Structural and Functional Projections of the Nucleus Basalis of Meynert and Their Changes After Cognitive Training in Individuals With Mild Cognitive Impairment

BackgroundMemory impairment is a predominant symptom in people with mild cognitive impairment (MCI) and dementia. Computerized cognitive training (CCT) has been proposed as a promising non‐pharmaceutical intervention to slow down the deterioration of cognitive functions. While previous studies have reported the benefits of CCT on global cognition, few have focused specifically on memory outcomes. Therefore, the aim of this study is to investigate the benefits of CCT on memory outcomes in adults with MCI or dementia.MethodA literature search was conducted via the PubMed, Medline, Embase and PsycINFO databases from inception to Sept 2022. Inclusion criteria included: (1) participants with MCI or dementia, (2) CCT as one of the interventions, (3) randomized trials with a non‐CCT comparison group, and (4) studies that reported changes in memory‐related neuropsychological scores before and after the intervention. The outcomes were measures of verbal memory, visual memory and working memory. With the heterogeneous definitions of CCT, the standardized mean differences (SMD) were pooled using a random‐effects model.ResultThirty‐nine clinical trials with 2,010 participants with MCI or dementia were included. The mean age ranged from 44 to 83, and the percentage of males ranged from 21% to 73%. Participants with MCI that received CCT demonstrated significantly better performance in verbal memory (SMD = 0.69, 95% CI = 0.41 to 0.90), visual memory (SMD = 0.49, 95% CI = 0.14 to 0.84) and working memory (SMD = 0.42, 95% CI = 0.12 to 0.72) than the control groups. In the sub‐group analyses of different control groups, those MCI patients who received CCT demonstrated better verbal memory performance than the usual care and the active control groups, but comparable results as the paper‐and‐pencil cognitive training group. For the studies that include dementia participants, CCT effects were not significantly better than the control groups.ConclusionComputerized cognitive training conferred significant benefits in preserving memory function in people with MCI, while the benefits were not statistically significant in patients with dementia. This study also supports that computerized cognitive training can be enhanced by using mobile devices, gamification and immersive technologies.

We aimed to investigate the effect of cerebral small vessel disease (SVD) on cholinergic system integrity in mild cognitive impairment (MCI) patients. Nucleus basalis of Meynert (NBM) volume and cholinergic pathways integrity was evaluated at baseline, 1-, 2-, and 4-year follow-ups in 40 cognitively unimpaired (CU) participants, 29 MCI patients without SVD, and 23 MCI patients with SVD. We compared cholinergic markers among three groups and examined their associations with SVD burden in MCI patients. We used linear mixed models to assess longitudinal changes in cholinergic markers over time among groups. Mediation analysis was employed to investigate the mediating role of cholinergic system degeneration between SVD and cognitive impairment. Increased mean diffusivity (MD) in medial and lateral pathways was observed in MCI patients with SVD compared to those without SVD and CU participants. Both MCI groups showed decreased NBM volume compared to CU participants, while there was no significant difference between the two MCI groups. Longitudinally, compared to CU participants, MCI patients with SVD displayed a more rapid change in MD in both pathways, but not in NBM volume. Furthermore, SVD burden was associated with cholinergic pathway disruption and its faster rate of change in MCI patients. However, mediation analyses showed that cholinergic pathways did not mediate significant indirect effects of SVD burden on cognitive impairment. Our findings suggest that SVD could accelerate the degeneration of cholinergic pathways in MCI patients. However, they do not provide evidence to support that SVD could contribute to cognitive impairment through cholinergic system injury.

BackgroundPeople with mild cognitive impairment (MCI) are at increased risk of converting to dementia. Cognitive training can improve the cognitive abilities of people with MCI. Computerised cognitive training (CCT) offers several advantages over traditional paper-and-pencil cognitive training and has the potential to be more individualised by matching task difficulty with individual performance. Recent systematic reviews have reported promising effects of CCT on improving the cognitive capacities of people with MCI. However, the quality of existing studies has been limited, and it is still unclear whether CCT can influence the progression to dementia. We developed an ‘individualised’ CCT (MAKSCog) specialised for people with MCI that automatically matches task difficulty with individual performance and an active control training (‘basic’ CCT). The aims of the present study are (a) to evaluate MAKSCog and (b) to investigate whether it can be applied to maintain the cognitive abilities of people with MCI.MethodsThe present study investigates the effects of CCT on cognition in a randomised controlled intervention study in Germany. Participants are community-dwelling people with a psychometric diagnosis of MCI based on the Montreal Cognitive Assessment (MoCA) and Mini-Mental Status Test (MMSE). Screening and baseline testing are conducted via a videoconferencing assessment and telephone. Participants are randomly allocated. The treatment phase is 6 months with an open phase in which participants can freely decide to continue to use the CCTs. Additionally, both CCTs contain a monthly computerised cognitive assessment that measures different cognitive abilities: information processing speed, memory span, short term memory, and logical reasoning.DiscussionThis is the first study to investigate the effect of MAKSCog, an individualised CCT, specifically developed for people with different subtypes of MCI. A methodological strength is the double-blind, randomised, controlled design and the use of basic CCT as an active control group. The study is conducted entirely virtually with valid telehealth assessments for cognitive function. Methodological limitations might include a restriction to participants who feel comfortable with the use of technology and who own a computer, laptop, or tablet.Trial registrationISRCTN ISRCTN14437015. Prospectively registered on 27 February 2020.

Computerized cognitive training (CCT) has been proposed as a potential therapy for cognitive decline. One of the benefits of CCT is a transfer effect, but its mechanism on the memory domain is unclear. This study aimed to investigate the transfer effect of non-memory multidomain CCT on the memory domain and its neural basis in patients with mild cognitive impairment (MCI) through a randomized controlled trial. Patients with MCI recruited from memory clinics were randomly assigned to either the CCT or the control group. The CCT group received multidomain CCT training excluding memory training, while the control group read educational books with learning-based quizzes twice a week for 8 weeks. Participants underwent memory tests yielding a composite score, other cognitive domain tests, non-cognitive scales, and resting-state functional magnetic resonance imaging (rsfMRI), at baseline and after intervention. Within- and between-group comparisons, group × time interactions, and seed-to-voxel analyses in memory-involving brain networks were performed. The CCT group showed improvement over the control group in memory domain (Group × time, F = 5.87, P = 0.03, η2 = 0.31), which was related with the increased connectivity in the hippocampal-frontal and fusiform-occipital network. No other cognitive and non-cognitive symptoms differed between groups after adjusting for covariates. Eight weeks of multidomain CCT without memory training improved memory function and restored functional network in the hippocampal and medial temporal region in MCI patients. These results can provide evidence for the transferring ability of CCT on memory functioning with its neural basis.

High Activities of BACE1 in Brains with Mild Cognitive Impairment

Background: Mild cognitive impairment (MCI) is the prodromal phase of Alzheimer’s disease (AD) and has a high risk of progression to AD. Cigarette smoking is one of the important modifiable risk factors in AD progression. Cholinergic dysfunction, especially the nucleus basalis of Meynert (NBM), is the converging target connecting smoking and AD. However, how cigarette smoking affects NBM connectivity in MCI remains unclear.Objective: This study aimed to evaluate the interaction effects of condition (non-smoking vs. smoking) and diagnosis [cognitively normal (CN) vs. MCI] based on the resting-state functional connectivity (rsFC) of the NBM.Methods: After propensity score matching, we included 86 non-smoking CN, 44 smoking CN, 62 non-smoking MCI, and 32 smoking MCI. All subjects underwent structural and functional magnetic resonance imaging scans and neuropsychological tests. The seed-based rsFC of the NBM with the whole-brain voxel was calculated. Furthermore, the mixed effect analysis was performed to explore the interaction effects between condition and diagnosis on rsFC of the NBM.Results: The interaction effects of condition × diagnosis on rsFC of the NBM were observed in the bilateral prefrontal cortex (PFC), bilateral supplementary motor area (SMA), and right precuneus/middle occipital gyrus (MOG). Specifically, the smoking CN showed decreased rsFC between left NBM and PFC and increased rsFC between left NBM and SMA compared with non-smoking CN and smoking MCI. The smoking MCI showed reduced rsFC between right NBM and precuneus/MOG compared with non-smoking MCI. Additionally, rsFC between the NBM and SMA showed a significant negative correlation with Wechsler Memory Scale-Logical Memory (WMS-LM) immediate recall in smoking CN (r = −0.321, p = 0.041).Conclusion: Our findings indicate that chronic nicotine exposure through smoking may lead to functional connectivity disruption between the NBM and precuneus in MCI patients. The distinct alteration patterns on NBM connectivity in CN smokers and MCI smokers suggest that cigarette smoking has different influences on normal and impaired cognition.

BackgroundWith rapid advances in technology, computerized cognitive training (CCT) is being widely used for cognitive training (CT) in elderly with mild cognitive impairment (MCI) aiming to preserve cognitive functioning. Various training protocols are developed with different levels of effectiveness. Therefore, this review aims at evaluating the effectiveness of CCT on cognitive and non‐cognitive domains, including mood condition and ADL performance, among elderly with MCI; examining the efficacy of multi‐model CCT and determining whether it is more superior than the single‐model ones; comparing CCT and traditional CT; and providing recommendations for future studies.MethodLiterature searches were conducted following PRISMA guidelines with the following criteria: participants with mean age greater than 58 and with a diagnosis of MCI. Fifteen studies that were conducted in the past ten years met the criteria with an average PEDro score of 7.2.ResultThere was a considerable variation in study design, training content, and technologies used. The major types of technologies used include computerized software, tablets, and gaming consoles. CCT was able to bring a positive effect with a small effect size on global cognition in 7 out of 10 studies and on memory in all of the ten studies that evaluated it, significant effect with a large effect size on attention in 5 out of 6 studies and on executive function in 6 out of 12 studies. Some CCT improved mood and activity of daily livings.ConclusionCCT showed promising effect in improving cognitive function and mood among elderly with MCI, however, different level of effectiveness on ADL observed relating to inconsistent training content and associated protocols. Multi‐model CCT was shown to be more superior to single‐model or traditional CT. To maximize training effect and maintain the positive gains, CCT should be initiated before being diagnosed with dementia and incorporated into daily activities.

Mild cognitive impairment (MCI) is a widespread condition in older individuals, posing significant risk of dementia. However, limited research has been conducted to explore effective interventions and clarify their impact at the neural level. Therefore, this study aimed to investigate the effects of computerized cognitive training (CCT) and explore the associated neural mechanisms in preventing dementia in older individuals with MCI, with a view to inform future intervention efforts. We reviewed the effects of CCT on biomarker outcomes in older adults with MCI. The search was conducted for studies published between 2010 and May 10, 2023, using three search engines: PubMed, Scopus, and Cumulative Index to Nursing and Allied Health Literature. The inclusion criteria were as follows: studies that involved participants diagnosed with MCI, included CCT, included quantitative assessment of biomarker results, and conducted randomized controlled trials. Sixteen studies that used biomarkers, including magnetic resonance imaging, electroencephalography (EEG), functional near-infrared spectroscopy (fNIRS), and blood or salivary biomarkers, were extracted. The results showed that CCT caused changes in structure and function within the main brain network, including the default mode network, and decreased both theta rhythm activity on EEG and prefrontal activity on fNIRS, with improvement in cognitive function. Furthermore, CCT combined with physical exercise showed more significant structural and functional changes in extensive brain regions compared with CCT alone. Virtual reality-based cognitive training improved not only executive function but also instrumental activities of daily living. CCT causes functional and structural changes in extensive brain regions and improves cognitive function in older adults with MCI. Our findings highlight the potential of individualized intervention methods and biomarker assessment according to the specific causes of MCI. Future research should aim to optimize these personalized therapeutic strategies to maximize the benefits of CCT in older adults with MCI.

BackgroundIncreased intraindividual variability of cognitive performance is a marker of cognitive decline. Whether computerized cognitive training (CCT) and aerobic exercise counteracts cognitive decline by reducing intraindividual variability is unknown. We investigated the effects of CCT with or without aerobic exercise on reaction time intraindividual variability in older adults.MethodThis was a secondary analysis of an 8‐week randomized controlled trial. Older adults (aged 65‐85 years) were randomized to CCT alone (n = 41), CCT with aerobic exercise (n = 41), or an active control group (n = 42). The CCT group trained using the Fit Brains® platform 3×/week for 1 hour (plus 3×/week of home‐based training). The CCT with aerobic exercise group received 15 min of walking plus 45 min of Fit Brains® 3×/week (plus 3×/week of home‐based training). The control group received sham exercise and cognitive training (3×/week for 1 hour). We extracted reaction times from the Dimensional Change Card Sort Test, Flanker Inhibitory Control and Attention Test (Flanker), and Pattern Comparison Processing Speed Test (PACPS). Intraindividual variability was measured as residual intraindividual standard deviation (residual ISD) of raw reaction time latencies. Residual ISD is an unbiased measure of variability that accounts for within and between participant source of variation that could influence reaction time latencies. We also calculated reaction time intraindividual SD (raw‐score ISD) and intraindividual coefficient of variation (ICV).ResultCompared with the control group, residual ISD improved in a processing speed task (PACPS) following CCT alone (mean difference [95% confidence interval]: ‐0.147 [‐0.230 to ‐0.065], p<0.001) and CCT with aerobic exercise (‐0.111 [‐0.195 to ‐0.027], p<0.01). Also, for processing speed, both CCT (‐0.173 [‐0.261 to ‐0.084], p<0.001) and CCT with aerobic exercise (‐0.122 [‐0.213 to ‐0.032], p<0.01) showed greater reduction in raw‐score ISD compared with controls, while only CCT reduced ICV for this task (‐0.108 [‐0.176 to ‐0.040], p<0.001). Inhibitory attention (Flanker) improved only after CCT with aerobic exercise (congruent = ‐0.128 [‐0.250 to ‐0.006], incongruent = ‐0.121 [‐0.237 to ‐0.005], both p<0.05).ConclusionA CCT program promoted cognitive health via reductions in intraindividual variability of cognitive performance and combining it with aerobic exercise resulted in broader benefits.

Expectancy Does Not Predict 18-month Treatment Outcomes with Cognitive Training in Mild Cognitive Impairment.

Computerised cognitive training (CCT) has been shown to enhance cognitive function in elderly individuals with cognitive deterioration, but evidence is controversial. Additionally, whether specific CCT is most effective and which stages of cognitive impairment benefit most is unclear. We systematically searched nine medical and technological databases to collect randomized controlled trials related to CCT primarily conducted in patients with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). We identified 12 studies in patients with SCD and MCI. Pooled analysis showed that CCT could significantly improve cognitive function (g = 0.518, p = 0.000), especially related to memory. In terms of different types of cognitive training, specific CCT was more efficacious than non-specific CCT (g = 0.381, p = 0.007) or placebo (g = 0.734, p = 0.000) but not traditional CT (p = 0.628). In terms of stages of cognitive deterioration, the effect of CCT on SCD (g = 0.926, p = 0.002) was almost double that of its effect on MCI (g = 0.502, p = 0.000). CCT was most effective in cognitive rehabilitation, particularly in the subdomain of memory. Early intervention in SCD is better.

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IntroductionPeople with mild cognitive impairment (MCI) are at increased risk of decreasing cognitive functioning. Computerised cognitive training (CCT) and nutrition have been shown to improve the cognitive capacities of people...

The number of people living with dementia is increasing rapidly. Clinical dementia does not develop suddenly, but rather is preceded by a period of cognitive decline beyond normal age-related change. People at this intermediate stage between normal cognitive function and clinical dementia are often described as having mild cognitive impairment (MCI). Considerable research and clinical efforts have been directed toward finding disease-modifying interventions that may prevent or delay progression from MCI to clinical dementia. To evaluate the effects of at least 12 weeks of computerised cognitive training (CCT) on maintaining or improving cognitive function and preventing dementia in people with mild cognitive impairment. We searched to 31 May 2018 in ALOIS (www.medicine.ox.ac.uk/alois) and ran additional searches in MEDLINE, Embase, PsycINFO, CINAHL, ClinicalTrials.gov, and the WHO portal/ICTRP (www.apps.who.int/trialsearch) to identify published, unpublished, and ongoing trials. We included randomised controlled trials (RCTs) and quasi-RCTs in which cognitive training via interactive computerised technology was compared with an active or inactive control intervention. Experimental computerised cognitive training (CCT) interventions had to adhere to the following criteria: minimum intervention duration of 12 weeks; any form of interactive computerised cognitive training, including computer exercises, computer games, mobile devices, gaming console, and virtual reality. Participants were adults with a diagnosis of mild cognitive impairment (MCI) or mild neurocognitive disorder (MND), or otherwise at high risk of cognitive decline. Two review authors independently extracted data and assessed risk of bias of the included RCTs. We expressed treatment effects as mean differences (MDs) or standardised mean differences (SMDs) for continuous outcomes and as risk ratios (RRs) for dichotomous outcomes. We used the GRADE approach to describe the overall quality of evidence for each outcome. Eight RCTs with a total of 660 participants met review inclusion criteria. Duration of the included trials varied from 12 weeks to 18 months. Only one trial used an inactive control. Most studies were at unclear or high risk of bias in several domains. Overall, our ability to draw conclusions was hampered by very low-quality evidence. Almost all results were very imprecise; there were also problems related to risk of bias, inconsistency between trials, and indirectness of the evidence.No trial provided data on incident dementia. For comparisons of CCT with both active and inactive controls, the quality of evidence on our other primary outcome of global cognitive function immediately after the intervention period was very low. Therefore, we were unable to draw any conclusions about this outcome.Due to very low quality of evidence, we were also unable to determine whether there was any effect of CCT compared to active control on our secondary outcomes of episodic memory, working memory, executive function, depression, functional performance, and mortality. We found low-quality evidence suggesting that there is probably no effect on speed of processing (SMD 0.20, 95% confidence interval (CI) -0.16 to 0.56; 2 studies; 119 participants), verbal fluency (SMD -0.16, 95% CI -0.76 to 0.44; 3 studies; 150 participants), or quality of life (mean difference (MD) 0.40, 95% CI -1.85 to 2.65; 1 study; 19 participants).When CCT was compared with inactive control, we obtained data on five secondary outcomes, including episodic memory, executive function, verbal fluency, depression, and functional performance. We found very low-quality evidence; therefore, we were unable to draw any conclusions about these outcomes. Currently available evidence does not allow us to determine whether or not computerised cognitive training will prevent clinical dementia or improve or maintain cognitive function in those who already have evidence of cognitive impairment. Small numbers of trials, small samples, risk of bias, inconsistency between trials, and highly imprecise results mean that it is not possible to derive any implications for clinical practice, despite some observed large effect sizes from individual studies. Direct adverse events are unlikely to occur, although the time and sometimes the money involved in computerised cognitive training programmes may represent significant burdens. Further research is necessary and should concentrate on improving methodological rigour, selecting suitable outcomes measures, and assessing generalisability and persistence of any effects. Trials with long-term follow-up are needed to determine the potential of this intervention to reduce the risk of dementia.

BackgroundPeople with mild cognitive impairment (MCI) experience a loss of cognitive functions, whose mechanism is characterized by aberrant structure‒function (SC-FC) coupling and topological attributes of multiple networks. This study aimed to reveal the network-level SC-FC coupling and internal topological changes triggered by computerized cognitive training (CCT) to explain the therapeutic effects of this training in individuals with MCI.MethodsIn this randomized block experiment, we recruited 60 MCI individuals and randomly divided them into an 8-week multidomain CCT group and a health education control group. The neuropsychological outcome measures were the Montreal Cognitive Assessment (MoCA), Chinese Auditory Verbal Learning Test (CAVLT), Chinese Stroop Color–Word Test (SCWT), and Rey–Osterrieth Complex Figure Test (Rey CFT). The brain imaging outcome measures were SC-FC coupling and topological attributes using functional MRI and diffusion tensor imaging methods. We applied linear model analysis to assess the differences in the outcome measures and identify the correspondence between the changes in the brain networks and cognitive functions before and after the CCT.ResultsFifty participants were included in the analyses after the exclusion of three dropouts and seven participants with low-quality MRI scans. Significant group × time effects were found on the changes in the MoCA, CAVLT, and Rey CFT recall scores. The changes in the SC-FC coupling values of the default mode network (DMN) and somatomotor network (SOM) were higher in the CCT group than in the control group (P(unc.) = 0.033, P(unc.) = 0.019), but opposite effects were found on the coupling values of the visual network (VIS) (P(unc.) = 0.039). Increasing clustering coefficients in the functional DMN and SOM and subtle changes in the nodal degree centrality and nodal efficiency of the right dorsal medial prefrontal cortex, posterior cingulate cortex, left parietal lobe, somatomotor area, and visual cortex were observed in the CCT group (P < 0.05, Bonferroni correction). Significant correspondences were found between global cognitive function and DMN coupling values (P(unc.) = 0.007), between immediate memory and SOM as well as FPC coupling values (P(unc.) = 0.037, P(unc.) = 0.030), between delayed memory and SOM coupling values (P(unc.) = 0.030), and between visual memory and VIS coupling values (P(unc.) = 0.007).ConclusionsEight weeks of CCT effectively improved global cognitive and memory functions; these changes were correlated with increases in SC-FC coupling and changes in the topography of the DMN and SOM in individuals with MCI. The CCT regimen also modulated the clustering coefficient and the capacity for information transformation in functional networks; these effects appeared to underlie the cognitive improvement associated with CCT.Trial registrationChinese Clinical Trial Registry, ChiCTR2000034012. Registered on 21 June 2020.