Preclinical Alzheimer's dementia:A useful concept or another dead end?

The term, preclinical dementia, was introduced in 2011 when new guidelines for the diagnosis of Alzheimer's dementia (AD) were published. In the intervening 11 years, many studies have appeared in the literature focusing on this early stage. A search conducted in English on Google Scholar on 06.23.2022 using the term "preclinical (Alzheimer's) dementia" produced 121, 000 results. However, the label is arguably more relevant for research purposes, and it is possible that the knowledge gained may lead to a cure for AD. The term has not been widely adopted by clinical practitioners. Furthermore, it is still not possible to predict who, after a diagnosis of preclinical dementia, will go on to develop AD, and if so, what the risk factors (modifiable and non-modifiable) might be. This Review/Theoretical article will focus on preclinical Alzheimer's dementia (hereafter called preclinical AD). We outline how preclinical AD is currently defined, explain how it is diagnosed and explore why this is problematic at a number of different levels. We also ask the question: Is the concept 'preclinical AD' useful in clinical practice or is it just another dead end in the Holy Grail to find a treatment for AD? Specific recommendations for research and clinical practice are provided

Working-memory training in younger and older adults: training gains, transfer, and maintenance

Working memory (WM), a key determinant of many higher-order cognitive functions, declines in old age. Current research attempts to develop process-specific WM training procedures, which may lead to general cognitive improvement. Adaptivity of the training as well as the comparison of training gains to performance changes of an active control group are key factors in evaluating the effectiveness of a specific training program. In the present study, 55 younger adults (20–30 years of age) and 45 older adults (60–70 years of age) received 5 weeks of computerized training on various spatial and verbal WM tasks. Half of the sample received adaptive training (i.e., individually adjusted task difficulty), whereas the other half-worked on the same task material but on a low task difficulty level (active controls). Performance was assessed using criterion, near-transfer, and far-transfer tasks before training, after 5 weeks of intervention, as well as after a 3-month follow-up interval. Results indicate that (a) adaptive training generally led to larger training gains than low-level practice, (b) training and transfer gains were somewhat greater for younger than for older adults in some tasks, but comparable across age groups in other tasks, (c) far-transfer was observed to a test on sustained attention and for a self-rating scale on cognitive functioning in daily life for both young and old, and (d) training gains and transfer effects were maintained across the 3-month follow-up interval across age

Training-Induced Changes in Subsequent-Memory Effects: No Major Differences Among Children, Younger Adults, and Older Adults

The neural correlates of encoding mode, or the state of forming new memory episodes, have been found to change with age and mnemonic training. However, it is unclear whether neural correlates of encoding success, termed subsequent memory (SM) effects, also differ by age and mnemonic skill. In a multi-session training study, we investigated whether SM effects are altered by instruction and training in a mnemonic skill, and whether such alterations differ among children, younger adults, and older adults. Before and after strategy training, fMRI data were collected while participants were memorizing word pairs. In all age groups, participants receiving training showed greater performance gains than control group participants. Analysis of task-relevant regions showed training-induced reductions in SM effects in left frontal regions. Reductions in SM effects largely generalized across age, and primarily reflected greater training-induced activation increases for omissions than for remembered items, indicating that training resulted in more consistent use of the mnemonic strategy. The present results reveal no major age differences in SM effects in children, younger adults, and older adults

Neural Activation Patterns of Successful Episodic Encoding: Reorganization During Childhood, Maintenance in Old Age

The two-component framework of episodic memory (EM) development posits that the contributions of medial temporal lobe (MTL) and prefrontal cortex (PFC) to successful encoding differ across the lifespan. To test the framework’s hypotheses, we compared subsequent memory effects (SME) of 10-12 year-old children, younger adults, and older adults using functional magnetic resonance imaging (fMRI). Memory was probed by cued recall, and SME were defined as regional activation differences during encoding between subsequently correctly recalled versus omitted items. In MTL areas, children’s SME did not differ in magnitude from those of younger and older adults. In contrast, children’s SME in PFC were weaker than the corresponding SME in younger and older adults, in line with the hypothesis that PFC contributes less to successful encoding in childhood. Differences in SME between younger and older adults were negligible. The present results suggest that, among individuals with high memory functioning, the neural circuitry contributing to successful episodic encoding is reorganized from middle childhood to adulthood. Successful episodic encoding in later adulthood, however, is characterized by the ability to maintain the activation patterns that emerged in young adulthood

Episodic memory across the lifespan: The contributions of associative and strategic components

The structural and functional brain circuitries supporting episodic memory undergo profound reorganization in childhood and old age. We propose a two-component framework that combines and integrates evidence from child development and aging. It posits that episodic memory builds on two interacting components: (a) the strategic component, which refers to memory control operations, and (b) the associative component, which refers to mechanisms that bind different features of a memory episode into a compound representation. We hypothesize that: (a) children's difficulties in episodic memory primarily originate from low levels of strategic operations, and reflect the protracted development of the prefrontal cortex (PFC); (b) deficits in episodic memory performance among older adults originate from impairments in both strategic and associative components, reflecting senescent changes in the PFC and the medio-temporal lobes (MTL). Initial behavioral and neural evidence is consistent with both hypotheses. The two-component framework highlights the specificities of episodic memory in different age periods, helps to identify and dissociate its components, and contributes to understanding the interplay among maturation, learning, and senescence

Selection of high-imagery words for the study of episodic memory from middle childhood to old age

The goal of the present study was to select a set of highly imaginable and concrete words that can be used in age-comparable memory research. The selection process included two steps. First, 10 children aged 7-9 years rated 400 high-imagery, concrete, and meaningful words selected from an existing corpus of 1082 spoken words (Singer et al., 2003) on a three-point scale of comprehensibility. Second, two independent raters further selected words to reduce the likelihood of lexical error during recall. As a result, 413 words were retained as stimulus materials for age-comparative investigations of episodic memory performance

Capability in research on cognition and well-being in ageing and retirement

In this chapter, we outline our thoughts on capability in relation to previous and ongoing research projects conducted by the Adult Development and Ageing (ADA-Gero) Research Group located at the Department of Psychology, University of Gothenburg, Sweden. More specifically, we relate our research on cognitive ageing and subjective well-being to the overarching capability framework implemented as a theoretical platform in the AgeCap research consortium

A Computational Approach to Finding Novel Targets for Existing Drugs

Repositioning existing drugs for new therapeutic uses is an efficient approach to drug discovery. We have developed a computational drug repositioning pipeline to perform large-scale molecular docking of small molecule drugs against protein drug targets, in order to map the drug-target interaction space and find novel interactions. Our method emphasizes removing false positive interaction predictions using criteria from known interaction docking, consensus scoring, and specificity. In all, our database contains 252 human protein drug targets that we classify as reliable-for-docking as well as 4621 approved and experimental small molecule drugs from DrugBank. These were cross-docked, then filtered through stringent scoring criteria to select top drug-target interactions. In particular, we used MAPK14 and the kinase inhibitor BIM-8 as examples where our stringent thresholds enriched the predicted drug-target interactions with known interactions up to 20 times compared to standard score thresholds. We validated nilotinib as a potent MAPK14 inhibitor in vitro (IC50 40 nM), suggesting a potential use for this drug in treating inflammatory diseases. The published literature indicated experimental evidence for 31 of the top predicted interactions, highlighting the promising nature of our approach. Novel interactions discovered may lead to the drug being repositioned as a therapeutic treatment for its off-target's associated disease, added insight into the drug's mechanism of action, and added insight into the drug's side effects

Electrophysiological correlates of selective attention: A lifespan comparison

<p>Abstract</p> <p>Background</p> <p>To study how event-related brain potentials (ERPs) and underlying cortical mechanisms of selective attention change from childhood to old age, we investigated lifespan age differences in ERPs during an auditory oddball task in four age groups including 24 younger children (9–10 years), 28 older children (11–12 years), 31 younger adults (18–25), and 28 older adults (63–74 years). In the Unattend condition, participants were asked to simply listen to the tones. In the Attend condition, participants were asked to count the deviant stimuli. Five primary ERP components (N1, P2, N2, P3 and N3) were extracted for deviant stimuli under Attend conditions for lifespan comparison. Furthermore, Mismatch Negativity (MMN) and Late Discriminative Negativity (LDN) were computed as difference waves between deviant and standard tones, whereas Early and Late Processing Negativity (EPN and LPN) were calculated as difference waves between tones processed under Attend and Unattend conditions. These four secondary ERP-derived measures were taken as indicators for change detection (MMN and LDN) and selective attention (EPN and LPN), respectively. To examine lifespan age differences, the derived difference-wave components for attended (MMN and LDN) and deviant (EPN and LPN) stimuli were specifically compared across the four age groups.</p> <p>Results</p> <p>Both primary and secondary ERP components showed age-related differences in peak amplitude, peak latency, and topological distribution. The P2 amplitude was higher in adults compared to children, whereas N2 showed the opposite effect. P3 peak amplitude was higher in older children and younger adults than in older adults. The amplitudes of N3, LDN, and LPN were higher in older children compared with both of the adult groups. In addition, both P3 and N3 peak latencies were significantly longer in older than in younger adults. Interestingly, in the young adult sample P3 peak amplitude correlated positively and P3 peak latency correlated negatively with performance in the Identical Picture test, a marker measure of fluid intelligence.</p> <p>Conclusion</p> <p>The present findings suggest that patterns of event-related brain potentials are highly malleable within individuals and undergo profound reorganization from childhood to adulthood and old age.</p