Jan Cees de Groot

Neuroinflammation in Schizophrenia-Related Psychosis: A PET Study

Schizophrenia is a chronic and disabling brain disease characterized by psychotic episodes with unknown etiology. It is suggested that neuroinflammation plays a role in the pathophysiology of schizophrenia. Neuroinflammation is characterized by the activation of microglia cells, which show an increase in the expression of the peripheral benzodiazepine receptor. The isoquinoline (R)-N-11C-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)isoquinoline-3-carboxamide (11C-(R)-PK11195) is a peripheral benzodiazepine receptor ligand that can be used for the imaging of activated microglia cells, and thus neuroinflammation, with PET. We hypothesized that neuroinflammation would be more profound in schizophrenic patients during psychosis, and it was therefore investigated whether neuroinflammation was present in patients within the schizophrenia spectrum who were in a psychotic phase. Methods: Seven patients within the schizophrenia spectrum who were recovering from psychosis were included. Recovering psychosis was defined by a score of 5 or more on 1 item of the positive scale of the positive and negative symptoms scale (PANSS) or a score of 4 on 2 items. The patients were compared with 8 age-matched healthy volunteers. Dynamic 60-min PET scans were acquired after the injection of 11C-(R)-PK11195. All subjects underwent T1- and T2-weighted MRI, and the scans were visually examined for abnormalities and used for anatomic coregistration in data analysis. The PET data were analyzed with a 2-tissue-compartment model to calculate the binding potential, using the metabolite-corrected plasma curve as input. Results: A significantly higher binding potential of 11C-(R)-PK11195, indicative of neuroinflammation, was found in the hippocampus of schizophrenic patients than in healthy volunteers (2.07 ± 0.42 vs. 1.37 ± 0.30; P = 0.004). A nonsignificant 30% higher 11C-(R)-PK11195 binding potential was found in the whole-brain gray matter of schizophrenic patients. The MR images did not reveal any visual abnormalities. Conclusion: The present study suggests that focal neuroinflammation may play an important role in schizophrenia during psychosis.

Brain lesions several years after eclampsia

OBJECTIVE Eclampsia is thought to have no long-term neurological consequences. We aimed to delineate the neurostructural sequelae of eclampsia, in particular brain white matter lesions, utilizing high-resolution 3-Tesla magnetic resonance imaging (MRI). STUDY DESIGN Formerly eclamptic women were matched for age and year of index pregnancy with normotensive parous controls. The presence and volume of brain white matter lesions were compared between the groups. RESULTS MRI scans of 39 women who formerly had eclampsia and 29 control women were performed on average 6.4 +/- 5.6 years following the index pregnancy at a mean age of 38 years. Women with eclampsia demonstrated subcortical white matter lesions more than twice as often as compared with controls (41% vs 17 %; odds ratio, 3.3; 95% confidence interval, 1.05-10.61; P = .04). CONCLUSION Cerebral white matter lesions occur more often in women who formerly had eclampsia compared with women with normotensive pregnancies. The exact pathophysiology underlying these imaging changes and their clinical relevance remain to be elucidated.

Regional distribution of cerebral white matter lesions years after preeclampsia and eclampsia

OBJECTIVE: To assess the distribution of cerebral white matter lesions in women who had eclampsia, preeclampsia, or normotensive pregnancies. The pathophysiology of these lesions, more often seen in formerly eclamptic and preeclamptic women, is unclear but may be related to a predisposition for vascular disease, the occurrence of the posterior reversible encephalopathy syndrome, or both while pregnant. Assessing the distribution of such lesions may give insight into their pathophysiology and possible consequences. METHODS: This retrospective cohort study determined the presence, severity, and location of white matter lesions on cerebral magnetic resonance imaging scans of 64 formerly eclamptic, 74 formerly preeclamptic, and 75 parous control women. RESULTS: Formerly preeclamptic and eclamptic women have white matter lesions more often (34.4% [n=47] compared with 21.3% [n=16]; P<.05) and more severely (0.07 compared with 0.02 mL; P<.05) than parous women in a control group. In all women, the majority of lesions was located in the frontal lobes followed by the parietal, insular, and temporal lobes. CONCLUSION: White matter lesions are more common in women with prior pregnancies complicated by preeeclampsia or eclampsia compared with parous women in a control group. In no group does regional white matter lesion distribution correspond to the occipitoparietal edema distribution seen in posterior reversible encephalopathy syndrome. LEVEL OF EVIDENCE: II

TGF-β antibody uptake in recurrent high grade glioma imaged with 89Zr-fresolimumab PET

Transforming growth factor–β (TGF-β) signaling is involved in glioma development. The monoclonal antibody fresolimumab (GC1008) can neutralize all mammalian isoforms of TGF-β, and tumor uptake can be visualized and quantified with 89Zr-fresolimumab PET in mice. The aim of this study was to investigate the fresolimumab uptake in recurrent high-grade gliomas using 89Zr-fresolimumab PET and to assess treatment outcome in patients with recurrent high-grade glioma treated with fresolimumab. Methods: Patients with recurrent glioma were eligible. After intravenous administration of 37 MBq (5 mg) of 89Zr-fresolimumab, PET scans were acquired on day 2 or day 4 after tracer injection. Thereafter, patients were treated with 5 mg of fresolimumab per kilogram intravenously every 3 wk. 89Zr-fresolimumab tumor uptake was quantified as maximum standardized uptake value (SUVmax). MR imaging for response evaluation was performed after 3 infusions or as clinically indicated. Results: Twelve patients with recurrent high-grade glioma were included: 10 glioblastomas, 1 anaplastic oligodendroglioma, and 1 anaplastic astrocytoma. All patients underwent 89Zr-fresolimumab PET 4 d after injection. In 4 patients, an additional PET scan was obtained on day 2 after injection. SUVmax on day 4 in tumor lesions was 4.6 (range, 1.5–13.9) versus a median SUVmean of 0.3 (range, 0.2–0.5) in normal brain tissue. All patients showed clinical or radiologic progression after 1–3 infusions of fresolimumab. Median progression-free survival was 61 d (range, 25–80 d), and median overall survival was 106 d (range, 37–417 d). Conclusion: 89Zr-fresolimumab penetrated recurrent high-grade gliomas very well but did not result in clinical benefit.

Volume, metabolites and neuroinflammation of the hippocampus in bipolar disorder - A combined magnetic resonance imaging and positron emission tomography study

BACKGROUND The hippocampus is one of the brain regions that is involved in several pathophysiological theories about bipolar disorder (BD), such as the neuroinflammation theory and the corticolimbic metabolic dysregulation theory. We compared hippocampal volume and hippocampal metabolites in bipolar I disorder (BD-I) patients versus healthy controls (HCs) with magnetic resonance imaging (MRI) and spectroscopy (MRS). We post hoc investigated whether hippocampal volume and hippocampal metabolites were associated with microglial activation and explored if potential illness modifying factors affected these hippocampal measurements and whether these were associated with experienced mood and functioning. MATERIALS AND METHODS Twenty-two BD-I patients and twenty-four HCs were included in the analyses. All subjects underwent psychiatric interviews as well as an MRI scan, including a T1 scan and PRESS magnetic resonance spectroscopy (MRS). Volumetric analysis was performed with Freesurfer. MRS quantification was performed with LC Model. A subgroup of 14 patients and 11 HCs also underwent a successful [(11)C]-(R)-PK11195 neuroinflammation positron emission tomography scan. RESULTS In contrast to our hypothesis, hippocampal volumes were not decreased in patients compared to HC after correcting for individual whole-brain volume variations. We demonstrated decreased N-acetylaspartate (NAA)+N-acetyl-aspartyl-glutamate (NAAG) and creatine (Cr)+phosphocreatine (PCr) concentrations in the left hippocampus. In the explorative analyses in the left hippocampus we identified positive associations between microglial activation and the NAA+NAAG concentration, between alcohol use and NAA+NAAG concentration, between microglial activation and the depression score and a negative relation between Cr+PCr concentration and experienced occupational disability. Duration of illness associated positively with volume bilaterally. CONCLUSION Compared to HCs, the decreased NAA+NAAG concentration in the left hippocampus of BD-I patients suggests a decreased neuronal integrity in this region. In addition we found a positive relation between microglial activation and neuronal integrity in vivo, corresponding to a differentiated microglial function where some microglia induce apoptosis while others stimulate neurogenesis.

Long-term Consequences of the Posterior Reversible Encephalopathy Syndrome in Eclampsia and Preeclampsia: A Review of the Obstetric and Nonobstetric Literature

&NA; This review summarizes the long-term consequences of the posterior reversible encephalopathy syndrome (PRES) that have been described in the obstetric literature (eclampsia and preeclampsia) and compares these with data from the nonobstetric literature. Preeclampsia is characterized by new-onset hypertension and proteinuria after the 20th week of pregnancy. Neurological symptoms include headache; visual deficits; confusion; seizures; and, in the most severe cases, intracranial hemorrhage. Eclampsia is an acute cerebral complication of preeclampsia, defined as the occurrence of tonic-clonic seizures in pregnant or recently postpartum women. With severe preeclampsia, in conjunction with neurological symptoms, or eclampsia, neuroimaging changes consistent with PRES can be seen. Posterior reversible encephalopathy syndrome is a specific clinicoradiological syndrome presenting with headaches, visual impairment, seizures, and altered mental status. Characteristic neuroimaging features are consistent with cerebral edema predominantly in the parietal and occipital lobes. In addition to preeclampsia/eclampsia, PRES has been associated with various conditions in the nonobstetric population, that is, severe hypertension, transplantation, or autoimmune disease, in combination with immunosuppressive therapy or high-dose chemotherapy for various malignant conditions. Long-term sequelae of both preeclampsia/eclampsia and other PRES-related conditions are poorly described. After eclampsia or preeclampsia, nonspecific white matter lesions may be found on magnetic resonance imaging, which may or may not be related to the PRES episode. Previously (pre)eclamptic women report cognitive failures; however, no neurocognitive impairment has been shown so far. Various nonobstetric PRES-related conditions have been described with long-term neuroimaging abnormalities as well as cognitive problems, epilepsy, or visual impairment. Although no firm conclusions can be drawn because of the heterogeneity of reported cases, some general comments can be made. Because most persistent long-term problems are present in the nonobstetric population, the main determinant for these long-term problems may be the underlying condition that gave rise to the PRES episode. In addition, most reports suggest that late diagnosis or inadequate therapy may contribute, emphasizing the need for early recognition, adequate treatment, follow-up, and support. Target Audience Obstetricians and gynecologists, neurologists, radiologists, ophthalmologists, psychologists Learning Objectives After completing this CME activity, the reader should be able to identify the clinicoradiological syndrome and pathophysiology of PRES in preeclampsia/eclampsia, evaluate long-term consequences and complaints in formerly preeclamptic and eclamptic women, and determine the need for early magnetic resonance imaging diagnosis of PRES.

Cerebral white matter lesions, subjective cognitive failures, and objective neurocognitive functioning: A follow-up study in women after hypertensive disorders of pregnancy

ABSTRACT Objective: Hypertensive disorders of pregnancy, like preeclampsia, are a leading cause of maternal and fetal morbidity/mortality worldwide. Preeclampsia can be complicated by the occurrence of convulsions (eclampsia). Women who experienced (pre)eclampsia more frequently report daily cognitive failures and showed increased emotional dysfunction several years later, but are not impaired on objective neurocognitive testing. In addition, women with preterm preeclampsia more often have cerebral white matter lesions (WML) on follow-up. We aimed to determine whether WML presence is related to cognitive dysfunction, anxiety, and depressive symptoms in (pre)eclamptic women. Method: Forty-one eclamptic, 49 preeclamptic, and 47 control women who had a normotensive pregnancy completed the Cognitive Failures Questionnaire (CFQ), the Hospital Anxiety and Depression Scale (HADS), and a broad neurocognitive test battery (visual perception and speed of information processing, motor functions, working memory, long-term memory, attention, and executive functioning). All underwent cerebral magnetic resonance imaging (MRI), and WML presence was recorded. Median elapsed time since index pregnancy was 6 years. Average age was 40 years. Results: WML were more prevalent in women who had experienced preterm (pre)eclampsia (<37 weeks; 40%) than in controls (21%, p = .03). In (pre)eclamptic women, CFQ and HADS scores were higher than those in controls (44± 16.1 vs. 36± 11.0, p < .001, and 11± 6.3 vs. 8± 5.5, p < .001). There was no difference in objective cognitive performance as measured by neurocognitive tests. Subjective and objective cognitive functioning, anxiety, and depressive symptoms were not related to WML presence. Conclusion: Formerly (pre)eclamptic women report cognitive dysfunction, but do not exhibit overt cognitive impairment when objectively tested on average 6 years following their pregnancy. The presence of WML is not related to objective nor to subjective cognitive impairment, anxiety, and depressive symptoms. Longitudinal studies are needed to study whether the presence of WML is a risk factor for developing objective cognitive impairment in the long term.

Cerebral white matter lesions and perceived cognitive dysfunction: the role of pregnancy

OBJECTIVE Women who suffered eclampsia or preterm preeclampsia are twice as likely to demonstrate cerebral white matter lesions (WML) on magnetic resonance imaging compared with age-matched women who had normotensive pregnancies, and they report more cognitive dysfunctions in everyday life. We aimed to determine whether pregnancy in and of itself has a relationship with the presence of WML and subjective cognitive dysfunction. STUDY DESIGN Eighty-one parous women who had a normotensive pregnancy were matched for age with 65 nulliparous women and all underwent cerebral magnetic resonance imaging. Presence of cerebral WML was rated and blood pressure was measured. Subjective cognitive functioning was assessed using the Cognitive Failures Questionnaire. RESULTS There was no difference in the presence (22% vs 19%) of WML between parous and nulliparous women. Age was a predictor for the presence of WML, whereas the presence of current hypertension was not. Average score on the Cognitive Failures Questionnaire was not different between both groups, nor related to WML. CONCLUSION A history of pregnancy in and of itself is not related to the presence of cerebral WML and the perception of cognitive dysfunction. Because of the relationship with preterm preeclampsia and eclampsia, future research should focus on the clinical importance and development throughout the years of such cerebral WML in young women and focus on risk factors for cardiovascular disease.

Diffusion tensor imaging in euthymic bipolar disorder – A tract-based spatial statistics study

BACKGROUND In the current DTI study we compared euthymic bipolar I disorder (BD-I) patients and healthy controls (HC). We subsequently divided the total patient group into lithium-users and non-lithium-users and estimated differences across the three groups. METHODS Twenty-one euthymic BD-I patients and twenty-two HC participants were included in psychiatric interviews and MRI image acquisition (diffusion-weighted (DW) and T1-weighted scans). Fractional anisotropy (FA), radial, mean and axial diffusivity (RD, MD, AD) were estimated from the DW data, using DTI. These measures were then compared between groups using FSL Tract Based Spatial Statistics (TBSS). Correlations with age at onset, number of episodes and depression score were analyzed. RESULTS A difference in FA, MD, RD and AD between the whole sample of euthymic BD-I patients and healthy controls could not be detected. Amongst others, lithium-using patients demonstrated a higher FA and lower RD when compared to non-lithium-using BD-I patients in the corpus callosum and left anterior corona radiata. Widespread clusters demonstrated negative FA associations and positive RD and MD associations with minor depressive symptoms. LIMITATIONS Patients were naturalistically treated. Although the sample size is comparable to several other DTI studies, a larger sample size would have been benificial. TBSS and DTI have their own limitations. CONCLUSION Our findings support the theory that previously described DTI-based microstructural differences between HC and BD patients could be less pronounced in euthymic BD patients. Differences in FA between patients using and not using lithium suggest a counteracting effect of lithium on white matter microstructural disturbances.

Three cases of bipartition of the atlas.

BACKGROUND CONTEXT A bipartite atlas is a rare coincidental finding, and it is reported in only 0.1% of the general population. It is a congenital disorder characterized by incomplete fusion of the anterior and the posterior arches of C1, and it is important to differentiate it from a Jefferson fracture. STUDY DESIGN/SETTING Case report and literature review. PURPOSE To report three cases of patients with bipartition of the atlas with a focus on imaging. To review the literature on these fusion defects, the embryologic basis, and the differentiation from a Jefferson fracture. METHODS We report three cases of patients with a bipartite atlas as a coincidental finding in a trauma setting. The bipartite atlas was assessed by multidetector computed tomography (CT). The first case, for example, describes a 36-year-old patient who was struck by a moped. The CT of the skull showed a bipartite atlas as an additional finding. The embryologic development of C1 is reviewed and also the imaging features and the management. Furthermore, a CT image of a Jefferson fracture is provided for comparison. RESULTS The CT scans of the three patients show midline clefts of the anterior and the posterior arches of C1 with similar imaging features: smooth margins lined by cortical bone and no lateral offset. The patients had no neurological symptoms relating to the C1 abnormality, and no follow-up was performed. The clefts at level C1 are the result of the failure of three ossification centers to fuse properly. Anterior and posterior clefts are caused by hypoplasia of the hypochordal bow and lateral parts of the C1 sclerotome, respectively. Because of the risk of instability, assessing atlantoaxial stability is advised. However, patients usually have no symptoms and require no specific treatment. CONCLUSIONS A bipartite atlas is a rare congenital abnormality, caused by a failure of anterior and lateral ossification centers to fuse. It needs to be differentiated from a Jefferson fracture in a trauma setting. It usually requires no specific treatment.