Real-world evidence and patient preference for subcutaneous versus intravenous natalizumab in the treatment of relapsing-remitting multiple sclerosis - initial results from the observational SISTER study.

Background: The consideration of patient preference for a certain drug route of administration (RoA) plays an important role in promoting patient adherence in chronic diseases. Natalizumab is an established treatment for relapsing-remitting multiple sclerosis (RRMS) and can be administered as intravenous (IV) infusion or subcutaneous (SC) injection developed to enable a shorter and easier administration versus IV RoA. Study objectives: Primary objective is to compare patients' preference for RoA and satisfaction with SC versus IV natalizumab at baseline and subsequent visits up to 12 months. Secondary objectives include drug utilization, clinical outcomes, safety, and treatment satisfaction in a usual care setting. Design and methods: SISTER (Subcutaneous: Non-Interventional Study for Tysabri Patient Preference - Experience from Real World) is an ongoing, prospective, observational study where natalizumab is utilized according to local label. RRMS patients are included in three natalizumab cohorts: Patients switching from current IV to SC administration (switcher) and patients newly starting natalizumab on either SC or IV route (starter SC/IV). This interim analysis includes 262 patients (184 switchers, 39 SC starters, and 39 IV starters), median observation period was 9 months. Results: 80.8% IV starters and 93.9% SC starters reported at baseline that they prefer the assigned RoA. Although initial satisfaction with chosen RoA was maintained over time from baseline through Month 12 in all three cohorts, the wish for change of the current RoA after 6 and 12 months was more frequently expressed among IV starters than in either SC cohort. Consistently, six patients (23.1%) starting with IV changed their RoA from IV to SC route.Mean global treatment satisfaction according to TSQM-II score at baseline remained high in the switcher group and increased through Month 12 in both IV and SC starter cohorts. Conclusion: Based on current data, there is a trend toward patients' preference for the natalizumab SC route over the IV route, which provides valuable insights into patients' preference for natalizumab RoA in routine care and complements available data from clinical studies with real-world data on SC natalizumab. Trial registration: This observational (non-interventional) study was registered in the local German PEI register for non-interventional studies (NIS-No. 611) and in the international CTgov register (NCT05304520).

Chronic Hyponatremia and Brain Structure and Function Before and After Treatment.

RATIONALE & OBJECTIVE: Hyponatremia is the most common electrolyte disorder and is associated with significant morbidity and mortality. This study investigated neurocognitive impairment, brain volume, and alterations in magnetic resonance imaging (MRI)-based measures of cerebral function in patients before and after treatment for hyponatremia. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Patients with presumed chronic hyponatremia without signs of hypo- or hypervolemia treated in the emergency department of a German tertiary-care hospital. EXPOSURE: Hyponatremia (ie, plasma sodium concentration [Na+]<125mmol/L) before and after treatment leading to [Na+]>130mmol/L. OUTCOMES: Standardized neuropsychological testing (Mini-Mental State Examination, DemTect, Trail Making Test A/B, Beck Depression Inventory, Timed Up and Go) and resting-state MRI were performed before and after treatment of hyponatremia to assess total brain and white and gray matter volumes as well as neuronal activity and its synchronization. ANALYTICAL APPROACH: Changes in outcomes after treatment for hyponatremia assessed using bootstrapped confidence intervals and Cohen d statistic. Associations between parameters were assessed using correlation analyses. RESULTS: During a 3.7-year period, 26 patients were enrolled. Complete data were available for 21 patients. Mean [Na+]s were 118.4mmol/L before treatment and 135.5mmol/L after treatment. Most measures of cognition improved significantly. Comparison of MRI studies showed a decrease in brain tissue volumes, neuronal activity, and synchronization across all gray matter after normalization of [Na+]. Volume effects were particularly prominent in the hippocampus. During hyponatremia, synchronization of neuronal activity was negatively correlated with [Na+] (r=-0.836; 95% CI, -0.979 to-0.446) and cognitive function (Mini-Mental State Examination, r=-0.523; 95% CI, -0.805 to-0.069; DemTect, r=-0.744; 95% CI, -0.951 to-0.385; and Trail Making Test A, r=0.692; 95% CI, 0.255-0.922). LIMITATIONS: Small sample size, insufficient quality of several MRI scans as a result of motion artifact. CONCLUSIONS: Resolution of hyponatremia was associated with improved cognition and reductions in brain volumes and neuronal activity. Impaired cognition during hyponatremia is closely linked to increased neuronal activity rather than to tissue volumes. Furthermore, the hippocampus appears to be particularly susceptible to hyponatremia, exhibiting pronounced changes in tissue volume. PLAIN-LANGUAGE SUMMARY: Hyponatremia is a common clinical problem, and patients often present with neurologic symptoms that are at least partially reversible. This study used neuropsychological testing and magnetic resonance imaging to examine patients during and after correction of hyponatremia. Treatment led to an improvement in patients' cognition as well as a decrease in their brain volumes, spontaneous neuronal activity, and synchronized neuronal activity between remote brain regions. Volume effects were particularly prominent in the hippocampus, an area of the brain that is important for the modulation of memory. During hyponatremia, patients with the lowest sodium concentrations had the highest levels of synchronized neuronal activity and the poorest cognitive test results.

Improved connectivity and cognition due to cognitive stimulation in Alzheimer's disease.

Background: Due to the increasing prevalence of Alzheimer's disease (AD) and the limited efficacy of pharmacological treatment, the interest in non-pharmacological interventions, e.g., cognitive stimulation therapy (CST), to improve cognitive dysfunction and the quality of life of AD patients are on a steady rise. Objectives: Here, we examined the efficacy of a CST program specifically conceptualized for AD dementia patients and the neural mechanisms underlying cognitive or behavioral benefits of CST. Methods: Using neuropsychological tests and MRI-based measurements of functional connectivity, we examined the (neuro-) psychological status and network changes at two time points: pre vs. post-stimulation (8 to 12 weeks) in the intervention group (n = 15) who received the CST versus a no-intervention control group (n = 15). Results: After CST, we observed significant improvement in the Mini-Mental State Examination (MMSE), the Alzheimer's Disease Assessment Scale, cognitive subsection (ADAS-cog), and the behavioral and psychological symptoms of dementia (BPSD) scores. These cognitive improvements were associated with an up-regulated functional connectivity between the left posterior hippocampus and the trunk of the left postcentral gyrus. Conclusion: Our data indicate that CST seems to induce short-term global cognition and behavior improvements in mild to moderate AD dementia and enhances resting-state functional connectivity in learning- and memory-associated brain regions. These convergent results prove that even in mild to moderate dementia AD, neuroplasticity can be harnessed to alleviate cognitive impairment with CST.

Fine-grained age-matching improves atrophy-based detection of mild cognitive impairment more than amyloid-negative reference subjects.

INTRODUCTION: In clinical practice, differentiating between age-related gray matter (GM) atrophy and neurodegeneration-related atrophy at early disease stages, such as mild cognitive impairment (MCI), remains challenging. We hypothesized that fined-grained adjustment for age effects and using amyloid-negative reference subjects could increase classification accuracy. METHODS: T1-weighted magnetic resonance imaging (MRI) data of 131 cognitively normal (CN) individuals and 91 patients with MCI from the Alzheimer's disease neuroimaging initiative (ADNI) characterized concerning amyloid status, as well as 19 CN individuals and 19 MCI patients from an independent validation sample were segmented, spatially normalized and analyzed in the framework of voxel-based morphometry (VBM). For each participant, statistical maps of GM atrophy were computed as the deviation from the GM of CN reference groups at the voxel level. CN reference groups composed with different degrees of age-matching, and mixed and strictly amyloid-negative CN reference groups were examined regarding their effect on the accuracy in distinguishing between CN and MCI. Furthermore, the effects of spatial smoothing and atrophy threshold were assessed. RESULTS: Approaches with a specific reference group for each age significantly outperformed all other age-adjustment strategies with a maximum area under the curve of 1.0 in the ADNI sample and 0.985 in the validation sample. Accounting for age in a regression-based approach improved classification accuracy over that of a single CN reference group in the age range of the patient sample. Using strictly amyloid-negative reference groups improved classification accuracy only when age was not considered. CONCLUSION: Our results demonstrate that VBM can differentiate between age-related and MCI-associated atrophy with high accuracy. Crucially, age-specific reference groups significantly increased accuracy, more so than regression-based approaches and using amyloid-negative reference groups.

Serum cortisol is negatively related to hippocampal volume, brain structure, and memory performance in healthy aging and Alzheimer's disease.

Objective: Elevated cortisol levels have been frequently reported in Alzheimer's disease (AD) and linked to brain atrophy, especially of the hippocampus. Besides, high cortisol levels have been shown to impair memory performance and increase the risk of developing AD in healthy individuals. We investigated the associations between serum cortisol levels, hippocampal volume, gray matter volume and memory performance in healthy aging and AD. Methods: In our cross-sectional study, we analyzed the relationships between morning serum cortisol levels, verbal memory performance, hippocampal volume, and whole-brain voxel-wise gray matter volume in an independent sample of 29 healthy seniors (HS) and 29 patients along the spectrum of biomarker-based AD. Results: Cortisol levels were significantly elevated in patients with AD as compared to HS, and higher cortisol levels were correlated with worse memory performance in AD. Furthermore, higher cortisol levels were significantly associated with smaller left hippocampal volumes in HS and indirectly negatively correlated to memory function through hippocampal volume. Higher cortisol levels were further related to lower gray matter volume in the hippocampus and temporal and parietal areas in the left hemisphere in both groups. The strength of this association was similar in HS and AD. Conclusion: In AD, cortisol levels are elevated and associated with worse memory performance. Furthermore, in healthy seniors, higher cortisol levels show a detrimental relationship with brain regions typically affected by AD. Thus, increased cortisol levels seem to be indirectly linked to worse memory function even in otherwise healthy individuals. Cortisol may therefore not only serve as a biomarker of increased risk for AD, but maybe even more importantly, as an early target for preventive and therapeutic interventions.

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.

Decreased Efficiency of Between-Network Dynamics During Early Memory Consolidation With Aging.

Aging is associated with memory decline and progressive disabilities in the activities of daily living. These deficits have a significant impact on the quality of life of the aging population and lead to a tremendous burden on societies and health care systems. Understanding the mechanisms underlying aging-related memory decline is likely to inform the development of compensatory strategies promoting independence in old age. Research on aging-related memory decline has mainly focused on encoding and retrieval. However, some findings suggest that memory deficits may at least partly be due to impaired consolidation. To date, it remains elusive whether aging-related memory decline results from defective consolidation. This study examined age effects on consolidation-related neural mechanisms and their susceptibility to interference using functional magnetic resonance imaging data from 13 younger (20-30 years, 8 female) and 16 older (49-75 years, 5 female) healthy participants. fMRI was performed before and during a memory paradigm comprised of encoding, consolidation, and retrieval phases. Consolidation was variously challenged: (1) control (no manipulation), (2) interference (repeated stimulus presentation with interfering information), and (3) reminder condition (repeated presentation without interfering information). We analyzed the fractional amplitude of low-frequency fluctuations (fALFF) to compare brain activity changes from pre- to post-encoding rest. In the control condition, fALFF was decreased in the left supramarginal gyrus, right middle temporal gyrus, and left precuneus but increased in parts of the occipital and inferior temporal cortex. Connectivity analyses between fALFF-derived seeds and network ROIs revealed an aging-related decrease in the efficiency of functional connectivity (FC) within the ventral stream network and between salience, default mode, and central executive networks during consolidation. Moreover, our results indicate increased interference susceptibility in older individuals with dynamics between salience and default mode networks as a neurophysiological correlate. Conclusively, aging-related memory decline is partly caused by inefficient consolidation. Memory consolidation requires a complex interplay between large-scale brain networks, which qualitatively decreases with age.

Age and Anterior Basal Forebrain Volume Predict the Cholinergic Deficit in Patients with Mild Cognitive Impairment due to Alzheimer's Disease.

BACKGROUND: Early and severe neuronal loss in the cholinergic basal forebrain is observed in Alzheimer's disease (AD). To date, cholinomimetics play a central role in the symptomatic treatment of AD dementia. Although basic research indicates that a cholinergic deficit is present in AD before dementia, the efficacy of cholinomimetics in mild cognitive impairment (MCI) remains controversial. Predictors of cholinergic impairment could guide individualized therapy. OBJECTIVE: To investigate if the extent of the cholinergic deficit, measured using positron emission tomography (PET) and the tracer 11C-N-methyl-4-piperidyl acetate (MP4A), could be predicted from the volume of cholinergic basal forebrain nuclei in non-demented AD patients. METHODS: Seventeen patients with a high likelihood of MCI due to AD and 18 age-matched cognitively healthy adults underwent MRI-scanning. Basal forebrain volume was assessed using voxel-based morphometry and a cytoarchitectonic atlas of cholinergic nuclei. Cortical acetylcholinesterase (AChE) activity was measured using MP4A-PET. RESULTS: Cortical AChE activity and nucleus basalis of Meynert (Ch4 area) volume were significantly decreased in MCI. The extent of the cholinergic deficit varied considerably across patients. Greater volumes of anterior basal forebrain nuclei (Ch1/2 area) and younger age (Spearman's rho (17) â€Š= -0.596, 95% -CI [-0.905, -0.119] and 0.593, 95% -CI [0.092, 0.863])) were associated with a greater cholinergic deficit. CONCLUSION: Data suggest that less atrophy of the Ch1/2 area and younger age are associated with a more significant cholinergic deficit in MCI due to AD. Further investigations are warranted to determine if the individual response to cholinomimetics can be inferred from these measures.

Differential neural structures, intrinsic functional connectivity, and episodic memory in subjective cognitive decline and healthy controls.

The neural correlates of subjective cognitive decline (SCD; i.e., without objectifiable deficit) remain to be elucidated. Possible causes of SCD include early neurodegeneration related to Alzheimer's disease or functional and structural changes related to sub-clinical depression. We investigated the relationship between episodic memory performance or memory complaints and structural or functional magnetic resonance imaging (MRI) measures in participants with SCD (n=18) but without psychiatric disorders and healthy controls (n=31). In SCD, memory complaints were not associated with memory performance but with sub-clinical depression and executive functions. SCD-associated memory complaints correlated with higher amygdala and parahippocampal gyrus (specifically subiculum) gray matter density. In controls, but not in SCD, mesiotemporal gray matter density and superior frontal gyrus functional connectivity predicted memory performance. In contrast, in SCD, only a trend toward a correlation between memory performance and gray matter density in the parietooccipital lobes was observed. In our memory-clinic sample of SCD, we did not observe incipient neurodegeneration (limited to structural and functional MRI) but rather sub-clinical depression underlying subjective cognitive complaints.

Finding New Communities: A Principle of Neuronal Network Reorganization in Alzheimer's Disease.

Background: Graph-theoretical analyses have been previously used to investigate changes in the functional connectome in patients with Alzheimer's disease (AD). However, these analyses generally assume static organizational principles, thereby neglecting a fundamental reconfiguration of functional connections in the face of neurodegeneration. Methods: Here, we focus on differences in the community structure of the functional connectome in young and old individuals and patients with AD. Patients with AD, moreover, underwent molecular imaging positron emission tomography by using [18F]AV1451 to measure tau burden, a major hallmark of AD. Results: Although the overall organizational principles of the community structure of the human functional connectome were preserved even in advanced healthy aging, they were considerably changed in AD. We discovered that the communities in AD are re-organized, with nodes changing their allegiance to communities, thus resulting in an overall less efficient re-organized community structure. We further discovered that nodes with a tendency to leave the communities displayed a relatively higher tau pathology burden. Discussion: Together, this study suggests that local tau pathology in AD is associated to fundamental changes in basic organizational principles of the human connectome. Our results shed new light on previous findings obtained by using the graph theory in AD and imply a general principle of the brain in response to neurodegeneration.

Entorhinal Tau Predicts Hippocampal Activation and Memory Deficits in Alzheimer's Disease.

BACKGROUND: To date, it remains unclear how amyloid plaques and neurofibrillary tangles are related to neural activation and, consequently, cognition in Alzheimer's disease (AD). Recent findings indicate that tau accumulation may drive hippocampal hyperactivity in cognitively normal aging, but it remains to be elucidated how tau accumulation is related to neural activation in AD. OBJECTIVE: To determine whether the association between tau accumulation and hippocampal hyperactivation persists in mild cognitive impairment (MCI) and mild dementia or if the two measures dissociate with disease progression, we investigated the relationship between local tau deposits and memory-related neural activation in MCI and mild dementia due to AD. METHODS: Fifteen patients with MCI or mild dementia due to AD underwent a neuropsychological assessment and performed an item memory task during functional magnetic resonance imaging. Cerebral tau accumulation was assessed using positron emission tomography and [18F]-AV-1451. RESULTS: Entorhinal, but not global tau accumulation, was highly correlated with hippocampal activation due to visual item memory encoding and predicted memory loss over time. Neural activation in the posterior cingulate cortex and the fusiform gyrus was not significantly correlated with tau accumulation. CONCLUSION: These findings extend previous observations in cognitively normal aging, demonstrating that entorhinal tau continues to be closely associated with hippocampal hyperactivity and memory performance in MCI and mild dementia due to AD. Furthermore, data suggest that this association is strongest in medial temporal lobe structures. In summary, our data provide novel insights into the relationship of tau accumulation to neural activation and memory 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.

Hysteresis in graphene nanoribbon field-effect devices.

Hysteresis in the current response to a varying gate voltage is a common spurious effect in carbon-based field effect transistors. Here, we use electric transport measurements to probe the charge transport in networks of armchair graphene nanoribbons with a width of either 5 or 9 carbon atoms, synthesized in a bottom-up approach using chemical vapor deposition. Our systematic study on the hysteresis of such graphene nanoribbon transistors, in conjunction with temperature-dependent transport measurements shows that the hysteresis can be fully accounted for by trapping/detrapping carriers in the SiO2 layer. We extract the trap densities and depth, allowing us to identify shallow traps as the main origin of the hysteresis effect.

Charge transport mechanism in networks of armchair graphene nanoribbons.

In graphene nanoribbons (GNRs), the lateral confinement of charge carriers opens a band gap, the key feature that enables novel graphene-based electronics. Despite great progress, reliable and reproducible fabrication of single-ribbon field-effect transistors (FETs) is still a challenge, impeding the understanding of the charge transport. Here, we present reproducible fabrication of armchair GNR-FETs based on networks of nanoribbons and analyze the charge transport mechanism using nine-atom wide and, in particular, five-atom-wide GNRs with large conductivity. We show formation of reliable Ohmic contacts and a yield of functional FETs close to unity by lamination of GNRs to electrodes. Modeling the charge transport in the networks reveals that transport is governed by inter-ribbon hopping mediated by nuclear tunneling, with a hopping length comparable to the physical GNR length. Overcoming the challenge of low-yield single-ribbon transistors by the networks and identifying the corresponding charge transport mechanism is a key step forward for functionalization of GNRs.

Spatial distributions of cholinergic impairment and neuronal hypometabolism differ in MCI due to AD.

Elucidating the relationship between neuronal metabolism and the integrity of the cholinergic system is prerequisite for a profound understanding of cholinergic dysfunction in Alzheimer's disease. The cholinergic system can be investigated specifically using positron emission tomography (PET) with [11C]N-methyl-4-piperidyl-acetate (MP4A), while neuronal metabolism is often assessed with 2-deoxy-2-[18F]fluoro-d-glucose-(FDG) PET. We hypothesised a close correlation between MP4A-perfusion and FDG-uptake, permitting inferences about metabolism from MP4A-perfusion, and investigated the patterns of neuronal hypometabolism and cholinergic impairment in non-demented AD patients. MP4A-PET was performed in 18 cognitively normal adults and 19 patients with mild cognitive impairment (MCI) and positive AD biomarkers. In nine patients with additional FDG-PET, the sum images of every combination of consecutive early MP4A-frames were correlated with FDG-scans to determine the optimal time window for assessing MP4A-perfusion. Acetylcholinesterase (AChE) activity was estimated using a 3-compartmental model. Group comparisons of MP4A-perfusion and AChE-activity were performed using the entire sample. The highest correlation between MP4A-perfusion and FDG-uptake across the cerebral cortex was observed 60-450 s after injection (r = 0.867). The patterns of hypometabolism (FDG-PET) and hypoperfusion (MP4A-PET) in MCI covered areas known to be hypometabolic early in AD, while AChE activity was mainly reduced in the lateral temporal cortex and the occipital lobe, sparing posterior midline structures. Data indicate that patterns of cholinergic impairment and neuronal hypometabolism differ significantly at the stage of MCI in AD, implying distinct underlying pathologies, and suggesting potential predictors of the response to cholinergic pharmacotherapy.

Reasons to switch: a noninterventional study evaluating immunotherapy switches in a large German multicentre cohort of patients with relapsing-remitting multiple sclerosis.

BACKGROUND: With a large array of disease modifying therapies (DMTs) for relapsing-remitting MS (RRMS), identifying the optimal treatment option for the individual patient is challenging and switching of immunotherapies is often required. The objective of this study was to systematically investigate reasons for DMT switching in patients on immunotherapies for mild/moderate MS, and provide real-life insights into currently applied therapeutic strategies. METHODS: This noninterventional, cross-sectional study (ML29913) at 50 sites in Germany included RRMS patients on therapies for mild/moderate MS who switched immunotherapy in the years 2014-2017. The key outcome variable was the reason to switch, as documented in the medical charts, based on failure of current therapy, cognitive decline, adverse events (AEs), patient wish, or a woman's wish to become pregnant. Expectations of the new DMT and patients' assessment of the decision maker were also recorded. RESULTS: The core analysis population included 595 patients, with a mean age of 41.6 years, of which 69.7% were female. More than 60% of patients had at least one relapse within 12 months prior to the switch. The main reasons to switch DMT were failure of current therapy (53.9%), patient wish (22.4%), and AEs (19.0%). Most patients (54.3%) were switched within DMTs for mild/moderate MS; only 43.5% received a subsequent DMT for active/highly active MS. While clinical and outcome-oriented aspects were the most frequently mentioned expectations of the new DMT for physicians, aspects relating to quality of life played a major role for patients. CONCLUSIONS: Our data indicate suboptimal usage of DMTs, including monoclonal antibodies, for active/highly active MS in German patients. This illustrates the medical need for DMTs combining high efficacy, low safety risk, and low therapy burden.

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.

Effect of cholinergic treatment depends on cholinergic integrity in early Alzheimer's disease.

In early Alzheimer's disease, which initially presents with progressive loss of short-term memory, neurodegeneration especially affects cholinergic neurons of the basal forebrain. Pharmacotherapy of Alzheimer's disease therefore often targets the cholinergic system. In contrast, cholinergic pharmacotherapy of mild cognitive impairment is debated since its efficacy to date remains controversial. We here investigated the relationship between cholinergic treatment effects and the integrity of the cholinergic system in mild cognitive impairment due to Alzheimer's disease. Fourteen patients with high likelihood of mild cognitive impairment due to Alzheimer's disease and 16 age-matched cognitively normal adults performed an episodic memory task during functional magnetic resonance imaging under three conditions: (i) without pharmacotherapy; (ii) with placebo; and (iii) with a single dose of rivastigmine (3 mg). Cortical acetylcholinesterase activity was measured using PET with the tracer 11C-N-methyl-4-piperidyl acetate (MP4A). Cortical acetylcholinesterase activity was significantly decreased in patients relative to controls, especially in the lateral temporal lobes. Without pharmacotherapy, mild cognitive impairment was associated with less memory-related neural activation in the fusiform gyrus and impaired deactivation in the posterior cingulate cortex, relative to controls. These differences were attenuated under cholinergic stimulation with rivastigmine: patients showed increased neural activation in the right fusiform gyrus but enhanced deactivation of the posterior cingulate cortex under rivastigmine, compared to placebo. Conversely, controls showed reduced activation of the fusiform gyrus and reduced deactivation of the posterior cingulate under rivastigmine, compared to placebo. In both groups, the change in neural activation in response to rivastigmine was negatively associated with local acetylcholinesterase activity. At the behavioural level, an analysis of covariance revealed a significant group × treatment interaction in episodic memory performance when accounting for hippocampal grey matter atrophy and function. Our results indicate that rivastigmine differentially affects memory-related neural activity in patients with mild cognitive impairment and cognitively normal, age-matched adults, depending on acetylcholinesterase activity as a marker for the integrity of the cortical cholinergic system. Furthermore, hippocampal integrity showed an independent association with the response of memory performance to acetylcholinesterase inhibition.

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.