Neuropsychological differential diagnosis of Alzheimer's disease and vascular dementia: a systematic review with meta-regressions.

Introduction: Diagnostic classification systems and guidelines posit distinguishing patterns of impairment in Alzheimer's (AD) and vascular dementia (VaD). In our study, we aim to identify which diagnostic instruments distinguish them. Methods: We searched PubMed and PsychInfo for empirical studies published until December 2020, which investigated differences in cognitive, behavioral, psychiatric, and functional measures in patients older than 64 years and reported information on VaD subtype, age, education, dementia severity, and proportion of women. We systematically reviewed these studies and conducted Bayesian hierarchical meta-regressions to quantify the evidence for differences using the Bayes factor (BF). The risk of bias was assessed using the Newcastle-Ottawa-Scale and funnel plots. Results: We identified 122 studies with 17,850 AD and 5,247 VaD patients. Methodological limitations of the included studies are low comparability of patient groups and an untransparent patient selection process. In the digit span backward task, AD patients were nine times more probable (BF = 9.38) to outperform VaD patients (ßg = 0.33, 95% ETI = 0.12, 0.52). In the phonemic fluency task, AD patients outperformed subcortical VaD (sVaD) patients (ßg = 0.51, 95% ETI = 0.22, 0.77, BF = 42.36). VaD patients, in contrast, outperformed AD patients in verbal (ßg = -0.61, 95% ETI = -0.97, -0.26, BF = 22.71) and visual (ßg = -0.85, 95% ETI = -1.29, -0.32, BF = 13.67) delayed recall. We found the greatest difference in verbal memory, showing that sVaD patients outperform AD patients (ßg = -0.64, 95% ETI = -0.88, -0.36, BF = 72.97). Finally, AD patients performed worse than sVaD patients in recognition memory tasks (ßg = -0.76, 95% ETI = -1.26, -0.26, BF = 11.50). Conclusion: Our findings show inferior performance of AD in episodic memory and superior performance in working memory. We found little support for other differences proposed by diagnostic systems and diagnostic guidelines. The utility of cognitive, behavioral, psychiatric, and functional measures in differential diagnosis is limited and should be complemented by other information. Finally, we identify research areas and avenues, which could significantly improve the diagnostic value of cognitive measures.

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.

Prevalence and risk factors of ischemic monocular vision loss and concurrent brain ischemia.

INTRODUCTION: We performed a retrospective cohort study to identify predictors of concurrent asymptomatic brain ischemia in patients with ischemic monocular vision loss. PATIENTS AND METHODS: An inpatient database research of admissions to the Helios University Hospital Wuppertal, Germany between 01/2016 and 12/2020 was conducted. Inclusion criteria were confirmed diagnosis of transient monocular vision loss (MVL), retinal artery occlusion (RAO), and magnetic resonance imaging (MRI) of the brain within 10 days of MVL. Silent brain ischemia (SBI) was defined as diffusion restrictions with corresponding reduced apparent diffusion coefficient in MRI and an absence of neurological deficits besides those complying with MVL in clinical examination. The prevalence and cardiovascular predictors of SBI were analyzed with logistic regression and an artificial neural network. RESULTS: One hundred fourteen out of 475 patients treated with monocular vision loss were included in this study. The mean age was 67.7 ± 13.6 years. 48.2% were male and 47.4% had RAO. MRI scan of the brain was performed after 3.9 ± 2.3 days and detected SBI in 17%. Age ⩾67 years, cardiac etiology of MVL, and cerebral ischemia in medical history were revealed as predictors of SBI in MRI. CONCLUSIONS: Patients older than 66 years, with a suspected cardiac embolism as the cause of RAO and previous cerebral ischemia, are more likely to present SBI in cerebral MRI. Therefore, MR imaging, particularly in these patients, can be useful.

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.

Identifying large vessel occlusion at first glance in telemedicine.

BACKGROUND: Telemedicine has rapidly emerged as an important tool in emergency neurology. In particular, reliable biomarkers of large vessel occlusions (LVOs) are critically necessary in order to identify the need for in-hospital mechanical thrombectomy (MT). Based on pathophysiological factors, we propose that the presence of head and/or gaze deviation alone signifies cortical hypoperfusion and is therefore a highly sensitive marker for the presence of LVO. METHODS: We retrospectively analyzed a cohort of 160 patients, examined via telemedicine and suspected to have had an acute stroke; this included patients with ischemic or hemorrhagic stroke, transient ischemic attack, and stroke mimics. An assessment of head and gaze deviation and NIHSS score evaluation was performed. In a second analysis, patients who only had ischemia in the anterior circulation (n = 110) were evaluated. RESULTS: Head and/or gaze deviation alone was found to be a reliable marker of LVO (sensitivity: 0.66/specificity: 0.92), as well as a sound indicator for MT (0.82/0.91), in patients with suspected ischemic stroke. The performance of this indicator further improved when patients with ischemia in the anterior circulation only were assessed (LVO: 0.70/0.93; MT: 0.86/0.90). In both analyses, head and/or gaze deviation served as a better indicator for LVO or MT compared to the prevalence of motor deficits or aphasia. Of note, in patients who had ischemia in the anterior circulation, head and/or gaze deviation performed better than the NIHSS score as an indicator for MT. CONCLUSION: These findings confirm that the presence of head and/or gaze deviation serves as a reliable biomarker in stroke-based telemedicine for the diagnosis of LVO, as well as a strong indicator for MT. Furthermore, this marker is just as reliable as the NIHSS score but easier to assess. We therefore suggest that any stroke patient who displays head and/or gaze deviation should immediately be scheduled for vessel imaging and subsequently transported to a MT-competent center.

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.

An individualized functional magnetic resonance imaging protocol to assess semantic congruency effects on episodic memory in an aging multilingual population.

The cognitive stimulation induced by multilingualism may slow down age-related memory impairment. However, a suitable neuroscientific framework to assess the influence of multilingualism on age-related memory processes is missing. We propose an experimental paradigm that assesses the effects of semantic congruency on episodic memory using functional magnetic resonance imaging (fMRI). To this end, we modified the picture-word interference (PWI) task to be suitable for the assessment of older multilingual subjects undergoing fMRI. In particular, stimulus materials were prepared in multiple languages (French, German, Luxembourgish, English) and closely matched in semantic properties, thus enabling participants to perform the experiment in a language of their choice. This paradigm was validated in a group (n = 62) of healthy, older participants (over 64 years) who were multilingual, all practicing three or more languages. Consistent with the engagement of semantic congruency processes, we found that the encoding and recognition of semantically related vs. unrelated picture-word pairs evoked robust differences in behavior and the neural activity of parietal-temporal networks. These effects were negligibly modulated by the language used to perform the task. Based on this validation in a multilingual population, we conclude that the proposed paradigm will allow future studies to evaluate whether multilingualism aptitude engages neural systems in a manner that protects long-term memory from aging-related decline.

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.

SOP: treatment of delirium.

INTRODUCTION: Delirium is a frequent complication in hospitalised patients, often leading to difficulties in patient management and is associated with increased morbidity and mortality. Most patients in intensive care units develop delirium, however, it is also frequently observed in non-intensive care unit settings. Risk factors are, among others, older age, brain pathology, severe trauma, orthopaedic or heart surgery, metabolic or electrolyte dysregulations, infections and polypharmacy. The most important measures to prevent and treat delirium are recognition and removal of risk factors and causes. Although delirium is a very common and serious complication, evidence for pharmacological treatment is poor, and guidelines remain controversial. Accordingly, non-pharmacological treatments have gained increasing attention and should be applied. Based on current literature, guidelines and personal recommendations, we developed a standard operating procedure (SOP) encompassing non-pharmacological and pharmacological treatment of delirium. COMMENTS: In order to prevent delirium, risk factors should be identified and taken into account when planning the hospital stay and treatment. Prevention should include multimodal non-pharmacological interventions. The treatment of delirium should encompass the elimination of potential causes and non-pharmacological interventions. Pharmacological treatment should be used in a time-limited manner and in the lowest possible dose for the management of highly stressful symptoms or high-risk behaviour. CONCLUSION: The SOP provides a pragmatic algorithm for the non-pharmacological and pharmacological treatment of delirium.

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.

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.

Level of education mitigates the impact of tau pathology on neuronal function.

PURPOSE: Using PET imaging in a group of patients with Alzheimer's disease (AD), we investigated whether level of education, a proxy for resilience, mitigates the harmful impact of tau pathology on neuronal function. METHODS: We included 38 patients with mild-to-moderate AD (mean age 67 ± 7 years, mean MMSE score 24 ± 4, mean years of education 14 ± 4; 20 men, 18 women) in whom a [18F]AV-1451 scan (a measure of tau pathology) and an [18F]FDG scan (a measure of neuronal function) were available. The preprocessed PET scans were z-transformed using templates for [18F]AV-1451 and [18F]FDG from healthy controls, and subsequently thresholded at a z-score of ≥3.0, representing an one-tailed p value of 0.001. Next, three volumes were computed in each patient: the tau-specific volume (tau pathology without neuronal dysfunction), the FDG-specific volume (neuronal dysfunction without tau pathology), and the overlap volume (tau pathology and neuronal dysfunction). Mean z-scores and volumes were extracted and used as dependent variables in regression analysis with years of education as predictor, and age and MMSE score as covariates. RESULTS: Years of education were positively associated with tau-specific volume (ß = 0.362, p = 0.022), suggesting a lower impact of tau pathology on neuronal function in patients with higher levels of education. Concomitantly, level of education was positively related to tau burden in the overlap volume (ß = 0.303, p = 0.036) implying that with higher levels of education more tau pathology is necessary to induce neuronal dysfunction. CONCLUSION: In patients with higher levels of education, tau pathology is less paralleled by regional and remote neuronal dysfunction. The data suggest that early life-time factors such as level of education support resilience mechanisms, which ameliorate AD-related effects later in life.

White matter hyperintensities in vascular contributions to cognitive impairment and dementia (VCID): Knowledge gaps and opportunities.

White matter hyperintensities (WMHs) are frequently seen on brain magnetic resonance imaging scans of older people. Usually interpreted clinically as a surrogate for cerebral small vessel disease, WMHs are associated with increased likelihood of cognitive impairment and dementia (including Alzheimer's disease [AD]). WMHs are also seen in cognitively healthy people. In this collaboration of academic, clinical, and pharmaceutical industry perspectives, we identify outstanding questions about WMHs and their relation to cognition, dementia, and AD. What molecular and cellular changes underlie WMHs? What are the neuropathological correlates of WMHs? To what extent are demyelination and inflammation present? Is it helpful to subdivide into periventricular and subcortical WMHs? What do WMHs signify in people diagnosed with AD? What are the risk factors for developing WMHs? What preventive and therapeutic strategies target WMHs? Answering these questions will improve prevention and treatment of WMHs and dementia.

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.

Networks of tau distribution in Alzheimer's disease.

See Whitwell (doi:10.1093/brain/awy001) for a scientific commentary on this article.A stereotypical anatomical propagation of tau pathology has been described in Alzheimer's disease. According to recent concepts (network degeneration hypothesis), this propagation is thought to be indicative of misfolded tau proteins possibly spreading along functional networks. If true, tau pathology accumulation should correlate in functionally connected brain regions. Therefore, we examined whether independent components could be identified in the distribution pattern of in vivo tau pathology and whether these components correspond with specific functional connectivity networks. Twenty-two 18F-AV-1451 PET scans of patients with amnestic Alzheimer's disease (mean age = 66.00 ± 7.22 years, 14 males/eight females) were spatially normalized, intensity standardized to the cerebellum, and z-transformed using the mean and deviation image of a healthy control sample to assess Alzheimer's disease-related tau pathology. First, to detect distinct tau pathology networks, the deviation maps were subjected to an independent component analysis. Second, to investigate if regions of high tau burden are associated with functional connectivity networks, we extracted the region with the maximum z-value in each of the generated tau pathology networks and used them as seeds in a subsequent resting-state functional MRI analysis, conducted in a group of healthy adults (n = 26) who were part of the 1000 Functional Connectomes Project. Third, to examine if tau pathology co-localizes with functional connectivity networks, we quantified the spatial overlap between the seed-based networks and the corresponding tau pathology network by calculating the Dice similarity coefficient. Additionally, we assessed if the tau-dependent seed-based networks correspond with known functional resting-state networks. Finally, we examined the relevance of the identified components in regard to the neuropathological Braak stages. We identified 10 independently coherent tau pathology networks with the majority showing a symmetrical bi-hemispheric expansion and coinciding with highly functionally connected brain regions such as the precuneus and cingulate cortex. A fair-to-moderate overlap was observed between the tau pathology networks and corresponding seed-based networks (Dice range: 0.13-0.57), which in turn resembled known resting-state networks, particularly the default mode network (Dice range: 0.42-0.56). Moreover, greater tau burden in the tau pathology networks was associated with more advanced Braak stages. Using the data-driven approach of an independent component analysis, we observed a set of independently coherent tau pathology networks in Alzheimer's disease, which were associated with disease progression and coincided with functional networks previously reported to be impaired in Alzheimer's disease. Together, our results provide novel information regarding the impact of tau pathology networks on the mechanistic pathway of Alzheimer's disease.

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.