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PurposeEarly-onset Alzheimer’s disease (EOAD) and late-onset Alzheimer’s disease (LOAD) differ in neuropathological burden and type of cognitive deficits. Assessing tau pathology and relative cerebral blood flow (rCBF) measured with [18F]flortaucipir PET in relation to cognition may help explain these differences between EOAD and LOAD.MethodsSeventy-nine amyloid-positive individuals with a clinical diagnosis of AD (EOAD: n=35, age-at-PET=59±5, MMSE=23±4; LOAD: n=44, age-at-PET=71±5, MMSE=23±4) underwent a 130 minutes dynamic [18F]flortaucipir PET scan and extensive neuropsychological assessment. We extracted binding potentials (BPND) and R1 (proxy of rCBF) from parametric images using receptor parametric mapping, in medial and lateral temporal, parietal, occipital and frontal regions-of-interest and used nine neuropsychological tests covering memory, attention, language and executive functioning. We first examined differences between EOAD and LOAD in BPND or R1 using ANOVA (region-of-interest analysis) and voxel-wise contrasts. Next, we performed linear regression models to test for potential interaction effects between age-at-onset and BPND/R1 on cognition.ResultsBoth region-of-interest and voxel-wise contrasts showed higher [18F]flortaucipir BPND values across all neocortical regions in EOAD. By contrast, LOAD patients had lower R1 values (indicative of more reduced rCBF) in medial temporal regions. For both tau and flow in lateral temporal, and occipito-parietal regions, associations with cognitive impairment were stronger in EOAD than in LOAD (EOAD BPND -0.76≤stβ≤-0.48 vs LOAD -0.18≤stβ≤-0.02; EOAD R1 0.37≤stβ≤0.84 vs LOAD -0.25≤stβ≤0.16).ConclusionsCompared to LOAD, the degree of lateral temporal and occipito-parietal tau pathology and relative cerebral blood-flow is more strongly associated with cognition in EOAD.

Highlights • The amount of tau binding in DLB was minimal and did not differ from controls. • Relative cerebral blood flow (rCBF), but not tau PET, was related to cognitive impairment. • rCBF is more strongly related to clinical characteristics in DLB than tau PET., Purpose Alpha-synuclein often co-occurs with Alzheimer’s disease (AD) pathology in Dementia with Lewy Bodies (DLB). From a dynamic [18F]flortaucipir PET scan we derived measures of both tau binding and relative cerebral blood flow (rCBF). We tested whether regional tau binding or rCBF differed between DLB patients and AD patients and controls and examined their association with clinical characteristics of DLB. Methods Eighteen patients with probable DLB, 65 AD patients and 50 controls underwent a dynamic 130-minute [18F]flortaucipir PET scan. DLB patients with positive biomarkers for AD based on cerebrospinal fluid or amyloid PET were considered as DLB with AD pathology (DLB-AD+). Receptor parametric mapping (cerebellar gray matter reference region) was used to extract regional binding potential (BPND) and R1, reflecting (AD-specific) tau pathology and rCBF, respectively. First, we performed regional comparisons of [18F]flortaucipir BPND and R1 between diagnostic groups. In DLB patients only, we performed regression analyses between regional [18F]flortaucipir BPND, R1 and performance on ten neuropsychological tests. Results Regional [18F]flortaucipir BPND in DLB was comparable with tau binding in controls (p > 0.05). Subtle higher tau binding was observed in DLB-AD+ compared to DLB-AD- in the medial temporal and parietal lobe (both p

ObjectiveThe clinical phenotype of the rare behavioral variant of Alzheimer’s disease (bvAD) is insufficiently understood. Given the strong clinico-anatomical correlations of tau pathology in AD, we investigated the distribution of tau deposits in bvAD, in-vivo and ex-vivo, using PET and postmortem examination.MethodsFor the tau PET study, seven amyloid-P positive bvAD patients underwent [18F]flortaucipir or [18F]RO948 PET. We converted tau PET uptake values into standardized (W-)scores, by adjusting for age, sex and MMSE in a “typical” memory-predominant AD (n=205) group. W-scores were computed within entorhinal, temporoparietal, medial and lateral prefrontal, insular and whole-brain regions-of-interest, frontal-to-entorhinal and frontal-to-parietal ratios and within intrinsic functional connectivity network templates. For the postmortem study, the percentage of AT8 (tau)-positive area in hippocampus CA1, temporal, parietal, frontal and insular cortices were compared between autopsy-confirmed bvAD (n=8) and typical AD (n=7) patients.ResultsRegional W-scores ≥1.96 (corresponding to p0.05).ConclusionBoth in-vivo and ex-vivo, bvAD patients showed heterogeneous patterns of tau pathology. Since key regions involved in behavioral regulation were not consistently disproportionally affected by tau pathology, other factors are more likely driving the clinical phenotype in bvAD.

Purpose To determine thresholds for amyloid beta pathology and evaluate associations with longitudinal memory performance with the aim to identify a grey zone of early amyloid beta accumulation and investigate its clinical relevance. Methods We included 162 cognitively normal participants with subjective cognitive decline from the SCIENCe cohort (64 ± 8 years, 38% F, MMSE 29 ± 1). Each underwent a dynamic [18F] florbetapir PET scan, a T1-weighted MRI scan and longitudinal memory assessments (RAVLT delayed recall, n = 655 examinations). PET scans were visually assessed as amyloid positive/negative. Additionally, we calculated the mean binding potential (BPND) and standardized uptake value ratio (SUVr50–70) for an a priori defined composite region of interest. We determined six amyloid positivity thresholds using various data-driven methods (resulting thresholds: BPND 0.19/0.23/0.29; SUVr 1.28/1.34/1.43). We used Cohen’s kappa to analyse concordance between thresholds and visual assessment. Next, we used quantiles to divide the sample into two to five subgroups of equal numbers (median, tertiles, quartiles, quintiles), and operationalized a grey zone as the range between the thresholds (0.19–0.29 BPND/1.28–1.43 SUVr). We used linear mixed models to determine associations between thresholds and memory slope. Results As determined by visual assessment, 24% of 162 individuals were amyloid positive. Concordance with visual assessment was comparable but slightly higher for BPND thresholds (range kappa 0.65–0.70 versus 0.60–0.63). All thresholds predicted memory decline (range beta − 0.29 to − 0.21, all p p for trend Conclusion We provide evidence that not only high but also grey zone amyloid burden subtly impacts memory function. Therefore, in case a binary classification is required, we suggest using a relatively low threshold which includes grey zone amyloid pathology.

Characteristic frontotemporal abnormalities on structural or functional neuroimaging are mandatory for a diagnosis of probable behavioral variant of frontotemporal dementia (bvFTD) according to the new criteria. 18-Fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) imaging is commonly reserved for patients with suspected bvFTD without characteristic structural neuroimaging results. We studied the diagnostic value of 18F-FDG-PET in these patients. Methods: The 18F-FDG-PET was performed in 52 patients with suspected bvFTD but lacking characteristic structural neuroimaging results. The clinical diagnosis of bvFTD in the presence of functional decline (bvFTD/fd+) after a follow-up period of 2 years was used as a golden standard. Results: The sensitivity of 18F-FDG-PET for bvFTD/fd+ was 47% at a specificity of 92%. The differential diagnosis comprised alternative neurodegenerative and psychiatric disorders and a benign phenocopy of bvFTD. Conclusions: The 18F-FDG-PET is able to identify nearly half of the patients with bvFTD who remain undetected by magnetic resonance imaging. In our selected group, high specificity enables exclusion of psychiatric and other neurodegenerative disorders.

An emerging issue in neuroimaging is to assess the diagnostic reliability of PET and its application in clinical practice. We aimed at assessing the accuracy of brain FDG-PET in discriminating patients with MCI due to Alzheimer's disease and healthy controls. Sixty-two patients with amnestic MCI and 109 healthy subjects recruited in five centers of the European AD Consortium were enrolled. Group analysis was performed by SPM8 to confirm metabolic differences. Discriminant analyses were then carried out using the mean FDG uptake values normalized to the cerebellum computed in 45 anatomical volumes of interest (VOIs) in each hemisphere (90 VOIs) as defined in the Automated Anatomical Labeling (AAL) Atlas and on 12 meta-VOIs, bilaterally, obtained merging VOIs with similar anatomo-functional characteristics. Further, asymmetry indexes were calculated for both datasets. Accuracy of discrimination by a Support Vector Machine (SVM) and the AAL VOIs was tested against a validated method (PALZ). At the voxel level SMP8 showed a relative hypometabolism in the bilateral precuneus, and posterior cingulate, temporo-parietal and frontal cortices. Discriminant analysis classified subjects with an accuracy ranging between .91 and .83 as a function of data organization. The best values were obtained from a subset of 6 meta-VOIs plus 6 asymmetry values reaching an area under the ROC curve of .947, significantly larger than the one obtained by the PALZ score. High accuracy in discriminating MCI converters from healthy controls was reached by a non-linear classifier based on SVM applied on predefined anatomo-functional regions and inter-hemispheric asymmetries. Data pre-processing was automated and simplified by an in-house created Matlab-based script encouraging its routine clinical use. Further validation toward nonconverter MCI patients with adequately long follow-up is needed., Highlights • 18F-FDG-PET/CT analysis of metabolic differences between MCI converting to AD and HC • Large and very well controlled cohorts from EADC-Consortium were investigated. • Data were analyzed by a friendly-to-use Matlab-based script and Support Vector Machine. • Excellent discrimination between MCI and HC (sensitivity 92%; specificity 91%) • Highest accuracy reported so far in MCI and promising implementation in clinical routine

The purpose of this study was to compare different kinetic and semi-quantitative methods for analysing human [18F]FP-β-CIT studies: plasma input models, simplified (SRTM) and full (FRTM) reference tissue models, standard uptake values (SUV) and SUV ratios (SUVr). Both simulations and clinical evaluations were performed to determine the effects of noise, scan duration and blood volume on Akaike model selection, and on precision and accuracy of estimated parameters. For typical noise levels (COV ∼ 2.5%) and scan durations (< 90 mins), simulations provided poor fits (Akaike criterion) in case of reversible plasma input models showing a relatively high number of outliers compared with the two-tissue irreversible model. Reference tissue models provided more reliable fits, which were nearly independent of noise and scan duration. For clinical data, two tissue irreversible and reversible plasma input models fitted striatum curves equally well (Akaike criterion). BP with plasma input models were less precise and contained more outliers than BP obtained with SRTM or FRTM. Among all methods tested, SRTM showed the highest contrast between patients and controls. When differentiating between patients and controls, SUVr performed almost equally well as SRTM, although contrast between striatum and background was lower. In conclusion, SRTM provided BP estimates with the highest precision and accuracy. Moreover, SRTM provided good contrast between patients and controls, and between striatum and background. SRTM is therefore the method of choice for quantitative [18F]FP-β-CIT studies. SUVr might be an alternative for larger clinical trials.

Measurements of the cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) provide useful information about cerebrovascular condition and regional metabolism. Pseudo-continuous arterial spin labeling (pCASL) is a promising non-invasive MRI technique to quantitatively measure the CBF, whereas additional hypercapnic pCASL measurements are currently showing great promise to quantitatively assess the CVR. However, the introduction of pCASL at a larger scale awaits further evaluation of the exact accuracy and precision compared to the gold standard. (15)O H₂O positron emission tomography (PET) is currently regarded as the most accurate and precise method to quantitatively measure both CBF and CVR, though it is one of the more invasive methods as well. In this study we therefore assessed the accuracy and precision of quantitative pCASL-based CBF and CVR measurements by performing a head-to-head comparison with (15)O H₂O PET, based on quantitative CBF measurements during baseline and hypercapnia. We demonstrate that pCASL CBF imaging is accurate during both baseline and hypercapnia with respect to (15)O H₂O PET with a comparable precision. These results pave the way for quantitative usage of pCASL MRI in both clinical and research settings.

Alzheimer's disease with early onset often presents with a distinct cognitive profile, potentially reflecting a different distribution of underlying neuropathology. The purpose of this study was to examine the relationships between age and both in vivo fibrillary amyloid deposition and glucose metabolism in patients with Alzheimer's disease. Dynamic [(11)C]Pittsburgh compound-B (90 min) and static [(18)F]fluorodeoxyglucose (15 min) scans were obtained in 100 patients with Alzheimer's disease and 20 healthy controls. Parametric non-displaceable binding potential images of [(11)C]Pittsburgh compound-B and standardized uptake value ratio images of [(18)F]fluorodeoxyglucose were generated using cerebellar grey matter as reference tissue. Nine [(11)C]Pittsburgh compound-B-negative patients were excluded. The remaining patients were categorized into younger (n=45, age: 56 ± 4 years) and older (n=46, age: 69 ± 5 years) groups, based on the median age (62 years) at time of diagnosis. Younger patients showed more severe impairment on visuo-spatial function, attention and executive function composite scores (P

Objective To evaluate visual assessment of [ 11 C]PIB and [ 18 F]FDDNP PET images as potential supportive diagnostic markers for Alzheimer9s disease (AD). Methods Twenty-one AD patients and 20 controls were included. Parametric [ 11 C]PIB and [ 18 F]FDDNP global binding potential (BP ND ) images were visually rated as ‘AD’ or ‘normal.’ Data were compared with ratings of [ 18 F]FDG PET images and MRI-derived medial temporal lobe atrophy (MTA) scores. Inter-rater agreement and agreement with clinical diagnosis were assessed for all imaging modalities. In addition, cut-off values for quantitative global [ 11 C]PIB and [ 18 F]FDDNP BP ND were determined. Visual ratings were compared with dichotomised quantitative values. Results Agreement between readers was excellent for [ 11 C]PIB, [ 18 F]FDDNP and MTA (Cohen kappa κ≥0.85) and moderate for [ 18 F]FDG (κ=0.56). The highest sensitivity was found for [ 11 C]PIB and [ 18 F]FDG (both 1.0). The highest specificity was found for MTA (0.90) and [ 11 C]PIB (0.85). [ 18 F]FDDNP had the lowest sensitivity and specificity (0.67 and 0.53, respectively). The cut-off for quantitative [ 11 C]PIB BP ND was 0.54 (sensitivity and specificity both 0.95) and for [ 18 F]FDDNP BP ND 0.07 (sensitivity 0.80, specificity 0.73). Agreement between quantitative analyses and visual ratings was excellent for [ 11 C]PIB (κ=0.85) and fair for [ 18 F]FDDNP (κ=0.40). Conclusion Visual assessment of [ 11 C]PIB images was straightforward and accurate, showing promise as a supportive diagnostic marker for AD. Moreover, [ 11 C]PIB showed the best combination of sensitivity and specificity. Visual assessment of [ 18 F]FDDNP images was insufficient. The quantitative analysis of [ 18 F]FDDNP data showed a considerably higher diagnostic value than the visual analysis.

Gamma-aminobutyric acid (GABA(A)) receptors are thought to play an important role in modulating the central nervous system in response to stress. Animal data have shown alterations in the GABA(A) receptor complex by uncontrollable stressors. SPECT imaging with benzodiazepine ligands showed lower distribution volumes of the benzodiazepine-GABA(A) receptor in the prefrontal cortex of patients with post-traumatic stress disorder (PTSD) in one, but not in another study. The objective of the present study was to assess differences in the benzodiazepine-GABA(A) receptor complex in veterans with and without PTSD using [(11)C]flumazenil and positron emission tomography (PET). Nine drug naive male Dutch veterans with deployment related PTSD and seven male Dutch veterans without PTSD were recruited, and matched for age, region and year of deployment. Each subject received a [(11)C]flumazenil PET scan and a structural magnetic resonance imaging scan. Dynamic 3D PET scans with a total duration of 60 min were acquired, and binding in template based and manually defined regions of interest (ROI) was quantified using validated plasma input and reference tissue models. In addition, parametric binding potential images were compared on a voxel-by-voxel basis using statistical parametric mapping (SPM2). ROI analyses using both template based and manual ROIs showed significantly reduced [(11)C]flumazenil binding in PTSD subjects throughout the cortex, hippocampus and thalamus. SPM analysis confirmed these results. The observed global reduction of [(11)C]flumazenil binding in patients with PTSD provides circumstantial evidence for the role of the benzodiazepine-GABA(A) receptor in the pathophysiology of PTSD and is consistent with previous animal research and clinical psychopharmacological studies.

The high-resolution research tomograph (HRRT) is a dedicated human brain positron emission tomography scanner. Currently available iterative reconstruction algorithms show bias due to nonnegativity constraints. Consequently, implementation of 3-D filtered backprojection (3-D-FBP) is of interest. To apply 3-D-FBP all missing data including those due to gaps between detector heads need to be estimated. The aim of this study was to evaluate various gap filling strategies for 3-D-FBP reconstructions of HRRT data, such as linear and bilinear interpolation or constraint Fourier space gap filling (confosp). Furthermore, missing planes were estimated using segment 0 image data only (noniterative) or by using reconstructed images based on all previous segments (iterative method). Use of bilinear interpolation showed worst correspondence between reconstructed and true activity concentration, especially for small structures. Moreover, phantom data indicated that use of linear interpolation resulted in artifacts in planes located near the edge of the field-of-view. Use of confosp did not show these artifacts. Iterative estimations of the missing planes for |segments| > 0 improved image quality at the cost of more computation time. Therefore, use of confosp for filling sinogram gaps with both iterative and noniterative estimation of missing planes are recommended for quantitative 3-D-FBP of HRRT studies.

The effects of D-cycloserine, a partial agonist of the N-Methyl-D-Aspartate (NMDA) receptor, were assessed in a (neuroendocrine) challenge paradigm to examine NMDA systems in male healthy volunteers, using a double-blind, placebo-controlled crossover design. Oral D-cycloserine (15, 50, and 150 mg) was readily absorbed and its plasma concentration increased dose-dependently. Behavioral and hormonal responses were measured for 240 minutes after administration of the drug. D-cycloserine was well tolerated and did not induce side-effects according to the Visual Analog Scales (VAS), the Brief Psychiatric Rating Scale (BPRS) and the Adverse Events Checklist (AEC) and codes. D-cycloserine failed to elicit a neuroendocrine response as evaluated by cortisol, prolactin, and luteinizing hormone (LH) plasma levels. The present result suggests that D-cycloserine can readily be administered to healthy volunteers but that, in the dosages used, neuroendocrine secretion fails to serve as a model for testing NMDA receptor function in humans.