Effects of Transcranial Magnetic Stimulation on the Default Mode Network in Minimal Cognitive Impairment and Alzheimer's disease: An ALE meta-analysis and systematic review

openObjective: This systematic review and meta-analysis sought to comprehensively assess the efficacy of repetitive transcranial magnetic stimulation (rTMS) on the default mode network (DMN) through functional magnetic resonance imaging (fMRI) among individuals diagnosed with mild cognitive impairment (MCI) and Alzheimer's disease (AD). The primary objective was to unravel the neuroimaging mechanisms underpinning cognitive intervention. Methods: A search encompassing English articles published until July 30, 2023, was conducted across prominent databases, including PubMed, Web of Science, Embase, and Cochrane Library. The study specifically focused on randomized controlled trials utilizing resting-state fMRI to investigate the impact of rTMS within the MCI and AD populations. The analysis of fMRI data was executed using GingerALE. Results: Our meta-analysis encompassed a total of seven studies focusing on AD, collectively 116 patients in the treatment group and 90 patients in the sham group. Additionally, in MCI group comprised 34 patients in the treatment groups and 39 patients in the sham group. The combined ALE quantitative analyses on group contrasts between Alzheimer's patients and the sham group showed no significant clusters of convergence. A similar outcome was observed when conducting meta-analyses of the MCI group. The restricted pool of eligible studies may have hindered our ability to detect meaningful clusters of convergence. Conclusions: The outcomes of this meta-analysis and systematic review collectively underscore the potential effectiveness and safety of rTMS intervention in addressing the needs of patients coping with MCI and AD. These improvements could likely be attributed to the favorable modulation that rTMS imparts upon spontaneous neural activity and cognitive networks. By elucidating the intricate neural mechanisms involved, this study contributes insights into the burgeoning field of cognitive intervention strategie

Abnormal Regional and Global Connectivity Measures in Subjective Cognitive Decline Depending on Cerebral Amyloid Status

Background: Amyloid-β accumulation was found to alter precuneus-based functional connectivity (FC) in mild cognitive impairment (MCI) and Alzheimer’s disease (AD) dementia, but its impact is less clear in subjective cognitive decline (SCD), which in combination with AD pathologic change is theorized to correspond to stage 2 of the Alzheimer’s continuum in the 2018 NIA-AA research framework. Objective: This study addresses how amyloid pathology relates to resting-state fMRI FC in SCD, especially focusing on the precuneus. Methods: From the DELCODE cohort, two groups of 24 age- and gender-matched amyloid-positive (SCDAβ+) and amyloidnegative SCD (SCDβ−) patients were selected according to visual [18F]-Florbetaben (FBB) PET readings, and studied with resting-state fMRI. Local (regional homogeneity [ReHo], fractional amplitude of low-frequency fluctuations [fALFF]) and global (degree centrality [DC], precuneus seed-based FC) measures were compared between groups. Follow-up correlation analyses probed relationships of group differences with global and precuneal amyloid load, as measured by FBB standard uptake value ratios (SUVR=⫖FBB). Results: ReHo was significantly higher (voxel-wise p < 0.01, cluster-level p < 0.05) in the bilateral precuneus for SCDAβ+patients, whereas fALFF was not altered between groups. Relatively higher precuneus-based FC with occipital areas (but no altered DC) was observed in SCDAβ+ patients. In this latter cluster, precuneus-occipital FC correlated positively with global (SCDAβ+) and precuneus SUVRFBB (both groups). Conclusion: While partial confounding influences due to a higher APOE ε4 carrier ratio among SCDAβ+ patients cannot be excluded, exploratory results indicate functional alterations in the precuneus hub region that were related to amyloid-β load, highlighting incipient pathology in stage 2 of the AD continuum

Affective and emotional dysregulation as pre-dementia risk markers: exploring the mild behavioral impairment symptoms of depression, anxiety, irritability, and euphoria

Background: Affective and emotional symptoms such as depression, anxiety, euphoria, and irritability are common neuropsychiatric symptoms (NPS) in pre-dementia and cognitively normal older adults. They comprise a domain of Mild Behavioral Impairment (MBI), which describes their emergence in later life as an at-risk state for cognitive decline and dementia, and as a potential manifestation of prodromal dementia. This selective scoping review explores the epidemiology and neurobiological links between affective and emotional symptoms, and incident cognitive decline, focusing on recent literature in this expanding field of research. Methods: Existing literature in prodromal and dementia states was reviewed, focusing on epidemiology, and neurobiology. Search terms included: “mild cognitive impairment,” “dementia,” “prodromal dementia,” “preclinical dementia,” “Alzheimer's,” “depression,” “dysphoria,” “mania,” “euphoria,” “bipolar disorder,” and “irritability.” Results: Affective and emotional dysregulation are common in preclinical and prodromal dementia syndromes, often being harbingers of neurodegenerative change and progressive cognitive decline. Nosological constraints in distinguishing between pre-existing psychiatric symptomatology and later life acquired NPS limit historical data utility, but emerging research emphasizes the importance of addressing time frames between symptom onset and cognitive decline, and age of symptom onset. Conclusion: Affective symptoms are of prognostic utility, but interventions to prevent dementia syndromes are limited. Trials need to assess interventions targeting known dementia pathology, toward novel pathology, as well as using psychiatric medications. Research focusing explicitly on later life onset symptomatology will improve our understanding of the neurobiology of NPS and neurodegeneration, enrich the study sample, and inform observational and clinical trial design for prevention and treatment strategies

The role of physical activity and bilingualism in the development of neurodegenerative disorders: Cross-sectional and neuroimaging evidence

Delaying Alzheimer’s disease (AD), the most common form of dementia, by five years could decrease the global prevalence of AD by 57% and halve the annual economic impact which is currently estimated to surpass US$2 trillion by 2030. Since no treatment or cure for dementia exist, identifying modifiable factors to reduce the incidence of dementia has become a public health priority. Increased physical activity (PA) has been associated with a lower risk of developing dementia in observational studies. Observational studies have also linked bilingualism (the ability to speak two languages) with a delayed onset of dementia but no risk-reduction in dementia in bilinguals relative to monolinguals. Differences in study outcomes in the fields of PA- and bilingualism- related research to methodological limitations including poor measurement of the exposure (PA and language profiles), small sample sizes, and recruitment of participants with different dementia etiologies. The purpose of this thesis was twofold: i) to explore the roles of PA and bilingualism in dementia risk and ii) to inform the development of a randomized controlled trial (RCT) to test whether studying a foreign language combined with increasing PA can improve cognitive performance in seniors who are at a higher risk of developing AD. The aim of Chapter two was to review the available evidence linking PA with the risk of developing dementia as well as to explore the effects of increasing PA on cognition in individuals with dementia. Results showed that aerobic, and high-intensity, habitual PA was associated with improved cognition-related biomarkers and lower dementia risk in epidemiological studies. Experimental evidence showed increasing PA improved cognition-related biomarkers and cognition in preclinical phases of dementia, but not in clinical phases. The findings showed that PA is linked with a lower risk of dementia in epidemiological studies, but experimental studies showed little to no improvements in cognition in participants with dementia following a structured PA program. There was evidence indicating that increasing PA levels in the preclinical phase of AD may result in greater translation impact than in participants at the more advanced clinical stage of AD. Most studies assessed PA with self-report measures questioning the accuracy and precision of exposure and recruited participants with dementia irrespective of aetiology, which makes it problematic to discern whether PA is differentially related to varying dementia aetiologies. The aim of Chapter three was to systematically review the association between bilingualism and the delay in the diagnosis of dementia and AD. Here, we retrieved a total of 20 studies, 15 of which were meta-analysed. Results showed that bilinguals were on average 3.2 (95% CI: 1.5, 4.9) years older than monolinguals at the time of dementia. Moreover, at the time of dementia diagnosis, bilinguals and monolinguals demonstrated a similar level of global cognitive impairment (Hedges’ g = 0.05 95% CI: -0.10, 0.21). Prediction intervals however showed a large dispersion of effect sizes in the meta-analysis comparing monolinguals to bilinguals on the age of dementia diagnosis. To explore possible reasons for the observed dispersion in effect sizes, we conducted subgroup analyses. In one subgroup meta-analysis comparing studies that had recruited participants with dementia to studies that had recruited participants with AD, bilinguals were 4.2 (95% CI: 2.0, 6.2) and 1.7 (95% CI: -1.4, 4.7) years older than monolinguals at dementia and AD diagnosis, respectively. Meta-analytic results combining prospective longitudinal studies showed no risk reduction in dementia among bilinguals compared to monolinguals (Odds Ratio: 0.85; 95% CI: 0.69-1.05). Risk of bias assessment revealed that most studies carried several methodological limitations including poor measurement of participants’ language profiles and small sample sizes. The aim of Chapter four was to explore the underlying mechanisms in the brain that may be responsible for the observed findings in the first systematic review (Chapter three). In this study, we observed that bilinguals compared to monolinguals had greater brain volume in the frontostriatal and frontoparietal circuits. Also, functional neuroimaging studies showed that bilinguals made use of relevant brain areas more efficiently than monolinguals when completing interference cognitive tasks. Results from the cross-sectional studies showed that higher levels of language acculturation were associated with significantly greater verbal and psychomotor speed performance than lower levels of language acculturation. The aim of the Chapter five was to explore the link between language acculturation and cognition in older individuals from ethnic minorities (Hispanic and Asian) living in the United States of America using an epidemiological dataset. In this cross-sectional epidemiological study, we analyzed data from the National Health and Nutrition Examination Survey using a larger sample size than previous studies. We found that higher levels of language acculturation (i.e. speaking the native language and that of the recipient’s country at home) was associated with greater psychomotor speed processing than lower levels of language acculturation (mostly speaking the native language at home) and some, but not all, measures of verbal fluency. Overall, the findings suggest that higher levels of language acculturation are associated with greater cognitive performance in older individuals from ethnic minorities. Overall, the evidence gathered in the previous chapters indicate that i) increasing PA in individuals who are at a higher risk of developing AD might be more useful in improving cognitive performance than in individuals who already have developed AD and ii) bilingualism might render the brain areas typically affected by AD such as the frontostriatal and frontoparietal brain circuits more resilient against neurodegeneration and in turn, delay the onset of AD symptoms and diagnosis. Therefore, because no randomized-controlled trial (RCT) testing the combined effects of increased PA with studying a foreign language currently exist, Chapter five presents a detailed study protocol for an RCT addressing this gap in the literature while addressing the limitations of previous studies in the fields of PA- and bilingualism-based research. The purpose of this thesis was to explore the roles of PA and bilingualism in dementia onset and risk and to inform the development of a randomized controlled trial (RCT) testing the effects of studying a foreign language with increased PA in individuals at a higher risk of dementia. Increasing PA levels are associated with greater cognition in individuals at the preclinical phase of AD rather than in participants with a diagnosis of dementia or AD. Bilingualism was also associated with later age of AD diagnosis on average by 4.7 years. This finding is clinically relevant because a five-year delay in the onset of AD could lower the number of individuals with AD worldwide by 57% and as a consequence, halving the associated economic costs. Moreover, we also showed that bilingualism may be responsible for rendering brain areas typically affected by AD more resilient against neuropathology. Moreover, this thesis revealed that studies in the field of exercise science and bilingualism research in dementia carry important methodological limitations that question the internal validity of these two lines of research. Consequently, the evidence gathered within this thesis led us to propose a novel RCT exploring the effects of increasing PA levels and studying a foreign language in monolingual individuals at a higher risk of AD while addressing the most important limitations of previous research

Using brain connectomics to detect functional connectivity differences in Alzheimer's disease

Indiana University-Purdue University Indianapolis (IUPUI)Prodromal Alzheimer’s disease (AD) has recently been identified as a disease state where pathophysiological changes may progress despite the absence of significant clinical symptoms. Yet, the specific processes of neural dysfunction occurring during this preclinical phase remain unclear. Resting state fMRI (RS-fMRI) in combination with brain connectomic measurements may be able to provide ways to measure subtle connectivity changes in different neurological disease states. For instance, RS-fMRI scans allow us to determine functionally connected yet spatially distinct brain regions that can then be separated into resting-state networks (RSNs). More recently, the exploration of RSNs in disease states have proved promising since they have been reliably altered when compared to a control population. By using brain connectomic approaches to assess functional connectivity we can evaluate the human connectome from a different and more global perspective to help us better understand and detect prodromal neurodegenerative disease states

Applying a Metacognitive Framework in the Neuropsychological Assessment of Subjective Cognitive Decline and Mild Cognitive Impairment

The characterization of the earliest stages of Alzheimer\u27s disease (AD) is a topic of major research interest because it is critical for early diagnosis and emerging interventions. Metamemory, or knowledge about memory, including awareness of one’s own memory functions, has been investigated in AD especially in relation to how impairment in memory and executive functions contribute to unawareness of cognitive deficits, termed anosognosia. Previous research, however, has not systematically investigated metamemory functioning in older adults with prodromal dementia conditions. Therefore, we investigated metamemory accuracy in cognitively healthy older adults (HC) and those with subjective cognitive decline but intact neuropsychological test scores (SCD), amnestic mild cognitive impairment (aMCI), and non-amnestic mild cognitive impairment (naMCI), all recruited from a longitudinal study of cognitive aging (Einstein Aging Study). Two studies respectively examined group differences in the accuracy of retrospective metamemory judgments (Empirical Study 1) and prospective metamemory judgments (Empirical Study 2) made during the monitoring of retrieval and encoding processes. Results showed that metamemory accuracy was weak in naMCI participants compared to controls, suggesting poor monitoring during both retrieval and encoding. In addition, although there was some evidence that retrospective monitoring processes may be suboptimal in aMCI compared to HC (Empirical Study 1), prospective metamemory monitoring processes were relatively intact in these individuals (Empirical Study 2), suggesting that performance monitoring of retrieval processes (which is more dependent on basic memory functions) may be differentially affected in aMCI. Furthermore, both studies revealed preserved metamemory accuracy in SCD, suggesting that performance monitoring of retrieval and encoding is intact in these older adults who present with subjective cognitive impairment and who may represent a pre-MCI condition. In addition, results revealed preserved memory self-awareness and self-knowledge in SCD (Empirical Study 2), providing further evidence that these individuals are capable of accurate self-assessment of their subjective experience of cognitive change. Overall, our novel findings support the hypothesis that metamemory performance varies across the neurodegenerative continuum and differentially impacts mechanisms in the metamemorial system that rely on memory (temporal lobe integrity) and/or executive functioning (prefrontal brain systems). Findings also inform remediation efforts such as the potential benefit of targeting specific metacognitive weaknesses (poor error detection, errors in evaluation during performance monitoring), in older adults with naMCI

Dysfunctional and compensatory duality in mild cognitive impairment during a continuous recognition memory task

One of the current issues of debate in the study of mild cognitive impairment (MCI) is deviations of oscillatory brain responses from normal brain states and its dynamics. This work aims to characterize the differences of power in brain oscillations during the execution of a recognition memory task in MCI subjects in comparison with elderly controls. Magnetoencephalographic (MEG) signals were recorded during a continuous recognition memory task performance. Oscillatory brain activity during the recognition phase of the task was analyzed by wavelet transform in the source space by means of minimum norm algorithm. Both groups obtained a 77% hit ratio. In comparison with healthy controls, MCI subjects showed increased theta (p < 0.001), lower beta reduction (p < 0.001) and decreased alpha and gamma power (p < 0.002 and p < 0.001 respectively) in frontal, temporal and parietal areas during early and late latencies. Our results point towards a dual pattern of activity (increase and decrease) which is indicative of MCI and specific to certain time windows, frequency bands and brain regions. These results could represent two neurophysiological sides of MCI. Characterizing these opposing processes may contribute to the understanding of the disorder

Understanding Cognitive Variability in Alzheimer’s Disease

Alzheimer’s Disease (AD) is highly heterogenous, both clinically and biologically. This variability is exacerbated by the ways within which, the clinical presentation is assessed with cognitive measures. This inhibits clinical trial success and earlier diagnosis of individuals. Marrying the clinical presentation to the pathology of the disease has so far proved troublesome. This thesis will look at how cognitive measures can best capture the clinical presentation of AD and how these measures can link to the underlying pathology using machine learning methods. This thesis studied this problem across four analyses and two cohorts. Each study looked at a different aspect of cognitive testing within AD. This was done with the overarching aim to interrogate the cognitive variability across the spectrum of AD. Study 1 showed a novel discrepancy score is different to memory measures at screening for AD. It also showed it tracks with AD severity, in the same way memory recall does. Studies 2 & 3 uncovered broad psychometric variance within amnestic measurement of impairment due to AD. This was done in two different populations across two different constructs of amnestic measurement, story recall and verbal list learning. These tests are frequently used interchangeably. These two studies show they should not be. Finally, Study 4 built models from cognitive measures to predict AD pathology. The performance of these models was moderate showing that even with novel cognitive measures, further work is needed to link the clinical and amyloid related biological presentations of AD. Bridging the gap between clinical presentation and pathology of AD using clinical and cognitive markers alone is not possible. Even when using a novel measure of discrepancy score. The discrepancy measure shows promise but was limited due to the inability of the MMSE to measure verbal ability. Conceptually a discrepancy score remains a promising avenue of research for screening, but broader language measures, as well as other AD biomarkers are needed to further test the construct validity of this measure

Functional connectivity differences in Alzheimer's disease and amnestic mild cognitive impairment associated with AT(N) classification and anosognosia

Alzheimer's continuum biological profiles (A+T-N-, A+T+N-, A+T-N+, and A+T+N+) were established in the 2018 National Institute on Aging and Alzheimer's Association research framework for Alzheimer's disease (AD). We aim to assess the relation between AT(N) biomarker profiles and brain functional connectivity (FC) and assess the neural correlates of anosognosia. We assessed local functional coupling and between-network connectivity through between-group intrinsic local correlation and independent component analyses. The neural correlates of anosognosia were assessed via voxel-wise linear regression analysis in prodromal AD. Statistical significance for the FC analysis was set at p ≤ 0.05 false discovery rate (FDR)-corrected for cluster size. One hundred and twenty-one and 73 participants were included in the FC and the anosognosia analysis, respectively. The FC in the default mode network is greater in prodromal AD than AD with dementia (i.e., local correlation: T = 8.26, p-FDR &lt; 0.001, k = 1179; independent component analysis: cerebellar network, T = 4.01, p-FDR = 0.0012, k = 493). The default mode network is persistently affected in the early stages of Alzheimer's biological continuum. The anterior cingulate cortex (T = 2.52, p-FDR = 0.043, k = 704) is associated with anosognosia in prodromal AD.</p

Multimodal magnetic resonance imaging on brain structure and function changes in subjective cognitive decline: a mini-review

Subjective cognitive decline (SCD) is the initial stage of Alzheimer’s disease (AD). Early identification of SCD and its risk factors is of great importance for targeted interventions and for delaying the onset of AD. We reviewed the relevant literature on structural magnetic resonance imaging (sMRI), diffusion tensor imaging (DTI), functional magnetic resonance imaging (fMRI), and other techniques regarding SCD research in recent years. This study applied sMRI and fMRI techniques to explore abnormal brain structures and functions, which may help provide a basis for SCD diagnosis