Matthias Schreckenberger

Clinical improvement in a case of frontotemporal dementia under aripiprazole treatment corresponds to partial recovery of disturbed frontal glucose metabolism

Frontotemporal dementia (FTD) is increasingly recognized as an important type of degenerative dementia but satisfactory pharmacological treatment has not yet been established. We examined the clinical effects of aripiprazole, a new antipsychotic with partial agonistic properties at serotonin 5-HT1A and dopamine D2 receptors, in parallel with cortical glucose metabolism changes. We conducted a follow-up investigation of clinical status and 18F-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET) in a 73-year-old male patient with FTD over a 13-month period. Under conventional drug treatment during the first 12 months a marked increase in dementia symptoms was observed. Frontal lobe glucose metabolism clearly decreased during this time period. Under consecutive treatment with aripiprazole a significant and stable improvement of clinical symptoms could be registered, while disturbed frontal glucose metabolism increased significantly. According to this case experience, further investigations should be undertaken to ascertain whether aripiprazole or other atypical antipsychotics with properties to improve impaired dopaminergic transmission in frontal brain regions could qualify for therapy of FTD.

Functional implications of hippocampal degeneration in early Alzheimer’s disease: a combined DTI and PET study

PurposeHypometabolism of the posterior cingulate cortex (PCC) in early Alzheimer’s disease (AD) is thought to arise in part due to AD-specific neuronal damage to the hippocampal formation. Here, we explored the association between microstructural alterations within the hippocampus and whole-brain glucose metabolism in subjects with AD, also in relation to episodic memory impairment.MethodsTwenty patients with early AD (Mini-Mental State Examination 25.7u2009±u20091.7) were studied with [18F]fluorodeoxyglucose (FDG) positron emission tomography and diffusion tensor imaging. Episodic memory performance was assessed using the free delayed verbal recall task (DVR). Voxel-wise relative FDG uptake was correlated to diffusivity indices of the hippocampus, followed by extraction of FDG uptake values from significant clusters. Linear regression analysis was performed to test forxa0uniquexa0contributions of diffusivity and metabolic indices in the prediction of memory function.ResultsDiffusivity in the left anterior hippocampus negatively correlated with FDG uptake primarily in the left anterior hippocampus, parahippocampal gyrus and the PCC (pu2009<u20090.005). The same correlation pattern was found for right hippocampal diffusivity (pu2009<u20090.05). In linear regression analysis, left anterior hippocampal diffusivity and FDG uptake from the PCC cluster were the only significant predictors for performance on DVR, together explaining 60.6% of the variance. We found an inverse association between anterior hippocampal diffusivity and PCC glucose metabolism, which was in turn strongly related to episodic memory performance in subjects with early AD.ConclusionThese findings support the diaschisis hypothesis of AD and implicate a dysfunction of structures along the hippocampal output pathways as a significant contributor to the genesis of episodic memory impairment.

Sympathetic activity at rest and motor brain areas: FDG-PET study

Although recent studies identified brain areas which are involved in short term activation of the sympathetic nervous system, little is known about brain mechanisms which generate the individual variability of basal autonomic activity. In this fluorodeoxyglucose positron emission tomography study (FDG-PET), we aimed to identify brain regions, which covary with function parameters of the autonomic nervous system at rest. Therefore, FDG-PET (Siemens, Germany) was performed twice in 14 healthy resting subjects (7 m, 7 f; mean age 29.5 years) while different parameters of autonomic function were assessed simultaneously: Blood pressure, heart rate, power spectra of heart rate variability (HF/LF ratio) and plasma catecholamines. In order to control for attention, subjects had to focus visual affective neutral presentations during the experiment. Correlation analysis was performed as a region of interest analysis using SPM2 software (p<0.001 uncorrected). Sympathetic activity at rest varied substantially between subjects. There were significant positive correlations between increase of regional cerebral glucose metabolism (rCGM) of the heads of caudate nuclei on both sides and the HF/LF ratio of heart rate variability. Furthermore, significant negative correlations between both heart rate and plasma catecholamines and rCGM decreases of caudate nuclei heads were found. In addition, there was a positive correlation between plasma catecholamines and primary motor cortex activation. Autonomic nervous system at rest seems to be partially interlocked with activity of motor brain regions - the caudate nuclei and the motor cortex. This might have clinical implications for the understanding of stress-related disorders, which are frequently accompanied by increased sympathetic activity as well as muscle tone.

Blood constituents trigger brain swelling, tissue death, and reduction of glucose metabolism early after acute subdural hematoma in rats

Outcome from acute subdural hematoma is often worse than would be expected from the pure increase of intracranial volume by bleeding. The aim was to test whether volume-independent pathomechanisms aggravate damage by comparing the effects of blood infusion with those of an inert fluid, paraffin oil, on intracranial pressure (ICP), cerebral perfusion pressure (CPP), local cerebral blood flow (CBF), edema formation, glucose metabolism ([18F]-deoxyglucose, MicroPET), and histological outcome. Rats were injured by subdural infusion of 300 μL venous blood or paraffin. ICP, CPP, and CBF changes, assessed during the first 30 mins after injury, were not different between the injury groups at most time points (n=8 per group). Already at 2 h after injury, blood caused a significantly more pronounced decrease in glucose metabolism in the injured cortex when compared with paraffin (P<0.001, n=5 per group). Ipsilateral brain edema did not differ between groups at 2 h, but was significantly more pronounced in the blood-treated groups at 24 and 48 h after injury (n=8 per group). These changes caused a 56.2% larger lesion after blood when compared with paraffin (48.1±23.0 versus 21.1±11.8 mm3; P<0.02). Blood constituent-triggered pathomechanisms aggravate the immediate effects due to ICP, CPP, and CBF during hemorrhage and lead to early reduction of glucose metabolism followed by more severe edema and histological damage.

Relationships between hippocampal microstructure, metabolism, and function in early Alzheimer’s disease

Abnormal microstructural integrity and glucose metabolism of the hippocampus are common in subjects with Alzheimer’s disease (AD) that typically manifest as episodic memory impairment. The above-tissue alterations can be captured in vivo using diffusion tensor imaging (DTI) and positron emission tomography with [18F]fluorodeoxyglucose (FDG-PET). Here, we explored relationships between the above neuroimaging and cognitive markers of early AD-specific hippocampal damage. Twenty patients with early AD (MMSE 25.7xa0±xa01.7) were studied using DTI and FDG-PET. Episodic memory performance was assessed using the free delayed verbal recall task (DVR). In the between-modality correlation analysis, FDG uptake was strongly associated with diffusivity in the left anterior hippocampus only (rxa0=xa0−0.81, pxa0<xa00.05 Bonferroni’s corrected for multiple tests). Performance on DVR significantly correlated with left anterior (rxa0=xa0−0.80, pxa0<xa00.05) and left mean (rxa0=xa0−0.72, pxa0<xa00.05) hippocampal diffusivity, while the correlation with left anterior FDG uptake did not reach statistical significance (rxa0=xa00.52, n.s.). DTI-derived diffusivity of the anterior hippocampus might be a sensitive early marker of hippocampal dysfunction as reflected at the synaptic and cognitive levels. This neurobiological distinction of the anterior hippocampus might be related to the disruption of the perforant pathway that is known to occur early in the course of AD.

Ventral and dorsal streams processing visual motion perception (FDG-PET study)

BackgroundEarlier functional imaging studies on visually induced self-motion perception (vection) disclosed a bilateral network of activations within primary and secondary visual cortex areas which was combined with signal decreases, i.e., deactivations, in multisensory vestibular cortex areas. This finding led to the concept of a reciprocal inhibitory interaction between the visual and vestibular systems. In order to define areas involved in special aspects of self-motion perception such as intensity and duration of the perceived circular vection (CV) or the amount of head tilt, correlation analyses of the regional cerebral glucose metabolism, rCGM (measured by fluorodeoxyglucose positron-emission tomography, FDG-PET) and these perceptual covariates were performed in 14 healthy volunteers. For analyses of the visual-vestibular interaction, the CV data were compared to a random dot motion stimulation condition (not inducing vection) and a control group at rest (no stimulation at all).ResultsGroup subtraction analyses showed that the visual-vestibular interaction was modified during CV, i.e., the activations within the cerebellar vermis and parieto-occipital areas were enhanced. The correlation analysis between the rCGM and the intensity of visually induced vection, experienced as body tilt, showed a relationship for areas of the multisensory vestibular cortical network (inferior parietal lobule bilaterally, anterior cingulate gyrus), the medial parieto-occipital cortex, the frontal eye fields and the cerebellar vermis. The “earlier” multisensory vestibular areas like the parieto-insular vestibular cortex and the superior temporal gyrus did not appear in the latter analysis. The duration of perceived vection after stimulus stop was positively correlated with rCGM in medial temporal lobe areas bilaterally, which included the (para-)hippocampus, known to be involved in various aspects of memory processing. The amount of head tilt was found to be positively correlated with the rCGM of bilateral basal ganglia regions responsible for the control of motor function of the head.ConclusionsOur data gave further insights into subfunctions within the complex cortical network involved in the processing of visual-vestibular interaction during CV. Specific areas of this cortical network could be attributed to the ventral stream (“what” pathway) responsible for the duration after stimulus stop and to the dorsal stream (“where/how” pathway) responsible for intensity aspects.

Osteoprotegerin: A new biomarker for impaired bone metabolism in complex regional pain syndrome?

Summary We provide evidence that elevated serum osteoprotegerin reflects pathophysiological processes of complex regional pain syndrome. ABSTRACT Osteoprotegerin (OPG) is important for bone remodeling and may contribute to complex regional pain syndrome (CRPS) pathophysiology. We aimed to assess the value of OPG as a biomarker for CRPS and a possible correlation with radiotracer uptake in 3‐phase bone scintigraphy (TPBS). OPG levels were analyzed in 23 CRPS patients (17 women; mean age 50 ± 9.0 years; disease duration: 12 weeks [IQR 8–24]), 10 controls (6 women; mean age 58 ± 9.6 years) and 21 patients after uncomplicated fractures (12 women; mean age: 43 ± 15 years; time after fracture: 15 weeks [IQR: 6–22]). The CRPS and control patients also underwent TPBS. OPG in CRPS patients was significantly increased by comparison with both control groups (P = 0.001; Kruskal‐Wallis test; CRPS patients: 74.1 pg/mL [IQR: 47.1–100.7]; controls: 46.7 pg/mL [IQR: 35.5–55.0]; P = 0.004; fracture patients: 45.9 pg/mL [IQR: 37.5–56.7]; P = 0.001). As a diagnostic test for CRPS, OPG had a sensitivity of 0.74, specificity of 0.80, positive predictive value of 68% and negative predictive value of 84%. Receiver operating characteristic curve analysis showed an area under the curve of 0.80 (CI: 0.68–0.91). For the CRPS‐affected hand, a significant correlation between OPG and TPBS region of interest analysis in phase III was detected (carpal bones; r = 0.391; P = 0.03). The persistent OPG increase in CRPS indicates enhanced osteoblastic activity shown by increased radiotracer uptake in TPBS phase III. A contribution of bone turnover to CRPS pathophysiology is likely. OPG might be useful as a biomarker for CRPS.

Evidence for modulation of opioidergic activity in central vestibular processing: A [18F] diprenorphine PET study

Animal and functional imaging studies had identified cortical structures such as the parieto‐insular vestibular cortex, the retro‐insular cortex, or the anterior cingulate cortex belonging to a vestibular cortical network. Basic animal studies revealed that endorphins might be important transmitters involved in cerebral vestibular processing. The aim of the present study was therefore to analyse whether the opioid system is involved in vestibular neurotransmission of humans or not. Changes in opioid receptor availability during caloric air stimulation of the right ear were studied with [18F] Fluoroethyl‐diprenorphine ([18F]FEDPN) PET scans in 10 right‐handed healthy volunteers and compared to a control condition. Decrease in receptor availability to [18F]FEDPN during vestibular stimulation in comparison to the control condition was significant at the right posterior insular cortex and the postcentral region indicating more endogenous opioidergic binding in these regions during stimulation. These data give evidence that the opioidergic system plays a role in the right hemispheric dominance of the vestibular cortical system in right‐handers. Hum Brain Mapp, 2010.

Visual‐Motion Suppression in Congenital Pendular Nystagmus

Patients with a congenital pendular nystagmus are known not to experience oscillopsia in a normal visual environment. The data of a 31‐year‐old female patient suffering from a congenital pendular nystagmus are presented. The aim of the fluorodeoxyglucose positron emission tomography (FDG‐PET) experiment was to analyze the regional cerebral glucose metabolism (rCGM) during minimal as well as maximal nystagmus. Video‐oculography showed a maximum in frequency of the horizontal pendular nystagmus during gaze to the left, whereas the zone of minimal nystagmus was 10° to the right. Two sessions with an 18F‐fluorodeoxyglucose tracer were performed to analyze cerebral blood‐glucose utilization when fixating an object in the areas of maximal and of minimal nystagmus. A structural MRI in a clinicial 1.5‐T scanner was acquired to superimpose the PET results onto the unique anatomy of the patient. By statistical analysis a significant increase in the rCGM in the cerebellar nodulus and a relative decrease in the area of MT/V5 bilaterally during maximal nystagmus were found. When the patient was looking in her null zone, rCGM was increased in V1 and MT/V5 bilaterally. To the best of the authors’ knowledge, this is the first proof by means of functional imaging of a suppression of oscillopsia in higher‐order visual cortex areas in a patient with a congenital nystagmus.

Evaluation of cannabinoid type 1 receptor expression in the rat brain using [18F]MK-9470 microPET

PurposeThe ligand [18F]MK-9470 is an inverse agonist binding with high affinity and specificity to the cannabinoid type 1 (CB1) receptor. In this study, a semiquantitative acquisition and analysis protocol for investigation of the CB1 receptor distribution in the rat brain was established.MethodsTwo C57BL/6N mice (one CB1−/− and one wild-type) and 19 Sprague Dawley rats were investigated using a Focus 120 microPET scanner. Seven rats were scanned twice for test–retest evaluation, six rats were scanned for blocking experiments using the inverse CB1 receptor agonist rimonabant, and 19 rats were scanned for baseline studies. Percentage injected dose per millilitre (%ID/ml) or uptake ratios (VOItarget/VOIwhole brain) were calculated. A Bland-Altman-plot was computed and mean values were compared using a two-sided paired t test.ResultsComparing the data from the CB1−/− mouse and the wild-type mouse, [18F]MK-9470 showed good specificity. Regarding the rat data, there was no relationship between the difference between the test and retest measurements or their mean value. The test and retest data showed a strong correlation (ρcu2009=u20090.846, pu2009≤u20090.01; rPearsonu2009=u20090.857). Equivalence was not found for all regions and not even in the pons at baseline or under blocking condition. Only the baseline studies showed the highest levels of uptake in the caudate-putamen and thalamus, whereas moderate uptake was found in the hippocampus, hypothalamus and cerebellum, and the lowest uptake was observed in the cortex, amygdala and pons.ConclusionA reference region is not available; however, the proposed analysis method using the parameter uptake ratio is simple and delivers stable results allowing the discrimination of distinct brain regions.