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

IntroductionDiagnostic 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.MethodsWe 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.ResultsWe 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 (βg = 0.33, 95% ETI = 0.12, 0.52). In the phonemic fluency task, AD patients outperformed subcortical VaD (sVaD) patients (βg = 0.51, 95% ETI = 0.22, 0.77, BF = 42.36). VaD patients, in contrast, outperformed AD patients in verbal (βg = −0.61, 95% ETI = −0.97, −0.26, BF = 22.71) and visual (βg = −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 (βg = −0.64, 95% ETI = −0.88, −0.36, BF = 72.97). Finally, AD patients performed worse than sVaD patients in recognition memory tasks (βg = −0.76, 95% ETI = −1.26, −0.26, BF = 11.50).ConclusionOur 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

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

Impact of tau and amyloid burden on glucose metabolism in Alzheimer's disease.

In a multimodal PET imaging approach, we determined the differential contribution of neurofibrillary tangles (measured with [18F]AV-1451) and beta-amyloid burden (measured with [11C]PiB) on degree of neurodegeneration (i.e., glucose metabolism measured with [18F]FDG-PET) in patients with Alzheimer's disease. Across brain regions, we observed an interactive effect of beta-amyloid burden and tau deposition on glucose metabolism which was most pronounced in the parietal lobe. Elevated beta-amyloid burden was associated with a stronger influence of tau accumulation on glucose metabolism. Our data provide the first in vivo insights into the differential contribution of Aβ and tau to neurodegeneration in Alzheimer's disease

Effects of a Cognitive Training With and Without Additional Physical Activity in Healthy Older Adults: A Follow-Up 1 Year After a Randomized Controlled Trial

Background: Combining cognitive training (CT) with physical activity (CPT) has been suggested to be most effective in maintaining cognition in healthy older adults, but data are scarce and inconsistent regarding long-term effects (follow-up; FU) and predictors of success.Objective: To investigate the 1-year FU effects of CPT versus CT and CPT plus counseling (CPT+C), and to identify predictors for CPT success at FU.Setting and Participants: We included 55 healthy older participants in the data analyses; 18 participants (CPT group) were used for the predictor analysis.Interventions: In a randomized controlled trial, participants conducted a CT, CPT, or CPT+C for 7 weeks.Outcome Measures: Overall cognition, verbal, figural, and working memory, verbal fluency, attention, planning, and visuo-construction.Results: While within-group comparisons showed cognitive improvements for all types of training, only one significant interaction Group × Time favoring CPT in comparison to CPT+C was found for overall cognition and verbal long-term memory. The most consistent predictor for CPT success (in verbal short-term memory, verbal fluency, attention) was an initial low baseline performance. Lower education predicted working memory gains. Higher levels of insulin-like growth factor 1 (IGF-1) and lower levels of brain-derived neurotrophic factor at baseline (BDNF) predicted alternating letter verbal fluency gains.Discussion: Within-group comparisons indicate that all used training types are helpful to maintain cognition. The fact that cognitive and sociodemographic data as well as nerve growth factors predict long-term benefits of CPT contributes to the understanding of the mechanisms underlying training success and may ultimately help to adapt training to individual profiles.Clinical Trial Registration: WHO ICTRP (http://apps.who.int/trialsearch/), identifier DRKS00005194

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

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\u27s 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

25th annual computational neuroscience meeting: CNS-2016

The same neuron may play different functional roles in the neural circuits to which it belongs. For example, neurons in the Tritonia pedal ganglia may participate in variable phases of the swim motor rhythms [1]. While such neuronal functional variability is likely to play a major role the delivery of the functionality of neural systems, it is difficult to study it in most nervous systems. We work on the pyloric rhythm network of the crustacean stomatogastric ganglion (STG) [2]. Typically network models of the STG treat neurons of the same functional type as a single model neuron (e.g. PD neurons), assuming the same conductance parameters for these neurons and implying their synchronous firing [3, 4]. However, simultaneous recording of PD neurons shows differences between the timings of spikes of these neurons. This may indicate functional variability of these neurons. Here we modelled separately the two PD neurons of the STG in a multi-neuron model of the pyloric network. Our neuron models comply with known correlations between conductance parameters of ionic currents. Our results reproduce the experimental finding of increasing spike time distance between spikes originating from the two model PD neurons during their synchronised burst phase. The PD neuron with the larger calcium conductance generates its spikes before the other PD neuron. Larger potassium conductance values in the follower neuron imply longer delays between spikes, see Fig. 17.Neuromodulators change the conductance parameters of neurons and maintain the ratios of these parameters [5]. Our results show that such changes may shift the individual contribution of two PD neurons to the PD-phase of the pyloric rhythm altering their functionality within this rhythm. Our work paves the way towards an accessible experimental and computational framework for the analysis of the mechanisms and impact of functional variability of neurons within the neural circuits to which they belong