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A major pathological hallmark of Alzheimer's disease is accumulation of amyloid-β in senile plaques in the brain. Evidence is accumulating that decreased clearance of amyloid-β from the brain may lead to these elevated amyloid-β levels. One of the clearance pathways of amyloid-β is transport across the blood-brain barrier via efflux transporters. P-glycoprotein, an efflux pump highly expressed at the endothelial cells of the blood-brain barrier, has been shown to transport amyloid-β. P-glycoprotein function can be assessed in vivo using (R)-[(11)C]verapamil and positron emission tomography. The aim of this study was to assess blood-brain barrier P-glycoprotein function in patients with Alzheimer's disease compared with age-matched healthy controls using (R)-[(11)C]verapamil and positron emission tomography. In 13 patients with Alzheimer's disease (age 65 ± 7 years, Mini-Mental State Examination 23 ± 3), global (R)-[(11)C]verapamil binding potential values were increased significantly (P = 0.001) compared with 14 healthy controls (aged 62 ± 4 years, Mini-Mental State Examination 30 ± 1). Global (R)-[(11)C]verapamil binding potential values were 2.18 ± 0.25 for patients with Alzheimer's disease and 1.77 ± 0.41 for healthy controls. In patients with Alzheimer's disease, higher (R)-[(11)C]verapamil binding potential values were found for frontal, parietal, temporal and occipital cortices, and posterior and anterior cingulate. No significant differences between groups were found for medial temporal lobe and cerebellum. These data show altered kinetics of (R)-[(11)C]verapamil in Alzheimer's disease, similar to alterations seen in studies where P-glycoprotein is blocked by a pharmacological agent. As such, these data indicate that P-glycoprotein function is decreased in patients with Alzheimer's disease. This is the first direct evidence that the P-glycoprotein transporter at the blood-brain barrier is compromised in sporadic Alzheimer's disease and suggests that decreased P-glycoprotein function may be involved in the pathogenesis of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

The objective of the study was to illustrate the utility of positron emission tomography (PET) imaging using [C]PIB and [F]FDDNP together with cerebrospinal fluid (CSF) measures of amyloid-beta1 to 42 (Abeta42), total tau (t-tau) and tau phosphorylated at threonine 181 (p-tau) in the in vivo diagnosis of specific dementia syndromes. Two siblings fulfilling diagnostic criteria for familial Alzheimer's disease (AD) were investigated using [C]PIB and [F]FDDNP PET in combination with CSF measures of Abeta42, t-tau and p-tau. PET data were compared with paired [C]PIB and [F]FDDNP data from age-matched sporadic AD patients (n=9) and healthy controls (n=6). [C]PIB retention and CSF levels of Abeta42 in both patients resembled those of controls suggesting the presence of nonamyloid pathology. Genetic testing confirmed the absence of mutations in the presenilin 1 gene in 1 patient; subsequent testing revealed the R406W tau mutation in both individuals leading to a diagnosis of frontotemporal dementia [F]FDDNP retention broadly correlated with CSF levels of t-tau and p-tau. Despite both individuals harbouring the same mutation, [F]FDDNP retention and CSF t-tau and p-tau were elevated in 1 patient, but not in the other. [C]PIB imaging and CSF measures of Abeta42 are useful in refuting the presence of underlying amyloid pathology. This, in combination with elevated levels of CSF t-tau and p-tau, has potential value in differential diagnosis of frontotemporal dementia from AD. [ABSTRACT FROM AUTHOR]

The cause of Parkinson's disease (PD) is unknown. Genetic susceptibility and exposure to environmental toxins contribute to specific neuronal loss in PD. Decreased blood-brain barrier (BBB) P-glycoprotein (P-gp) efflux function has been proposed as a possible causative link between toxin exposure and PD neurodegeneration. In the present study BBB P-gp function was investigated in vivo in 10 early stage PD patients and 8 healthy control subjects using (R)-[(11)C]-verapamil and PET. Cerebral volume of distribution (V(d)) of verapamil was used as measure of P-gp function. Both region of interest (ROI) analysis and voxel analysis using statistical parametric mapping (SPM) were performed to assess regional brain P-gp function. In addition, MDR1 genetic polymorphism was assessed. In the present study, a larger variation in V(d) of (R)-[(11)C]-verapamil was seen in the PD group as compared to the control group. However, decreased BBB P-gp function in early stage PD patients could not be confirmed. [ABSTRACT FROM AUTHOR]

Background: Accurate image-derived input function (IDIF) from highly sensitive large axial field of view (LAFOV) PET/CT scanners could avoid the need of invasive blood sampling for kinetic modelling. The aim is to validate the use of IDIF for two kinds of tracers, 3 different IDIF locations and 9 different reconstruction settings., Methods: Eight [ 18 F]FDG and 10 [ 18 F]DPA-714 scans were acquired respectively during 70 and 60 min on the Vision Quadra PET/CT system. PET images were reconstructed using various reconstruction settings. IDIFs were taken from ascending aorta (AA), descending aorta (DA), and left ventricular cavity (LV). The calibration factor (CF) extracted from the comparison between the IDIFs and the manual blood samples as reference was used for IDIFs accuracy and precision assessment. To illustrate the effect of various calibrated-IDIFs on Patlak linearization for [ 18 F]FDG and Logan linearization for [ 18 F]DPA-714, the same target time-activity curves were applied for each calibrated-IDIF., Results: For [ 18 F]FDG, the accuracy and precision of the IDIFs were high (mean CF ≥ 0.82, SD ≤ 0.06). Compared to the striatum influx (K i ) extracted using calibrated AA IDIF with the updated European Association of Nuclear Medicine Research Ltd. standard reconstruction (EARL2), K i mean differences were < 2% using the other calibrated IDIFs. For [ 18 F]DPA714, high accuracy of the IDIFs was observed (mean CF ≥ 0.86) except using absolute scatter correction, DA and LV (respectively mean CF = 0.68, 0.47 and 0.44). However, the precision of the AA IDIFs was low (SD ≥ 0.10). Compared to the distribution volume (V T ) in a frontal region obtained using calibrated continuous arterial sampler input function as reference, V T mean differences were small using calibrated AA IDIFs (for example V T mean difference = -5.3% using EARL2), but higher using calibrated DA and LV IDIFs (respectively + 12.5% and + 19.1%)., Conclusions: For [ 18 F]FDG, IDIF do not need calibration against manual blood samples. For [ 18 F]DPA-714, AA IDIF can replace continuous arterial sampling for simplified kinetic quantification but only with calibration against arterial blood samples. The accuracy and precision of IDIF from LAFOV PET/CT system depend on tracer, reconstruction settings and IDIF VOI locations, warranting careful optimization., (© 2024. The Author(s).)

Alzheimer's disease is characterized by regional reductions in cerebral blood flow (CBF). Although the gold standard for measuring CBF is [ 15 O]H 2 O PET, proxies of relative CBF, derived from the early distribution phase of amyloid and tau tracers, have gained attention. The present study assessed precision of [ 15 O]H 2 O derived relative and absolute CBF, and compared precision of these measures with that of (relative) CBF proxies. Dynamic [ 15 O]H 2 O, [ 18 F]florbetapir and [ 18 F]flortaucipir PET test-retest (TrT) datasets with eleven, nine and fourteen subjects, respectively, were included. Analyses were performed using an arterial input model and/or a simplified reference tissue model, depending on the data available. Relative CBF values (i.e. K 1 / K 1 ' and/or R 1 ) were obtained using cerebellar cortex as reference tissue and TrT repeatability (i.e. precision) was calculated and compared between tracers, parameters and clinical groups. Relative CBF had significantly better TrT repeatability than absolute CBF derived from [ 15 O]H 2 O ( r  = -0.53), while best TrT repeatability was observed for [ 18 F]florbetapir and [ 18 F]flortaucipir R 1 ( r  = -0.23, r  = -0.33). Furthermore, only R 1 showed, better TrT repeatability for cognitively normal individuals. High precision of CBF proxies could be due to a compensatory effect of the extraction fraction, although changes in extraction fraction could also bias these proxies, but not the gold standard.

[ 11 C]UCB-J is a novel radioligand that binds to synaptic vesicle glycoprotein 2A (SV2A). The main objective of this study was to determine the 28-day test-retest repeatability (TRT) of quantitative [ 11 C]UCB-J brain positron emission tomography (PET) imaging in Alzheimer's disease (AD) patients and healthy controls (HCs). Nine HCs and eight AD patients underwent two 60 min dynamic [ 11 C]UCB-J PET scans with arterial sampling with an interval of 28 days. The optimal tracer kinetic model was assessed using the Akaike criteria (AIC). Micro-/macro-parameters such as tracer delivery (K 1 ) and volume of distribution (V T ) were estimated using the optimal model. Data were also analysed for simplified reference tissue model (SRTM) with centrum semi-ovale (white matter) as reference region. Based on AIC, both 1T2k&#95;V B and 2T4k&#95;V B described the [ 11 C]UCB-J kinetics equally well. Analysis showed that whole-brain grey matter TRT for V T , DVR and SRTM BP ND were -2.2% ± 8.5, 0.4% ± 12.0 and -8.0% ± 10.2, averaged over all subjects. [ 11 C]UCB-J kinetics can be well described by a 1T2k&#95;V B model, and a 60 min scan duration was sufficient to obtain reliable estimates for both plasma input and reference tissue models. TRT for V T , DVR and BP ND was <15% (1SD) averaged over all subjects and indicates adequate quantitative repeatability of [ 11 C]UCB-J PET.

Accumulation of amyloid beta (Aβ) is one of the pathological hallmarks of Alzheimer's disease (AD), which can be visualized using [ 18 F]florbetapir positron emission tomography (PET). The aim of this study was to evaluate various parametric methods and to assess their test-retest (TRT) reliability. Two 90 min dynamic [ 18 F]florbetapir PET scans, including arterial sampling, were acquired ( n  = 8 AD patient, n  = 8 controls). The following parametric methods were used; (reference:cerebellum); Logan and spectral analysis (SA), receptor parametric mapping (RPM), simplified reference tissue model2 (SRTM2), reference Logan (rLogan) and standardized uptake value ratios (SUV r(50-70) ). BP ND +1, DVR, V T and SUVr were compared with corresponding estimates (V T or DVR) from the plasma input reversible two tissue compartmental (2T4k&#95;V B ) model with corresponding TRT values for 90-scan duration. RPM ( r 2  = 0.92; slope = 0.91), Logan ( r 2  = 0.95; slope = 0.84) and rLogan ( r 2  = 0.94; slope = 0.88), and SRTM2 ( r 2  = 0.91; slope = 0.83), SA ( r 2  = 0.91; slope = 0.88), SUVr ( r 2  = 0.84; slope = 1.16) correlated well with their 2T4k&#95;V B counterparts. RPM (controls: 1%, AD: 3%), rLogan (controls: 1%, AD: 3%) and SUV r(50-70) (controls: 3%, AD: 8%) showed an excellent TRT reliability. In conclusion, most parametric methods showed excellent performance for [ 18 F]florbetapir, but RPM and rLogan seem the methods of choice, combining the highest accuracy and best TRT reliability.

Introduction: We examined associations between nutritional biomarkers and clinical progression in individuals with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and Alzheimer's disease (AD)-type dementia., Methods: We included 528 individuals (64 ± 8 years, 46% F, follow-up 2.1 ± 0.87 years) with SCD (n = 204), MCI (n = 130), and AD (n = 194). Baseline levels of cholesterol, triglycerides, glucose, homocysteine, folate, vitamin A, B12, E and uridine were measured in blood and S-adenosylmethionine and S-adenosylhomocysteine in cerebrospinal fluid. We determined associations between nutritional biomarkers and clinical progression using Cox proportional hazard models., Results: Twenty-two (11%) patients with SCD, 45 (35%) patients with MCI, and 100 (52%) patients with AD showed clinical progression. In SCD, higher levels of low-density lipoprotein (LDL) cholesterol were associated with progression (hazard ratio [HR] [95% confidence interval (CI)] 1.88 [1.04 to 3.41]). In AD, lower uridine levels were associated with progression (0.79 [0.63 to 0.99])., Discussion: Our findings suggest that LDL cholesterol and uridine play a-stage-dependent-role in the clinical progression of AD., Competing Interests: Francisca A. de Leeuw, Betty M. Tijms, Astrid S. Doorduijn, Heleen M. A. Hendriksen, Ondine van de Rest, Marian A. E. de van der Schueren, Marjolein Visser, Jorgen Bierau, and Maartje I. Kester report no disclosures. Ellen G. H. M. Heuvel is an employee of FrieslandCampina. Nick van Wijk is an employee of Danone Nutricia Research. Bart N. van Berckel received research support from ZonMW, AVID radiopharmaceuticals, CTMM,. and Janssen Pharmaceuticals. He is a trainer for Piramal and GE. He receives no personal honoraria. Philip Scheltens has received consultancy/speaker fees (paid to the institution) from Novartis, Vivoryon, Genentech, and EIP Pharma. C. E. Teunissen has a collaboration contract with ADx Neurosciences, performed contract research or received grants from Probiodrug, Biogen, Esai, Toyama, Janssen prevention center, Boehringer, AxonNeurosciences, Fujirebio, EIP farma, PeopleBio, and Roche. Research programs of Wiesje M. van der Flier have been funded by ZonMW, NWO, EU‐FP7, EU‐JPND, Alzheimer Nederland, CardioVascular Onderzoek Nederland, Health∼Holland, Topsector Life Sciences and Health, stichting Dioraphte, Gieskes‐Strijbis fonds, stichting Equilibrio, Pasman stichting, Biogen MA Inc, Boehringer Ingelheim, Life‐MI, AVID, Roche BV, Janssen Stellar, Combinostics. Wiesje M. van der Flier has performed contract research for Biogen MA Inc and Boehringer Ingelheim. Wiesje M. van der Flier has been an invited speaker at Boehringer Ingelheim and Biogen MA Inc. All funding is paid to her institution., (© 2020 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

The aim of this study was to investigate the test-retest (TRT) repeatability of various parametric quantification methods for [ 18 F]Flortaucipir positron emission tomography (PET). We included eight subjects with dementia or mild cognitive impairment due to Alzheimer's disease and six cognitively normal subjects. All underwent two 130-min dynamic [ 18 F]Flortaucipir PET scans within 3 ± 1 weeks. Data were analyzed using reference region models receptor parametric mapping (RPM), simplified reference tissue method 2 (SRTM2) and reference logan (RLogan), as well as standardized uptake value ratios (SUVr, time intervals 40-60, 80-100 and 110-130 min post-injection) with cerebellar gray matter as reference region. We obtained distribution volume ratio or SUVr, first for all brain regions and then in three tau-specific regions-of-interest (ROIs). TRT repeatability (%) was defined as |retest-test|/(average (test + retest)) × 100. For all methods and across ROIs, TRT repeatability ranged from (median (IQR)) 0.84% (0.68-2.15) to 6.84% (2.99-11.50). TRT repeatability was good for all reference methods used, although semi-quantitative models (i.e. SUVr) performed marginally worse than quantitative models, for instance TRT repeatability of RPM: 1.98% (0.78-3.58) vs. SUVr 80-100 : 3.05% (1.28-5.52), p  < 0.001. Furthermore, for SUVr 80-100 and SUVr 110-130 , with higher average SUVr, more variation was observed. In conclusion, while TRT repeatability was good for all models used, quantitative methods performed slightly better than semi-quantitative methods.

The prevalence of brain pathologies increases with age and cognitive and physical functions worsen over the lifetime. It is unclear whether these processes show a similar increase with age. We studied the association of markers for brain pathology cognitive and physical functions with age in 288 cognitively normal individuals aged 60-102 years selected from the cross-sectional EMIF-AD PreclinAD and 90+ Study at the Amsterdam UMC. An abnormal score was consistent with a score below the 5th percentile in the 60- to 70-year-old individuals. Prevalence of abnormal scores was estimated using Generalized Estimating Equations (GEE) models. The prevalence of abnormal handgrip strength, the Digit Symbol Substitution Test, and hippocampal volume showed the fastest increase with age and abnormal MMSE score, muscle mass, and amyloid aggregation the lowest. The increase in prevalence of abnormal markers was partly dependent on sex, level of education, and amyloid aggregation. We did not find a consistent pattern in which markers of brain pathology cognitive and physical processes became abnormal with age., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Gerontological Society of America.)

[ 18 F]Flortaucipir is a PET tau tracer used to visualize tau binding in Alzheimer's disease (AD) in vivo. The present study evaluated the performance of several methods to obtain parametric images of [ 18 F]flortaucipir. One hundred and thirty minutes dynamic PET scans were performed in 10 AD patients and 10 controls. Parametric images were generated using different linearization and basis function approaches. Regional binding potential (BP ND ) and volume of distribution (V T ) values obtained from the parametric images were compared with corresponding values derived using the reversible two-tissue compartment model (2T4k&#95;V B ). Performance of SUVr parametric images was assessed by comparing values with distribution volume ratio (DVR) and SRTM-derived BP ND estimates obtained using non-linear regression (NLR). Spectral analysis (SA) ( r 2  = 0.92; slope = 0.99) derived V T correlated well with NLR-derived V T . RPM ( r 2  = 0.95; slope = 0.98) derived BP ND correlated well with NLR-derived DVR. Although SUVr 80-100 min correlated well with NLR-derived DVR ( r 2  = 0.91; slope = 1.09), bias in SUVr appeared to depend on uptake time and underlying level of specific binding. In conclusion, RPM and SA provide parametric images comparable to the NLR estimates. Individual SUVr values are biased compared with DVR and this bias requires further study in a larger dataset in order to understand its consequences.

Background: Off-target [ 18 F]flortaucipir (tau) PET binding in the choroid plexus causes spill-in into the nearby hippocampus, which may influence the correlation between [ 18 F]flortaucipir binding and measures of cognition. Previously, we showed that partial volume correction (combination of Van Cittert iterative deconvolution and HYPR denoising; PVC HDH) and manually eroding the hippocampus resulted in a significant decrease of the choroid plexus spill-in. In this study, we compared three different approaches for the quantification of hippocampal [ 18 F]flortaucipir signal using a semi-automated technique, and assessed correlations with cognitive performance across methods., Methods: Dynamic 130 min [ 18 F]flortaucipir PET scans were performed in 109 subjects (45 cognitively normal subjects (CN) and 64 mild cognitive impairment/Alzheimer's disease (AD) dementia patients. We extracted hippocampal binding potential (BP ND ) using receptor parametric mapping with cerebellar grey matter as reference region. PVC HDH was performed. Based on our previous study in which we manually eroded 40% ± 10% of voxels of the hippocampus, three hippocampal volumes-of-interest (VOIs) were generated: a non-optimized 100% hippocampal VOI [100%], and combining HDH with eroding a percentage of the highest hippocampus BP ND voxels (i.e. lowering spill-in) resulting in optimized 50%[50%HDH] and 40%[40%HDH] hippocampal VOIs. Cognitive performance was assessed with the Mini-Mental State Examination (MMSE) and Rey auditory verbal learning delayed recall. We performed receiver operating characteristic analyses to investigate which method could best discriminate MCI/AD from controls. Subsequently, we performed linear regressions to investigate associations between the hippocampal [ 18 F]flortaucipir BP ND VOIs and MMSE/delayed recall adjusted for age, sex and education., Results: We found higher hippocampal [ 18 F]flortaucipir BP ND in MCI/AD patients (BP ND100% =0.27±0.15) compared to CN (BP ND100% = 0.07±0.13) and all methods showed comparable discriminative effects (AUC 100% =0.85[CI=0.78-0.93]; AUC 50%HDH =0.84[CI=0.74-0.92]; AUC 40%HDH =0.83[CI=0.74-0.92]). Across groups, higher [ 18 F]flortaucipir BP ND was related to lower scores on MMSE (standardized β 100% =-0.38[CI=-0.57-0.20]; β 50%HDH = -0.37[CI=-0.54-0.19]; β 40%HDH =-0.35[CI=-0.53-0.17], all p<0.001) and delayed recall (standardized β 100% =-0.64[CI=-0.79-0.49]; β 50%HDH = -0.61[CI=-0.76-0.46]; β 40%HDH =-0.59[CI=-0.75-0.44]; all p<0.001), with comparable effect sizes for all hippocampal VOIs., Conclusions: Hippocampal tau load measured with [ 18 F]flortaucipir PET is strongly associated with cognitive function. Both discrimination between diagnostic groups and associations between hippocampal [ 18 F]flortaucipir BP ND and memory were comparable for all methods. The non-optimized 100% hippocampal VOI may be sufficient for clinical interpretation. However, proper correction for choroid plexus spillover and may be required in case of smaller effect sizes between subject groups or for longitudinal studies., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The objective of this study was to assess the usefulness of the appropriate use criteria (AUC) for amyloid imaging in an unselected cohort., Methods: We calculated sensitivity and specificity of appropriate use (increased confidence and management change), as defined by Amyloid Imaging Taskforce in the AUC, and other clinical utility outcomes. Furthermore, we compared differences in post-positron emission tomography diagnosis and management change between "AUC-consistent" and "AUC-inconsistent" patients., Results: Almost half (250/507) of patients were AUC-consistent. In both AUC-consistent and AUC-inconsistent patients, post-positron emission tomography diagnosis (28%-21%) and management (32%-17%) change was substantial. The Amyloid Imaging Taskforce's definition of appropriate use occurred in 55/507 (13%) patients, detected by the AUC with a sensitivity of 93%, and a specificity of 56%. Diagnostic changes occurred independently of AUC status (sensitivity: 57%, specificity: 53%)., Discussion: The current AUC are not sufficiently able to discriminate between patients who will benefit from amyloid positron emission tomography and those who will not., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Accumulation of amyloid beta can be visualized using [ 18 F]florbetapir positron emission tomography. The aim of this study was to identify the optimal model for quantifying [ 18 F]florbetapir uptake and to assess test-retest reliability of corresponding outcome measures. Eight Alzheimer's disease patients (age: 67 ± 6 years, Mini-Mental State Examination (MMSE): 23 ± 3) and eight controls (age: 63 ± 4 years, MMSE: 30 ± 0) were included. Ninety-minute dynamic positron emission tomography scans, together with arterial blood sampling, were acquired immediately following a bolus injection of 294 ± 32 MBq [ 18 F]florbetapir. Several plasma input models and the simplified reference tissue model (SRTM) were evaluated. The Akaike information criterion was used to identify the preferred kinetic model. Compared to controls, Alzheimer's disease patients had lower MMSE scores and evidence for cortical Aβ pathology. A reversible two-tissue compartment model with fitted blood volume fraction (2T4k&#95;V B ) was the preferred model for describing [ 18 F]florbetapir kinetics. SRTM-derived non-displaceable binding potential (BP ND ) correlated well (r 2  = 0.83, slope = 0.86) with plasma input-derived distribution volume ratio. Test-retest reliability for plasma input-derived distribution volume ratio, SRTM-derived BP ND and SUVr (50-70) were r  = 0.88, r =  0.91 and r =  0.86, respectively. In vivo kinetics of [ 18 F]florbetapir could best be described by a reversible two-tissue compartmental model and [ 18 F]florbetapir BP ND can be reliably estimated using an SRTM.

Objective: To apply the ATN scheme to memory clinic patients, to assess whether it discriminates patient populations with specific features., Methods: We included 305 memory clinic patients (33% subjective cognitive decline [SCD]: 60 ± 9 years, 61% M; 19% mild cognitive impairment [MCI]: 68 ± 9 years, 68% M; 48% dementia: 66 ± 10 years, 58% M) classified for positivity (±) of amyloid (A) ([ 18 F]Florbetaben PET), tau (T) (CSF p-tau), and neurodegeneration (N) (medial temporal lobe atrophy). We assessed ATN profiles' demographic, clinical, and cognitive features at baseline, and cognitive decline over time., Results: The proportion of A+T+N+ patients increased with syndrome severity (from 1% in SCD to 14% in MCI and 35% in dementia), while the opposite was true for A-T-N- (from 48% to 19% and 6%). Compared to A-T-N-, patients with the Alzheimer disease profiles (A+T+N- and A+T+N+) were older (both p < 0.05) and had a higher prevalence of APOE ε4 (both p < 0.05) and lower Mini-Mental State Examination (MMSE) (both p < 0.05), memory (both p < 0.05), and visuospatial abilities (both p < 0.05) at baseline. Non-Alzheimer profiles A-T-N+ and A-T+N+ showed more severe white matter hyperintensities (both p < 0.05) and worse language performance (both p < 0.05) than A-T-N-. A linear mixed model showed faster decline on MMSE over time in A+T+N- and A+T+N+ ( p = 0.059 and p < 0.001 vs A-T-N-), attributable mainly to patients without dementia., Conclusions: The ATN scheme identified different biomarker profiles with overlapping baseline features and patterns of cognitive decline. The large number of profiles, which may have different implications in patients with vs without dementia, poses a challenge to the application of the ATN scheme., (© 2019 American Academy of Neurology.)

Introduction: Retinal thickness measured with optical coherence tomography has been proposed as a noninvasive biomarker for Alzheimer's disease (AD). We therefore measured retinal thickness in well-characterized AD and control participants, considering ophthalmological confounders., Methods: We included 57 amyloid-proven AD cases and 85 cognitively normal, amyloid-negative controls. All subjects underwent retinal thickness measurements with spectral domain optical coherence tomography and an ophthalmological assessment to exclude ocular disease., Results: Retinal thickness did not discriminate cases from controls, including stratified analyses for early- versus late-onset AD. We found significant associations between macular thickness and global cortical atrophy [β -0.358; P  = .01] and parietal cortical atrophy on magnetic resonance imaging [β -0.371; P  < .01] in AD cases., Discussion: In this study, representing the largest optical coherence tomography cohort with amyloid-proven AD cases, we show that retinal thickness does not discriminate AD from controls, despite evident changes on clinical, neuroimaging, and CSF measures, querying the use of retinal thickness measurements as an AD biomarker.

Introduction: The retina is a potential source of noninvasive vascular biomarkers for Alzheimer's disease (AD). We assessed retinal microvasculature in well-characterized AD cases, taking ophthalmological confounders into account., Methods: We included 48 amyloid-positive AD patients and 38 amyloid-negative cognitively normal control subjects. All participants underwent ophthalmological screening to exclude interfering ocular disease. Using a multimodal approach, we measured retinal vascular parameters, choroidal thickness, macular vascular density, and foveal avascular zone size., Results: We found no disease effects on retinal vascular measures (all β's < |0.15|, all P  > .2), adjusted for confounders. Venular tortuosity was inversely associated with Fazekas score in control subjects (β -0.56, P  < .01), while vessel density in the outer ring of the macula was inversely associated with Fazekas score in AD cases (β -0.64, P  < .01)., Discussion: In conclusion, retinal vasculature did not discriminate patients with AD from control subjects, despite evident changes on clinical, neuroimaging, and cerebrospinal fluid biomarkers, challenging the use of retinal vasculature measurements as AD biomarker.

Quantification of regional cerebral blood flow (CBF) using [ 15 O]H 2 O positron emission tomography (PET) requires the use of an arterial input function. Arterial sampling, however, is not always possible, for example in ill-conditioned or paediatric patients. Therefore, it is of interest to explore the use of non-invasive methods for the quantification of CBF. For validation of non-invasive methods, test-retest normal and hypercapnia data from 15 healthy volunteers were used. For each subject, the data consisted of up to five dynamic [ 15 O]H 2 O brain PET studies of 10 min and including arterial sampling. A measure of CBF was estimated using several non-invasive methods earlier reported in literature. In addition, various parameters were derived from the time-activity curve (TAC). Performance of these methods was assessed by comparison with full kinetic analysis using correlation and agreement analysis. The analysis was repeated with normalization to the whole brain grey matter value, providing relative CBF distributions. A reliable, absolute quantitative estimate of CBF could not be obtained with the reported non-invasive methods. Relative (normalized) CBF was best estimated using the double integration method.

Importance: Previous studies have evaluated the diagnostic effect of amyloid positron emission tomography (PET) in selected research cohorts. However, these research populations do not reflect daily practice, thus hampering clinical implementation of amyloid imaging., Objective: To evaluate the association of amyloid PET with changes in diagnosis, diagnostic confidence, treatment, and patients' experiences in an unselected memory clinic cohort., Design, Setting, and Participants: Amyloid PET using fluoride-18 florbetaben was offered to 866 patients who visited the tertiary memory clinic at the VU University Medical Center between January 2015 and December 2016 as part of their routine diagnostic dementia workup. Of these patients, 476 (55%) were included, 32 (4%) were excluded, and 358 (41%) did not participate. To enrich this sample, 31 patients with mild cognitive impairment from the University Medical Center Utrecht memory clinic were included. For each patient, neurologists determined a preamyloid and postamyloid PET diagnosis that existed of both a clinical syndrome (dementia, mild cognitive impairment, or subjective cognitive decline) and a suspected etiology (Alzheimer disease [AD] or non-AD), with a confidence level ranging from 0% to 100%. In addition, the neurologist determined patient treatment in terms of ancillary investigations, medication, and care. Each patient received a clinical follow-up 1 year after being scanned., Main Outcomes and Measures: Primary outcome measures were post-PET changes in diagnosis, diagnostic confidence, and patient treatment., Results: Of the 507 patients (mean [SD] age, 65 (8) years; 201 women [39%]; mean [SD] Mini-Mental State Examination score, 25 [4]), 164 (32%) had AD dementia, 70 (14%) non-AD dementia, 114 (23%) mild cognitive impairment, and 159 (31%) subjective cognitive decline. Amyloid PET results were positive for 242 patients (48%). The suspected etiology changed for 125 patients (25%) after undergoing amyloid PET, more often due to a negative (82 of 265 [31%]) than a positive (43 of 242 [18%]) PET result (P < .01). Post-PET changes in suspected etiology occurred more frequently in patients older (>65 years) than younger (<65 years) than the typical age at onset of 65 years (74 of 257 [29%] vs 51 of 250 [20%]; P < .05). Mean diagnostic confidence (SD) increased from 80 (13) to 89 (13%) (P < .001). In 123 patients (24%), there was a change in patient treatment post-PET, mostly related to additional investigations and therapy., Conclusions and Relevance: This prospective diagnostic study provides a bridge between validating amyloid PET in a research setting and implementing this diagnostic tool in daily clinical practice. Both amyloid-positive and amyloid-negative results had substantial associations with changes in diagnosis and treatment, both in patients with and without dementia.

Previous studies have demonstrated that the chimeric monoclonal antibody rituximab significantly reduces clinical and radiological disease activity in relapsing-remitting multiple sclerosis as early as 4 weeks after the first administration. The exact mechanisms leading to this rapid effect have not yet been clarified. The aim of this positron emission tomography study was to assess central nervous system penetration as a possible explanation, using zirconium-89-labelled rituximab. No evidence was found for cerebral penetration of [ 89 Zr]rituximab.

We investigated whether dementia risk factors were associated with prodromal Alzheimer's disease (AD) according to the International Working Group-2 and National Institute of Aging-Alzheimer's Association criteria, and with cognitive decline. A total of 1394 subjects with mild cognitive impairment from 14 different studies were classified according to these research criteria, based on cognitive performance and biomarkers. We compared the frequency of 10 risk factors between the subgroups, and used Cox-regression to examine the effect of risk factors on cognitive decline. Depression, obesity, and hypercholesterolemia occurred more often in individuals with low-AD-likelihood, compared with those with a high-AD-likelihood. Only alcohol use increased the risk of cognitive decline, regardless of AD pathology. These results suggest that traditional risk factors for AD are not associated with prodromal AD or with progression to dementia, among subjects with mild cognitive impairment. Future studies should validate these findings and determine whether risk factors might be of influence at an earlier stage (i.e., preclinical) of AD., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: The Alzheimer's biomarkers in daily practice (ABIDE) project is designed to translate knowledge on diagnostic tests (magnetic resonance imaging [MRI], cerebrospinal fluid [CSF], and amyloid positron emission tomography [PET]) to daily clinical practice with a focus on mild cognitive impairment (MCI)., Methods: ABIDE is a 3-year project with a multifaceted design and is structured into interconnected substudies using both quantitative and qualitative research methods., Results: Based on retrospective data, we develop personalized risk estimates for MCI patients. Prospectively, we collect MRI and CSF data from 200 patients from local memory clinics and amyloid PET from 500 patients in a tertiary setting, to optimize application of these tests in daily practice. Furthermore, ABIDE will develop strategies for optimal patient-clinician conversations., Discussion: Ultimately, this will result in a set of practical tools for clinicians to support the choice of diagnostic tests and facilitate the interpretation and communication of their results.

Background: Early-onset dementia patients often present with atypical clinical symptoms, hampering an accurate clinical diagnosis. The purpose of the present study was to assess the diagnostic impact of the amyloid-positron emission tomography (PET) imaging agent [ 18 F]flutemetamol in early-onset dementia patients, in terms of change in (confidence in) diagnosis and patient management plan., Methods: This prospective bi-center study included 211 patients suspected of early-onset dementia who visited a tertiary memory clinic. Patients were eligible with Mini Mental State Examination ≥ 18 and age at diagnosis ≤ 70 years and in whom the diagnostic confidence was <90% after routine diagnostic work-up. All patients underwent [ 18 F]flutemetamol PET, which was interpreted as amyloid-negative or amyloid-positive based on visual rating. Before and after disclosing the PET results, we assessed the diagnostic confidence (using a visual analog scale of 0-100%) and clinical diagnosis. The impact of [ 18 F]flutemetamol PET on the patient management plan was also evaluated., Results: [ 18 F]flutemetamol PET scans were positive in 133 out of 211 (63%) patients, of whom 110 out of 144 (76%) patients had a pre-PET Alzheimer's disease (AD) diagnosis and 23 out of 67 (34%) patients had a non-AD diagnosis. After disclosure of PET results, 41/211 (19%) diagnoses changed. Overall, diagnostic confidence increased from 69 ± 12% to 88 ± 15% after disclosing PET results (P < 0.001; in 87% of patients). In 79 (37%) patients, PET results led to a change in patient management and predominantly the initiation of AD medication when PET showed evidence for amyloid pathology., Conclusions: [ 18 F]flutemetamol PET changed clinical diagnosis, increased overall diagnostic confidence, and altered the patient management plan. Our results suggest that amyloid PET may have added value over the standardized diagnostic work-up in early-onset dementia patients with uncertain clinical diagnosis. This study provides evidence for the recommendations put forward in the appropriate use criteria for amyloid PET in clinical practice., Trial Registration: Nederlands Trial Register NTR3743 . Registered 7 December 2012.

Until a few years ago, amyloid plaques in the brains of patients with Alzheimer's disease could only be demonstrated by means of neuropathological examination. New PET tracers allow for visualisation of these amyloid plaques in living patients. Biological validity and clinical relevance of this technique have been established. Expertise in interpretation of the images and the diagnostic impact is required. Cost effectiveness and added value over existing methods in terms of diagnosis and prognosis are still being investigated.

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 < .01), good performance for AD versus MCI (AUC, 0.89; P < .01), and poor performance for MCI versus SCD (AUC, 0.63; P = .06). Application of the AD versus SCD discrimination map for prediction of MCI subgroups resulted in good performance for patients with MCI diagnosis converted to AD versus subjects with SCD (AUC, 0.84; P < .01) and fair performance for patients with MCI diagnosis converted to AD versus those with stable MCI (AUC, 0.71; 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.

18 F-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 18 F-DPA-714 binding., Methods: Ninety-minute dynamic 18 F-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 (V T ) 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 (BP ND ) images., Results: Plasma-input Logan analysis (r 2 = 0.99; slope, 0.88) and spectral analysis (r 2 = 0.99, slope, 0.93) generated estimates of V T that correlated well with values obtained using nonlinear regression. BP ND values generated using SRTM2 (r 2 = 0.83; slope, 0.95) and reference Logan analysis (r 2 = 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 V T images of 18 F-DPA-714. In addition, SRTM2 and reference Logan analysis can provide accurate BP ND images. These parametric images could be used for voxel-based comparisons., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

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., (© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Evidence is accumulating that immune dysfunction is involved in the pathophysiology of schizophrenia. It has been hypothesized that microglia activation is present in patients with schizophrenia. Various in vivo and post-mortem studies have investigated this hypothesis, but as yet with inconclusive results. Microglia activation is associated with elevations in 18 kDa translocator protein (TSPO) levels, which can be measured with the positron emission tomography (PET) tracer (R)-[(11)C]PK11195. The purpose of the present study was to investigate microglia activation in psychosis in vivo at an early stage of the disease. (R)-[(11)C]PK11195 binding potential (BPND) was measured in 19 patients with recent onset psychosis and 17 age and gender-matched healthy controls. Total gray matter, as well as five gray matter regions of interest (frontal cortex, temporal cortex, parietal cortex, striatum, and thalamus) were defined a priori. PET data were analysed using a reference tissue approach and a supervised cluster analysis algorithm to identify the reference region. No significant difference in (R)-[(11)C]PK11195 BPND between patients and controls was found in total gray matter, nor one of the regions of interest. These findings suggest that microglia activation is not present in recent onset psychosis or that it is a subtle phenomenon that could not be detected using the design of the present study.

The N-Methyl-d-Aspartate receptor (NMDAR) is involved in many neurological and psychiatric disorders including Alzheimer's disease and schizophrenia. The aim of this study was to develop a positron emission tomography (PET) ligand to assess the bio-availability of the NMDAR ion channel in vivo. A series of tri-N-substituted diarylguanidines was synthesized and their in vitro binding affinities for the NMDAR ion channel assessed in rat forebrain membrane fractions. Compounds 21, 23 and 26 were radiolabeled with either carbon-11 or fluorine-18 and ex vivo biodistribution and metabolite studies were performed in Wistar rats. Biodistribution studies showed high uptake especially in prefrontal cortex and lowest uptake in cerebellum. Pre-treatment with MK-801, however, did not decrease uptake of the radiolabeled ligands. In addition, all three ligands showed fast metabolism., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Purpose: 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., Procedures: Healthy subjects received dynamic HRRT scans using either (R)-[(11)C]verapamil (n = 5), [(11)C]raclopride (n = 5) or [(11)C]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)., Results: Some (R)-[(11)C]verapamil studies showed prominent artefacts that disappeared with an ACF-margin of 10 mm or more. Use of 3D SSS for (R)-[(11)C]verapamil showed a statistically significant increase in volume of distribution compared with 2D SSS (p < 0.05), but not for [(11)C]raclopride and [(11)C]flumazenil studies (p > 0.05)., Conclusions: 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.

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.

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.

The purpose of this study was to assess whether there was an agreement between quantitative cerebral blood flow (CBF) and arterial cerebral blood volume (CBVA) measurements by [(15)O]H2O positron emission tomography (PET) and model-free QUASAR MRI. Twelve healthy subjects were scanned within a week in separate MRI and PET imaging sessions, after which quantitative and qualitative agreement between both modalities was assessed for gray matter, white matter and whole brain region of interests (ROI). The correlation between CBF measurements obtained with both modalities was moderate to high (r(2): 0.28-0.60, P < 0.05), although QUASAR significantly underestimated CBF by 30% (P < 0.001). CBVA was moderately correlated (r(2): 0.28-0.43, P < 0.05), with QUASAR yielding values that were only 27% of the [(15)O]H2O-derived values (P < 0.001). Group-wise voxel statistics identified minor areas with significant contrast differences between [(15)O]H2O PET and QUASAR MRI, indicating similar qualitative CBVA and CBF information by both modalities. In conclusion, the results of this study demonstrate that QUASAR MRI and [(15)O]H2O PET provide similar CBF and CBVA information, but with systematic quantitative discrepancies., (Copyright © 2016 John Wiley & Sons, Ltd.)

Neuroinflammation is thought to play a pivotal role in many diseases affecting the brain, including Alzheimer's disease, multiple sclerosis and stroke. Neuroinflammation is characterised predominantly by microglial activation, which can be visualised using positron emission tomography (PET). Traditionally, translocator protein 18kDa (TSPO) is the target for imaging of neuroinflammation using PET. In this review, recent preclinical and clinical research using PET in Alzheimer's disease, multiple sclerosis and stroke is summarised. In addition, new molecular targets for imaging of neuroinflammation, such as monoamine oxidases, adenosine receptors and cannabinoid receptor type 2, are discussed. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger., (Copyright © 2015 Elsevier B.V. All rights reserved.)

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.

Objectives: To investigate arterial spin-labelling (ASL) cerebral blood flow (CBF) changes in predementia stages of Alzheimer's disease (AD)., Methods: Data were obtained from 177 patients with subjective complaints, mild cognitive impairment and AD from the Amsterdam Dementia Cohort. AD stages were based on diagnosis and cerebrospinal fluid biomarkers amyloid-β (Aβ) and total-tau (tau). General-linear-models were used to assess relationships between AD stages and total and regional CBF, correcting for age and sex., Results: Decreasing CBF was related to more advanced AD stages in all supratentorial regions (p for trend < 0.05). Post-hoc testing revealed that CBF was lower in AD compared to controls and stage-1 predementia patients (i.e. abnormal Aβ and normal tau) in temporal and parietal regions, and compared to stage-2 predementia patients (i.e. abnormal Aβ and tau) in temporal regions. CBF values of stage-2 predementia patients were numerically in between those of stage-1 predementia patients and AD., Conclusion: The continuing decrease of CBF along the continuum of AD indicates the potential of ASL-CBF as a measure for disease progression., Key Points: • Decreasing CBF relates to more advanced AD stages in all supratentorial regions. • The reduction of CBF does not reach a bottom level. • ASL-CBF has potential as a measure for disease progression in AD.

Objectives: To define CSF β-amyloid 1-42 (Aβ42) cutpoints to detect cortical amyloid deposition as assessed by 11C-Pittsburgh compound B ([11C]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 Aβ42 and Aβ42/tau ratio cutpoints for cortical amyloid deposition based on visual interpretation of [11C]PiB-PET images., Results: Amyloid-PET-based calculated CSF Aβ42 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 Aβ42 and amyloid-PET was 84%. Similar concordance was found when using a dichotomized Aβ42/tau ratio. Exploratory analysis showed that participants with a positive amyloid-PET and normal CSF Aβ42 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 Aβ42 levels., Conclusions: Amyloid-PET-based CSF Aβ42 cutpoints were higher and tended to reduce intercenter variability compared with clinical-based cutpoints. Discordant participants with normal CSF Aβ42 and a positive amyloid-PET may be more likely to have AD-related amyloid pathology than participants with abnormal CSF Aβ42 and a negative amyloid-PET., Classification of Evidence: This study provides Class II evidence that an amyloid-PET-based CSF Aβ42 cutpoint identifies individuals with amyloid deposition with a sensitivity of 87% and specificity of 80%., (© 2015 American Academy of Neurology.)

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.

Background: The criteria for behavioral variant frontotemporal dementia (bvFTD) incorporate MRI and [18F]-FDG-PET. Cerebrospinal fluid (CSF) analysis is merely advised for excluding Alzheimer's disease., Aims: We aimed to assess the impact of biomarkers on diagnostic certainty and contingent changes of bvFTD diagnosis within the clinically relevant neuropsychiatric differential diagnosis of subjects with a late-onset frontal lobe syndrome (LOF)., Methods: We included 137 patients with LOF, aged 45-75 years, 72% males. Biomarker disclosure was considered contributing after any substantial difference in diagnostic certainty or a diagnostic change. Percentages of contributing biomarkers were compared between three major diagnostic groups (bvFTD, psychiatry, other neurological disorders). Certainty levels in stable diagnostic groups were compared to those with a diagnostic change., Results: Biomarkers contributed in 53, 60 and 41% of the LOF patients for MRI, [18F]-FDG-PET and CSF, respectively. Biomarkers changed the diagnosis in 14% of cases towards bvFTD and in 13% from bvFTD into an alternative. Those that changed had a lower level of a priori diagnostic certainty compared to stable diagnoses., Conclusion: Our study not only supports the widely accepted use of MRI and [18F]-FDG-PET in diagnosing or excluding bvFTD, but also shows that CSF biomarkers aid clinicians in the diagnostic process., (© 2015 S. Karger AG, Basel.)

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., (© 2016 S. Karger AG, Basel.)

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.

Non-pharmacological therapies, such as physical activity interventions, are an appealing alternative or add-on to current pharmacological treatment of cognitive symptoms in patients with dementia. In this meta-analysis, we investigated the effect of physical activity interventions on cognitive function in dementia patients, by synthesizing data from 802 patients included in 18 randomized control trials that applied a physical activity intervention with cognitive function as an outcome measure. Post-intervention standardized mean difference (SMD) scores were computed for each study, and combined into pooled effect sizes using random effects meta-analysis. The primary analysis yielded a positive overall effect of physical activity interventions on cognitive function (SMD[95% confidence interval]=0.42[0.23;0.62], p<.01). Secondary analyses revealed that physical activity interventions were equally beneficial in patients with Alzheimer's disease (AD, SMD=0.38[0.09;0.66], p<.01) and in patients with AD or a non-AD dementia diagnosis (SMD=0.47[0.14;0.80], p<.01). Combined (i.e. aerobic and non-aerobic) exercise interventions (SMD=0.59[0.32;0.86], p<.01) and aerobic-only exercise interventions (SMD=0.41[0.05;0.76], p<.05) had a positive effect on cognition, while this association was absent for non-aerobic exercise interventions (SMD=-0.10[-0.38;0.19], p=.51). Finally, we found that interventions offered at both high frequency (SMD=0.33[0.03;0.63], p<.05) and at low frequency (SMD=0.64[0.39;0.89], p<.01) had a positive effect on cognitive function. This meta-analysis suggests that physical activity interventions positively influence cognitive function in patients with dementia. This beneficial effect was independent of the clinical diagnosis and the frequency of the intervention, and was driven by interventions that included aerobic exercise., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Unlabelled: Overexpression of the multidrug efflux transport P-glycoprotein may play an important role in pharmacoresistance. (11)C-laniquidar is a newly developed tracer of P-glycoprotein expression. The aim of this study was to develop a pharmacokinetic model for quantification of (11)C-laniquidar uptake and to assess its test-retest variability., Methods: Two (test-retest) dynamic (11)C-laniquidar PET scans were obtained in 8 healthy subjects. Plasma input functions were obtained using online arterial blood sampling with metabolite corrections derived from manual samples. Coregistered T1 MR images were used for region-of-interest definition. Time-activity curves were analyzed using various plasma input compartmental models., Results: (11)C-laniquidar was metabolized rapidly, with a parent plasma fraction of 50% at 10 min after tracer injection. In addition, the first-pass extraction of (11)C-laniquidar was low. (11)C-laniquidar time-activity curves were best fitted to an irreversible single-tissue compartment (1T1K) model using conventional models. Nevertheless, significantly better fits were obtained using 2 parallel single-tissue compartments, one for parent tracer and the other for labeled metabolites (dual-input model). Robust K1 results were also obtained by fitting the first 5 min of PET data to the 1T1K model, at least when 60-min plasma input data were used. For both models, the test-retest variability of (11)C-laniquidar rate constant for transfer from arterial plasma to tissue (K1) was approximately 19%., Conclusion: The accurate quantification of (11)C-laniquidar kinetics in the brain is hampered by its fast metabolism and the likelihood that labeled metabolites enter the brain. Best fits for the entire 60 min of data were obtained using a dual-input model, accounting for uptake of (11)C-laniquidar and its labeled metabolites. Alternatively, K1 could be obtained from a 5-min scan using a standard 1T1K model. In both cases, the test-retest variability of K1 was approximately 19%., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Alzheimer's disease (AD) can present with distinct clinical variants. Identifying the earliest neurodegenerative changes associated with each variant has implications for early diagnosis, and for understanding the mechanisms that underlie regional vulnerability and disease progression in AD. We performed voxel-based morphometry to detect atrophy patterns in early clinical stages of four AD phenotypes: Posterior cortical atrophy (PCA, "visual variant," n=93), logopenic variant primary progressive aphasia (lvPPA, "language variant," n=74), and memory-predominant AD categorized as early age-of-onset (EOAD, <65 years, n=114) and late age-of-onset (LOAD, >65 years, n=114). Patients with each syndrome were stratified based on: (1) degree of functional impairment, as measured by the clinical dementia rating (CDR) scale, and (2) overall extent of brain atrophy, as measured by a neuroimaging approach that sums the number of brain voxels showing significantly lower gray matter volume than cognitively normal controls (n=80). Even at the earliest clinical stage (CDR=0.5 or bottom quartile of overall atrophy), patients with each syndrome showed both common and variant-specific atrophy. Common atrophy across variants was found in temporoparietal regions that comprise the posterior default mode network (DMN). Early syndrome-specific atrophy mirrored functional brain networks underlying functions that are uniquely affected in each variant: Language network in lvPPA, posterior cingulate cortex-hippocampal circuit in amnestic EOAD and LOAD, and visual networks in PCA. At more advanced stages, atrophy patterns largely converged across AD variants. These findings support a model in which neurodegeneration selectively targets both the DMN and syndrome-specific vulnerable networks at the earliest clinical stages of AD., (© 2015 Wiley Periodicals, Inc.)