Cognitive reserve impacts on inter-individual variability in resting-state cerebral metabolism in normal aging

peer reviewedThere is a great deal of heterogeneity in the impact of aging on cognition and cerebral functioning. One potential factor contributing to individual differences among the elders is the cognitive reserve, which designates the partial protection from the deleterious effects of aging that lifetime experience provides. Neuroimaging studies examining task-related activation in elderly people suggested that cognitive reserve takes the form of more efficient use of brain networks and/or greater ability to recruit alternative networks to compensate for age-related cerebral changes. In this multi-centre study, we examined the relationships between cognitive reserve, as measured by education and verbal intelligence, and cerebral metabolism at rest (FDG-PET) in a sample of 74 healthy older participants. Higher degree of education and verbal intelligence was associated with less metabolic activity in the right posterior temporoparietal cortex and the left anterior intraparietal sulcus. Functional connectivity analyses of resting-state fMRI images in a subset of 41 participants indicated that these regions belong to the default mode network and the dorsal attention network respectively. Lower metabolism in the temporoparietal cortex was also associated with better memory abilities. The findings provide evidence for an inverse relationship between cognitive reserve and resting-state activity in key regions of two functional networks respectively involved in internal mentation and goal-directed attention

Cognitive Efficiency in Alzheimer's Disease is Associated with Increased Occipital Connectivity

There are cognitive domains which remain fully functional in a proportion of Alzheimer's disease (AD) patients. It is unknown, however, what distinctive mechanisms sustain such efficient processing. The concept of "cognitive efficiency" was investigated in these patients by operationalizing it as a function of the level of performance shown on the Letter Fluency test, on which, very often, patients in the early stages of AD show unimpaired performance. Forty-five individuals at the prodromal/early stage of AD (diagnosis supported by subsequent clinical follow-ups) and 45 healthy controls completed a battery of neuropsychological tests and an MRI protocol which included resting-state acquisitions. The Letter Fluency test was the only task on which no between-group difference in performance was found. Participants were divided into "low-performing" and "high-performing" according to the global median. Dual-regression methods were implemented to compute six patterns of network connectivity. The diagnosis-by-level of performance interaction was inferred on each pattern to determine the network distinctiveness of efficient performance in AD. Significant interactions were found in the anterior default mode network, and in both left and right executive control networks. For all three circuits, high-performing patients showed increased connectivity within the ventral and dorsal part of BA19, as confirmed by post-hoc t tests. Peristriate remapping is suggested to play a compensatory role. Since the occipital lobe is the neurophysiological source of long-range cortical connectivity, it is speculated that the physiological mechanisms of functional connectivity might sustain occipital functional remapping in early AD, particularly for those functions which are sustained by areas not excessively affected by the prodromal disease

Salience and default mode network coupling predicts cognition in aging and Parkinson’s disease

OBJECTIVES: Cognitive impairment is common in Parkinson’s disease (PD). Three neurocognitive networks support efficient cognition: the salience network, the default mode network, and the central executive network. The salience network is thought to switch between activating and deactivating the default mode and central executive networks. Anti-correlated interactions between the salience and default mode networks in particular are necessary for efficient cognition. Our previous work demonstrated altered functional coupling between the neurocognitive networks in non-demented individuals with PD compared to age-matched control participants. Here, we aim to identify associations between cognition and functional coupling between these neurocognitive networks in the same group of participants. METHODS: We investigated the extent to which intrinsic functional coupling among these neurocognitive networks is related to cognitive performance across three neuropsychological domains: executive functioning, psychomotor speed, and verbal memory. Twenty-four non-demented individuals with mild to moderate PD and 20 control participants were scanned at rest and evaluated on three neuropsychological domains. RESULTS: PD participants were impaired on tests from all three domains compared to control participants. Our imaging results demonstrated that successful cognition across healthy aging and Parkinson’s disease participants was related to anti-correlated coupling between the salience and default mode networks. Individuals with poorer performance scores across groups demonstrated more positive salience network/default-mode network coupling. CONCLUSIONS: Successful cognition relies on healthy coupling between the salience and default mode networks, which may become dysfunctional in PD. These results can help inform non-pharmacological interventions (repetitive transcranial magnetic stimulation) targeting these specific networks before they become vulnerable in early stages of Parkinson’s disease.Published versio

Decreased Default Mode Network connectivity correlates with age-associated structural and cognitive changes

Ageing entails cognitive and motor decline as well as brain changes such as loss of gray (GM) and white matter (WM) integrity, neurovascular and functional connectivity alterations. Regarding connectivity, reduced resting-state fMRI connectivity between anterior and posterior nodes of the Default Mode Network (DMN) relates to cognitive function and has been postulated to be a hallmark of ageing. However, the relationship between age-related connectivity changes and other neuroimaging-based measures in ageing is fragmentarily investigated. In a sample of 116 healthy elders we aimed to study the relationship between antero-posterior DMN connectivity and measures of WM integrity, GM integrity and cerebral blood flow (CBF), assessed with an arterial spin labeling sequence. First, we replicated previous findings demonstrating DMN connectivity decreases in ageing and an association between antero-posterior DMN connectivity and memory scores. The results showed that the functional connectivity between posterior midline structures and the medial prefrontal cortex was related to measures of WM and GM integrity but not to CBF. Gray and WM correlates of anterio-posterior DMN connectivity included, but were not limited to, DMN areas and cingulum bundle. These results resembled patterns of age-related vulnerability which was studied by comparing the correlates of antero-posterior DMN with age-effect maps. These age-effect maps were obtained after performing an independent analysis with a second sample including both young and old subjects. We argue that antero-posterior connectivity might be a sensitive measure of brain ageing over the brain. By using a comprehensive approach, the results provide valuable knowledge that may shed further light on DMN connectivity dysfunctions in ageing

The Association of Aerobic Fitness with Resting State Functional Connectivity and Verbal Learning and Memory in Healthy Young Adults

The beneficial effects of exercise and cardiopulmonary fitness on general health, quality of life, and reduction of mortality are well known in older adults. There is evidence to support the positive effects of exercise and aerobic fitness on psychiatric and neurocognitive function in children, adults, and older adults. Indeed, many studies have explored the positive effects of aerobic fitness on slowing cognitive decline associated with normal and pathological aging. However, comparatively fewer empirical studies in the literature exist to support and understand the effects of aerobic fitness on the developing brain, particularly during adolescence and young adulthood, especially as it relates to resting state functional connectivity during this dynamic stage of development. The current study investigated the association of aerobic fitness on functional connectivity with the left hippocampus in healthy young adults and the degree to which differential resting state functional connectivity is associated with verbal learning and memory. The sample was comprised of healthy young adults with varying degrees of aerobic fitness as part of a larger study of the effects of cardiorespiratory health on neurocognitive performance, brain structure and function. Results of the study indicated that better aerobic fitness is associated with increased functional connectivity to the left parahippocampal gyrus, a region known for its role in working memory and encoding. Results from this study contribute to a better understanding of the factors that may underlie the beneficial effects of exercise on brain health and neurocognition and further offer insights into the value of early preventive health behaviors to reduce the risk of later of cognitive decline and impairment

Congenital adrenal hyperplasia : pre-and postnatal treatment effects on cognition, behavior and brain resting-state functional connectivity

Congenital adrenal hyperplasia (CAH), an autosomal recessive disorder affecting adrenal steroid synthesis, is linked to impaired adrenal synthesis of cortisol and aldosterone. The increased production of androgen precursors in the adrenal cortex during fetal life leads to the virilization of external genitalia in girls with CAH already in utero. Prenatal virilization can be reduced or alleviated entirely by dexamethasone (DEX) treatment in affected girls, but with potentially adverse effects on growth parameters, cognition, behavior, brain structure and brain networks and metabolism. The effects of synthetic glucocorticoids (GCs) on fetal development are time- and dose-dependent, with different outcomes in early vs. late gestational treatment. Patients with CAH are also treated postnatally with life-long GC replacement therapy to mimic the physiological levels following the circadian rhythm. Because of the inherent difficulties in mimicking the natural rhythm of cortisol secretion, there is a risk of under- or over-treatment during the individual’s life span, with potentially adverse effects on brain function and structure, metabolism and quality of life. In this thesis the long-term effects of pre-and postnatal DEX treatment were investigated in a cohort of 206 individuals: patients with CAH not prenatally treated with DEX (n=71), a small cohort of patients with CAH prenatally treated with DEX (n=13), individuals at risk of CAH who were prenatally treated during the first trimester of fetal life (n=18) and population controls (n=104). Patients with CAH were diagnosed through the national neonatal screening program. We hypothesized that GC treatment could impact cognitive performance, behavior and resting-state functional connectivity of the brain. Compared to controls, we did not identify significant differences in cognitive performance in children and adolescents aged 7- 17 years (mean age 11.5 years) with CAH compared with the population controls. However, patients with the salt-wasting (SW) genotype performed worse on a subtest assessing visuospatial working memory compared to patients with simple-virilizing (SV) CAH. The scores on this subtest were in the average range for the general population. In summary, early diagnosis may optimize treatment and benefit cognitive development. The small cohort of CAH cases prenatally treated with DEX (6 females, 5 males) showed poorer performance in a subtest assessing verbal intelligence than patients not treated with DEX. The behavioral outcomes evaluated using parental and self-rated questionnaires reflected a good overall adjustment in children and adolescents with CAH compared to controls. The parental questionnaires suggested more social problems in CAH patients. Moreover, the parents of children with CAH prenatally treated with DEX (8 girls, 5 boys) scored their children as having more social problems (males) and more withdrawn/depressed problems (girls). Additional studies in larger cohorts are needed to draw more definitive conclusions. To our knowledge there are no studies on resting-state functional connectivity in patients with CAH or persons at risk of CAH prenatally treated with DEX. When we performed whole-brain analyses to investigate the functional connectivity of the brain during rest in 31 patients with CAH (18 females), aged 16-33 years (mean age 23.7 years), we found increased functional connectivity in the precuneus in patients with CAH compared to controls. Post hoc analyses within the precuneus revealed that patients with SV CAH had stronger connectivity. The altered functional connectivity may reflect a reorganization of the brain in patients with CAH. Looking at the resting-state functional connectivity in 18 participants (8 females), aged 16-33 years (mean age 20.8 years) exposed to DEX treatment during the first trimester of fetal life because of the risk of having CAH, we used two approaches: an exploratory whole-brain analysis and a seed-based analysis. We chose three brain regions (amygdala, hippocampus, superior frontal gyrus) for the seed-based analysis based on our previous findings and literature evidence. We did not find any differences in resting-state functional connectivity between DEX-exposed individuals and controls. In conclusion, this thesis extends the existing literature on GC effects on functional connectivity in the brain and cognitive and behavioral outcomes in patients with CA

Association between resting-state functional connectivity, glucose metabolism and task-related activity of neural networks

The brain is organized into several large-scale functional networks. Such networks are primarily characterized by intrinsic functional connectivity, i.e. temporally synchronous activity between the different brain regions of a network. The functional connectivity of networks can be identified via functional MRI during resting state, i.e. without engaging the subject in a particular task. Resting-state fMRI is thus less demanding on the subject and therefore of particular interest from a clinical point of view to detect alterations in brain function. Applied to neurodegenerative disease including Alzheimer’s disease, resting-state fMRI has shown alterations in several resting-state networks, suggesting that basic network function is altered in AD. However, the interpretation of alterations in resting-state fMRI connectivity is inherently limited since no cognitive states are explicitly expressed during fMRI. In this regard, we aimed to elucidate how resting-state fMRI connectivity relates to 1) cognition-related brain activity and 2) markers of pathologically altered brain function in AD. In order to understand at a more basic level the association between resting-state and task-related fMRI, we first examined, in a group of elderly healthy subjects, the association between functional connectivity of major networks assessed during resting-state fMRI with those acquired during memory-task related fMRI, in the same individuals. Secondly, in order to assess whether alterations in AD are associated with already well-established markers of pathological brain function in AD, we compared resting-state fMRI functional network connectivity with that in FDG-PET metabolism in AD. Project 1: We investigated the association between functional connectivity acquired during rest and the level of activation obtained during an episodic memory task that included the encoding and forced-choice recognition of face-name pairs in elderly cognitively normal subjects. Independent component analysis (ICA) was used to identify major resting-state networks in the brain. Next, we applied ICA to the task-fMRI data to determine the components (networks) that were significantly associated with the task regressors of successful vs unsuccessful learning or recognition trials. Spatial correlation analysis between the resulting extracted resting-state and task-related fMRI components showed a spatial match in several components such as medial temporal lobe centered components and posterior components. However, apart from the spatial correspondence, the level of resting state functional connectivity did not predict the level of task-related functional connectivity in spatially matching components. Together these results suggested that particular resting-state networks are activated during a memory task, however, the level of baseline connectivity does not predict to what extent a network becomes activated during a task. Future studies may assess whether pathological resting-state connectivity predicts altered task-related connectivity in the same networks in AD. Project 2: We examined the association between resting-state fMRI functional connectivity within major functional networks and FDG-PET metabolism in those networks, assessed in elderly healthy controls, subjects with prodromal AD (mild cognitive impairment and amyloid PET biomarker confirmed AD etiology) and AD dementia. We found that FDG-PET was generally reduced in all networks in the course of AD. The main finding was that lower network functional connectivity was associated with lower FDG-PET uptake in the Default mode network and fronto-parietal attention network across the whole group and specifically in prodromal AD, suggesting that both modalities are associated in higher networks affected in the course of AD. These results provide insightful comprehension of the hypometabolism patterns that are typically found in AD

Cardiorespiratory fitness as a predictor of effective connectivity in the default mode network

Previous work has linked the onset and progression of Alzheimer’s Disease (AD) to changes in the Default Mode Network (DMN), including greater atrophy within the hippocampus (HC) as well as diminished functional connectivity and effective connectivity between anatomical DMN structures. Animal models have described the HC as a primary region of interest in studying the effects of exercise on adult neurogenesis and memory performance. Human studies have demonstrated that aerobic exercise leads to greater cardiorespiratory fitness and improved functional connectivity in the DMN for healthy adults. The goal of this study is to go beyond the predictions of human and animal studies to investigate how cardiorespiratory fitness may be used to estimate effective connectivity between the HC and the other DMN structures for young adults using resting state fMRI. Due to the data driven nature of this study, no hypothesis has been formulated. To investigate, data from 25 sedentary young adults was analyzed. Data included a resting state fMRI procedure and a cardiorespiratory fitness test, each taken from part of a larger ongoing clinical trial in the Brain Plasticity and Neuroimaging (BPN) Lab at Boston University (BU). We utilized group independent component analysis (GICA) to identify the regions that define the DMN and Conditional Granger Causality Analysis (CGCA) to determine effective connectivity between these regions. GICA indicated 9 structural regions in the DMN, consistent with previous work. This resulted in 72 possible instances of effective connectivity. The difference of causal influence between regions was calculated for each pair of DMN regions for CGCA, resulting in 36 possible instances of causal connectivity. Linear regression models were created to analyze the effect of cardiorespiratory fitness on effective connectivity between DMN regions and found 11 linear models which exhibited a significant (p > 0.05) relationship. Eight of eleven models involved the left or right hippocampus, showing that greater cardiorespiratory fitness is correlated with changes effective connectivity between the HC and the PCC, MPFC, or LTC. These results provide proof of concept that cardiorespiratory fitness in young adults is associated with changes DMN effective connectivity, particularly involving the hippocampus. This adds to the literature suggesting extended aerobic exercise, which is known to increase cardiorespiratory fitness and has been shown to increase the volume of the HC in older adults, may be neuroprotective of the HC across the lifespan. Further investigation is required to explore how effective connectivity in the DMN changes following an aerobic exercise intervention

Plasticity of Brain Networks in a Randomized Intervention Trial of Exercise Training in Older Adults

Research has shown the human brain is organized into separable functional networks during rest and varied states of cognition, and that aging is associated with specific network dysfunctions. The present study used functional magnetic resonance imaging (fMRI) to examine low-frequency (0.008 < f < 0.08 Hz) coherence of cognitively relevant and sensory brain networks in older adults who participated in a 1-year intervention trial, comparing the effects of aerobic and non-aerobic fitness training on brain function and cognition. Results showed that aerobic training improved the aging brain's resting functional efficiency in higher-level cognitive networks. One year of walking increased functional connectivity between aspects of the frontal, posterior, and temporal cortices within the Default Mode Network and a Frontal Executive Network, two brain networks central to brain dysfunction in aging. Length of training was also an important factor. Effects in favor of the walking group were observed only after 12 months of training, compared to non-significant trends after 6 months. A non-aerobic stretching and toning group also showed increased functional connectivity in the DMN after 6 months and in a Frontal Parietal Network after 12 months, possibly reflecting experience-dependent plasticity. Finally, we found that changes in functional connectivity were behaviorally relevant. Increased functional connectivity was associated with greater improvement in executive function. Therefore the study provides the first evidence for exercise-induced functional plasticity in large-scale brain systems in the aging brain, using functional connectivity techniques, and offers new insight into the role of aerobic fitness in attenuating age-related brain dysfunction