Increased Functional Connectivity in the Default Mode Network in Mild Cognitive Impairment: A Maladaptive Compensatory Mechanism Associated with Poor Semantic Memory Performance

Semantic memory decline and changes of default mode network (DMN) connectivity have been reported in mild cognitive impairment (MCI). Only a few studies, however, have investigated the role of changes of activity in the DMN on semantic memory in this clinical condition. The present study aimed to investigate more extensively the relationship between semantic memory impairment and DMN intrinsic connectivity in MCI. Twenty-one MCI patients and 21 healthy elderly controls matched for demographic variables took part in this study. All participants underwent a comprehensive semantic battery including tasks of category fluency, visual naming and naming from definition for objects, actions and famous people, word-association for early and late acquired words and reading. A subgroup of the original sample (16 MCI patients and 20 healthy elderly controls) was also scanned with resting state functional magnetic resonance imaging and DMN connectivity was estimated using a seed-based approach. Compared with healthy elderly, patients showed an extensive semantic memory decline in category fluency, visual naming, naming from definition, words-association, and reading tasks. Patients presented increased DMN connectivity between the medial prefrontal regions and the posterior cingulate and between the posterior cingulate and the parahippocampus and anterior hippocampus. MCI patients also showed a significant negative correlation of medial prefrontal gyrus connectivity with parahippocampus and posterior hippocampus and visual naming performance. Our findings suggest that increasing DMN connectivity may contribute to semantic memory deficits in MCI, specifically in visual naming. Increased DMN connectivity with posterior cingulate and medio-temporal regions seems to represent a maladaptive reorganization of brain functions in MCI, which detrimentally contributes to cognitive impairment in this clinical population

Evaluation by magnetic resonance imaging of functional and structural connectivities of neurofunctional networks in mild Alzheimer's disease dementia and amnestic mild cognitive impairment subjects

Orientador: Márcio Luiz Figueredo BalthazarTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: A demência por doença de Alzheimer (DA) é uma doença neurodegenerativa na qual ocorrem alterações cognitivas, neuropsiquiátricas e funcionais. Avanços recentes no estudo da neuroimagem na DA mostraram que as alterações presentes nesse grupo de pacientes não se restringem apenas às estruturas anatômicas particulares (tema abordado no ARTIGO 2), mas estendem-se também às redes neurofuncionais, as quais podem gerar problemas de memória e função executiva, entre outros. Devido às alterações estruturais apresentadas por atrofia, ao depósito de placas senis e emaranhados neurofibrilares, bem como à redução no metabolismo de glicose presente nas suas regiões, a Default Mode Network (DMN) tornou-se a rede neurofuncional de maior interesse no campo da DA. O principal objetivo desta Tese foi, dessa maneira, avaliar a conectividade de redes neurofuncionais na DA - enfatizando sobretudo na DMN, e suas relações com a cognição. Além disso, estudamos também outros aspectos anatômicos na DA - como alterações de substância branca e cinzenta no cérebro inteiro. No ARTIGO 1 mostramos que as alterações causadas pela doença afetam também áreas subcorticais como o tálamo e o corpo caloso, o que se relaciona com o déficit cognitivo dos pacientes. Em outro estudo com carácter mais exploratório (ARTIGO 6), mostramos que à medida em que a doença progrediu, as alterações na substância branca ocorreram de maneira mais extensa do que o esperado, levando em consideração as alterações estruturais encontradas na substância cinzenta. Assim, nossos dados sugerem que danos na substância branca possam ocorrer de maneira independente ao dano cortical. O ARTIGO 8, nesse contexto, traz um apanhado de resultados moleculares e de imagem que reforçam a hipótese de uma degeneração de redes neurofuncionais específicas em doenças neurodegenerativas, onde a propagação de proteínas alteradas ocorre ao longo dos tratos de substância branca (no caso da DA, em especial e primariamente nos tratos da DMN). Com isso em mente, no ARTIGO 4 tivemos como objetivo isolar apenas os tratos da DMN para avaliar o quão íntegro estruturalmente eles se apresentam na doença. De fato, observamos que pacientes com DA apresentam alterações microestruturais nos tratos da DMN, que contribuem para o déficit na performance cognitiva desses pacientes. No ARTIGO 5, investigamos não apenas a conectividade funcional das regiões da DMN, como também a média das amplitudes de baixa frequência (ALFF) do sinal BOLD dessas regiões. Encontramos que sujeitos com Comprometimento Cognitivo Leve amnéstico (CCLa, sujeitos sob risco de desenvolverem DA) por exemplo, possuem ALFF reduzido em regiões específicas da DMN, porém sem apresentar desconexão funcional entre elas. Pacientes com DA, entretanto, possuem não apenas ALFF reduzido em algumas regiões, mas também desconexão funcional entre elas. As amplitudes de ambos os grupos, entretanto, não possuem relação com o déficit cognitivo apresentado pelos pacientes; ao contrário da conectividade funcional dessas regiões. No ARTIGO 3, mostramos que outras redes neurofuncionais, como a de Linguagem e a de Controle Executivo também estão alteradas na DA. Em termos de correlatos neuropsicológicos apenas a conectividade da DMN mostrou relação com a performance em testes de memória episódica. No ARTIGO 7, por vez, tivemos como objetivo explorar outras hipóteses envolvendo a função da DMN. Nele, abordamos a questão da alteração do self nos pacientes com DA, e sugerimos uma relação com a atividade intrínseca do cérebro e o sentimento de auto-continuidade no tempoAbstract: Alzheimer¿s (AD) is a neurodegenerative disease that presents with cognitive, neuropsychiatric and functional alterations. Recent studies in the neuroimaging field of AD have shown that the alterations observed in these patients are not limited to specific anatomic structures (as shown in chapter 2) but also compromise neurofunctional networks, which can lead to memory and executive function impairment, among others. Due to the structural alterations such as atrophy, burden of amyloid beta and hyperphosphorilated tau, and metabolism reduction presented in its regions, the Default Mode Network (DMN) has become the most studied network in the AD field. Thus, the main objective of this thesis was to evaluate the functional and structural connectivities of the neurofunctional networks in AD ¿ emphasizing the DMN, and the relationship with cognition. Besides that, we have also studied some other anatomical aspects in AD, such as alterations in white and grey matter. In Chapter 1, we have shown that the alterations caused by the disease also affect subcortical areas such as the thalamus and the corpus callosum, which correlates to the cognitive deficit of the patients. In another exploratory study (Chapter 6), we observed that as the disease progressed, the alterations in white matter occurred were more extensive than expected, considering the structural alterations of the grey matter. Our results suggest that damage in white matter can occur independently of grey matter damage. In this context, Chapter 8 brings molecular and imaging results that reinforce the hypothesis that neurodegenerative diseases affect specific neurofunctional networks, and the propagation of altered proteins occur through white matter tracts (along DMN tracts). Keeping this in mind, in Chapter 4 we had as a main objective to isolate only the DMN tracts, in order to evaluate its structural connectivity in AD. Indeed, we observed that structural microalterations are present in DMN tracts of AD patients, contributing to their cognitive deficits. In Chapter 5, we not only investigated the functional connectivity of DMN regions, but also the amplitude of low frequency fluctuations (ALFF) of the blood oxygenation level signal of these regions. We found that amnestic mild cognitive impairment subjects (aMCI ¿ subjects at risk for developing AD) for instance, have decreased ALFF in specific regions of the DMN, though not presenting alterations in functional connectivity. AD patients, however, present both reduced ALFF and connectivity in the DMN regions. Interestingly, ALFF values did not correlate with the cognitive impairment of the patients; but connectivity values did. In Chapter 3, we have shown that other networks such as the Language and Executive Functions are also altered in AD. The functional connectivity of the DMN, in turn, correlated with episodic memory function. In Chapter 7, our main objective was to explore some other hypothesis involving the DMN function. Here, we mentioned the alterations in the self presented in AD patients and suggest a relationship with the brain intrinsic activity and the feeling of self continuity across timeDoutoradoCiencias BiomedicasDoutora em Ciências Médicas2013/10431-9FAPES

Meditation Interventions in Subjects with Amnestic Mild Cognitive Impairment

The prodromal stage of Alzheimer’s Disease, amnestic mild cognitive impairment, is characterized by subjective and objective memory impairment beginning with episodic memory. Few treatments have been identified to effectively slow disease progression to dementia. Meditation is an emerging novel treatment to improve deficits in subjects with these progressive cognitive impairments. Meditation and other novel treatments are critical for prolonging patients’ independence, reducing caregiver burden, and healthcare costs. This study will examine the effectiveness of an eight-week intervention using two meditation methods and two control groups on cognition and mood in participants with amnestic mild cognitive impairment. The primary outcome is episodic memory. Secondary outcomes include verbal fluency, executive function, working memory, and mood symptoms. We believe meditation interventions are low-cost, safe, easily implemented interventions that could improve cognition and mood symptoms in patients with amnestic mild cognitive impairment through induced changes within the Default Mode Network

Neural mechanisms of cognitive reserve in Alzheimer's disease

Alzheimer’s disease (AD) is the most common cause of age-related dementia, where neuropathological changes develop gradually over years before the onset of dementia symptoms. Yet, despite the progression of AD pathology, the decline in cognitive abilities such as episodic memory can be relatively slow. A slower decline of cognition and delayed onset of dementia relative to the progression of neuropathology has been associated with particular intellectual and lifestyle factors such as more years of education and IQ. Thus education and IQ are seen as protective factors that are associated with an increased ability to cope with brain pathology, i.e. cognitive reserve. While numerous studies showed that education, IQ and other lifestyle factors are associated with relatively high cognitive abilities in AD, little is known about the underlying brain mechanisms of reserve. Most previous studies tested the association between protective factors such as education or IQ and differences in brain structure and function in order to identify brain mechanisms underlying reserve. Since such protective factors are global in nature and unspecific with regard to reserve, the results were highly variable. So far, there is a lack of knowledge of brain features that are associated with a higher ability to maintain cognition in the face of AD pathology. The overall aim of this dissertation was to test a priori selected functional network features that may underlie cognitive reserve. We focused on resting-state functional networks, and in particular the fronto-parietal control network as correlate of cognitive reserve. Such functional networks are thought to be composed of brain regions that are co-activated during a particular task, where the interaction between brain regions may be critical to support cognitive function. During task-free resting-state periods, the different and often distant brain regions of such network show correlated activity, i.e. functional connectivity. For the fronto-parietal control network, and in particular its globally connected hub in the left frontal cortex (LFC), higher resting-state connectivity has been previously shown to be associated with higher cognitive abilities as well as higher education and IQ, i.e. protective factors associated with reserve. Since that network and its LFC hub are relatively spared in AD, in contrast to more posterior parietal networks, we investigated whether higher connectivity of the fronto-parietal control network is associated with higher reserve in AD. We argued that the fronto-parietal control network is relatively stable during the initial stages of AD and may thus be well posited to subserve reserve in AD. In contrast, networks like the default mode network (DMN) that cover midline brain structures including the medial frontal lobe and the posterior cingulate may be highly vulnerable to AD pathology, given the previous observations of altered DMN connectivity and posterior parietal FDG-PET hypometabolism in AD. In particular, the resting-state connectivity between the DMN and the dorsal attention network (DAN) may be predictive of lower episodic memory in AD. Both networks interact in a competitive (i.e. anti-correlated) way during task and resting-state, which is critical for cognitive processes such as episodic memory. In a first step, we tested whether the resting-state connectivity between the DMN and theDAN (i.e. anti-correlated activity) is associated with lower episodic memory in subjects with amnestic mild cognitive impairment (MCI), i.e. subjects at increased risk to convertto AD dementia. Furthermore, we tested whether protective factors such as higher education moderate the association between the DMN-DAN anti-correlation andcognition. Here, the DMN-DAN anti-correlation was a measure of AD relatedpathological change rather than a substrate of reserve.We could show in two independent samples of patients at risk of AD dementia that a weaker DMN-DAN anti-correlation was associated with lower episodic memory, where the decrements in episodic memory were however weaker in subjects with higher education or IQ (interaction DMN-DAN x education/IQ). These results suggest that MCI subjects with higher protective factors (education, IQ) maintain episodic memory relatively well at a given level of AD-related brain changes. In the second step, we sought to identify those network differences that support cognitive reserve, i.e. that may explain the association between higher education and milder cognitive impairment in AD. Here, we could show that greater resting-state fMRI assessed global connectivity of the LFC, i.e. a key hub of the fronto-parietal control network, was associated with greater education and attenuated effects of neurodegeneration (measured by parietal FDG-PET hypometabolism) on memory in prodromal AD. Together, these results support the idea that global connectivity of a fronto-parietal control network hub supports cognitive reserve in AD. Based on this finding, we developed a novel restingstate fMRI index of fronto-parietal control network connectivity as a functional imaging marker of cognitive reserve. This marker is highly correlated with education and may thus be used as an imaging-based index of cognitive reserve. Together, our results provide for the first time evidence that cognitive reserve in AD is supported by higher functional connectivity of the fronto-parietal control network, in particular its LFC hub

Neural mechanisms of cognitive reserve in Alzheimer's disease

Alzheimer’s disease (AD) is the most common cause of age-related dementia, where neuropathological changes develop gradually over years before the onset of dementia symptoms. Yet, despite the progression of AD pathology, the decline in cognitive abilities such as episodic memory can be relatively slow. A slower decline of cognition and delayed onset of dementia relative to the progression of neuropathology has been associated with particular intellectual and lifestyle factors such as more years of education and IQ. Thus education and IQ are seen as protective factors that are associated with an increased ability to cope with brain pathology, i.e. cognitive reserve. While numerous studies showed that education, IQ and other lifestyle factors are associated with relatively high cognitive abilities in AD, little is known about the underlying brain mechanisms of reserve. Most previous studies tested the association between protective factors such as education or IQ and differences in brain structure and function in order to identify brain mechanisms underlying reserve. Since such protective factors are global in nature and unspecific with regard to reserve, the results were highly variable. So far, there is a lack of knowledge of brain features that are associated with a higher ability to maintain cognition in the face of AD pathology. The overall aim of this dissertation was to test a priori selected functional network features that may underlie cognitive reserve. We focused on resting-state functional networks, and in particular the fronto-parietal control network as correlate of cognitive reserve. Such functional networks are thought to be composed of brain regions that are co-activated during a particular task, where the interaction between brain regions may be critical to support cognitive function. During task-free resting-state periods, the different and often distant brain regions of such network show correlated activity, i.e. functional connectivity. For the fronto-parietal control network, and in particular its globally connected hub in the left frontal cortex (LFC), higher resting-state connectivity has been previously shown to be associated with higher cognitive abilities as well as higher education and IQ, i.e. protective factors associated with reserve. Since that network and its LFC hub are relatively spared in AD, in contrast to more posterior parietal networks, we investigated whether higher connectivity of the fronto-parietal control network is associated with higher reserve in AD. We argued that the fronto-parietal control network is relatively stable during the initial stages of AD and may thus be well posited to subserve reserve in AD. In contrast, networks like the default mode network (DMN) that cover midline brain structures including the medial frontal lobe and the posterior cingulate may be highly vulnerable to AD pathology, given the previous observations of altered DMN connectivity and posterior parietal FDG-PET hypometabolism in AD. In particular, the resting-state connectivity between the DMN and the dorsal attention network (DAN) may be predictive of lower episodic memory in AD. Both networks interact in a competitive (i.e. anti-correlated) way during task and resting-state, which is critical for cognitive processes such as episodic memory. In a first step, we tested whether the resting-state connectivity between the DMN and theDAN (i.e. anti-correlated activity) is associated with lower episodic memory in subjects with amnestic mild cognitive impairment (MCI), i.e. subjects at increased risk to convertto AD dementia. Furthermore, we tested whether protective factors such as higher education moderate the association between the DMN-DAN anti-correlation andcognition. Here, the DMN-DAN anti-correlation was a measure of AD relatedpathological change rather than a substrate of reserve.We could show in two independent samples of patients at risk of AD dementia that a weaker DMN-DAN anti-correlation was associated with lower episodic memory, where the decrements in episodic memory were however weaker in subjects with higher education or IQ (interaction DMN-DAN x education/IQ). These results suggest that MCI subjects with higher protective factors (education, IQ) maintain episodic memory relatively well at a given level of AD-related brain changes. In the second step, we sought to identify those network differences that support cognitive reserve, i.e. that may explain the association between higher education and milder cognitive impairment in AD. Here, we could show that greater resting-state fMRI assessed global connectivity of the LFC, i.e. a key hub of the fronto-parietal control network, was associated with greater education and attenuated effects of neurodegeneration (measured by parietal FDG-PET hypometabolism) on memory in prodromal AD. Together, these results support the idea that global connectivity of a fronto-parietal control network hub supports cognitive reserve in AD. Based on this finding, we developed a novel restingstate fMRI index of fronto-parietal control network connectivity as a functional imaging marker of cognitive reserve. This marker is highly correlated with education and may thus be used as an imaging-based index of cognitive reserve. Together, our results provide for the first time evidence that cognitive reserve in AD is supported by higher functional connectivity of the fronto-parietal control network, in particular its LFC hub

Visual processing speed in the aging brain

Either reading a text in the office or looking for an apple in the supermarket, we are continuously flooded with visual stimuli. But how does the human brain support the efficient processing of those stimuli? And, if pathological changes occur in the brain, how do these changes lead to reductions in such efficient processing? In the present dissertation, aging is used as a model to address these two questions. First, individual differences in visual processing speed are examined in association with the coherence of the brain’s spontaneous activity and how this coherence is affected by normal aging. Second, individual differences in visual processing speed are studied in association with behavior in tasks that measure complex visual object perception in patients at risk of Alzheimer’s dementia and healthy aging adults. Based on these two approaches, evidence will be presented for an association of a slowed visual processing with (a) decreased coherent activity of a frontoinsular network in healthy aging and (b) simultaneous object perception deficits in patients at risk of Alzheimer’s dementia. This evidence provides critical insights into the particular link between visual processing speed and the coherence of the brain’s spontaneous activity and reveals perceptual deficits in patients whose clinically most apparent impairments lie in memory

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

Hyperconnectivity is a fundamental response to neurological disruption

In the cognitive and clinical neurosciences, the past decade has been marked by dramatic growth in a literature examining brain "connectivity" using noninvasive methods. We offer a critical review of the blood oxygen level dependent functional MRI (BOLD fMRI) literature examining neural connectivity changes in neurological disorders with focus on brain injury and dementia. The goal is to demonstrate that there are identifiable shifts in local and large-scale network connectivity that can be predicted by the degree of pathology. We anticipate that the most common network response to neurological insult is hyperconnectivity but that this response depends upon demand and resource availability

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

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