Henryk Barthel

Cerebral amyloid-β PET with florbetaben (18F) in patients with Alzheimer's disease and healthy controls: a multicentre phase 2 diagnostic study

BACKGROUND Imaging with amyloid-β PET can potentially aid the early and accurate diagnosis of Alzheimers disease. Florbetaben (¹⁸F) is a promising ¹⁸F-labelled amyloid-β-targeted PET tracer in clinical development. We aimed to assess the sensitivity and specificity of florbetaben (¹⁸F) PET in discriminating between patients with probable Alzheimers disease and elderly healthy controls. METHODS We did a multicentre, open-label, non-randomised phase 2 study in 18 centres in Australia, Germany, Switzerland, and the USA. Imaging with florbetaben (¹⁸F) PET was done on patients with probable Alzheimers disease (age 55 years or older, mini-mental state examination [MMSE] score=18-26, clinical dementia rating [CDR]=0·5-2·0) and age-matched healthy controls (MMSE ≥ 28, CDR=0). Our primary objective was to establish the diagnostic efficacy of the scans in differentiating between patients with probable disease and age-matched healthy controls on the basis of neocortical tracer uptake pattern 90-110 min post-injection. PET images were assessed visually by three readers masked to the clinical diagnosis and all other clinical findings, and quantitatively by use of pre-established brain volumes of interest to obtain standard uptake value ratios (SUVRs), taking the cerebellar cortex as the reference region. This study is registered with ClinicalTrials.gov, number NCT00750282. FINDINGS 81 participants with probable Alzheimers disease and 69 healthy controls were assessed. Independent visual assessment of the PET scans showed a sensitivity of 80% (95% CI 71-89) and a specificity of 91% (84-98) for discriminating participants with Alzheimers disease from healthy controls. The SUVRs in all neocortical grey-matter regions in participants with Alzheimers disease were significantly higher (p < 0·0001) compared with the healthy controls, with the posterior cingulate being the best discriminator. Linear discriminant analysis of regional SUVRs yielded a sensitivity of 85% and a specificity of 91%. Regional SUVRs also correlated well with scores of cognitive impairment such as the MMSE and the word-list memory and word-list recall scores (r -0·27 to -0·33, p ≤ 0·021). APOE ɛ4 was more common in participants with positive PET images compared with those with negative scans (65%vs 22% [p=0·027] in patients with Alzheimers disease; 50%vs 16% [p = 0·074] in healthy controls). No safety concerns were noted. INTERPRETATION We provide verification of the efficacy, safety, and biological relevance of florbetaben (¹⁸F) amyloid-β PET and suggest its potential as a visual adjunct in the diagnostic algorithm of dementia. FUNDING Bayer Schering Pharma AG.

Florbetaben PET imaging to detect amyloid beta plaques in Alzheimer's disease: Phase 3 study

Evaluation of brain β‐amyloid by positron emission tomography (PET) imaging can assist in the diagnosis of Alzheimer disease (AD) and other dementias.

Serotonin and dopamine transporter imaging in patients with obsessive-compulsive disorder.

In obsessive-compulsive disorder (OCD), the success of pharmacological treatment with serotonin re-uptake inhibitors and atypical antipsychotic drugs suggests that both the central serotonergic and dopaminergic systems are involved in the pathophysiology of the disorder. We applied [123I]-2beta-carbomethoxy-3beta-(4-idiophenyl)tropane (beta-CIT) and a brain-dedicated high-resolution single photon emission computed tomography (SPECT) system to quantify dopamine transporter (DAT) and serotonin transporter (SERT) availability. By comparing 15 drug-naïve patients with OCD and 10 controls, we found a significantly reduced availability (corrected for age) of striatal DAT and of thalamic/hypothalamic, midbrain and brainstem SERT in OCD patients. Severity of OCD symptoms showed a significant negative correlation with thalamic/hypothalamic SERT availability, corrected for age and duration of symptoms. Our data provide evidence for imbalanced monoaminergic neurotransmitter modulation in OCD. Further studies with more selective DAT and SERT radiotracers are needed.

99mTechnetium-Ethyl-Cysteinate-Dimer Single-Photon Emission CT Can Predict Fatal Ischemic Brain Edema

BACKGROUND AND PURPOSE We sought to study the prognostic value of early 99mtechnetium-ethyl-cysteinate-dimer single-photon emission CT (99mTc-ECD SPECT) for fatal ischemic brain edema in patients with middle cerebral artery (MCA) stroke compared with the prognostic value of CT and of clinical findings. METHODS We prospectively studied 108 patients clinically, with 99mTc-ECD SPECT, and with CT within 6 hours of symptom onset (Scandinavian Stroke Scale <40 points) appropriate to MCA ischemia. The follow-up consisted of Scandinavian Stroke Scale and CT on days 1 and 7, Barthel Index, and Modified Rankin Scale after 3 months. An activity deficit of the complete MCA territory on the SPECT scans and a parenchymal hypoattenuation of the complete MCA territory on CT scans were considered as predictors for a fatal MCA infarction due to mass effect and midbrain herniation. RESULTS In 11 of 108 patients (10%), the MCA infarction was the cause of death. The sensitivity of SPECT for fatal outcome was 82% in both visual and semiquantitative analyses, while specificity was 98% and 99%, respectively. The sensitivity and specificity of baseline CT were 36% and 100%, respectively; the sensitivity and specificity of clinical findings (Scandinavian Stroke Scale, depressed level of consciousness, gaze deviation) varied from 36% to 73% and from 45% to 88%, respectively. In a multivariate logistic regression model, only SPECT findings were found to be independent predictors of malignant MCA infarction/death. CONCLUSIONS We were able to identify patients with fatal MCA infarction with high accuracy by using 99mTc-ECD SPECT within 6 hours of stroke onset. This technique offers great potential to select stroke patients for specific therapies, eg, decompressive hemicraniectomy, soon after onset of symptoms.

Inhalation of Nitric Oxide Prevents Ischemic Brain Damage in Experimental Stroke by Selective Dilatation of Collateral Arterioles

Rationale: Stroke is the third most common cause of death in industrialized countries. The main therapeutic target is the ischemic penumbra, potentially salvageable brain tissue that dies within the first few hours after blood flow cessation. Hence, strategies to keep the penumbra alive until reperfusion occurs are needed. Objective: To study the effect of inhaled nitric oxide on cerebral vessels and cerebral perfusion under physiological conditions and in different models of cerebral ischemia. Methods and Results: This experimental study demonstrates that inhaled nitric oxide (applied in 30% oxygen/70% air mixture) leads to the formation of nitric oxide carriers in blood that distribute throughout the body. This was ascertained by in vivo microscopy in adult mice. Although under normal conditions inhaled nitric oxide does not affect cerebral blood flow, after experimental cerebral ischemia induced by transient middle cerebral artery occlusion it selectively dilates arterioles in the ischemic penumbra, thereby increasing collateral blood flow and significantly reducing ischemic brain damage. This translates into significantly improved neurological outcome. These findings were validated in independent laboratories using two different mouse models of cerebral ischemia and in a clinically relevant large animal model of stroke. Conclusions: Inhaled nitric oxide thus may provide a completely novel strategy to improve penumbral blood flow and neuronal survival in stroke or other ischemic conditions.

Reduced α4β2*–Nicotinic Acetylcholine Receptor Binding and Its Relationship to Mild Cognitive and Depressive Symptoms in Parkinson Disease

CONTEXT Cognitive or depressive disorders are frequently noted in patients with Parkinson disease (PD) and may be related to altered signaling through alpha4beta2*-nicotinic acetylcholine receptors (alpha4beta2*-nAChRs). OBJECTIVE To assess the availability of alpha4beta2*-nAChRs and their relationship to mild cognitive and mild depressive symptoms in vivo in patients with PD. DESIGN Crossover comparison between patients with PD and healthy volunteers (control group) using the alpha4beta2*-nAChR-specific radioligand 2-[(18)F]fluoro-3-(2[S]-2-azetidinylmethoxy)-pyridine (2-[(18)F]FA-85380) and positron emission tomography. SETTING Departments of Neurology and Nuclear Medicine, University of Leipzig, Leipzig, Germany. PARTICIPANTS Twenty-two nonsmoking patients with PD and 9 nonsmoking healthy volunteers. MAIN OUTCOME MEASURES Level of 2-[(18)F]FA-85380 binding potential (2-FA BP), a measure of alpha4beta2*-nAChR availability. The relationship between severity of cognitive symptoms as rated using the Mini-Mental State Examination and DemTect scale and the level of depressive symptoms as indicated using the Beck Depression Inventory, and 2-FA BP were assessed. RESULTS In patients with PD compared with healthy volunteers, there was widespread reduced 2-FA BP, especially in the midbrain, pons, anterior cingulate cortex, frontoparietal cortex, and cerebellum. In subgroups of patients with PD with possible depression, reduced 2-FA BP was most pronounced in the cingulate cortex and frontoparieto-occipital cortex, whereas in patients with PD with mild cognitive impairment, 2-FA BP was reduced in the midbrain, pons, and cerebellum. In patients with PD, the strongest associations between depressive symptoms and reduced 2-FA BP were noted in the anterior cingulate cortex, putamen, midbrain, and occipital cortex. In contrast, cognitive symptoms correlated only weakly with reduced 2-FA BP in the thalamus, midbrain, temporal cortex, hippocampus, and cerebellum. CONCLUSIONS There is a broad reduction of alpha4beta2*-nAChR availability in patients with PD without clinically manifest dementia or depression compared with healthy volunteers. Reduced alpha4beta2*-nAChR binding in patients with PD within the subcortical and cortical regions is associated with the severity of mild cognitive or depressive symptoms. These results provide novel in vivo evidence for a role of the cholinergic neurotransmission in psychiatric comorbidity of PD.

Combined Evaluation of FDG-PET and MRI Improves Detection and Differentiation of Dementia

Introduction Various biomarkers have been reported in recent literature regarding imaging abnormalities in different types of dementia. These biomarkers have helped to significantly improve early detection and also differentiation of various dementia syndromes. In this study, we systematically applied whole-brain and region-of-interest (ROI) based support vector machine classification separately and on combined information from different imaging modalities to improve the detection and differentiation of different types of dementia. Methods Patients with clinically diagnosed Alzheimers disease (AD: n = 21), with frontotemporal lobar degeneration (FTLD: n = 14) and control subjects (n = 13) underwent both [F18]fluorodeoxyglucose positron emission tomography (FDG-PET) scanning and magnetic resonance imaging (MRI), together with clinical and behavioral assessment. FDG-PET and MRI data were commonly processed to get a precise overlap of all regions in both modalities. Support vector machine classification was applied with varying parameters separately for both modalities and to combined information obtained from MR and FDG-PET images. ROIs were extracted from comprehensive systematic and quantitative meta-analyses investigating both disorders. Results Using single-modality whole-brain and ROI information FDG-PET provided highest accuracy rates for both, detection and differentiation of AD and FTLD compared to structural information from MRI. The ROI-based multimodal classification, combining FDG-PET and MRI information, was highly superior to the unimodal approach and to the whole-brain pattern classification. With this method, accuracy rate of up to 92% for the differentiation of the three groups and an accuracy of 94% for the differentiation of AD and FTLD patients was obtained. Conclusion Accuracy rate obtained using combined information from both imaging modalities is the highest reported up to now for differentiation of both types of dementia. Our results indicate a substantial gain in accuracy using combined FDG-PET and MRI information and suggest the incorporation of such approaches to clinical diagnosis and to differential diagnostic procedures of neurodegenerative disorders.

PET/MR in children. Initial clinical experience in paediatric oncology using an integrated PET/MR scanner

Use of PET/MR in children has not previously been reported, to the best of our knowledge. Children with systemic malignancies may benefit from the reduced radiation exposure offered by PET/MR. We report our initial experience with PET/MR hybrid imaging and our current established sequence protocol after 21 PET/MR studies in 15 children with multifocal malignant diseases. The effective dose of a PET/MR scan was only about 20% that of the equivalent PET/CT examination. Simultaneous acquisition of PET and MR data combines the advantages of the two previously separate modalities. Furthermore, the technique also enables whole-body diffusion-weighted imaging (DWI) and statements to be made about the biological cellularity and nuclear/cytoplasmic ratio of tumours. Combined PET/MR saves time and resources. One disadvantage of PET/MR is that in order to have an effect, a significantly longer examination time is needed than with PET/CT. In our initial experience, PET/MR has turned out to be an unexpectedly stable and reliable hybrid imaging modality, which generates a complementary diagnostic study of great additional value.

Multimodal imaging in Alzheimer's disease: Validity and usefulness for early detection

Alzheimers disease is a progressive neurodegenerative disease that typically manifests clinically as an isolated amnestic deficit that progresses to a characteristic dementia syndrome. Advances in neuroimaging research have enabled mapping of diverse molecular, functional, and structural aspects of Alzheimers disease pathology in ever increasing temporal and regional detail. Accumulating evidence suggests that distinct types of imaging abnormalities related to Alzheimers disease follow a consistent trajectory during pathogenesis of the disease, and that the first changes can be detected years before the disease manifests clinically. These findings have fuelled clinical interest in the use of specific imaging markers for Alzheimers disease to predict future development of dementia in patients who are at risk. The potential clinical usefulness of single or multimodal imaging markers is being investigated in selected patient samples from clinical expert centres, but additional research is needed before these promising imaging markers can be successfully translated from research into clinical practice in routine care.

Differential effects of global and cerebellar normalization on detection and differentiation of dementia in FDG-PET studies

FDG-PET ([18F]fluorodeoxyglucose positron emission tomography) is frequently used to improve the differential diagnosis of dementia. However, a fundamental methodological issue of the reference area for the intensity normalization procedure is still unsolved. Here, we systematically compared the two most commonly used normalization methods to the cerebral and to the cerebellar metabolic rate for glucose with regard to detection and differentiation of dementia syndromes. FDG-PET imaging was performed on 19 subjects with early Alzheimers disease, 13 subjects with early frontotemporal lobar degeneration and 10 subjects complaining of memory impairment, which had not been confirmed by comprehensive clinical testing. Images were normalized to either the cerebral or the cerebellar metabolic rate for glucose. Differences in relative regional glucose metabolism were assessed by voxelwise comparison. Analysis using the two normalization procedures revealed remarkable differential effects. Whereas cerebellar normalization was superior in identifying dementia patients in comparison to control subjects, cerebral normalization showed better results for differential diagnosis between types of dementia. These effects were shown for both, Alzheimers disease and frontotemporal lobar degeneration. Relative hypermetabolism in comparison to the control group was only detected in both kinds of dementia using global normalization. The results indicate that normalization has a decisive impact on diagnostic accuracy in dementia. While cerebellar normalization seems to be more sensitive for early diagnosis, cerebral global normalization might be superior for differential diagnostic purposes in dementia syndromes.