Robust Detection of Impaired Resting State Functional Connectivity Networks in Alzheimer's Disease Using Elastic Net Regularized Regression

The large number of multicollinear regional features that are provided by resting state (rs) fMRI data requires robust feature selection to uncover consistent networks of functional disconnection in Alzheimer's disease (AD). Here, we compared elastic net regularized and classical stepwise logistic regression in respect to consistency of feature selection and diagnostic accuracy using rs-fMRI data from four centers of the German resting-state initiative for diagnostic biomarkers (psymri.org), comprising 53 AD patients and 118 age and sex matched healthy controls. Using all possible pairs of correlations between the time series of rs-fMRI signal from 84 functionally defined brain regions as the initial set of predictor variables, we calculated accuracy of group discrimination and consistency of feature selection with bootstrap cross-validation. Mean areas under the receiver operating characteristic curves as measure of diagnostic accuracy were 0.70 in unregularized and 0.80 in regularized regression. Elastic net regression was insensitive to scanner effects and recovered a consistent network of functional connectivity decline in AD that encompassed parts of the dorsal default mode as well as brain regions involved in attention, executive control, and language processing. Stepwise logistic regression found no consistent network of AD related functional connectivity decline. Regularized regression has high potential to increase diagnostic accuracy and consistency of feature selection from multicollinear functional neuroimaging data in AD. Our findings suggest an extended network of functional alterations in AD, but the diagnostic accuracy of rs-fMRI in this multicenter setting did not reach the benchmark defined for a useful biomarker of AD

Association between composite scores of domain-specific cognitive functions and regional patterns of atrophy and functional connectivity in the Alzheimer's disease spectrum

Background: Cognitive decline has been found to be associated with gray matter atrophy and disruption of functional neural networks in Alzheimer’s disease (AD) in structural and functional imaging (fMRI) studies. Most previous studies have used single test scores of cognitive performance among monocentric cohorts. However, cognitive domain composite scores could be more reliable than single test scores due to the reduction of measurement error. Adopting a multicentric resting state fMRI (rs-fMRI) and cognitive domain approach, we provide a comprehensive description of the structural and functional correlates of the key cognitive domains of AD. Method: We analyzed MRI, rs-fMRI and cognitive domain score data of 490 participants from an interim baseline release of the multicenter DELCODE study cohort, including 54 people with AD, 86 with Mild Cognitive Impairment (MCI), 175 with Subjective Cognitive Decline (SCD), and 175 Healthy Controls (HC) in the ADspectrum. Resulting cognitive domain composite scores (executive, visuo-spatial, memory, working memory and language) from the DELCODE neuropsychological battery (DELCODE-NP), were previously derived using confirmatory factor analysis. Statistical analyses examined the differences between diagnostic groups, and the association of composite scores with regional atrophy and network-specific functional connectivity among the patient subgroup of SCD, MCI and AD. Result: Cognitive performance, atrophy patterns and functional connectivity significantly differed between diagnostic groups in the AD-spectrum. Regional gray matter atrophy was positively associated with visuospatial and other cognitive impairments among the patient subgroup in the AD-spectrum. Except for the visual network, patterns of network-specific resting-state functional connectivity were positively associated with distinct cognitive impairments among the patient subgroup in the AD-spectrum. Conclusion: Consistent associations between cognitive domain scores and both regional atrophy and networkspecific functional connectivity (except for the visual network), support the utility of a multicentric and cognitive domain approach towards explicating the relationship between imaging markers and cognition in the AD-spectrum

Cognitive Profiles of Amyotrophic Lateral Sclerosis Differ in Resting-State Functional Connectivity: An fMRI Study

BackgroundHalf of all amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTSD) patients are classified as cognitively impaired, of which 10% have frontotemporal dementia (FTD), and an additional 40% suffer from a frontotemporal syndrome not severe enough to be described as dementia (cognitively impaired/ALSci). As changes in cerebral function measured by resting-state magnet resonance imaging (rs-fMRI) are known in ALS, we investigated whether group differences in resting-state functional connectivity (RSFC) networks could be observed between ALS patients with different cognitive profiles against healthy controls (HC). Furthermore, we correlated cognition and motor functioning with network connectivity.MethodsHealthy controls, 69, and 97 ALS patients underwent functional MRI scanning and cognitive assessment. The ALS patients were categorized as non-impaired (ALSni; n = 68), cognitively impaired (ALSci; n = 21), and ALS-FTD (n = 8). Group differences in connectivity of the default mode network (DMN), motor network (MN), and ventral attention network (VAN) were investigated using a full-factorial model; correlations between global cognitive performance, shifting, and motor symptom severity were established using Pearson’s correlation.ResultsAt a liberal alpha level of uncorrected p < 0.005 and a cluster size exceeding 20 voxels, we found widespread decreases in functional connectivity in all three networks when comparing ALS patients to HC. Similar patterns of hypoconnectivity in the bilateral motor cortices and frontotemporal emerged when comparing the ALSci and ALS-FTD patients to those not cognitively impaired. Hyperconnectivity in the DMN temporal gyrus correlated with worse global cognition; moreover, hyperconnectivity in the VAN thalamus, insula, and putamen correlated with worse shifting ability. Better-preserved motor function correlated with higher MN connectivity. Only the motor-related effects prevailed at a more conservative significance level of pFDR< 0.001.ConclusionResting-state functional connectivity differs between cognitive profiles of ALS and is directly associated with clinical presentation, specifically with motor function, and cognitive shifting

Association of Cholinergic Basal Forebrain Volume and Functional Connectivity with Markers of Inflammatory Response in the Alzheimer's Disease Spectrum

BACKGROUND: Inflammation has been described as a key pathogenic event in Alzheimer's disease (AD), downstream of amyloid and tau pathology. Preclinical and clinical data suggest that the cholinergic basal forebrain may moderate inflammatory response to different pathologies. OBJECTIVE: To study the association of cholinergic basal forebrain volume and functional connectivity with measures of neuroinflammation in people from the AD spectrum. METHODS: We studied 261 cases from the DELCODE cohort, including people with subjective cognitive decline, mild cognitive impairment, AD dementia, first degree relatives, and healthy controls. Using Bayesian ANCOVA, we tested associations of MRI indices of cholinergic basal forebrain volume and functional connectivity with cerebrospinal fluid (CSF) levels of sTREM2 as a marker of microglia activation, and serum levels of complement C3. Using Bayesian elastic net regression, we determined associations between basal forebrain measures and a large inflammation marker panel from CSF and serum. RESULTS: We found anecdotal to moderate evidence in favor of the absence of an effect of basal forebrain volume and functional connectivity on CSF sTREM2 and serum C3 levels both in Aβ42/ptau-positive and negative cases. Bayesian elastic net regression identified several CSF and serum markers of inflammation that were associated with basal forebrain volume and functional connectivity. The effect sizes were moderate to small. CONCLUSION: Our data-driven analyses generate the hypothesis that cholinergic basal forebrain may be involved in the neuroinflammation response to Aβ42 and phospho-tau pathology in people from the AD spectrum. This hypothesis needs to be tested in independent samples

CSF total tau levels are associated with hippocampal novelty irrespective of hippocampal volume

We examined the association between cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease, neural novelty responses, and brain volume in predementia old age. Methods: We conducted a cross-sectional analysis of the observational, multicentric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) study. Seventy-six participants completed task functional magnetic resonance imaging and provided CSF (40 cognitively unimpaired, 21 experiencing subjective cognitive decline, and 15 with mild cognitive impairment). We assessed the correlation between CSF biomarkers and whole-brain functional magnetic resonance imaging novelty responses to scene images. Results: Total tau levels were specifically and negatively associated with novelty responses in the right amygdala and right hippocampus. Mediation analyses showed no evidence that these associations were dependent on the volume of hippocampus/amygdala. No relationship was found between phosphorylated-tau or Aβ42 levels and novelty responses. Discussion: Our data show that CSF levels of total tau are associated with anatomically specific reductions in novelty processing, which cannot be fully explained by atrophy

Association of latent factors of neuroinflammation with Alzheimer's disease pathology and longitudinal cognitive decline

INTRODUCTION: We investigated the association of inflammatory mechanisms with markers of Alzheimer's disease (AD) pathology and rates of cognitive decline in the AD spectrum. METHODS: We studied 296 cases from the Deutsches Zentrum für Neurodegenerative Erkrankungen Longitudinal Cognitive Impairment and Dementia Study (DELCODE) cohort, and an extension cohort of 276 cases of the Alzheimer's Disease Neuroimaging Initiative study. Using Bayesian confirmatory factor analysis, we constructed latent factors for synaptic integrity, microglia, cerebrovascular endothelial function, cytokine/chemokine, and complement components of the inflammatory response using a set of inflammatory markers in cerebrospinal fluid. RESULTS: We found strong evidence for an association of synaptic integrity, microglia response, and cerebrovascular endothelial function with a latent factor of AD pathology and with rates of cognitive decline. We found evidence against an association of complement and cytokine/chemokine factors with AD pathology and rates of cognitive decline. DISCUSSION: Latent factors provided access to directly unobservable components of the neuroinflammatory response and their association with AD pathology and cognitive decline