18 ]. Given that stromal microglia show increased signs of activity and contain Aβ after passive Aβ immunization [ 20 ], one interpretation is that the immunization-induced shift in amyloid from the parenchyma to the vasculature is mediated by phagocytic microglia attempting to discard the Aβ into the bloodstream. Such a phenomenon is tenuously supported by the analogous transport of pyknotic neuronal nuclei to the vasculature by microglia, observed in 3-D time-lapse videos by Dailey and coworkers [ 21 ]. In those images, microglia are occasionally seen to transfer the nuclei to another cell, conceivably a perivascular macrophage or dendritic cell. Thus, it is not clear whether the CD45 +  cells observed by Wilcock and coworkers are microglia or another cell type. It is also unclear whether the accumulation of amyloid and inflammatory cells at the blood vessels represents an arrested state in Aβ clearance or simply a bottleneck in the transport, one that would eventually yield to complete removal of the peptide. However, the appearance of CAA in the human subjects that suffered from acute encephalitis suggests that the vascular accumulation is an untoward event, created or facilitated by inflammation. Another vascular irregularity caused by Aβ has been linked to inflammatory events in both transgenic mice and isolated human blood vessels [ 22 ].et alet alet alThe apparent contributions of inflammatory mechanisms to both Aβ clearance and vascular pathology illustrate a somewhat unique example of microglial ambivalence. While many had argued that microglial "activation" by Aβ was at least partially responsible for AD-associated degeneration, others had pointed to microglial phagocytosis as a desirable consequence of activation. For the purposes of discussion, the term " mal activation" will be applied here to microglial activation which produces neurodegeneration. One obvious question is whether there might be a mode of "activation" that permits phagocytosis while limiting malactivation. In fact, stimulation of Fc receptors – the antibody receptors that initiate a good deal of antibody-triggered phagocytosis – can inhibit cytotoxicity in macrophages [ 23 ]. Similarly, phagocytosis of apoptotic cells inhibits macrophage expression of proinflammatory cytokines like IL-1, IL-8, tumor necrosis factor, and several prostanoids through stimulation of a phosphatidylserine receptor [ 24 ]. Evidence indicates that malactivation involves the production of reactive oxygen species like superoxide and peroxide, nitric oxide, and excitotoxins (glutamate, quinolinate, and D-serine). If these criteria are germane, malactivation certainly can be suppressed by specific cytokines, such as transforming growth factor β (TGFβ) [ 25 ]. Although TGFβ has often been characterized broadly as "anti-inflammatory," it does not inhibit the phagocytic activity of microglia in a setting where another "anti-inflammatory" cytokine (IL-4) does [ 26 ]. Interestingly, TGFβ1 transgenesis promotes the same apparent shift of Aβ from parenchyma to vessel that is observed after Aβ immunization [ 27 ].malConclusions While some have argued that CAA is of little consequence in AD [ 28 ], the elaboration of the deposition that appears to occur under conditions of "beneficial inflammation" is on par with that seen in hereditary cerebral hemorrhage with angiopathy-Dutch type and is certainly a risk factor for devastating levels of hemorrhage. If such a response reflects a broad-acting realignment of cytokine profiles contingent upon immunization, it behooves careful consideration (and extensive animal testing) for any strategy for antibody-mediated reduction of Aβ in the AD brain.
Conclusions
While some have argued that CAA is of little consequence in AD [ 28 ], the elaboration of the deposition that appears to occur under conditions of "beneficial inflammation" is on par with that seen in hereditary cerebral hemorrhage with angiopathy-Dutch type and is certainly a risk factor for devastating levels of hemorrhage. If such a response reflects a broad-acting realignment of cytokine profiles contingent upon immunization, it behooves careful consideration (and extensive animal testing) for any strategy for antibody-mediated reduction of Aβ in the AD brain.List of abbreviations AD: Alzheimer's disease Aβ: amyloid β-peptide CAA: cerebral amyloid angiopathy IL-1, -6, -8: interleukin-1, -6, -8 NSAID: nonsteroidal antiinflammatory drug TGFβ: transforming growth factor β
List of abbreviations
AD: Alzheimer's diseaseAβ: amyloid β-peptideCAA: cerebral amyloid angiopathyIL-1, -6, -8: interleukin-1, -6, -8NSAID: nonsteroidal antiinflammatory drugTGFβ: transforming growth factor βCompeting interests The author(s) declare that they have no competing interests.
Competing interests
The author(s) declare that they have no competing interests.