Jewell B. Thomas

Loss of Intranetwork and Internetwork Resting State Functional Connections with Alzheimer's Disease Progression

Alzheimers disease (AD) is the most common cause of dementia. Much is known concerning AD pathophysiology but our understanding of the disease at the systems level remains incomplete. Previous AD research has used resting-state functional connectivity magnetic resonance imaging (rs-fcMRI) to assess the integrity of functional networks within the brain. Most studies have focused on the default-mode network (DMN), a primary locus of AD pathology. However, other brain regions are inevitably affected with disease progression. We studied rs-fcMRI in five functionally defined brain networks within a large cohort of human participants of either gender (n = 510) that ranged in AD severity from unaffected [clinical dementia rating (CDR) 0] to very mild (CDR 0.5) to mild (CDR 1). We observed loss of correlations within not only the DMN but other networks at CDR 0.5. Within the salience network (SAL), increases were seen between CDR 0 and CDR 0.5. However, at CDR 1, all networks, including SAL, exhibited reduced correlations. Specific networks were preferentially affected at certain CDR stages. In addition, cross-network relations were consistently lost with increasing AD severity. Our results demonstrate that AD is associated with widespread loss of both intranetwork and internetwork correlations. These results provide insight into AD pathophysiology and reinforce an integrative view of the brains functional organization.

Functional connectivity and graph theory in preclinical Alzheimer’s disease

Alzheimers disease (AD) has a long preclinical phase in which amyloid and tau cerebral pathology accumulate without producing cognitive symptoms. Resting state functional connectivity magnetic resonance imaging has demonstrated that brain networks degrade during symptomatic AD. It is unclear to what extent these degradations exist before symptomatic onset. In this study, we investigated graph theory metrics of functional integration (path length), functional segregation (clustering coefficient), and functional distinctness (modularity) as a function of disease severity. Further, we assessed whether these graph metrics were affected in cognitively normal participants with cerebrospinal fluid evidence of preclinical AD. Clustering coefficient and modularity, but not path length, were reduced in AD. Cognitively normal participants who harbored AD biomarker pathology also showed reduced values in these graph measures, demonstrating brain changes similar to, but smaller than, symptomatic AD. Only modularity was significantly affected by age. We also demonstrate that AD has a particular effect on hub-like regions in the brain. We conclude that AD causes large-scale disconnection that is present before onset of symptoms.

Pathways to neurodegeneration Effects of HIV and aging on resting-state functional connectivity

Objective: Resting-state functional connectivity MRI (rs-fcMRI) may provide insight into the neurophysiology of HIV and aging. Methods: In this cross-sectional study, we used rs-fcMRI to investigate intra- and internetwork connectivity among 5 functional brain networks in 58 HIV-infected (HIV+) participants (44% receiving highly active antiretroviral therapy) and 53 HIV-uninfected (HIV−) controls. An analysis of covariance assessed the relationship among age, HIV laboratory markers, or degree of cognitive impairment and brain networks. Results: Individuals who were HIV+ had decreased rs-fcMRI intranetwork correlations in the default mode (DMN, p = 0.01), control (CON, p = 0.02), and salience (SAL, p = 0.02) networks, but showed no changes in the sensorimotor (SMN) or dorsal attention (DAN) network. Compared with HIV− controls, participants who were HIV+ had a significant loss of internetwork correlations between the DMN-DAN (p = 0.02), trending loss in DMN-SAL (p = 0.1) and CON-SMN (p = 0.1), and trending increase in CON-SAL (p = 0.1). Neither HIV markers (plasma HIV viral load or CD4+ cell count) nor degree of cognitive impairment correlated with rs-fcMRI measures. Aging correlated with a decrease in the magnitude of intranetwork functional connectivity within the DMN (p = 0.04) and SAL (p = 0.006) and with decreased magnitude of internetwork functional connectivity between DMN and SAL (p = 0.009) for both HIV+ and HIV− participants. No interaction was observed between HIV and aging. Conclusions: HIV and aging may cause independent decreases in rs-fcMRI. HIV may lead to a baseline decrease in brain function similar to deterioration that occurs with aging.

Network Dysfunction in Alzheimer's Disease: Refining the Disconnection Hypothesis

Much effort in recent years has focused on understanding the effects of Alzheimers disease (AD) on neural function. This effort has resulted in an enormous number of papers describing different facets of the functional derangement seen in AD. A particularly important tool for these investigations has been resting-state functional connectivity. Attempts to comprehensively synthesize resting-state functional connectivity results have focused on the potential utility of functional connectivity as a biomarker for disease risk, disease staging, or prognosis. While these are all appropriate uses of this technique, the purpose of this review is to examine how functional connectivity disruptions inform our understanding of AD pathophysiology. Here, we examine the rationale and methodological considerations behind functional connectivity studies and then provide a critical review of the existing literature. In conclusion, we propose a hypothesis regarding the development and spread of functional connectivity deficits seen in AD.

Functional connectivity in autosomal dominant and late-onset Alzheimer disease.

IMPORTANCE Autosomal dominant Alzheimer disease (ADAD) is caused by rare genetic mutations in 3 specific genes in contrast to late-onset Alzheimer disease (LOAD), which has a more polygenetic risk profile. OBJECTIVE To assess the similarities and differences in functional connectivity changes owing to ADAD and LOAD. DESIGN, SETTING, AND PARTICIPANTS We analyzed functional connectivity in multiple brain resting state networks (RSNs) in a cross-sectional cohort of participants with ADAD (n = 79) and LOAD (n = 444), using resting-state functional connectivity magnetic resonance imaging at multiple international academic sites. MAIN OUTCOMES AND MEASURES For both types of AD, we quantified and compared functional connectivity changes in RSNs as a function of dementia severity measured by the Clinical Dementia Rating Scale. In ADAD, we qualitatively investigated functional connectivity changes with respect to estimated years from onset of symptoms within 5 RSNs. RESULTS A decrease in functional connectivity with increasing Clinical Dementia Rating scores were similar for both LOAD and ADAD in multiple RSNs. Ordinal logistic regression models constructed in one type of Alzheimer disease accurately predicted clinical dementia rating scores in the other, further demonstrating the similarity of functional connectivity loss in each disease type. Among participants with ADAD, functional connectivity in multiple RSNs appeared qualitatively lower in asymptomatic mutation carriers near their anticipated age of symptom onset compared with asymptomatic mutation noncarriers. CONCLUSIONS AND RELEVANCE Resting-state functional connectivity magnetic resonance imaging changes with progressing AD severity are similar between ADAD and LOAD. Resting-state functional connectivity magnetic resonance imaging may be a useful end point for LOAD and ADAD therapy trials. Moreover, the disease process of ADAD may be an effective model for the LOAD disease process.

Alzheimer disease family history impacts resting state functional connectivity

Offspring whose parents have Alzheimer disease (AD) are at increased risk for developing dementia. Patients with AD typically exhibit disruptions in the default mode network (DMN). The aim of this study was to investigate the effect of a family history of late onset AD on DMN integrity in cognitively normal individuals. In particular, we determined whether a family history effect is detectable in apolipoprotein E (APOE) ε4 allele noncarriers.

The Effects of HIV and Combination Antiretroviral Therapy on White Matter Integrity

Objective:HIV preferentially affects white matter in the brain. Although combination antiretroviral therapy (cART) reduces HIV viral load within the brain, continued inflammation can persist. We investigated the effect of HIV and cART on white matter integrity. Design:We used diffusion tensor imaging (DTI) to examine the effects of HIV and cART on white matter integrity within the corpus callosum and centrum semiovale (CSO). Methods:Neuropsychological testing and DTI measures (fractional anisotropy, mean diffusivity, axial diffusivity, radial diffusivity) were obtained from 21 HIV-uninfected controls, 21 HIV-infected patients naive to cART (HIV+/cART−), and 21 HIV+ patients receiving stable cART (HIV+/cART+). A subset of the HIV+/cART− individuals (n = 10) was assessed before and 6 months after receiving medications. Differences among the cross-sectional groups were assessed using an analysis of variance, whereas paired t-tests evaluated longitudinal changes. Results:HIV+/cART− participants had significantly lower mean diffusivity, axial diffusivity, and radial diffusivity for the corpus callosum and CSO compared to HIV− controls and HIV+/cART+ individuals. No significant difference existed between HIV− controls and HIV+/cART+ patients. cART initiation significantly improved mean diffusivity, radial diffusivity, and axial diffusivity, but not fractional anisotropy, in the corpus callosum and CSO in some HIV-infected patients. Conclusion:Observed decreases in DTI parameters between HIV+/cART+ and HIV+/cART− individuals could reflect the presence of inflammatory cells or cytotoxic edema in HIV+/cART− patients. Initiating cART could lead to a reduction in neuro-inflammation and improvement in DTI measures. Future DTI studies may be useful for evaluating the efficacy higher brain penetrating cART regimens.

Unrecognized preclinical Alzheimer disease confounds rs-fcMRI studies of normal aging.

Objective: To determine whether, and to what degree, preclinical Alzheimer disease (AD) confounds studies of healthy aging where “healthy” is based on cognitive normality alone. Methods: We examined the effects of preclinical AD in cognitively normal older individuals using resting-state functional connectivity MRI. We investigated 2 groups of cognitively normal participants: one group with evidence of preclinical AD as assessed by CSF markers of AD and the other group with normal CSF biomarkers. Results: There were significant interactions between age and biomarker status in the default-mode, dorsal attention, and salience resting-state networks. In the group with evidence of preclinical AD, there were dramatic changes in functional connectivity with age. In the group without evidence of preclinical AD, those changes were greatly attenuated. In most regions with significant interactions of age and biomarker status, the age-related change in functional connectivity in the normal biomarker group was indistinguishable from zero. Conclusions: These results suggest that preclinical AD accounts for a substantial portion of the reported effects of aging in the extant functional connectivity literature.

Relationship Between Stroop Performance and Resting State Functional Connectivity in Cognitively Normal Older Adults

OBJECTIVE Early biomarkers of Alzheimers disease (AD) are needed for developing therapeutic interventions. Measures of attentional control in Stroop-type tasks discriminate healthy aging from early stage AD and predict future development of AD in cognitively normal individuals. Disruption in resting state functional connectivity MRI (rs-fcMRI) has been reported in AD and in healthy controls at risk for AD. We explored the relationship among Stroop performance, rs-fcMRI, and CSF Aβ₄₂ levels in cognitively normal older adults. METHOD A computerized Stroop task (along with standard neuropsychological measures), rs-fcMRI, and CSF were obtained in 237 cognitively normal older adults. We compared the relationship between Stroop performance, including measures from reaction distributional analyses, and composite scores from four resting state networks (RSNs; default mode [DMN], salience [SAL], dorsal attention [DAN], and sensory-motor [SMN]), and the modulatory influence of CSF Aβ₄₂ levels. RESULTS A larger Stroop effect in errors was associated with reduced rs-fcMRI within the DMN and SAL. Reaction time (RT) distributional analyses indicated the slow tail of the RT distribution was related to reduced rs-fcMRI functional connectivity within the SAL. Standard psychometric measures were not related to RSN composite scores. A relationship between Stroop performance and DMN (but not SAL) functional connectivity was stronger in CSF Aβ₄₂-positive individuals. CONCLUSIONS A link exists between RSN composite scores and specific attentional performance measures. Both measures may be sensitive biomarkers for AD.

Weighted brain networks in disease: centrality and entropy in human immunodeficiency virus and aging

Graph theory models can produce simple, biologically informative metrics of the topology of resting-state functional connectivity (FC) networks. However, typical graph theory approaches model FC relationships between regions (nodes) as unweighted edges, complicating their interpretability in studies of disease or aging. We extended existing techniques and constructed fully connected weighted graphs for groups of age-matched human immunodeficiency virus (HIV) positive (n = 67) and HIV negative (n = 77) individuals. We compared test-retest reliability of weighted versus unweighted metrics in an independent study of healthy individuals (n = 22) and found weighted measures to be more stable. We quantified 2 measures of node centrality (closeness centrality and eigenvector centrality) to capture the relative importance of individual nodes. We also quantified 1 measure of graph entropy (diversity) to measure the variability in connection strength (edge weights) at each node. HIV was primarily associated with differences in measures of centrality, and age was primarily associated with differences in diversity. HIV and age were associated with divergent measures when evaluated at the whole graph level, within individual functional networks, and at the level of individual nodes. Graph models may allow us to distinguish previously indistinguishable effects related to HIV and age on FC.