Concordance of Intrinsic Brain Connectivity Measures Is Disrupted in Alzheimer's Disease.

Background: Recently, a new resting-state functional magnetic resonance imaging (rs-fMRI) measure to evaluate the concordance between different rs-fMRI metrics has been proposed and has not been investigated in Alzheimer's disease (AD). Methods: 3T rs-fMRI data were obtained from healthy young controls (YC, n = 26), healthy senior controls (SC, n = 29), and AD patients (n = 35). The fractional amplitude of low-frequency fluctuations (fALFF), regional homogeneity (ReHo), and degree centrality (DC) were analyzed, followed by the calculation of their concordance using Kendall's W for each brain voxel across time. Group differences in the concordance were compared globally, within seven intrinsic brain networks, and on a voxel-by-voxel basis with covariates of age, sex, head motion, and gray matter volume. Results: The global concordance was lowest in AD among the three groups, with similar differences for the single metrics. When comparing AD to SC, reductions of concordance were detected in each of the investigated networks apart from the limbic network. For SC in comparison to YC, lower global concordance without any network-level difference was observed. Voxel-wise analyses revealed lower concordance in the right middle temporal gyrus in AD compared to SC and lower concordance in the left middle frontal gyrus in SC compared to YC. Lower fALFF were observed in the right angular gyrus in AD in comparison to SC, but ReHo and DC showed no group differences. Conclusions: The concordance of resting-state measures differentiates AD from healthy aging and may represent a novel imaging marker in AD.

Graph Theory Analysis Reveals Resting-State Compensatory Mechanisms in Healthy Aging and Prodromal Alzheimer's Disease.

Several theories of cognitive compensation have been suggested to explain sustained cognitive abilities in healthy brain aging and early neurodegenerative processes. The growing number of studies investigating various aspects of task-based compensation in these conditions is contrasted by the shortage of data about resting-state compensatory mechanisms. Using our proposed criterion-based framework for compensation, we investigated 45 participants in three groups: (i) patients with mild cognitive impairment (MCI) and positive biomarkers indicative of Alzheimer's disease (AD); (ii) cognitively normal young adults; (iii) cognitively normal older adults. To increase reliability, three sessions of resting-state functional magnetic resonance imaging for each participant were performed on different days (135 scans in total). To elucidate the dimensions and dynamics of resting-state compensatory mechanisms, we used graph theory analysis along with volumetric analysis. Graph theory analysis was applied based on the Brainnetome atlas, which provides a connectivity-based parcellation framework. Comprehensive neuropsychological examinations including the Rey Auditory Verbal Learning Test (RAVLT) and the Trail Making Test (TMT) were performed, to relate graph measures of compensatory nodes to cognition. To avoid false-positive findings, results were corrected for multiple comparisons. First, we observed an increase of degree centrality in cognition related brain regions of the middle frontal gyrus, precentral gyrus and superior parietal lobe despite local atrophy in MCI and healthy aging, indicating a resting-state connectivity increase with positive biomarkers. When relating the degree centrality measures to cognitive performance, we observed that greater connectivity led to better RAVLT and TMT scores in MCI and, hence, might constitute a compensatory mechanism. The detection and improved understanding of the compensatory dynamics in healthy aging and prodromal AD is mandatory for implementing and tailoring preventive interventions aiming at preserved overall cognitive functioning and delayed clinical onset of dementia.

Successful Treatment of Myasthenia Gravis Following PD-1/CTLA-4 Combination Checkpoint Blockade in a Patient With Metastatic Melanoma.

Currently, the blockade of certain immune checkpoints such as the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death-1 (PD-1) using checkpoint inhibitors is standard of care in patients with metastatic melanoma, especially with BRAF wild-type. However, several checkpoint inhibitor-related complications have been reported, including severe adverse events in the central and peripheral nervous system. In particular, in the recent past, the occurrence of myasthenia gravis following checkpoint inhibitor monotherapy, particularly nivolumab or ipilimumab, has been reported. In contrast, reports on PD-1/CTLA-4 combination blockade-usually with fatal clinical outcome-are scarce. We here report a case with combination immune checkpoint blockade-related myasthenia gravis with favorable clinical outcome.

Differential Effect of Retroactive Interference on Object and Spatial Memory in the Course of Healthy Aging and Neurodegeneration.

Objective: In subjects with mild cognitive impairment (MCI), interference during memory consolidation may further degrade subsequent recall of newly learned information. We investigated whether spatial and object memory are differentially susceptible to interference. Method: Thirty-nine healthy young subjects, 39 healthy older subjects, and 12 subjects suffering from MCI encoded objects and their spatial position on a 4-by-5 grid. Encoding was followed by either: (i) a pause; (ii) an interference task immediately following encoding; or (iii) an interference task following encoding after a 6-min delay. Type of interference (no, early, delayed) was applied in different sessions and order was counterbalanced. Twelve minutes after encoding, subjects saw objects previously presented or new ones. Subjects indicated whether they recognized the object, and if so, the objects' position during encoding. Results: Interference during consolidation provoked a negative effect on spatial memory in young more than older controls. In MCI, object but not spatial memory was affected by interference. Furthermore, a shift from fine- to coarse-grained spatial representation was observed in MCI. No differential effect of early vs. late interference (EI vs. LI) in either of the groups was detected. Conclusions: Data show that consolidation in healthy aging and MCI differs from consolidation in young controls. Data suggest differential processes underlying object and spatial memory and that these are differentially affected by aging and MCI.

On the Extraction and Analysis of Graphs From Resting-State fMRI to Support a Correct and Robust Diagnostic Tool for Alzheimer's Disease.

The diagnosis of Alzheimer's disease (AD), especially in the early stage, is still not very reliable and the development of new diagnosis tools is desirable. A diagnosis based on functional magnetic resonance imaging (fMRI) is a suitable candidate, since fMRI is non-invasive, readily available, and indirectly measures synaptic dysfunction, which can be observed even at the earliest stages of AD. However, the results of previous attempts to analyze graph properties of resting state fMRI data are contradictory, presumably caused by methodological differences in graph construction. This comprises two steps: clustering the voxels of the functional image to define the nodes of the graph, and calculating the graph's edge weights based on a functional connectivity measure of the average cluster activities. A variety of methods are available for each step, but the robustness of results to method choice, and the suitability of the methods to support a diagnostic tool, are largely unknown. To address this issue, we employ a range of commonly and rarely used clustering and edge definition methods and analyze their graph theoretic measures (graph weight, shortest path length, clustering coefficient, and weighted degree distribution and modularity) on a small data set of 26 healthy controls, 16 subjects with mild cognitive impairment (MCI) and 14 with Alzheimer's disease. We examine the results with respect to statistical significance of the mean difference in graph properties, the sensitivity of the results to model and parameter choices, and relative diagnostic power based on both a statistical model and support vector machines. We find that different combinations of graph construction techniques yield contradicting, but statistically significant, relations of graph properties between health conditions, explaining the discrepancy across previous studies, but casting doubt on such analyses as a method to gain insight into disease effects. The production of significant differences in mean graph properties turns out not to be a good predictor of future diagnostic capacity. Highest predictive power, expressed by largest negative surprise values, are achieved for both atlas-driven and data-driven clustering (Ward clustering), as long as graphs are small and clusters large, in combination with edge definitions based on correlations and mutual information transfer.

Neural Network Connectivity During Post-encoding Rest: Linking Episodic Memory Encoding and Retrieval.

Commonly, a switch between networks mediating memory encoding and those mediating retrieval is observed. This may not only be due to differential involvement of neural resources due to distinct cognitive processes but could also reflect the formation of new memory traces and their dynamic change during consolidation. We used resting state fMRI to measure functional connectivity (FC) changes during post-encoding rest, hypothesizing that during this phase, new functional connections between encoding- and retrieval-related regions are created. Interfering and reminding tasks served as experimental modulators to corroborate that the observed FC differences indeed reflect changes specific to post-encoding rest. The right inferior occipital and fusiform gyri (active during encoding) showed increased FC with the left inferior frontal gyrus and the left middle temporal gyrus (MTG) during post-encoding rest. Importantly, the left MTG subsequently also mediated successful retrieval. This finding might reflect the formation of functional connections between encoding- and retrieval-related regions during undisturbed post-encoding rest. These connections were vulnerable to experimental modulation: Cognitive interference disrupted FC changes during post-encoding rest resulting in poorer memory performance. The presentation of reminders also inhibited FC increases but without affecting memory performance. Our results contribute to a better understanding of the mechanisms by which post-encoding rest bridges the gap between encoding- and retrieval-related networks.

Functional Disintegration of the Default Mode Network in Prodromal Alzheimer's Disease.

Neurodegenerative brain changes can affect the functional connectivity strength between nodes of the default-mode network (DMN), which may underlie changes in cognitive performance. It remains unclear how the functional connectivity strength of DMN nodes differs from healthy to pathological aging and whether these changes are cognitively relevant. We used resting-state functional magnetic resonance imaging to investigate the functional connectivity strength across five DMN nodes in 25 healthy controls (HC), 28 subjective cognitive decline (SCD) participants, and 25 prodromal Alzheimer's disease (AD) patients. After identifying the ventral medial prefrontal cortex (vmPFC), posterior cingulate cortex (PCC), retrosplenial cortex (RSC), inferior parietal lobule, and the hippocampus we investigated the functional strength between DMN nodes using temporal network modeling. Functional coupling of the vmPFC and PCC in prodromal AD patients was disrupted. This vmPFC-PCC coupling correlated positively with memory performance in prodromal AD. Furthermore, the hippocampus de-coupled from posterior DMN nodes in SCD and prodromal AD patients. There was no coupling between the hippocampus and the anterior DMN. Additional mediation analyses indicated that the RSC enables communication between the hippocampus and DMN regions in HC but none of the other two groups. These results suggest an anterior-posterior disconnection and a hippocampal de-coupling from posterior DMN nodes with disease progression. Hippocampal de-coupling already occurring in SCD may provide valuable information for the development of a functional biomarker.

In vivo Patterns of Tau Pathology, Amyloid-ß Burden, and Neuronal Dysfunction in Clinical Variants of Alzheimer's Disease.

The clinical heterogeneity of Alzheimer's disease is not reflected in the rather diffuse cortical deposition of amyloid-ß. We assessed the relationship between clinical symptoms, in vivo tau pathology, amyloid distribution, and hypometabolism in variants of Alzheimer's disease using novel multimodal PET imaging techniques. Tau pathology was primarily observed in brain regions related to clinical symptoms and overlapped with areas of hypometabolism. In contrast, amyloid-ß deposition was diffusely distributed over the entire cortex. Tau PET imaging may thus serve as a valuable biomarker for the localization of neuronal injury in vivo and may help to validate atypical subtypes of Alzheimer's disease.

Aberrant functional connectivity differentiates retrosplenial cortex from posterior cingulate cortex in prodromal Alzheimer's disease.

The posterior cingulate cortex (PCC) is a key hub of the default mode network, a resting-state network involved in episodic memory, showing functional connectivity (FC) changes in Alzheimer's disease (AD). However, PCC is a cytoarchitectonically heterogeneous region. Specifically, the retrosplenial cortex (RSC), often subsumed under the PCC, is an area functionally and microanatomically distinct from PCC. To investigate FC patterns of RSC and PCC separately, we used resting-state functional magnetic resonance imaging in healthy aging participants, patients with subjective cognitive impairment, and prodromal AD. Compared to the other 2 groups, we found higher FC from RSC to frontal cortex in subjective cognitive impairment but higher FC to occipital cortex in prodromal AD. Conversely, FC from PCC to the lingual gyrus was higher in prodromal AD. Furthermore, data indicate that RSC and PCC are characterized by differential FC patterns represented by hub-specific interactions with memory and attentions scores in prodromal AD compared to cognitively normal individuals, possibly reflecting compensatory mechanisms for RSC and neurodegenerative processes for PCC. Data thus confirm and extend previous studies suggesting that the RSC is functionally distinct from PCC.

FIBT versus florbetaben and PiB: a preclinical comparison study with amyloid-PET in transgenic mice.

BACKGROUND: Over the last decade, an increasing number of studies have been published on the use of amyloid-ß (Aß) PET imaging with different (18)F-radiopharmaceuticals for clinical characterization of Alzheimer's disease (AD) in different stages. However, distinct study cohorts and different quantification techniques allow only for an indirect comparison between the different tracers. Thus, the aim of this study was the direct intra-individual in vivo comparison of different Aß-targeted radiopharmaceuticals for PET imaging, including the newly developed agent [(18)F]FIBT. METHODS: A small group of four animals of a well-characterized APP/PS1 transgenic (tg) mouse model of AD and gender-matched control (ctl) animals underwent a sequential and standardized PET imaging regimen for direct comparison of [(18)F]FIBT, [(18)F]florbetaben, and [(11)C]PiB. The quantitative PET imaging data were cross-validated with the cerebral Aß plaque load as quantified ex vivo on histological sections. RESULTS: We found that FIBT (2-(p-methylaminophenyl)-7-(2-[(18)F]fluoroethoxy)imidazo[2,1-b]benzothiazole) compares favorably to florbetaben as a high-contrasting PET radiopharmaceutical for imaging Aß pathology. The excellent pharmacokinetics of FIBT in combination with its high-binding affinity towards Aß resulted in feasible high-contrast imaging of Aß with high global cortex to cerebellum standard uptake value ratio (SUVR) in 24-month-old tg mice (tg 1.68 ± 0.15 vs. ctl 0.95 ± 0.02). The SUVRs in transgenic versus control animals (SUVRtg/SUVRctl) for FIBT (1.78 ± 0.16) were similar to the ratios as observed in humans (SUVRAD/SUVRctl) for the established gold standard Pittsburgh compound B (PiB) (1.65 ± 0.41). CONCLUSIONS: This head-to-head PET tracer comparison study in mice indicated the good imaging properties of [(18)F]FIBT, such as high initial brain uptake, fast clearance of the brain, and high binding affinity towards Aß as directly compared to the established amyloid tracers. Moreover, the preclinical study design is recommendable for reliable assessment and comparison of novel radiopharmaceuticals.

Characterization and first human investigation of FIBT, a novel fluorinated Aß plaque neuroimaging PET radioligand.

Imidazo[2,1-b]benzothiazoles (IBTs) are a promising novel class of amyloid positron emission tomography (PET) radiopharmaceuticals for diagnosis of neurodegenerative disorders like Alzheimer's disease (AD). Their good in vivo imaging properties have previously been shown in preclinical studies. Among IBTs, fluorinated [(18)F]FIBT was selected for further characterization and advancement toward use in humans. [(18)F]FIBT characteristics were analyzed in relation to Pittsburgh compound B (PiB) as reference ligand. [(18)F]FIBT and [(3)H]PiB were coinjected to an APP/PS1 mouse for ex vivo dual-label autoradiographic correlation. Acute dose toxicity of FIBT was examined in two groups of healthy mice. Preexisting in vivo stability and biodistribution studies in mice were complemented with analogous studies in rats. [(18)F]FIBT was titrated against postmortem human AD brain homogenate in a saturation binding assay previously performed with [(3)H]PiB. Binding of [(18)F]FIBT to human AD brain was further analyzed by in vitro incubation of human AD brain sections in comparison to [(11)C]PiB in relation to standard immunohistochemistry. Finally, [(18)F]FIBT was administered to two human subjects for a dynamic 90 min PET/MR brain investigation. Ex vivo autoradiography confirmed good uptake of [(18)F]FIBT to mouse brain and its excellent correlation to [(3)H]PiB binding. No toxicity of FIBT could be found in mice at a concentration of 33.3 nmol/kg. As in mice, [(18)F]FIBT was showing high in vivo stability in rats and comparable regional brain biodistribution dynamics to [(3)H]PiB. Radioligand saturation binding confirmed at least one high-affinity binding component of [(18)F]FIBT around 1 nM. Good binding of FIBT relative to PiB was further confirmed in binding assays and autoradiographies using post-mortem AD brain. First use of [(18)F]FIBT in humans successfully yielded clinical [(18)F]FIBT PET/MR images with very good contrast. In summary, [(18)F]FIBT has been characterized to be a new lead compound with improved binding characteristics and pharmacokinetics on its own as well as in comparison to PiB. A pilot human PET investigation provided high-quality images with a plausible tracer distribution pattern. Detailed clinical investigations are needed to confirm these first results and to explore the specific qualities of [(18)F]FIBT PET for dementia imaging in relation to established ligands.

Voxel-based analysis of amyloid-burden measured with [(11)C]PiB PET in a double transgenic mouse model of Alzheimer's disease.

PURPOSE: The purpose of this study is to validate the feasibility of a voxel-based analysis of in vivo amyloid-ß positron emission tomography (PET) imaging studies in transgenic mouse models of Alzheimer's disease. PROCEDURES: We performed [(11)C]PiB PET imaging in 20 APP/PS1 mice and 16 age-matched controls, and histologically determined the individual amyloid-ß plaque load. Using SPM software, we performed a voxel-based group comparison plus a regression analysis between PiB retention and actual plaque load, both thresholded at p FWE < 0.05. In addition, we carried out an individual ROI analysis in every animal. RESULTS: The automated voxel-based group comparison allowed us to identify voxels with significantly increased PiB retention in the cortical and hippocampal regions in transgenic animals compared to controls. The voxel-based regression analysis revealed a significant association between this signal increase and the actual cerebral plaque load. The validity of these results was corroborated by the individual ROI-based analysis. CONCLUSIONS: Voxel-based analysis of in vivo amyloid-ß PET imaging studies in mouse models of Alzheimer's disease is feasible and allows studying the PiB retention patterns in whole brain maps. Furthermore, the selected approach in our study also allowed us to establish a quantitative relation between tracer retention and actual plaque pathology in the brain in a voxel-wise manner.

Synthesis and evaluation of 11C-labeled imidazo[2,1-b]benzothiazoles (IBTs) as PET tracers for imaging ß-amyloid plaques in Alzheimer's disease.

We report a novel series of (11)C-labeled imidazo[2,1-b]benzothiazoles (IBTs) as tracers for imaging of cerebral ß-amyloid (Aß) deposits in patients with Alzheimer's disease (AD) by means of positron emission tomography (PET). From a series of 11 compounds, candidates were identified to have a high binding affinity for Aß. Selected compounds were prepared as O- or N-[(11)C]methyl derivatives and shown to have a high initial brain uptake in wild-type mice (range 1.9-9.2% I.D./g at 5 min). 2-(p-[(11)C]Methylaminophenyl)-7-methoxyimidazo[2,1-b] benzothiazole ([(11)C]5) was identified as a lead based on the combined favorable properties of high initial brain uptake, rapid clearance from normal brain, and high in vitro affinity for Aß(1-40) (K(i) = 3.5 nM) and Aß(1-42) (5.8 nM), which were superior to the Pittsburgh compound B (1a). In an APP/PS1 mouse model of AD (Tg), we demonstrate a specific uptake of [(11)C]5 in Aß-containing telencephalic brain regions by means of small-animal PET that was confirmed by regional brain biodistribution, ex vivo autoradiography, and immunohistochemistry. Analysis of brain sections of Tg mice receiving a single bolus injection of [(11)C]5 and [(3)H]1a together revealed that the tracers bind to Aß plaques in the brain of Tg mice in a comparable pattern. Taken together, these data suggest that IBTs represent useful PET imaging agents for high-sensitivity detection of Aß plaques.

A Novel (18)F-Labeled Imidazo[2,1-b]benzothiazole (IBT) for High-Contrast PET Imaging of ß-Amyloid Plaques.

(18)F-labeled imidazo[2,1-b]benzothiazole ([(18)F]8) was synthesized and evaluated as a tracer for cerebral ß-amyloid deposits (Aß) by means of positron emission tomography (PET). [(18)F]8 exhibits a high affinity to Aß and suitable brain uptake kinetics combined with a high metabolic stability in the brain. In a double transgenic APP/PS1 mouse model of Alzheimer's disease, we demonstrated a specific uptake of [(18)F]8 in Aß-containing telencephalic brain regions. The specific binding of [(18)F]8 to Aß was confirmed by regional brain biodistribution and autoradiography and correlated to immunohistochemistry staining. Analysis of brain sections of APP/PS1 mouse injected with a cocktail of [(18)F]8 and reference compound [(3)H]PiB revealed that the two tracers bind to Aß plaques in the brain of mouse in a comparable binding pattern. [(18)F]8 represents the first high-contrast PET imaging agent for detection of Aß plaques in transgenic mouse model of Alzheimer's disease and holds promise for transfer to a clinical evaluation.