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Introduction This study examined a longitudinal trajectory of β-amyloid (Aβ) accumulation at the predementia stage of Alzheimer's disease in the context of clinical trials. Methods Analyzed were baseline (BL) and 2 years' follow-up 18F-florbetapir positron emission tomography data of 246 Aβ-positive subjects with normal cognition and mild cognitive impairment. We studied the relationship between annual accumulation rates of 18F-florbetapir and BL standard uptake value ratios in whole gray matter (SUVRGM). Results Subjects with BL SUVRGM of 0.56 to 0.92 (n = 134) appeared to accumulate Aβ approximately 1.5 times faster than remaining subjects. In subjects with SUVRGM above 0.95, most regions with the highest annual accumulation rate were outside the established set of Alzheimer's disease typical regions. Conclusion There are global and regional variations in annual accumulation rate at the predementia stage of Alzheimer's disease. When taken into account, the sample size in anti-amyloid trials can be substantially reduced. Critically, treated and placebo groups should be matched for BL SUVRGM.

Purpose Positron emission tomography (PET) in non-human primates (NHP) is commonly performed under anesthesia, with sevoflurane being a widely used inhaled anesthetic. PET measurement in NHP can be repeated, and a difference in radioligand kinetics has previously been observed between the first and second PET measurement on the same day using sevoflurane anesthesia. In this study, we evaluated the effect of prolonged sevoflurane anesthesia on kinetics and binding potential (BPND) of [11C]raclopride in NHP. Procedures Three cynomolgus monkeys underwent two to three PET measurements with [11C]raclopride under continuous sevoflurane anesthesia on the same day. The concentration of sevoflurane was adjusted according to the general conditions and safety parameters of the NHP. Time to peak (TTP) radioactivity in the striatum was estimated from time-activity curves (TACs). The BPND in the striatum was calculated by the simplified reference tissue model using the cerebellum as reference region. Results In each NHP, the TTP became shorter in the later PET measurements than in the first one. Across all measurements (n = 8), concentration of sevoflurane correlated with TTP (Spearman’s ρ = − 0.79, p = 0.03), but not with BPND (ρ = − 0.25, p = 0.55). Conclusions These data suggest that sevoflurane affects the shape of TACs but has no evident effect on BPND in consecutive PET measurements.

Metabolic connectivity modelling aims to detect functionally interacting brain regions based on PET recordings with the glucose analogue [F]fluorodeoxyglucose (FDG). Here, we outline the most popular metabolic connectivity methods and summarize recent applications in clinical and basic neuroscience.Metabolic connectivity is modelled by various methods including a seed correlation, sparse inverse covariance estimation, independent component analysis and graph theory. Given its multivariate nature, metabolic connectivity possess added value relative to conventional univariate analyses of FDG-PET data. As such, metabolic connectivity provides valuable insights into pathophysiology and diagnosis of dementing, movement disorders, and epilepsy. Metabolic connectivity can also identify resting state networks resembling patterns of functional connectivity as derived from functional MRI data.Metabolic connectivity is a valuable concept in the fast-developing field of brain connectivity, at least as reasonable as functional connectivity of functional MRI. So far, the value of metabolic connectivity is best established in neurodegenerative disorders, but studies in other brain diseases as well as in the healthy state are emerging. Growing evidence indicates that metabolic connectivity may serve a marker of normal and pathological cognitive function. A relationship of metabolic connectivity with structural and functional connectivity is yet to be established.

In Alzheimer's disease (AD), amyloid-β (Aβ) pathology and intrinsic functional connectivity (iFC) interact. Across stages of AD, we expected individual spatial correspondence of Aβ and iFC to reveal both Aβ accumulation and its detrimental effects on iFC. We used resting-state functional magnetic imaging and Aβ imaging in a cross-sectional sample of 90 subjects across stages of AD and healthy older adults. Global and local correspondence of Aβ and iFC were assessed within the posterior default mode network (pDMN) by within-subject voxel-wise correlations. Beginning at preclinical stages, global Aβ-iFC correspondence was positive for the whole pDMN, showing that Aβ accumulates in areas of high connectivity, and reached a plateau at prodromal stages. Starting at preclinical stages, local correspondence was negative in network centers, indicating that Aβ reduces connectivity of the pDMN as a function of local plaque concentration, and peaked at prodromal stages. Positive global correspondence suggests that Aβ accumulation progresses along iFC, with this effect starting in preclinical stages, and being constant along clinical periods. Negative local correspondence suggests detrimental effects of Aβ on iFC in network centers, starting at preclinical stages, and peaking when first symptoms appear. Data reveal a complex trajectory of Aβ and iFC correspondence, affecting both Aβ accumulation and iFC impairments.

Idiopathic Parkinsons disease (PD) and atypical parkinsonian syndromes may have similar symptoms at the early disease stage. Pattern recognition on metabolic imaging has been confirmed of distinct value in the early differential diagnosis of Parkinsonism. However, the principal component analysis (PCA) based method ends up with a unique probability score of each disease pattern. This restricts the exploration of heterogeneous characteristic features for differentiation. There is no visualization of the underlying mechanism to assist the radiologist/neurologist either. We propose a tensor factorization based method to extract the characteristic patterns of the diseases. By decomposing the 3D data, we can capture the intrinsic characteristic pattern in the data. In particular, the disease-related patterns can be visualized individually for the inspection by physicians. The test on PET images of 206 early parkinsonian patients has confirmed differential patterns on the visualized feature images using the proposed method. Computer-aided diagnosis based on multi-class support vector machine (SVM) shown improved diagnostic accuracy of Parkinsonism using the tensor-factorized feature images compared to the state-of-the-art PCA-based scores [Tang et al. Lancet Neurol. 2010].

In patients with Alzheimer's disease (AD), prominent hypometabolism has been observed in brain regions with minor amyloid load. These hypometabolism-only (HO) areas cannot be explained merely as a consequence of local amyloid toxicity. The aim of this multimodal imaging study was to explore whether such HO phenomenon may be related to pathologies in functionally connected, remote brain regions. Nineteen AD patients and 15 matched controls underwent examinations with [(11)C]PiB-PET and [(18)F]FDG-PET. Voxel-based statistical group comparisons were performed to obtain maps of significantly elevated amyloid burden and reduced cerebral glucose metabolism, respectively, in patients. An HO area was identified by subtraction of equally thresholded result maps (hypometabolism minus amyloid burden). To identify the network typically functionally connected to this HO area, it was used as a seed region for a functional connectivity analysis in resting-state functional magnetic resonance imaging data of 17 elderly healthy controls. The resulting intrinsic connectivity network (HO-ICN) was retransferred into the brains of AD patients to be able to analyze pathologies within this network in the positron emission tomography (PET) datasets. The most prominent HO area was detected in the left middle frontal gyrus of AD patients. The HO-ICN in healthy controls showed a major overlap with brain areas significantly affected by both amyloid deposition and hypometabolism in patients. This association was substantiated by the results of region-of-interest-based and voxel-wise correlation analyses, which revealed strong correlations between the degree of hypometabolism within the HO region and within the HO-ICN. These results support the notion that hypometabolism in brain regions not strongly affected by locoregional amyloid pathology may be related to ongoing pathologies in remote but functionally connected regions, that is, by reduced neuronal input from these regions.

New diagnostic criteria for Alzheimer's disease (AD) treat different biomarkers of neuronal injury as equivalent. Here, we quantified the degree of agreement between hippocampal volume on structural magnetic resonance imaging, regional glucose metabolism on positron emission tomography, and levels of phosphorylated tau in cerebrospinal fluid (CSF) in 585 subjects from all phases of the AD Neuroimaging Initiative. The overall chance-corrected agreement was poor (Cohen κ, 0.24–0.34), in accord with a high rate of conflicting findings (26%–41%). Neither diagnosis nor APOE e4 status significantly influenced the distribution of agreement between the biomarkers. The degree of agreement tended to be higher in individuals with abnormal versus normal CSF β-amyloid (Aβ 1-42 ) levels. Prospective diagnostic criteria for AD should address the relative importance of markers of neuronal injury and elaborate a way of dealing with conflicting biomarker findings.

Introduction Central nervous system lymphoma (CNSL) is a rare neoplasia and arises as primary (PCNSL) or secondary CNSL (SCNSL) and most commonly occurs as diffuse large B-cell lymphoma. Although prognosis of this disease has significantly improved due to advantages in diagnostic procedures and intensification of treatment over the last decade there remain major challenges in the clinical management. Magnetic resonance imaging (MRI) - as the standard imaging modality - has difficulties to discriminate CNSL from other brain-derived tumors or metastasis. Moreover, prognostic scores in CNSL lack the ability to reliable define patients with high relapse risk 1. Therefore, novel strategies to facilitate diagnosis and to select patients that profit from intense treatment protocols are urgently needed. The C-X-C chemokine receptor 4 (CXCR4) is a transmembrane chemokine receptor with pivotal roles in cell homing and is often overexpressed in hematologic malignancies. CXCR4-directed positron emission tomography (PET) imaging with the tracer [68Ga]Pentixafor has been proven to be a suitable in vivo imaging modality for CXCR4 expression in lymphoid malignancies 2. To evaluate the feasibility of CXCR4-directed PET and the prognostic value of this imaging modality this retrospective proof-of-concept study evaluated [68Ga]Pentixafor PET imaging in patients with CNSL. Methods 11 patients with lymphoma of the CNS (n=8 PCNSL, n=3 SCNSL) were imaged with the CXCR4-directed PET tracer [68Ga]Pentixafor in this retrospective proof-of-concept study after signing inform consent. Lymphoma tissue was assessed for CXCR4 expression ex vivo by immunohistochemistry. The prognostic value of CXCR4-directed PET imaging was evaluated in a computed analysis in 7 patients with follow-up MRI. Treatment response calculated as treatment efficiency η by sequential MRI was correlated with [68Ga]Pentixafor PET derived parameters at diagnosis such as volume of PET positive lymphoma lesion V(PET), maximal PET uptake value within the lesion max(PET) or integrated uptake values over the lymphoma lesion ∫(PET). Analysis was performed in a lesion- and patient-based manner. Results [68Ga]Pentixafor PET imaging was positive in all patients with active disease (10/11 patients) with excellent contrast characteristics to the surrounding brain parenchyma. PET positive lesions correlated well with lymphoma lesions in MRI-T1c sequences. The surrounding edema depicted in MRI-FLAIR sequences was evaluated as PET negative (Figure 1). Semi-quantitative analysis revealed maximum standard uptake values of [68Ga]Pentixafor-derived PET from 4.2 to 23.3 within the lesions with a high tumor-to-background-ratio ranging from 13.2 to 83.0. The computed analysis revealed that CXCR4-directed PET parameters at diagnosis given by max(PET) and ∫(PET) significantly correlated with treatment response in the lesion-based as well as in the patient-based analysis. Specifically, ∫(PET) was the most significant prognostic factor in the present study (Figure 2 C, D, F). On the other hand tumor volume at diagnosis measured either by MRI or by [68Ga]Pentixafor PET did not denote a predictive marker for treatment response (Figure 2 A, B, E). Conclusion/Outlook CXCR4-directed PET imaging represents a novel imaging modality for CNSL. Due to its excellent contrast properties it might help to facilitate diagnosis and refine response assessment. Moreover, owing the predictive value for treatment response, CXCR4-directed PET could serve as a biomarker for the selection of patients profiting from intense treatment protocols. Furthermore, the feasibility of endoradiotherapeutic approaches targeting CXCR4 with Pentixather - the therapeutic twin of the imaging peptide Pentixafor - has been shown in hematologic malignancies and could be incorporated in the treatment of CNSL. References 1. Han CH, Batchelor TT. Diagnosis and management of primary central nervous system lymphoma. Cancer. 2017;123(22):4314-4324. 2.Kircher M, Herhaus P, Schottelius M, et al. CXCR4-directed theranostics in oncology and inflammation. Ann Nucl Med. 2018;32(8):503-511. Disclosures Wester: Scintomics: Other: Spouse CEO of Company; CXCR4-targeted radiopharmaceuticals: Other: Inventor; Scintomics GmbH, Germany: Other: Shareholder. Bassermann:Celgene: Consultancy, Research Funding.

e13542 Background: Modern radiotherapy (RT) techniques such as IMRT combined with IGRT increased safety and precision over the years. However, during treatment planning, the definition of the planning target volume (PTV) remains challenging, and differentiation between healthy tissue, i.e., meninges, post-operative changes, and residual tumor can be difficult using MR and CT imaging alone. In this study, we evaluated the impact of additional PET-imaging on local control (LCR) and overall survival (OS). Methods: We analyzed 351 patients with primary RT of meningiomas treated between 1996 and 2018 and divided the cohort into low-grade (n = 283) and high-grade (n = 68) cases. All patients were treated with fractionated stereotactic radiotherapy (FSRT) with a median dose of 54.0 Gy and a median single dose of 1.8 Gy. A radiation oncologist delineated PTV based on diagnostic CT and MRI and, if available, additional PET-imaging. We used only PET-images acquired within 50 days before RT. In our clinic, PET-planned meningioma treatment started in 2000 with Methionine (2001-2010), between 2004 and 2011 F-18 FET tracer was used, and since 2011 only 68Ga-Dotanoc/Dotatoc PETs are acquired. This study is registered under the open science framework: DOI 10.17605/OSF.IO/RYX9D. Results: Median follow-up was 6.9 years (95%-KI: 6.3-7.4). For low-grade meningiomas, mean OS was 15.5 years (95%-KI: 14.7-16.2) and mean PFS was 15.7 years (95%-KI: 14.9-16.6); for high-grade cases, median OS was 13.8 years (95%-KI: 10.4-17.1), and median PFS was 8.9 years (95%-KI: 6.4-11.4). PET imaging had a significant impact on OS (p = 0.030) and PFS (p = 0.023) for low-grade meningiomas; however, in the multivariate analysis (with the prognostic factors age, gender, PTV, Karnofsky index, and time from resection to RT), it remained only significant for LCR. For high-grade cases, PET-imaging had no influence. Conclusions: PET-imaging improves the detection of tumor cells, especially during treatment planning. It showed a significant influence on OS and LCR. Further analyses will investigate the influence of PET regarding, e.g., residual tumor tissue, tumor size, and establish cut-off values for which tumors additional PET-imaging might be beneficial. With the further prognostic a weighted scoring system will be developed for prognostic assessment. [Table: see text]

Background According to new diagnostic guidelines for Alzheimer’s disease (AD), biomarkers enable estimation of the individual likelihood of underlying AD pathophysiology and the associated risk of progression to AD dementia for patients with mild cognitive impairment (MCI). Nonetheless, how conflicting biomarker constellations affect the progression risk is still elusive. The present study explored the impact of different cerebrospinal fluid (CSF) biomarker constellations on the progression risk of MCI patients. Methods A multicentre cohort of 469 patients with MCI and available CSF biomarker results and clinical follow-up data was considered. Biomarker values were categorized as positive for AD, negative or borderline. Progression risk differences between patients with different constellations of total Tau (t-Tau), phosphorylated Tau at threonine 181 (p-Tau) and amyloid-beta 1–42 (Aβ42) were studied. Group comparison analyses and Cox regression models were employed. Results Patients with all biomarkers positive for AD (N = 145) had the highest hazard for progression to dementia due to AD, whilst patients with no positive biomarkers (N = 111) had the lowest. The risk of patients with only abnormal p-Tau and/or t-Tau (N = 49) or with positive Aβ42 in combination with positive t-Tau or p-Tau (N = 119) is significantly lower than that of patients with all biomarkers positive. Conclusions The risk of progression to dementia due to AD differs between patients with different CSF biomarker constellations.

There is a great deal of heterogeneity in the impact of aging on cognition and cerebral functioning. One potential factor contributing to individual differences among the elderly is the cognitive reserve, which designates the partial protection from the deleterious effects of aging that lifetime experience provides. Neuroimaging studies examining task-related activation in elderly people suggested that cognitive reserve takes the form of more efficient use of brain networks and/or greater ability to recruit alternative networks to compensate for age-related cerebral changes. In this exploratory multi-center study, we examined the relationships between cognitive reserve, as measured by education and verbal intelligence, and cerebral metabolism at rest (FDG-PET) in a sample of 74 healthy older participants. Higher degree of education and verbal intelligence was associated with less metabolic activity in the right posterior temporoparietal cortex and the left anterior intraparietal sulcus. Functional connectivity analyses of resting-state fMRI images in a subset of 41 participants indicated that these regions belong to the default mode network and the dorsal attention network respectively. Lower metabolism in the temporoparietal cortex was also associated with better memory abilities. The findings provide evidence for an inverse relationship between cognitive reserve and resting-state activity in key regions of two functional networks respectively involved in internal mentation and goal-directed attention.

Although cognitive training usually improves cognitive test performance, the capability to transfer these training gains into respective or functionally related cognitive domains varies significantly. Since most studies demonstrate rather limited transfer effects in older adults, aging might be an important factor in transfer capability differences. This study investigated the transfer capability of logical reasoning training gains to a measure of Fluid Intelligence (Gf) in relation to age, general intelligence, and brain structural integrity as measured by diffusion tensor imaging. In a group of 41 highly educated healthy elderly, 71% demonstrated successful transfer immediately after a 4-week training session (i.e. short-term transfer). In a subgroup of 22% of subjects transfer maintained over a 3-month follow-up period (i.e. long-term transfer). While short-term transfer was not related to structural integrity, long-term transfer was associated with increased structural integrity in corpus and genu of the corpus callosum. Since callosal structural integrity was also related to age (in the present and foregoing studies), previously observed associations between age and transfer might be moderated by the structural integrity. Surprisingly, age was not directly associated with transfer in this study which could be explained by the multi-dependency of the structural integrity (modulating factors beside age, e.g. genetics). In this highly educated sample, general intelligence was not related to transfer suggesting that high intelligence is not sufficient for transfer in normal aging. Further studies are needed to reveal the interaction of transfer, age, and structural integrity and delineate mechanisms of age-dependent transfer capabilities. Hum Brain Mapp 35:309–318, 2014. © 2012 Wiley Periodicals, Inc.

Purpose: To evaluate the feasibility of multicenter tractography of the cingulate bundle (CB) in Alzheimer's disease (AD). Materials and Methods: Automated deterministic tractography of the CB was applied to scans of 45 patients with probable AD and 58 healthy controls (HC) acquired with Siemens Sonata (1.5T; 60 gradients), Trio (3T; 61 gradients), and Avanto (1.5T; 30 gradients). Diagnosis and center effects on the tracking indices fractional anisotropy (FA), mean diffusivity (MD), track density, and volume were estimated with analysis of variance. Results: The multicenter coefficients of variance (CVs) in HC and AD patients were 7% and 7% for FA, 10% and 8% for MD, 18% and 20% for density, and 21% and 21% for volume. Multicenter and single-center CVs were within a similar range. Significant center effects declined in the order MD > FA > density > volume. After adjustment for center and age, the AD group showed significantly higher MD (P < 0.001) and lower FA (P < 0.05) as compared with the HC group. Conclusion: Despite strong center effects, we detected significantly altered microstructural integrity of the CB in AD patients. Diffusion-tensor imaging indices of the CB as obtained by automated tractography might qualify as a biologically sustained surrogate marker for diagnostic and monitoring purposes in multicenter AD trials. J. Magn. Reson. Imaging 2012;36:84–91. © 2012 Wiley Periodicals Inc.

The combination of Positron Emission Tomography (PET) with magnetic resonance imaging (MRI) in hybrid PET/MRI scanners offers a number of advantages in investigating brain structure and function. A critical step of PET data reconstruction is attenuation correction (AC). Accounting for bone in attenuation maps (μ-map) was shown to be important in brain PET studies. While there are a number of MRI-based AC methods, no systematic comparison between them has been performed so far. The aim of this work was to study the different performance obtained by some of the recent methods presented in the literature. To perform such a comparison, we focused on [18F]-Fluorodeoxyglucose-PET/MRI neurodegenerative dementing disorders, which are known to exhibit reduced levels of glucose metabolism in certain brain regions. Four novel methods were used to calculate μ-maps from MRI data of 15 patients with Alzheimer’s dementia (AD). The methods cover two atlas-based methods, a segmentation method, and a hybrid template/segmentation method. Additionally, the Dixon-based and a UTE-based method, offered by a vendor, were included in the comparison. Performance was assessed at three levels: tissue identification accuracy in the μ-map, quantitative accuracy of reconstructed PET data in specific brain regions, and precision in diagnostic images at identifying hypometabolic areas. Quantitative regional errors of −20–−10 % were obtained using the vendor’s AC methods, whereas the novel methods produced errors in a margin of ±5 %. The obtained precision at identifying areas with abnormally low levels of glucose uptake, potentially regions affected by AD, were 62.9 and 79.5 % for the two vendor AC methods, the former ignoring bone and the latter including bone information. The precision increased to 87.5–93.3 % in average for the four new methods, exhibiting similar performances. We confirm that the AC methods based on the Dixon and UTE sequences provided by the vendor are inferior to alternative techniques. As a novel finding, there was no substantial difference between the recently proposed atlas-based, template-based and segmentation-based methods.

The hippocampus is among the first brain structures to be affected by Alzheimer's disease (AD) pathology. Microstructural alterations within this region have been quantified in vivo using diffusion tensor imaging (DTI), a relatively novel MRI-based technique for mapping diffusion properties of water. Existing evidence indicates that DTI-derived mean diffusivity (MD) of the anterior hippocampus is more predictive than ordinary volumetric indices of the degree of episodic memory impairment in patients with early AD. Thus, altered MD of the (anterior) hippocampus might be highly indicative of hippocampal dysfunction, thereby potentially qualifying this measure as a candidate marker for monitoring progression of AD. Longitudinal studies are needed to confirm this concept. DTI-based assessment of hippocampal microstructure might be also of value for early AD diagnosis and for predicting the course of cognitive decline in subjects at risk for Alzheimer's dementia. Mean diffusivity as microstructural and volume as macrostructural index of hippocampal integrity seem to reflect different, albeit overlapping, aspects of the neurodegenerative process. In contrast, fractional anisotropy is less efficient for quantifying microstructural integrity of the diseased hippocampus in the clinical context. Development of automatic algorithms, providing MD measurements of the hippocampus for routine use, is a task for future studies.

Hypometabolism of the posterior cingulate cortex (PCC) in early Alzheimer's disease (AD) is thought to arise in part due to AD-specific neuronal damage to the hippocampal formation. Here, we explored the association between microstructural alterations within the hippocampus and whole-brain glucose metabolism in subjects with AD, also in relation to episodic memory impairment.Twenty patients with early AD (Mini-Mental State Examination 25.7 ± 1.7) were studied with [(18)F]fluorodeoxyglucose (FDG) positron emission tomography and diffusion tensor imaging. Episodic memory performance was assessed using the free delayed verbal recall task (DVR). Voxel-wise relative FDG uptake was correlated to diffusivity indices of the hippocampus, followed by extraction of FDG uptake values from significant clusters. Linear regression analysis was performed to test for unique contributions of diffusivity and metabolic indices in the prediction of memory function.Diffusivity in the left anterior hippocampus negatively correlated with FDG uptake primarily in the left anterior hippocampus, parahippocampal gyrus and the PCC (p0.005). The same correlation pattern was found for right hippocampal diffusivity (p0.05). In linear regression analysis, left anterior hippocampal diffusivity and FDG uptake from the PCC cluster were the only significant predictors for performance on DVR, together explaining 60.6% of the variance. We found an inverse association between anterior hippocampal diffusivity and PCC glucose metabolism, which was in turn strongly related to episodic memory performance in subjects with early AD.These findings support the diaschisis hypothesis of AD and implicate a dysfunction of structures along the hippocampal output pathways as a significant contributor to the genesis of episodic memory impairment.

Abnormal microstructural integrity and glucose metabolism of the hippocampus are common in subjects with Alzheimer’s disease (AD) that typically manifest as episodic memory impairment. The above-tissue alterations can be captured in vivo using diffusion tensor imaging (DTI) and positron emission tomography with [18F]fluorodeoxyglucose (FDG-PET). Here, we explored relationships between the above neuroimaging and cognitive markers of early AD-specific hippocampal damage. Twenty patients with early AD (MMSE 25.7 ± 1.7) were studied using DTI and FDG-PET. Episodic memory performance was assessed using the free delayed verbal recall task (DVR). In the between-modality correlation analysis, FDG uptake was strongly associated with diffusivity in the left anterior hippocampus only (r = −0.81, p < 0.05 Bonferroni’s corrected for multiple tests). Performance on DVR significantly correlated with left anterior (r = −0.80, p < 0.05) and left mean (r = −0.72, p < 0.05) hippocampal diffusivity, while the correlation with left anterior FDG uptake did not reach statistical significance (r = 0.52, n.s.). DTI-derived diffusivity of the anterior hippocampus might be a sensitive early marker of hippocampal dysfunction as reflected at the synaptic and cognitive levels. This neurobiological distinction of the anterior hippocampus might be related to the disruption of the perforant pathway that is known to occur early in the course of AD.

Background: Neuropsychiatric symptoms (NPS), mainly cognitive deficits up to dementia and depressive syndromes have been described repeatedly in Fabry disease (FD). However, examinations regarding the pattern, extent, and frequency of the NPS in FD are still lacking. Moreover, the relationship between NPS and brain structural alterations in FD is unknown. The aim of this study was 1) to characterize NPS in a relatively large cohort of adult subjects with FD, and 2) to explore the association of cognitive performance and depressive syndromes with the FD-typical brain structural findings. Methods: Twenty-five Fabry patients (age 36.5 ± 11.0) with mild to moderate disease involvement and 20 age, gender-, and education-matched healthy controls were extensively studied by neuropsychiatric assessment, structural magnetic resonance imaging, magnetic resonance angiography, and diffusion-tensor imaging. Results: Patients with FD showed deficits only in the attention domain. Clinically relevant depressive syndromes were noted in 60% of the patients. The subgroup of patients with markedly elevated volumes of white matter lesions (not associated with actual stroke; n = 7) showed slightly more learning and memory deficits, but no higher depression rate compared to less affected patients. Conclusions: Against the prevailing assumption, Fabry patients, even those with marked brain structural alterations, showed only mild cognitive deficits. The high frequency of depression in FD is likely to be related to the burden of this chronic multiorganic hereditary disease, but not to the FD-typical brain structural alterations. Longitudinal studies are necessary to clear, if the mild cognitive deficits in FD might precede clinically relevant cognitive decline.

Background: Fabry disease (FD) is a rare hereditary lysosomal storage disease that has been highlighted as a possible etiology of stroke at a young age. Enlarged basilar artery diameters (BADs) have been demonstrated in FD, and we hypothesize that they might be useful for the screening of FD in young stroke patients. The aim of this study was to compare BADs of young stroke patients without FD to those of FD patients and of healthy age-matched controls. Methods: BADs were measured using MR angiography in 3 age- and gender-matched groups: 25 FD patients (aged 36.5 ± 11.0 years), 26 non-FD stroke patients and 20 healthy controls. Results: Compared to the non-FD stroke patients, FD patients had significantly enlarged BADs. FD patients could be significantly separated from stroke patients by BADs (area under the curve = 0.89, 95% confidence interval 0.81–0.98). Eighty-six percent of all subjects could be correctly classified by BADs (sensitivity 84%, specificity 88.5%). Conclusions: Enlarged BADs were able to detect FD within a cohort of FD, stroke patients and healthy controls. BAD measurement could be an easily obtainable and sensitive screening tool for FD in young stroke patients.

The author listing has been updated to indicate that Timo Grimmer and Kuangyu Shi are equally contributing authors.

We used [18F]fluorodeoxyglucose (FDG) PET analysis to determine performance in different olfactory domains of patients with early AD compared to cognitively healthy subjects, and to map the functional metabolic representation of olfactory impairment in the patient sample. A cohort of patients with early AD (n=24), consisting of 6 subjects with incipient AD and 18 subjects with mild AD, and a control group of 28 age-matched non-demented individuals were assembled. Patients and controls were tested for olfactory performance using the "Sniffin' Sticks" test battery [odor identification (ID), discrimination (DIS) and threshold (THR)], while patients additionally underwent resting state FDG-PET. Voxel-wise PET results in the patients were correlated with olfaction scores using the general linear model in SPM5. Patients with early AD showed significantly reduced function in all three olfactory subdomains compared to controls. After controlling for effects due to patients' age, gender, cognitive status, and treating scores in the two other olfactory subdomains as nuisance variables, ID scores correlated with normalized FDG uptake in clusters with peaks in the right superior parietal lobule, fusiform gyrus, inferior frontal gyrus, and precuneus, while DIS scores correlated with a single cluster in the left postcentral cortex, and THR scores correlated with clusters in the right thalamus and cerebellum. The subtests employed in the "Sniffin' Sticks" test battery are complementary indicators of different aspects of olfactory dysfunction in early AD, and support the theory of a parallel organized olfactory system, revealed by FDG-PET correlation analysis.

REPLY: We appreciate the comment by Trotta and colleagues ([1][1]) on our recent study ([2][2]). Their results contribute to the developing field of metabolic connectivity imaging ([3][3]). Specifically, Trotta et al. applied a seed-based functional connectivity (sbFC) analysis of 18F-FDG PET data

The anatomical basis of visuo-constructive impairment in AD is widely unexplored. FDG-PET can be used to determine functional neuronal networks underlying specific cognitive performance in the human brain. In the present study, we determined the pattern of cortical metabolism that was associated with visuo-constructive performance in AD. We employed two widely used visuo-constructive tests that differ in their demand on visual perception and processing capacity. Resting state FDG-PET scans were obtained in 29 probable AD patients, and cognitive tests were administered. We made a voxel-based regression analysis of FDG uptake to scores in visual test performance, using the SPM5 software. Performance in the CERAD Drawing test correlated with FDG uptake in the bilateral inferior temporal gyri, bilateral precuneus, right cuneus, right supramarginal gyrus and right middle temporal gyrus covering areas of dorsal and ventral visual streams. In contrast, performance in the more complex RBANS Figure Copy test correlated with FDG uptake in the bilateral fusiform gyri, right inferior temporal gyrus, left anterior cingulate gyrus, left parahippocampal gyrus, right middle temporal gyrus and right insula, encompassing the ventral visual stream and areas of higher-level visual processing. The study revealed neuronal networks underlying impaired visual test performance in AD. The extent of involvement of visual and higher order association cortex increased with greater test complexity. From a clinical point of view, both of these widely used visual tests evaluate the integrity of complementary cortical networks and may contribute complementary information on the integrity of visual processing in AD.

Recent neuroanatomical and functional neuroimaging studies indicate that the anterior part of the hippocampus, rather than the whole structure, may be specifically involved in episodic memory. In the present work, we examined whether anterior structural measurements are superior to other regional or global measurements in mapping functionally relevant degenerative alterations of the hippocampus in Alzheimer's disease (AD). Twenty patients with early AD (MMSE 25.7+/-1.7) and 18 healthy controls were studied using magnetic resonance and diffusion-tensor imaging. Using a regions-of-interest analysis, we obtained volumetric and diffusivity measures of the hippocampal head and body-tail-section as well as of the whole hippocampus. Detailed cognitive evaluation was based on the CERAD battery. All volumetric measures as well as diffusivity of the hippocampus head were significantly (p0.01) altered in patients as compared to controls. In patients, increased left head diffusivity significantly (p0.01) correlated with performance on free delayed verbal recall test (DVR) (r=-0.74, p=0.0002) and with the CERAD global score. Reduced volume of the left body-tail was also associated with performance on DVR (r=0.62, p=0.004). Stepwise regression analyses revealed that increased left head diffusivity was the only predictor for performance on DVR (R(2)=52%, p0.0005). These findings suggest that anterior hippocampus diffusivity is more closely related to verbal episodic memory impairment than other regional or global structural measures. Our data support the hypothesis of functional differentiation in general and the specific role of the anterior hippocampus in episodic memory in particular. Diffusivity measurements might be highly sensitive to functionally relevant degenerative alterations of the hippocampus.

Alterations in dopamine neurotransmission in animal models of epilepsies have been frequently demonstrated using invasive neuroscience or ex vivo techniques. We aimed to test whether corresponding alterations could be detected by noninvasive in vivo brain imaging with positron emission tomography (PET) in the chronic phase of the rat pilocarpine model of temporal lobe epilepsy.Six pilocarpine-treated Wistar rats exhibiting spontaneous recurrent seizures and nine control rats were studied with PET using [(18)F]-fallypride, a high-affinity dopamine D(2/3) receptor ligand. Parametric images of [(18)F]-fallypride specific binding were calculated using a reference tissue method, and the two groups were contrasted by whole-brain voxel-based analysis implemented in statistical parametric mapping (SPM5).Dopamine D(2/3) receptor availability was 27% lower in the bilateral anterior caudate-putamen of pilocarpine-treated rats as compared to controls (p0.05), but binding was unaffected in other striatal or extrastriatal regions.The finding of substantially reduced availability of dopamine D(2/3) receptors in the anterior caudate-putamen of rats during the chronic phase of the pilocarpine model is in agreement with results of invasive (microinjection, microdialysis) animal studies that have revealed increased dopamine tonus and a D(2/3) receptor-mediated anticonvulsant action of dopamine in the anterior segment of the rat striatum. The present PET approach could be prospectively applied for monitoring dopamine receptor changes longitudinally, that is, at different phases of the epileptogenic process, and opens perspectives for testing dopaminergic agents as potential antiepileptogenic drugs.

Aims: In this study, we aimed to compare cerebrospinal fluid (CSF) levels of total tau (t-tau), phosphorylated tau (p-tau181) and positron emission tomography with 18F-fluorodeoxyglucose (FDG-PET) in the differential diagnosis of Alzheimer’s disease (AD) under clinical conditions. Method: In a cross-sectional, blinded, single-center study, we examined a sample of 75 unselected memory clinic patients with clinical diagnoses of dementia of Alzheimer type (DAT; n = 24), amnestic mild cognitive impairment (MCI; n = 16), other dementias (n = 13) and nondemented controls (n = 22). Discriminative accuracy, sensitivity and specificity were calculated and compared using ROC analyses. Results: p-tau181 and FDG-PET were comparable in separating DAT from controls (sensitivity: 67 vs. 79%; specificity: 91% for both) and patients with other dementias (sensitivity: 71 vs. 79%; specificity: 100% for both). The sensitivity of p-tau181 in differentiating MCI patients from controls was significantly (p < 0.05) superior to that of FDG-PET (75 vs. 44%) at a comparably high specificity (82 vs. 91%); t-tau measures were less accurate in all analyses. Conclusions: FDG-PET and CSF p-tau181 levels are able to discriminate DAT in heterogeneous and unselected samples with a high accuracy. CSF p-tau181 might be somewhat superior for a sensitive detection of patients with MCI.

Neurologic hallmarks of Fabry disease (FD) include small fiber neuropathy as well as cerebral micro- and macroangiopathy with premature stroke. Cranial MRI shows progressive white matter lesions (WML) at an early age, increased signal intensity in the pulvinar, and tortuosity and dilatation of the larger vessels. To unravel the most promising imaging tool for the detection of CNS involvement in FD we compared the diagnostic utility of the different MR imaging findings.Twenty-five clinically affected patients with FD (age 36.5 +/- 11.0) and 20 age-matched controls were investigated by structural MRI, MR angiography, and diffusion tensor imaging (DTI). Individual WML volumes, global mean diffusivity (MD), and mean cerebral artery diameters were determined.Using receiver operating characteristic analyses, enlarged diameters of the following cerebral arteries significantly separated patients with FD from controls: middle cerebral artery: area under curve (AUC) = 0.75, p = 0.005; posterior cerebral artery: AUC = 0.69, p = 0.041; carotid artery: 0.69, p = 0.041; basilar artery: AUC = 0.96, p0.0005. A total of 87% of the individuals were correctly classified by basilar artery diameters (sensitivity 95%, specificity 83%). WML volumes and global MD values did not significantly separate patients from controls.With an accuracy of 87%, basilar artery diameters were superior to all other MR measures for separating patients with Fabry disease (FD) from controls. Future studies should adopt basilar artery measurements for early detection and monitoring of brain involvement in FD. Moreover, further investigations should reveal if the dilated vasculopathy in FD could be a screening marker to detect FD in a cohort of other cerebrovascular diseases, especially in cryptogenic stroke.

Statistical comparisons of [(18)F]FDG PET scans between healthy subjects and patients with Alzheimer's disease (AD) or amnestic mild cognitive impairment (aMCI) using Statistical Parametric Mapping (SPM) usually require normalization of regional tracer uptake via ROIs defined using additional software. Here, we validate a simple SPM-based method for count normalization. FDG PET scans of 21 mild, 15 very mild AD, 11 aMCI patients and 15 age-matched controls were analyzed. First, we obtained relative increases in the whole patient sample compared to controls (i.e. areas relatively preserved in patients) with proportional scaling to the cerebral global mean (CGM). Next, average absolute counts within the cluster with the highest t-value were extracted. Statistical comparisons of controls versus three patients groups were then performed using count normalization to CGM, sensorimotor cortex (SMC) as standard, and to the cluster-derived counts. Compared to controls, relative metabolism in aMCI patients was reduced by 15%, 20%, and 23% after normalization to CGM, SMC, and cluster-derived counts, respectively, and 11%, 21%, and 25% in mild AD patients. Logistic regression analyses based on normalized values extracted from AD-typical regions showed that the metabolic values obtained using CGM, SMC, and cluster normalization correctly classified 81%, 89% and 92% of aMCI and controls; classification accuracies for AD groups (very mild and mild) were 91%, 97%, and 100%. The proposed algorithm of fully SPM-based count normalization allows for a substantial increase of statistical power in detecting very early AD-associated hypometabolism, and very high accuracy in discriminating mild AD and aMCI from healthy aging.

At present, there is still no consensus on the choice of the reference area in positron emission tomography (PET) studies of Alzheimer's disease (AD). In this study, PET scans with fluorodeoxyglucose-F18 were carried out in the following groups of subjects: 47 patients with probable AD, 8 patients with mild cognitive impairment, and 15 age-similar healthy subjects. Scans normalized to the cerebral global mean (CGM), cerebellum (CBL), and the primary sensorimotor cortex (SMC). We evaluated the effect of the different count normalization procedures on the accuracy of (18)F-FDG PET to detect AD-specific metabolic abnormalities (voxel-based group comparison) and to differentiate between patients and healthy subjects (ROI-based discriminant analysis) with regard to the degree of clinical deterioration. Metabolic reductions in groups of very mildly, mildly and moderate-to-severely affected patients appeared, respectively, 2.2, 2.6, and 2.7 times greater in spatial extent when tracer uptake was normalized to SMC rather than to CGM. The overall accuracy of discrimination was 94%, 91%, and 80% after normalization to SMC, CBL, and CGM, respectively. In general, normalization to SMC was somewhat superior to cerebellar normalization, allowing the detection of more pronounced metabolic deficits and the more accurate discrimination of patients from non-patients. Normalization to CGM should be used with great caution not only in advanced stages of dementia, but also in very mild AD cases.

All drugs of abuse induce a phasic dopamine release within the striatum that does not undergo habituation. Prolonged substance consumption impairs the natural function of the mesolimbic dopamine system, as shown by a decrease in the availability of striatal dopamine 2 (D(2)) receptors in patients suffering from cocaine, heroin, amphetamine, and alcohol dependence. However, it is unclear whether similar changes can also be observed in heavy-smoking nicotine-dependent smokers.In vivo D(2)/D(3) receptor availability was determined with [ (18)F]fallypride positron emission tomography in 17 heavy-smoking nicotine-dependent subjects and in 21 age-matched never-smoking comparison subjects. The smokers were scanned twice: first, during a period of usual consumption and second, 24 hours after smoking cessation.Independent of the withdrawal status, the nicotine-dependent smokers displayed significantly less availability of D(2)/D(3) receptors within the bilateral putamen functionally covering parts of the dorsal striatum, as compared to the never-smoking subjects. Nicotine craving under the consumption condition correlated positively with D(2)/D(3) receptor availability within the ventral striatum but negatively with D(2)/D(3) receptor availability within the anterior cingulate and inferior temporal cortex.Similar to other types of substance abuse, nicotine dependence is associated with low availability of dorsal striatal D(2)/D(3) receptors. In contrast to previous findings on abstinent alcohol-dependent patients, nicotine craving seems to be maintained by a region-specific shift in D(2)/D(3) receptor availabilities, with higher availability within the ventral striatum but lower availability within the anterior cingulate and inferior temporal cortex.

The National Institute on Aging-Alzheimer's Association (NIA-AA) guidelines for Alzheimer's disease (AD) propose the categorization of individuals according to their biomarker constellation. Though the NIA-AA criteria for preclinical AD and AD dementia have already been applied in conjunction with imaging AD biomarkers, the application of the criteria using comprehensive cerebrospinal fluid (CSF) biomarker information has not been thoroughly studied yet. The study included a monocentric cohort with healthy (N = 41) and disease (N = 22) controls and patients with AD dementia (N = 119), and a multicentric sample with healthy controls (N = 116) and patients with AD dementia (N = 102). The CSF biomarkers β-amyloid 1-42, total tau, and phosphorylated tau at threonine 181 were measured with commercially available assays. Biomarker values were trichotomized into positive for AD, negative, or borderline. In controls the presence of normal CSF profiles varied between 13.6 and 25.4 % across the studied groups, while up to 8.6 % of them had abnormal CSF biomarkers. In 40.3-52.9 % of patients with AD dementia, a typical CSF profile for AD was detected. Approximately 40 % of the potential biomarker constellations are not considered in the NIA-AA guidelines, and more than 40 % of participants could not be classified into the NIA-AA categories with distinct biomarker constellations. Here, a refined scheme covering all potential biomarker constellations is proposed. These results enrich the discussion on the NIA-AA guidelines and point to a discordance between clinical symptomatology and CSF biomarkers even in patients with full-blown AD dementia, who are supposed to have a clearly positive for AD neurochemical profile.

Positron emission tomography (PET) data are commonly analyzed in terms of regional intensity, while covariant information is not taken into account. Here, we searched for network correlates of healthy cognitive function in resting state PET data. PET with [18F]-fluorodeoxyglucose and a test of verbal working memory (WM) were administered to 35 young healthy adults. Metabolic connectivity was modeled at a group level using sparse inverse covariance estimation. Among 13 WM-relevant Brodmann areas (BAs), 6 appeared to be robustly connected. Connectivity within this network was significantly stronger in subjects with above-median WM performance. In respect to regional intensity, i.e., metabolism, no difference between groups was found. The results encourage examination of covariant patterns in FDG-PET data from non-neurodegenerative populations.

In PET studies of patients with Alzheimer disease (AD), prominent hypometabolism can occur in brain regions without major amyloid load. These hypometabolism-only (HO) areas may not be explained easily as a consequence of local amyloid toxicity. The aim of this longitudinal multimodal imaging study was the investigation of locoregional and remote relationships between metabolism in HO areas and longitudinal amyloid increase in functionally connected brain areas, with a particular focus on intrinsic functional connectivity as a relevant linking mechanism between pathology and dysfunction. Methods: Fifteen AD patients underwent longitudinal examinations with 11C-Pittsburgh compound B (11C-PiB) and 18F-FDG PET (mean follow-up period, 2 y). The peak HO region was identified by the subtraction of equally thresholded statistical T maps (hypometabolism minus amyloid burden), resulting from voxel-based statistical parametric mapping group comparisons between the AD patients and 15 healthy controls. Then functionally connected and nonconnected brain networks were identified by means of seed-based intrinsic functional connectivity analysis of the resting-state functional MRI data of healthy controls. Finally, network-based, region-of-interest–based, and voxel-based correlations were calculated between longitudinal changes of normalized 11C-PiB binding and 18F-FDG metabolism. Results: Positive voxel-based and region-of-interest–based correlations were demonstrated between longitudinal 11C-PiB increases in the HO-connected network, encompassing bilateral temporoparietal and frontal brain regions, and metabolic changes in the peak HO region as well as locoregionally within several AD-typical brain regions. Conclusion: Our results indicate that in AD amyloid accumulation in remote but functionally connected brain regions may significantly contribute to longitudinally evolving hypometabolism in brain regions not strongly affected by local amyloid pathology, supporting the amyloid- and network-degeneration hypothesis.

Based on the hippocampus disconnection hypothesis in Alzheimer disease (AD), which postulates that uncoupling from cortical inputs contributes to disinhibition-like changes in hippocampus activity, we suggested that in patients with AD, the more the intrinsic functional connectivity between hippocampus and precuneus is decreased, the higher hippocampal glucose metabolism will be.Forty patients with mild AD dementia, 21 patients with mild cognitive impairment, and 26 healthy controls underwent simultaneous PET/MRI measurements on an integrated PET/MR scanner. (18)F-fluorodeoxyglucose-PET was used to measure local glucose metabolism as proxy for neural activity, and resting-state functional MRI with seed-based functional connectivity analysis was performed to measure intrinsic functional connectivity as proxy for neural coupling. Group comparisons and correlation analysis were corrected for effects of regional atrophy, partial volume effect, age, and sex.In both patient groups, intrinsic connectivity between hippocampus and precuneus was significantly reduced. Moreover, in both patient groups, glucose metabolism was reduced in the precuneus (ADmild cognitive impairmentcontrols) while unchanged in the hippocampus. Critically, the lower connectivity between hippocampus and precuneus was in patients with AD dementia, the higher was hippocampus metabolism.Results provide evidence that in patients with AD dementia, stronger decrease of intrinsic connectivity between hippocampus and precuneus is linked with higher intrahippocampal metabolism (probably reflecting higher neuronal activity). These data support the hippocampus disconnection hypothesis, i.e., uncoupling from cortical inputs may contribute to disinhibition-like changes of hippocampal activity with potentially adverse consequences on both intrahippocampal physiology and clinical outcome.

Studies of functional connectivity suggest that the default mode network (DMN) might be relevant for cognitive functions. Here, we examined metabolic and structural connectivity between major DMN nodes, the posterior cingulate (PCC) and medial prefrontal cortex (MPFC), in relation to normal working memory (WM). DMN was captured using independent component analysis of [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) data from 35 young healthy adults (27.1 ± 5.1 years). Metabolic connectivity, a correlation between FDG uptake in PCC and MPFC, was examined in groups of subjects with (relative to median) low (n = 18) and high (n = 17) performance on digit span backward test as an index of verbal WM. In addition, fiber tractography based on PCC and MPFC nodes as way points was performed in a subset of subjects. FDG uptake in the DMN nodes did not differ between high and low performers. However, significantly (p = 0.01) lower metabolic connectivity was found in the group of low performers. Furthermore, as compared to high performers, low performers showed lower density of the left superior cingulate bundle. Verbal WM performance is related to metabolic and structural connectivity within the DMN in young healthy adults. Metabolic connectivity as quantified with FDG-PET might be a sensitive marker of the normal variability in some cognitive functions.

(MCI). Methods: Twenty-eight MCI patients (14 males, age1⁄46767yrs, clinical dementia rating score1⁄40.5) and 30 ageand education-matched cognitively normal adults (14 males, age1⁄46767yrs) participated. The carotid arterial (b) stiffness index and the intima-media thickness (IMT) were measured using high resolution 2D Doppler ultrasonography and applanation tonometry in the left and right common carotid arteries (CCA). Peripheral and central pulse-wave-velocity (PWV) were measured between the right common carotid artery and the right radial and left femoral artery, respectively. WMH was assessed in 22 patients with MCI (12 males, age1⁄46767yrs) and 19 controls (5 males, age1⁄46767yrs) using MRI Fluid-Attenuated-Inversion-Recovery (FLAIR) images on a 3T Philips Achieva MR system. Periventricular and deep-brain WMH volumes were quantified and differentiated using semi-automatic programs (MRICro and MatLab). Results: MCI patients showed higher b-stiffness index (7.361.8 vs. 6.361.5, p