Highlights • CX3CR1-deficient mice are resistant to chronic stress in the CDM model. • Microglia in wild type animals show hyper-ramification in the CDM model. • Microglia hyper-ramification may be ...crucial for depressive-like behavior development.
Abstract Cerebral atrophy is a key finding in patients with dementia and usually determined on MRI. We tested whether cerebral atrophy can be imaged with FDG PET by applying deformation-based ...morphometry (DBM). We retrospectively identified 26 patients with a biomarker-supported clinical diagnosis of Alzheimer’s disease (AD) who had received FDG PET on a fully-digital PET/CT system and structural MRI and compared them to 13 healthy elderly controls (HEC). We performed DBM with FDG PET data (FDG-DBM). As a reference standard for determining atrophy we used voxel-based morphometry of MRI data (MRI-VBM). For conventional analysis of hypometabolism, scaled FDG PET scans (reference: brain parenchyma) were compared between groups. Receiver operating characteristic (ROC) analyses were performed. ROI read-outs were tested for associations with cognitive test performance. FDG-DBM showed abnormalities in AD mainly in the bilateral hippocampi. Similarly, MRI-VBM showed hippocampal atrophy. By contrast, conventional FDG PET analysis revealed reduced bilateral temporo-parietal FDG uptake (all p < 0.05, FWE-corrected). FDG-DBM measures of the hippocampus significantly separated AD from HEC with an AUC of 0.81; MRI-VBM achieved an AUC of 0.87; the difference between the two ROC curves was not significant ( p = 0.40). Whereas FDG uptake of the hippocampus did not separate AD from HEC, FDG uptake of the Landau Meta-ROI achieved an AUC of 0.88. Verbal memory was significantly associated with FDG-DBM measures of the hippocampus ( p = 0.009), but not of the Landau Meta-ROI ( p > 0.1). The opposite held true for conventional FDG uptake ( p > 0.1 and p = 0.001, respectively). Hippocampal atrophy in AD can be detected by applying DBM to clinical, fully-digital FDG PET. It correlates with cognitive performance and might constitute a biomarker of neurodegeneration that is complementary to conventional FDG PET analysis of regional hypometabolism.
Positron emission tomography (PET) with the glucose analog F-18-fluorodeoxyglucose (FDG) is widely used in the diagnosis of neurodegenerative diseases. Guidelines recommend voxel-based statistical ...testing to support visual evaluation of the PET images. However, the performance of voxel-based testing strongly depends on each single preprocessing step involved.
To optimize the processing pipeline of voxel-based testing for the prognosis of dementia in subjects with amnestic mild cognitive impairment (MCI).
The study included 108 ADNI MCI subjects grouped as 'stable MCI' (n = 77) or 'MCI-to-AD converter' according to their diagnostic trajectory over 3 years. Thirty-two ADNI normals served as controls. Voxel-based testing was performed with the statistical parametric mapping software (SPM8) starting with default settings. The following modifications were added step-by-step: (i) motion correction, (ii) custom-made FDG template, (iii) different reference regions for intensity scaling, and (iv) smoothing was varied between 8 and 18 mm. The t-sum score for hypometabolism within a predefined AD mask was compared between the different settings using receiver operating characteristic (ROC) analysis with respect to differentiation between 'stable MCI' and 'MCI-to-AD converter'. The area (AUC) under the ROC curve was used as performance measure.
The default setting provided an AUC of 0.728. The modifications of the processing pipeline improved the AUC up to 0.832 (p = 0.046). Improvement of the AUC was confirmed in an independent validation sample of 241 ADNI MCI subjects (p = 0.048).
The prognostic value of voxel-based single subject analysis of brain FDG PET in MCI subjects can be improved considerably by optimizing the processing pipeline.
Whole brain radiation therapy (WBRT) is the standard therapy for multiple brain metastases. However, WBRT has a poor local tumor control and is associated with a decline in neurocognitive function ...(NCF). Aim of this trial is to assess the efficacy and safety of a new treatment method, the WBRT with hippocampus avoidance (HA) combined with the simultaneous integrated boost (SIB) on metastases/resection cavities (HA-WBRT+SIB).
This is a prospective, randomized, two-arm phase II multicenter trial comparing the impact of HA on NCF after HA-WBRT+SIB versus WBRT+SIB in patients with multiple brain metastases. The study design is double-blinded. One hundred thirty two patients are to be randomized with a 1:1 allocation ratio. Patients between 18 and 80 years old are recruited, with at least 4 brain metastases of solid tumors and at least one, but not exceeding 10 metastases ≥5 mm. Patients must be in good physical condition and have no metastases/resection cavities in or within 7 mm of the hippocampus. Patients with dementia, meningeal disease, cerebral lymphomas, germ cell tumors, or small cell carcinomas are excluded. Previous irradiation and resection of metastases, as well as the number and size of metastases to be boosted have to comply with certain restrictions. Patients are randomized between the two treatment arms: HA-WBRT+SIB and WBRT+SIB. WBRT is to be performed with 30 Gy in 12 daily fractions and the SIB with 51 Gy/42 Gy in 12 daily fractions on 95% of volume for metastases/resection cavities. In the experimental arm, the dose to the hippocampi is restricted to 9 Gy in 98% of the volume and 17Gy in 2% of the volume. NCF testing is scheduled before WBRT, after 3 (primary endpoint), 9, 18 months and yearly thereafter. Clinical and imaging follow-ups are performed 6 and 12 weeks after WBRT, after 3, 9, 18 months and yearly thereafter.
This is a protocol of a randomized phase II trial designed to test a new strategy of WBRT for preventing cognitive decline and increasing tumor control in patients with multiple brain metastases.
The HIPPORAD trial is registered with the German Clinical Trials Registry (DRKS00004598, registered 2 June 2016).
Identification of patients with idiopathic normal pressure hydrocephalus (iNPH) in a collective with suspected neurodegenerative disease is essential. This study aimed to determine the metabolic ...spatial covariance pattern of iNPH on FDG PET using an established technique based on scaled subprofile model principal components analysis (SSM-PCA).We identified 11 patients with definite iNPH. By applying SSM-PCA to the FDG PET data, they were compared to 48 age-matched healthy controls to determine the whole-brain voxel-wise metabolic spatial covariance pattern of definite iNPH (iNPH-related pattern, iNPHRP). The iNPHRP score was compared between groups of patients with definite iNPH, possible iNPH (N = 34), Alzheimer's (AD, N = 38), and Parkinson's disease (PD, N = 35) applying pairwise Mann-Whitney U tests and correction for multiple comparisons.SSM-PCA of FDG PET revealed an iNPHRP that is characterized by relative negative voxel weights at the vicinity of the lateral ventricles and relative positive weights in the paracentral midline region. The iNPHRP scores of patients with definite iNPH were substantially higher than in patients with AD and PD (both p < 0.05) and non-significantly higher than those of patients with possible iNPH. Subject scores of the iNPHRP discriminated definite iNPH from AD and PD with 96% and 100% accuracy and possible iNPH from AD and PD with 83% and 86% accuracy.We defined a novel metabolic spatial covariance pattern of iNPH that might facilitate the differential diagnosis of iNPH versus other neurodegenerative disorders. The knowledge of iNPH-associated alterations in the cerebral glucose metabolism is of high relevance as iNPH constitutes an important differential diagnosis to dementia and movement disorders.
Left-predominant neurodegeneration of the anterior temporal lobe (ATL) and the associated syndrome termed semantic variant primary progressive aphasia (svPPA) are well characterized. Less is known ...about right-predominant neurodegeneration of the ATL, which has been associated with the clinical syndrome named right temporal variant of frontotemporal dementia (rtvFTD). Here, we assessed glucose metabolism across the brain, cognitive performance, and mortality in patients with right-predominant neurodegeneration of the ATL.
Patients with predominant hypometabolism of the ATL on FDG PET (as a measure of neurodegeneration) were retrospectively identified and categorized into those with asymmetrical right, left, or symmetric bilateral involvement (N = 10, 17, and 8). We compared whole-brain, normalized regional glucose metabolism using SPM12, cognitive performance on the CERAD Neuropsychological Assessment Battery, and mortality risk (age- and sex-adjusted Cox proportional hazard model) between groups.
Hypometabolism was most pronounced and extensive in patients with right-predominant neurodegeneration of the ATL. Beyond the right temporal lobe, right frontal and left temporal lobes were affected in these patients. Cognitive performance was similarly impaired in all three groups, with predominant naming and hippocampal-dependent memory deficits. Mortality risk was 6.1 times higher in patients with right- than left-predominant ATL neurodegeneration (p < 0.05). Median survival duration after PET was shortest in patients with right- and longest in patients with left-predominant ATL neurodegeneration (5.7 vs 8.3 years after examination).
More extensive neurodegeneration and shorter survival duration in patients with right- than left-predominant neurodegeneration of the ATL might indicate that the former consult memory clinics at a later disease stage, when symptoms like naming and episodic memory deficits have already emerged. At the time of diagnosis, the shorter survival duration of patients with right- than left-predominant ATL neurodegeneration should be kept in mind when counseling patients and caregivers.
Positron emission tomography (PET) has been successfully used to investigate central nervous processes, including the central auditory pathway. Unlike early water-cooled PET-scanners, novel PET/CT ...scanners employ air cooling and include a CT system, both of which result in higher background noise levels. In the present study, we describe the background noise generated by two state-of-the-art air-cooled PET/CT scanners. We measured speech recognition in background noise: recorded PET noise and a speech-shaped noise applied in clinical routine to subjects with normal hearing. Background noise produced by air-cooled PET/CT is considerable: 75.1 dB SPL (64.5 dB(A)) for the Philips Gemini TF64 and 76.9 dB SPL (68.4 dB(A)) for the Philips Vereos PET/CT (Philips Healthcare, The Netherlands). Subjects with normal hearing exhibited better speech recognition in recorded PET background noise compared with clinically applied speech-shaped noise. Speech recognition in both background noises correlated significantly. Background noise generated by PET/CT scanners should be considered when PET is used for the investigation of the central auditory pathway. Speech in PET noise is better than in speech-shaped noise because of the minor masking effect of the background noise of the PET/CT.
Behavioural variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD) dementia are characterised by progressive brain atrophy. Longitudinal MRI volumetry may help to characterise ongoing ...structural degeneration and support the differential diagnosis of dementia subtypes. Automated, observer-independent atlas-based MRI volumetry was applied to analyse 102 MRI data sets from 15 bvFTD, 14 AD, and 10 healthy elderly control participants with consecutive scans over at least 12 months. Anatomically defined targets were chosen a priori as brain structures of interest. Groups were compared regarding volumes at clinic presentation and annual change rates. Baseline volumes, especially of grey matter compartments, were significantly reduced in bvFTD and AD patients. Grey matter volumes of the caudate and the gyrus rectus were significantly smaller in bvFTD than AD. The bvFTD group could be separated from AD on the basis of caudate volume with high accuracy (79% cases correct). Annual volume decline was markedly larger in bvFTD and AD than controls, predominantly in white matter of temporal structures. Decline in grey matter volume of the lateral orbitofrontal gyrus separated bvFTD from AD and controls. Automated longitudinal MRI volumetry discriminates bvFTD from AD. In particular, greater reduction of orbitofrontal grey matter and temporal white matter structures after 12 months is indicative of bvFTD.
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