Showing papers by "Bart N.M. van Berckel published in 2016"

Cerebral perfusion in the predementia stages of Alzheimer’s disease

Abstract: Objectives To investigate arterial spin-labelling (ASL) cerebral blood flow (CBF) changes in predementia stages of Alzheimer’s disease (AD).

Atrophy, hypometabolism and clinical trajectories in patients with amyloid-negative Alzheimer's disease.

Abstract: See O'Sullivan and Vann (doi:10.1093/aww166) for a scientific commentary on this article.About 15% of patients clinically diagnosed with Alzheimer's disease do not show high tracer retention on amyloid positon emission tomography imaging. The present study investigates clinical and demographic features, patterns of brain atrophy and hypometabolism and longitudinal clinical trajectories of these patients. Forty amyloid-negative patients carrying a pre-scan diagnosis of Alzheimer's disease dementia from four centres were included (11/29 females/males; mean age = 67 ± 9). Detailed clinical histories, including the clinical diagnoses before and after the amyloid scan and at follow-up, were collected. Patients were classified according to their pre-scan clinical phenotype as amnestic (memory predominant), non-amnestic (predominant language, visuospatial or frontal symptoms), or non-specific (diffuse cognitive deficits). Demographic, clinical, neuropsychological, magnetic resonance imaging and (18)F-fluorodeoxyglucose positon emission tomography data were compared to 27 amyloid-positive typical Alzheimer's disease cases (14/13 females/males; mean age = 71 ± 10) and 29 amyloid-negative controls (15/14 females/males; mean age = 69 ± 12) matched for age, gender and education. There were 21 amnestic, 12 non-amnestic, and seven non-specific amyloid-negative Alzheimer's disease cases. Amyloid-negative subgroups did not differ in age, gender or education. After the amyloid scan, clinicians altered the diagnosis in 68% of amyloid-negative patients including 48% of amnestic versus 94% of non-amnestic and non-specific cases. Amnestic amyloid-negative cases were most often reclassified as frontotemporal dementia, non-amnestic as frontotemporal dementia or corticobasal degeneration, and non-specific as dementia with Lewy bodies or unknown diagnosis. The longer-term clinical follow-up was consistent with the post-scan diagnosis in most cases (90%), including in amnestic amyloid-negative cases whose post-positon emission tomography diagnosis remained Alzheimer's disease. While the non-amnestic and non-specific amyloid-negative cases usually showed patterns of atrophy and hypometabolism suggestive of another degenerative disorder, the amnestic amyloid-negative cases had subtle atrophy and hypometabolism, restricted to the retrosplenial/posterior cingulate cortex. Patients with a negative amyloid positon emission tomography scan following an initial clinical diagnosis of Alzheimer's disease have heterogeneous clinical presentations and neuroimaging profiles; a majority showed a clinical progression that was consistent with a neurodegenerative condition. In contrast, in the subgroup of amnestic amyloid-negative cases, the clinical presentation and follow-up usually remained consistent with Alzheimer's disease. An alternative diagnosis was not made in about half of the amnestic amyloid-negative cases, highlighting the need for a clinical framework and terminology to define these patients, who may have underlying limbic-predominant, non-amyloid-related pathologies.

Application of Machine Learning to Arterial Spin Labeling in Mild Cognitive Impairment and Alzheimer Disease.

Abstract: Purpose To investigate whether multivariate pattern recognition analysis of arterial spin labeling (ASL) perfusion maps can be used for classification and single-subject prediction of patients with Alzheimer disease (AD) and mild cognitive impairment (MCI) and subjects with subjective cognitive decline (SCD) after using the W score method to remove confounding effects of sex and age. Materials and Methods Pseudocontinuous 3.0-T ASL images were acquired in 100 patients with probable AD; 60 patients with MCI, of whom 12 remained stable, 12 were converted to a diagnosis of AD, and 36 had no follow-up; 100 subjects with SCD; and 26 healthy control subjects. The AD, MCI, and SCD groups were divided into a sex- and age-matched training set (n = 130) and an independent prediction set (n = 130). Standardized perfusion scores adjusted for age and sex (W scores) were computed per voxel for each participant. Training of a support vector machine classifier was performed with diagnostic status and perfusion maps. Discrimination maps were extracted and used for single-subject classification in the prediction set. Prediction performance was assessed with receiver operating characteristic (ROC) analysis to generate an area under the ROC curve (AUC) and sensitivity and specificity distribution. Results Single-subject diagnosis in the prediction set by using the discrimination maps yielded excellent performance for AD versus SCD (AUC, 0.96; P .05). Conclusion With automated methods, age- and sex-adjusted ASL perfusion maps can be used to classify and predict diagnosis of AD, conversion of MCI to AD, stable MCI, and SCD with good to excellent accuracy and AUC values. © RSNA, 2016.

Use of amyloid-PET to determine cutpoints for CSF markers: A multicenter study

Abstract: Objectives: To define CSF β-amyloid 1–42 (Aβ 42 ) cutpoints to detect cortical amyloid deposition as assessed by 11 C-Pittsburgh compound B ([ 11 C]PiB)-PET and to compare these calculated cutpoints with cutpoints currently used in clinical practice. Methods: We included 433 participants (57 controls, 99 with mild cognitive impairment, 195 with Alzheimer disease [AD] dementia, and 82 with non-AD dementia) from 5 European centers. We calculated for each center and for the pooled cohort CSF Aβ 42 and Aβ 42 /tau ratio cutpoints for cortical amyloid deposition based on visual interpretation of [ 11 C]PiB-PET images. Results: Amyloid-PET–based calculated CSF Aβ 42 cutpoints ranged from 521 to 616 pg/mL, whereas existing clinical-based cutpoints ranged from 400 to 550 pg/mL. Using the calculated cutpoint from the pooled sample (557 pg/mL), concordance between CSF Aβ 42 and amyloid-PET was 84%. Similar concordance was found when using a dichotomized Aβ 42 /tau ratio. Exploratory analysis showed that participants with a positive amyloid-PET and normal CSF Aβ 42 levels had higher CSF tau and phosphorylated tau levels and more often had mild cognitive impairment or AD dementia compared with participants who had negative amyloid-PET and abnormal CSF Aβ 42 levels. Conclusions: Amyloid-PET–based CSF Aβ 42 cutpoints were higher and tended to reduce intercenter variability compared with clinical-based cutpoints. Discordant participants with normal CSF Aβ 42 and a positive amyloid-PET may be more likely to have AD-related amyloid pathology than participants with abnormal CSF Aβ 42 and a negative amyloid-PET. Classification of evidence: This study provides Class II evidence that an amyloid-PET–based CSF Aβ 42 cutpoint identifies individuals with amyloid deposition with a sensitivity of 87% and specificity of 80%.

Diagnostic Accuracy of MRI and Additional [18F]FDG-PET for Behavioral Variant Frontotemporal Dementia in Patients with Late Onset Behavioral Changes.

Abstract: Background: Neuroimaging has a reasonable accuracy to differentiate behavioral variant frontotemporal dementia (bvFTD) from other neurodegenerative disorders, its value for the differentiation of bvFTD among subjects with acquired behavioral disturbances is unknown. Objective: To determine the diagnostic accuracy of MRI, additional [18F]FDG-PET, and their combination for bvFTD among subjects with late onset behavioral changes. Methods: Patients with late onset behavioral changes referred to a memory clinic or psychiatric services were included. At baseline, 111 patients had a brain MRI scan and 74 patients received an additional [18F]FDG-PET when the MRI was inconclusive. The consensus diagnosis after two-year-follow-up was used as the gold standard to calculate sensitivity and specificity for baseline neuroimaging. Results: 27 patients had probable/definite bvFTD and 84 patients had a non-bvFTD diagnosis (primary psychiatric diagnosis or other neurological disorders). MRI had a sensitivity of 70% (95% CI 52–85%) with a specificity of 93% (95% CI 86–97%). Additional [18F]FDG-PET had a sensitivity of 90% (95% CI 66–100%) with a specificity of 68% (95% CI 56–79%). The sensitivity of combined neuroimaging was 96% (95% CI 85–100%) with a specificity of 73% (95% CI 63–81%). In 66% of the genetic FTD cases, MRI lacked typical frontotemporal atrophy. 40% of cases with a false positive [18F]FDG-PET scan had a primary psychiatric diagnosis. Conclusion: A good diagnostic accuracy was found for MRI and additional [18F]FDG-PET for bvFTD in patients with late onset behavioral changes. Caution with the interpretation of neuroimaging results should especially be taken in cases with a genetic background and in cases with a primary psychiatric differential diagnosis where [18F]FDG-PET is the only abnormal investigation.

Heterogeneous Language Profiles in Patients with Primary Progressive Aphasia due to Alzheimer's Disease

Abstract: Background: The logopenic variant of Primary Progressive Aphasia (lvPPA) is associated with underlying Alzheimer’s disease (AD) pathology and characterized by impaired single word retrieval and repetition of phrases and sentences. Objective: We set out to study whether logopenic aphasia is indeed the prototypic language profile in PPA patients with biomarker evidence of underlying AD pathology and to correlate language profiles with cortical atrophy patterns on MRI. Methods: Inclusion criteria: (I) clinical diagnosis of PPA; (II) CSF profile and/or PiB-PET scan indicative for amyloid pathology; (III) availability of expert language evaluation. Based on language evaluation, patients were classified as lvPPA (fulfilling lvPPA core criteria), lvPPA extended (fulfilling core criteria plus other language disturbances), or PPA unclassifiable (not fulfilling lvPPA core criteria). Cortical atrophy patterns on MRI were visually rated and quantitative measurements of cortical thickness were performed using FreeSurfer. Results: We included 22 patients (age 67 ± 7 years, 50% female, MMSE 21 ± 6). 41% were classified as lvPPA, 36% as lvPPA extended with additional deficits in language comprehension and/or confrontation naming, and 23% as PPA unclassifiable. By both qualitative and quantitative measurements, patients with lvPPA showed mild global cortical atrophy on MRI, whereas patients with lvPPA extended showed more focal cortical atrophy, predominantly at the left tempo-parietal side. For PPA unclassifiable, qualitative measurements revealed a heterogeneous atrophy pattern. Conclusion: Although most patients fulfilled the lvPPA criteria, we found that their language profiles were heterogeneous. The clinical and radiological spectrum of PPA due to underlying AD pathology is broader than pure lvPPA.

Diagnostic Accuracy of the Frontotemporal Dementia Consensus Criteria in the Late-Onset Frontal Lobe Syndrome

Abstract: Background/Aims: We aimed to prospectively assess the diagnostic accuracy of the revised criteria for behavioural variant frontotemporal dementia (bvFTD) among subjects presenting with a frontal lobe syndrome in middle-late adulthood. Methods: Patients were included based on a predominant behavioural clinical presentation, a Frontal Behavioural Inventory (FBI) score of ≥11 and/or a Stereotypy Rating Inventory (SRI) score of ≥10. At baseline, the fulfilment of the international consensus criteria for behavioural variant FTD (FTDC) was systematically recorded. The 2-year follow-up consensus diagnosis was used as the gold standard to calculate sensitivity and specificity of the FTDC criteria for possible and probable bvFTD. Results: Two-year follow-up data were available for 116 patients (85%). Two-year follow-up consensus diagnoses consisted of probable/definite bvFTD (n = 27), other dementia (n = 30), psychiatric disorders (n = 46) and other neurological disorders (n = 13). Sensitivity for possible bvFTD was 85% (95% CI 70-95%) at a specificity of 27% (95% CI 19-37%). Sensitivity for probable bvFTD was 85% (95% CI 69-95%), whereas their specificity was 82% (95% CI 73-89%). Conclusions: We found a good diagnostic accuracy for FTDC probable bvFTD. However, the specificity for FTDC possible bvFTD was low. Our results reflect the symptomatic overlap between bvFTD, other neurological conditions and psychiatric disorders, and the relevance of adding neuroimaging to the diagnostic process.

Novel MRI and PET markers of neuroinflammation in multiple sclerosis.

Abstract: PURPOSE OF REVIEW: Gadolinium-enhancement depicts blood-brain barrier disruption associated with new inflammatory MRI lesions in multiple sclerosis (MS) and is widely used for diagnosis and therapeutic monitoring. However, earlier and more specific markers of inflammation are urgently needed. RECENT FINDINGS: Susceptibility-weighted images demonstrate the importance of the central vein in the formation of MS lesions. Perfusion weighted imaging techniques can show focal and diffuse low-grade inflammatory changes not visible on conventional MRI. Leptomeningeal enhancement could be part of the aetiology of subpial cortical MS lesions. Ultrasmall superparamagnetic particles of iron oxide can identify neuroinflammatory changes in addition to gadolinium enhancement and as such identify different types and phases of MS lesions. 18kD-translocator protein PET tracers identify activated microglia and an increase in TSPO uptake in both MS lesions and normal appearing brain tissue is related to disease severity and progression. A range of novel tracers for microglia activation is under development as well as radioligands that can label therapeutic drugs. SUMMARY: Novel MRI and PET techniques improve in-vivo visualization and quantification of the pleomorphic aspects of neuroinflammation, providing us with a unique insight in its pathogenesis, clinical relevance, and therapy responsiveness in MS.

Parametric Binding Images of the TSPO Ligand 18F-DPA-714

Abstract: 18F-labeled N,N-diethyl-2-(2-[4-(2-fluoroethoxy)phenyl]-5,7-dimethylpyrazolo[1,5-α]pyrimidine-3-yl)acetamide (DPA-714) is a radioligand for the 18-kDa translocator protein. The purpose of the present study was to identify the best method for generating quantitative parametric images of 18F-DPA-714 binding. Methods: Ninety-minute dynamic 18F-DPA-714 PET scans with full arterial sampling from 6 healthy subjects and 9 Alzheimer disease (AD) patients were used. Plasma-input–based Logan graphical analysis and spectral analysis were used to generate parametric volume of distribution (VT) images. Five versions of Ichise, reference Logan, and 2 basis function implementations (receptor parametric mapping and simplified reference tissue model 2 [SRTM2]) of SRTM, all using gray matter cerebellum as the reference region, were applied to generate nondisplaceable binding potential (BPND) images. Results: Plasma-input Logan analysis (r2 = 0.99; slope, 0.88) and spectral analysis (r2 = 0.99, slope, 0.93) generated estimates of VT that correlated well with values obtained using nonlinear regression. BPND values generated using SRTM2 (r2 = 0.83; slope, 0.95) and reference Logan analysis (r2 = 0.88; slope, 1.01) correlated well with nonlinear regression–based estimates. Conclusion: Both Logan analysis and spectral analysis can be used to obtain quantitatively accurate VT images of 18F-DPA-714. In addition, SRTM2 and reference Logan analysis can provide accurate BPND images. These parametric images could be used for voxel-based comparisons.

The Association of Glucose Metabolism and Eigenvector Centrality in Alzheimer's Disease

Abstract: Both fluorine-18-labeled fluorodeoxyglucose ([(18)F]FDG) positron emission tomography, examining glucose metabolism, and resting-state functional magnetic resonance imaging (rs-fMRI), using covarying blood oxygen levels, can be used to explore neuronal dysfunction in Alzheimer's disease (AD). Both measures are reported to identify similar brain regions affected in AD patients. The spatial overlap and association of [(18)F]FDG with rs-fMRI in AD patients and controls were examined to investigate whether these two measures are associated, and if so, to what extent. For 24 AD patients and 18 controls, [(18)F]FDG and rs-fMRI data were available. [(18)F]FDG standardized uptake value ratios (SUVr), with cerebellar gray matter (GM) as reference tissue, were calculated. Eigenvector centrality (EC) mapping was used to spatially analyze the functional brain network. Group differences were calculated for [(18)F]FDG and eigenvector centrality mapping (ECM) values in four cortical regions (occipital, parietal, frontal, and temporal) and across voxels, with age, gender, and GM as covariates. Correlation of [(18)F]FDG with ECM was calculated within groups. Both lowered [(18)F]FDG SUVr and EC values were seen in the parietal and occipital cortex of AD patients. However, [(18)F]FDG yielded more robust and widespread brain areas affected in AD patients; hypometabolism was also observed in the temporal cortex and regions within frontal brain areas. Poor spatial overlap of both measures was observed. No associations were found between local [(18)F]FDG SUVr and ECM. In conclusion, agreement of [(18)F]FDG and ECM in AD patients seems moderate at best. [(18)F]FDG was most accurate in distinguishing AD patients from controls.

Quantification of the novel N-methyl-d-aspartate receptor ligand [11C]GMOM in man

Abstract: [11C]GMOM (carbon-11 labeled N-(2-chloro-5-thiomethylphenyl)-N′-(3-[11C]methoxy-phenyl)-N′-methylguanidine) is a PET ligand that binds to the N-methyl-d-aspartate receptor with high specificity and affinity. The purpose of this first in human study was to evaluate kinetics of [11C]GMOM in the healthy human brain and to identify the optimal pharmacokinetic model for quantifying these kinetics, both before and after a pharmacological dose of S-ketamine. Dynamic 90 min [11C]GMOM PET scans were obtained from 10 subjects. In six of the 10 subjects, a second PET scan was performed following an S-ketamine challenge. Metabolite corrected plasma input functions were obtained for all scans. Regional time activity curves were fitted to various single- and two-tissue compartment models. Best fits were obtained using a two-tissue irreversible model with blood volume parameter. The highest net influx rate (Ki) of [11C]GMOM was observed in regions with high N-methyl-d-aspartate receptor density, such as hippocampus and thalamus. A significant reduction in the Ki was observed for the entire brain after administration of ketamine, suggesting specific binding to the N-methyl-d-aspartate receptors. This initial study suggests that the [11C]GMOM could be used for quantification of N-methyl-d-aspartate receptors.

Blood-Brain Barrier ABC-transporter P-glycoprotein in Alzheimer's Disease: still a suspect?

Abstract: Alzheimer's disease is a neurodegenerative disorder and the most common form of dementia. One of the pathological hallmarks of the disease is amyloid deposition in the brain. The major cause of amyloid deposition in sporadic Alzheimer's disease is thought to be decreased brain clearance of amyloid. There is compelling preclinical evidence that the blood-brain barrier, a structure that maintains homeostasis in the central nervous system and protects the brain from harmful substances, plays an important role in amyloid clearance. Indeed, several dedicated transporter systems are present at the blood-brain barrier which may have a role in brain amyloid clearance, such as P-glycoprotein (P-gp). In vitro experiments and animal studies indicated increased amyloid deposition when P-gp was eliminated by pharmacological blockade or by genetic modification. And as decreased P-gp expression has been found in AD brains, P-gp became more and more a suspect. Using an imaging technique called positron emission tomography, P-gp transporter function was found to be decreased in Alzheimer's disease patients compared to healthy controls, further establishing the important role of P-gp in the pathogenesis of the disease. In this review, we summarize what is now known about P-gp in Alzheimer's disease pathology, as these transporters may provide a novel target for therapeutic strategies.

Impact of Imaging and Cerebrospinal Fluid Biomarkers on Behavioral Variant Frontotemporal Dementia Diagnosis within a Late-Onset Frontal Lobe Syndrome Cohort

Abstract: Background: The criteria for behavioral variant frontotemporal dementia (bvFTD) incorporate MRI and [18F]-FDG-PET. Cerebrospinal fluid (CSF) analysis i

Schizophrenia as a mimic of behavioral variant frontotemporal dementia

Abstract: Recently, the diagnostic criteria for the behavioral variant of frontotemporal dementia were revised. Although these criteria offer a relatively high sensitivity, their specificity is yet unknown. We describe a 54-year-old woman fulfilling criteria for both late-onset schizophrenia and probable behavioral variant frontotemporal dementia. Following an initial presentation with psychosis, she developed progressive apathy, compulsiveness, and executive dysfunction. Moreover, bilateral frontotemporal hypometabolism was seen on [(18)F]fludeoxyglucose-positron emission tomography. A post-mortem diagnosis of schizophrenia was established, given the clinical picture combined with the pathological exclusion of a neurodegenerative cause. Our case suggests that patients with other brain disorders may meet the current diagnostic criteria for probable frontotemporal dementia. Further clinicopathological validation of these criteria is needed to determine their exact specificity.

Impact of New Scatter Correction Strategies on High-Resolution Research Tomograph Brain PET Studies

Abstract: The aim of this study is to evaluate the impact of different scatter correction strategies on quantification of high-resolution research tomograph (HRRT) data for three tracers covering a wide range in kinetic profiles. Healthy subjects received dynamic HRRT scans using either (R)-[11C]verapamil (n = 5), [11C]raclopride (n = 5) or [11C]flumazenil (n = 5). To reduce the effects of patient motion on scatter scaling factors, a margin in the attenuation correction factor (ACF) sinogram was applied prior to 2D or 3D single scatter simulation (SSS). Some (R)-[11C]verapamil studies showed prominent artefacts that disappeared with an ACF-margin of 10 mm or more. Use of 3D SSS for (R)-[11C]verapamil showed a statistically significant increase in volume of distribution compared with 2D SSS (p 0.05). When there is a patient motion-induced mismatch between transmission and emission scans, applying an ACF-margin resulted in more reliable scatter scaling factors but did not change (and/or deteriorate) quantification.

Improved image derived input functions using Iterative deconvolution and HYPR denoising

Abstract: 39 Objectives Ten subjects, each undergoing three [15O]H2O PET scans (2 baseline: test and retest, 1 after hypercapnia) were included in this study. Methods The following steps were used to generate each IDIF: (a) to accurately draw the region of interest (ROI), a gradient image was generated from an early frame of the dynamic scan highlighting the vessel walls; (b) a ROI (lumen of carotid artery) was drawn manually on this gradient image; (c) to reduce partial volume effects, the Van Cittert iterative deconvolution method (IDM) with 8 iterations and FWHM of 6.75 mm was used; (d) to reduce noise, HYPR with a moving composite (3 parts: Influx, efflux and equilibrium phases of the blood input) was used. Parametric CBF images were generated using the original dynamic [15O]H2O images in combination with (1) measured on-line arterial input functions and (2) IDIFS derived from both original images and those processed as indicated above. Regional parametric test, retest and hypercapnia CBF values were used to test accuracy and precision when using image derived input functions. Results Average absolute test-retest variabilities of 7±5 (measured arterial input function), 20±16 (original IDIF) and 13±11% (IDM and HYPR processed IDIF) were obtained for whole brain grey matter CBF. Biases of 82±30, 20±14% in CBF were found using original and improved IDIs, respectively, as compared with CBF values obtained with measured arterial input functions. Conclusions IDIFs obtained using iterative deconvolution in combination with HYPR denoising resulted in CBF repeatability and accuracy than were substantially better than those for original IDIFs. Nevertheless, CBF values were, on average, still 20% higher than those obtained using measured arterial input functions. The reduced precision and accuracy are possibly caused by higher noise levels in the IDIFs at later time points (>300 s p.i.). Further studies will be performed using shorter scan durations (<300 s) which might improve repeatability and accuracy of CBF based on IDIFs. References: 1. Teo BK, Seo Y, Bacharach SL, Carrasquillo JA, Libutti SK, Shukla H, et al. Partial-volume correction in PET: validation of an iterative postreconstruction method with phantom and patient data. J Nucl Med 2007 May;48(5):802-810. 2. Lucy L. An iterative technique for the rectification of observed distributions. 79 ed. Astron. J.: 1974, pp. 745-765. 3. Christian BT, Vandehey NT, Floberg JM, Mistretta CA. Dynamic PET denoising with HYPR processing. J Nucl Med. 2010;51(7):1147-54.