Grey zone amyloid burden affects memory function: the SCIENCe project.

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 < 0.05). Analyses in subgroups showed memory slopes gradually became steeper with higher amyloid load (all p for trend < 0.05). Participants with a low amyloid burden benefited from a practice effect (i.e. increase in memory), whilst high amyloid burden was associated with memory decline. Memory slopes of individuals in the grey zone were intermediate. 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.

Tau PET and relative cerebral blood flow in dementia with Lewy bodies: A PET study.

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 < 0.05). Occipital and lateral parietal R1 was lower in DLB compared to AD and controls (all p < 0.01). Lower frontal R1 was associated with impaired performance on digit span forward (standardized beta, stß = 0.72) and category fluency (stß = 0.69) tests. Lower parietal R1 was related to lower delayed (stß = 0.50) and immediate (stß = 0.48) recall, VOSP number location (stß = 0.70) and fragmented letters (stß = 0.59) scores. Lower occipital R1 was associated to worse performance on VOSP fragmented letters (stß = 0.61), all p < 0.05. CONCLUSION: The amount of tau binding in DLB was minimal and did not differ from controls. However, there were DLB-specific occipital and lateral parietal relative cerebral blood flow reductions compared to both controls and AD patients. Regional rCBF, but not tau binding, was related to cognitive impairment. This indicates that assessment of rCBF may give more insight into disease mechanisms in DLB than tau PET.

[Amyloid PET imaging in patients with Alzheimer's disease]. / Amyloïd-PET bij patiënten met de ziekte van Alzheimer.

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.

Quantitative agreement between [(15)O]H2O PET and model free QUASAR MRI-derived cerebral blood flow and arterial blood volume.

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.

The effect of physical activity on cognitive function in patients with dementia: A meta-analysis of randomized control trials.

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.

Volume of interest-based [18F]fluorodeoxyglucose PET discriminates MCI converting to Alzheimer's disease from healthy controls. A European Alzheimer's Disease Consortium (EADC) study.

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 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.

The added value of 18-fluorodeoxyglucose-positron emission tomography in the diagnosis of the behavioral variant of frontotemporal dementia.

UNLABELLED: 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.

Accuracy and precision of pseudo-continuous arterial spin labeling perfusion during baseline and hypercapnia: a head-to-head comparison with ¹5O H2O positron emission tomography.

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.

Differential association of [11C]PIB and [18F]FDDNP binding with cognitive impairment.

OBJECTIVE: To evaluate associations of [(11)C]Pittsburgh compound B (PIB) and [(18)F]FDDNP with impairment in specific cognitive domains over the broader spectrum comprising cognitively normal elderly subjects, patients with mild cognitive impairment (MCI), and patients with Alzheimer disease (AD). METHODS: Twelve patients with AD, 13 patients with MCI, and 15 cognitively normal elderly subjects were included. Paired [(11)C]PIB and [(18)F]FDDNP PET scans were performed in all subjects. Binding potential (BP(ND)) was calculated using parametric images of BP(ND) for global, frontal, parietal, and temporal cortex; medial temporal lobe; and posterior cingulate. Cognitive functions were assessed using a battery of neuropsychological tests. Linear regression analyses were used to assess associations of [(11)C]PIB and [(18)F]FDDNP binding with cognitive measures. RESULTS: Adjusted for age, sex, and [(18)F]FDDNP binding, higher global [(11)C]PIB binding was associated with lower scores on the Mini-Mental State Examination, immediate and delayed recall of the Rey Auditory Verbal Learning Task (RAVLT), Visual Association Task, and Trail Making Test part B. Conversely, higher [(18)F]FDDNP binding was independently associated with lower scores on immediate recall of the RAVLT. After additional adjustment for diagnosis, higher [(11)C]PIB binding remained independently associated with delayed recall (standardized beta = -0.39, p = 0.01), whereas higher [(18)F]FDDNP binding remained independently associated with immediate recall (standardized beta = -0.32, p = 0.03). When regional binding was assessed using stepwise models, both increased frontal [(11)C]PIB and temporal [(18)F]FDDNP binding were associated with memory, whereas increased parietal [(11)C]PIB binding was associated with nonmemory functions. CONCLUSION: Increased [(18)F]FDDNP binding is specifically associated with impairment of episodic memory, whereas increased [(11)C]Pittsburgh compound B binding is associated with impairment in a broader range of cognitive functions.

Blood-brain barrier P-glycoprotein function is not impaired in early Parkinson's disease.

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.

Synthesis of 2-(1,1-dicyanopropen-2-yl)-6-(2-[18F]-fluoroethyl)-methylamino-naphthalene ([18F]FDDNP).

2-(1,1-dicyanopropen-2-yl)-6-(2-[18F]-fluoroethyl)-methylamino-naphthalene ([18F]FDDNP) was synthesized in a single step labeling procedure. The precursor, 2-(1,1-dicyanopropen-2-yl)-6-(2-tosyloxyoethyl)-methylamino-naphthalene, was fluorinated with 18F in acetonitrile. After 15 min the reaction mixture was subjected to preparative HPLC purification. The product was isolated from the HPLC eluent with solid-phase extraction, and formulated in an ascorbic acid solution to prevent formation of side products during formulation. Quantitative sticking to tubing and filters was overcome by the addition of polysorbatum-80. This formulation yielded an isotonic, pyrogen-free and sterile solution of [18F]FDDNP. The overall decay-corrected radiochemical yield was 41+/-11% (n=22). Radiochemical purity was >98% and the specific activity was 102+/-56 GBq/micromol at the end of synthesis.

Reduced GABAA benzodiazepine receptor binding in veterans with post-traumatic stress disorder.

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.