Multi-pathological contributions toward atrophy patterns in the Alzheimer's disease continuum.

Introduction: Heterogeneity in downstream atrophy in Alzheimer's disease (AD) is predominantly investigated in relation to pathological hallmarks (Aß, tau) and co-pathologies (cerebrovascular burden) independently. However, the proportional contribution of each pathology in determining atrophy pattern remains unclear. We assessed heterogeneity in atrophy using two recently conceptualized dimensions: typicality (typical AD atrophy at the center and deviant atypical atrophy on either extreme including limbic predominant to hippocampal sparing patterns) and severity (overall neurodegeneration spanning minimal atrophy to diffuse typical AD atrophy) in relation to Aß, tau, and cerebrovascular burden. Methods: We included 149 Aß + individuals on the AD continuum (cognitively normal, prodromal AD, AD dementia) and 163 Aß- cognitively normal individuals from the ADNI. We modeled heterogeneity in MRI-based atrophy with continuous-scales of typicality (ratio of hippocampus to cortical volume) and severity (total gray matter volume). Partial correlation models investigated the association of typicality/severity with (a) Aß (global Aß PET centiloid), tau (global tau PET SUVR), cerebrovascular (total white matter hypointensity volume) burden (b) four cognitive domains (memory, executive function, language, visuospatial composites). Using multiple regression, we assessed the association of each pathological burden and typicality/severity with cognition. Results: (a) In the AD continuum, typicality (r = -0.31, p < 0.001) and severity (r = -0.37, p < 0.001) were associated with tau burden after controlling for Aß, cerebrovascular burden and age. Findings imply greater tau pathology in limbic predominant atrophy and diffuse atrophy. (b) Typicality was associated with memory (r = 0.49, p < 0.001) and language scores (r = 0.19, p = 0.02). Severity was associated with memory (r = 0.26, p < 0.001), executive function (r = 0.24, p = 0.003) and language scores (r = 0.29, p < 0.001). Findings imply better cognitive performance in hippocampal sparing and minimal atrophy patterns. Beyond typicality/severity, tau burden but not Aß and cerebrovascular burden explained cognition. Conclusion: In the AD continuum, atrophy-based severity was more strongly associated with tau burden than typicality after accounting for Aß and cerebrovascular burden. Cognitive performance in memory, executive function and language domains was explained by typicality and/or severity and additionally tau pathology. Typicality and severity may differentially reflect burden arising from tau pathology but not Aß or cerebrovascular pathologies which need to be accounted for when investigating AD heterogeneity.

Predicting amyloid-PET status in a memory clinic: The role of the novel antero-posterior index and visual rating scales.

INTRODUCTION: Visual rating scales are increasingly utilized in clinical practice to assess atrophy in crucial brain regions among patients with cognitive disorders. However, their capacity to predict Alzheimer's disease (AD)-related pathology remains unexplored, particularly within a heterogeneous memory clinic population. This study aims to assess the accuracy of a novel visual rating assessment, the antero-posterior index (API) scale, in predicting amyloid-PET status. Furthermore, the study seeks to determine the optimal cohort-based cutoffs for the medial temporal atrophy (MTA) and parietal atrophy (PA) scales and to integrate the main visual rating scores into a predictive model. METHODS: We conducted a retrospective analysis of brain MRI and high-resolution TC scans from 153 patients with cognitive disorders who had undergone amyloid-PET assessments due to suspected AD pathology in a real-world memory clinic setting. RESULTS: The API scale (cutoff ≥1) exhibited the highest accuracy (AUC = 0.721) among the visual rating scales. The combination of the cohort-based MTA and PA threshold with the API yielded favorable accuracy (AUC = 0.787). Analyzing a cohort of MCI/Mild dementia patients below 75 years of age, the API scale and the predictive model improved their accuracy (AUC = 0.741 and 0.813, respectively), achieving excellent results in the early-onset population (AUC = 0.857 and 0.949, respectively). CONCLUSION: Our study emphasizes the significance of visual rating scales in predicting amyloid-PET positivity within a real-world memory clinic. Implementing the novel API scale, alongside our cohort-based MTA and PA thresholds, has the potential to substantially enhance diagnostic accuracy.

Differential response to donepezil in MRI subtypes of mild cognitive impairment.

BACKGROUND: Donepezil is an approved therapy for the treatment of Alzheimer's disease (AD). Results across clinical trials have been inconsistent, which may be explained by design-methodological issues, the pathophysiological heterogeneity of AD, and diversity of included study participants. We investigated whether response to donepezil differs in mild cognitive impaired (MCI) individuals demonstrating different magnetic resonance imaging (MRI) subtypes. METHODS: From the Hippocampus Study double-blind, randomized clinical trial, we included 173 MCI individuals (donepezil = 83; placebo = 90) with structural MRI data, at baseline and at clinical follow-up assessments (6-12-month). Efficacy outcomes were the annualized percentage change (APC) in hippocampal, ventricular, and total grey matter volumes, as well as in the AD cortical thickness signature. Participants were classified into MRI subtypes as typical AD, limbic-predominant, hippocampal-sparing, or minimal atrophy at baseline. We primarily applied a subtyping approach based on continuous scale of two subtyping dimensions. We also used the conventional categorical subtyping approach for comparison. RESULTS: Donepezil-treated MCI individuals showed slower atrophy rates compared to the placebo group, but only if they belonged to the minimal atrophy or hippocampal-sparing subtypes. Importantly, only the continuous subtyping approach, but not the conventional categorical approach, captured this differential response. CONCLUSIONS: Our data suggest that individuals with MCI, with hippocampal-sparing or minimal atrophy subtype, may have improved benefit from donepezil, as compared with MCI individuals with typical or limbic-predominant patterns of atrophy. The newly proposed continuous subtyping approach may have advantages compared to the conventional categorical approach. Future research is warranted to demonstrate the potential of subtype stratification for disease prognosis and response to treatment. TRIAL REGISTRATION: ClinicalTrial.gov NCT00403520. Submission Date: November 21, 2006.

Associations between different tau-PET patterns and longitudinal atrophy in the Alzheimer's disease continuum: biological and methodological perspectives from disease heterogeneity.

BACKGROUND: Subtypes and patterns are defined using tau-PET (tau pathology) and structural MRI (atrophy) in Alzheimer's disease (AD). However, the relationship between tau pathology and atrophy across these subtypes/patterns remains unclear. Therefore, we investigated the biological association between baseline tau-PET patterns and longitudinal atrophy in the AD continuum; and the methodological characterization of heterogeneity as a continuous phenomenon over the conventional discrete subgrouping. METHODS: In 366 individuals (amyloid-beta-positive cognitively normal, prodromal AD, AD dementia; amyloid-beta-negative cognitively normal), we examined the association between tau-PET patterns and longitudinal MRI. We modeled tau-PET patterns as a (a) continuous phenomenon with key dimensions: typicality and severity; and (b) discrete phenomenon by categorization into patterns: typical, limbic predominant, cortical predominant and minimal tau. Tau-PET patterns and associated longitudinal atrophy were contextualized within the Amyloid/Tau/Neurodegeneration (A/T/N) biomarker scheme. RESULTS: Localization and longitudinal atrophy change vary differentially across different tau-PET patterns in the AD continuum. Atrophy, a downstream event, did not always follow a topography akin to the corresponding tau-PET pattern. Further, heterogeneity as a continuous phenomenon offered an alternative and useful characterization, sharing correspondence with the conventional subgrouping. Tau-PET patterns also show differential A/T/N profiles. CONCLUSIONS: The site and rate of atrophy are different across the tau-PET patterns. Heterogeneity should be treated as a continuous, not discrete, phenomenon for greater sensitivity. Pattern-specific A/T/N profiles highlight differential multimodal interactions underlying heterogeneity. Therefore, tracking multimodal interactions among biomarkers longitudinally, modeling disease heterogeneity as a continuous phenomenon, and examining heterogeneity across the AD continuum could offer avenues for precision medicine.

MRI data-driven clustering reveals different subtypes of Dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is a neurodegenerative disorder with a wide heterogeneity of symptoms, which suggests the existence of different subtypes. We used data-driven analysis of magnetic resonance imaging (MRI) data to investigate DLB subtypes. We included 165 DLB from the Mayo Clinic and 3 centers from the European DLB consortium and performed a hierarchical cluster analysis to identify subtypes based on gray matter (GM) volumes. To characterize the subtypes, we used demographic and clinical data, as well as ß-amyloid, tau, and cerebrovascular biomarkers at baseline, and cognitive decline over three years. We identified 3 subtypes: an older subtype with reduced cortical GM volumes, worse cognition, and faster cognitive decline (n = 49, 30%); a subtype with low GM volumes in fronto-occipital regions (n = 76, 46%); and a subtype of younger patients with the highest cortical GM volumes, proportionally lower GM volumes in basal ganglia and the highest frequency of cognitive fluctuations (n = 40, 24%). This study shows the existence of MRI subtypes in DLB, which may have implications for clinical workout, research, and therapeutic decisions.

Genetic and environmental influence on resting state networks in young male and female adults: a cartographer mapping study.

We propose a unique, minimal assumption, approach based on variance analyses (compared with standard approaches) to investigate genetic influence on individual differences on the functional connectivity of the brain using 65 monozygotic and 65 dizygotic healthy young adult twin pairs' low-frequency oscillation resting state functional Magnetic Resonance Imaging (fMRI) data from the Human Connectome Project. Overall, we found high number of genetically-influenced functional (GIF) connections involving posterior to posterior brain regions (occipital/temporal/parietal) implicated in low-level processes such as vision, perception, motion, categorization, dorsal/ventral stream visuospatial, and long-term memory processes, as well as high number across midline brain regions (cingulate) implicated in attentional processes, and emotional responses to pain. We found low number of GIF connections involving anterior to anterior/posterior brain regions (frontofrontal > frontoparietal, frontotemporal, frontooccipital) implicated in high-level processes such as working memory, reasoning, emotional judgment, language, and action planning. We found very low number of GIF connections involving subcortical/noncortical networks such as basal ganglia, thalamus, brainstem, and cerebellum. In terms of sex-specific individual differences, individual differences in males were more genetically influenced while individual differences in females were more environmentally influenced in terms of the interplay of interactions of Task positive networks (brain regions involved in various task-oriented processes and attending to and interacting with environment), extended Default Mode Network (a central brain hub for various processes such as internal monitoring, rumination, and evaluation of self and others), primary sensorimotor systems (vision, audition, somatosensory, and motor systems), and subcortical/noncortical networks. There were >8.5-19.1 times more GIF connections in males than females. These preliminary (young adult cohort-specific) findings suggest that individual differences in the resting state brain may be more genetically influenced in males and more environmentally influenced in females; furthermore, standard approaches may suggest that it is more substantially nonadditive genetics, rather than additive genetics, which contribute to the differences in sex-specific individual differences based on this young adult (male and female) specific cohort. Finally, considering the preliminary cohort-specific results, based on standard approaches, environmental influences on individual differences may be substantially greater than that of genetics, for either sex, frontally and brain-wide. [Correction added on 10 May 2023, after first online publication: added: functional Magnetic Resonance Imaging. Added: individual differences in, twice. Added statement between furthermore … based on standard approaches.].

Perioperative ischaemic brain injury and plasma neurofilament light: a secondary analysis of two prospective cohort studies.

BACKGROUND: Ischaemic brain infarction can occur without acute neurological symptoms (covert strokes) or with symptoms (overt strokes), both associated with poor health outcomes. We conducted a pilot study of the incidence of preoperative and postoperative (intraoperative or postoperative) covert strokes, and explored the relationship of postoperative ischaemic brain injury to blood levels of neurofilament light, a biomarker of neuronal damage. METHODS: We analysed 101 preoperative (within 2 weeks of surgery) and 58 postoperative research MRIs on postoperative days 2-9 from two prospective cohorts collected at the University of Wisconsin (NCT01980511 and NCT03124303). Participants were aged >65 yr and undergoing non-intracranial, non-carotid surgery. RESULTS: Preoperative covert stroke was identified in 2/101 participants (2%; Bayesian 95% confidence interval [CI], 0.2-5.4). This rate was statistically different from the postoperative ischaemic brain injury rate of 7/58 (12%, 4.9-21.3%; P=0.01) based on postoperative imaging. However, in a smaller group of participants with paired imaging (n=30), we did not identify the same effect (P=0.67). Patients with postoperative brain injury had elevated peak neurofilament light levels (median [inter-quartile range], 2.34 [2.24-2.64] log10 pg ml-1) compared with those without (1.86 [1.48-2.21] log10 pg ml-1; P=0.025). Delirium severity scores were higher in those with postoperative brain injury (19 [17-21]) compared with those without (7 [4-12]; P=0.01). CONCLUSION: Although limited by a small sample size, these data suggest that preoperative covert stroke occurs more commonly than previously anticipated. Plasma neurofilament light is a potential screening biomarker for postoperative ischaemic brain injury.

The hippocampal sparing subtype of Alzheimer's disease assessed in neuropathology and in vivo tau positron emission tomography: a systematic review.

Neuropathology and neuroimaging studies have identified several subtypes of Alzheimer's disease (AD): hippocampal sparing AD, typical AD, and limbic predominant AD. An unresolved question is whether hippocampal sparing AD cases can present with neurofibrillary tangles (NFT) in association cortices while completely sparing the hippocampus. To address that question, we conducted a systematic review and performed original analyses on tau positron emission tomography (PET) data. We searched EMBASE, PubMed, and Web of Science databases until October 2022. We also implemented several methods for AD subtyping on tau PET to identify hippocampal sparing AD cases. Our findings show that seven out of the eight reviewed neuropathologic studies included cases at Braak stages IV or higher and therefore, could not identify hippocampal sparing cases with NFT completely sparing the hippocampus. In contrast, tau PET did identify AD participants with tracer retention in the association cortex while completely sparing the hippocampus. We conclude that tau PET can identify hippocampal sparing AD cases with NFT completely sparing the hippocampus. Based on the accumulating data, we suggest two possible pathways of tau spread: (1) a canonical pathway with early involvement of transentorhinal cortex and subsequent involvement of limbic regions and association cortices, and (2) a less common pathway that affects association cortices with limbic involvement observed at end stages of the disease or not at all.

Translingual neural stimulation affects resting-state functional connectivity in mild-moderate traumatic brain injury.

BACKGROUND AND PURPOSE: Traumatic brain injury (TBI) can lead to movement and balance deficits. In addition to physical therapy, brain-based neurorehabilitation efforts have begun to show promise in improving these deficits. The present study investigated the effectiveness of translingual neural stimulation (TLNS) on patients with mild-to-moderate TBI (mmTBI) and related brain connectivity using a resting-state functional connectivity (RSFC) approach. METHODS: Resting-state images with 5-min on GE750 3T scanner were acquired from nine participants with mmTBI. Paired t-test was used for calculating changes in RSFC and behavioral scores before and after the TLNS intervention. The balance and movement performances related to mmTBI were evaluated by Sensory Organization Test (SOT) and Dynamic Gait Index (DGI). RESULTS: Compared to pre-TLNS intervention, significant behavioral changes in SOT and DGI were observed. The analysis revealed increased RSFC between the left postcentral gyrus and left inferior parietal lobule and left Brodmann Area 40, as well as the increased RSFC between the right culmen and right declive, indicating changes due to TLNS treatment. However, there were no correlations between the sensory/somatomotor (or visual or cerebellar) network and SOT/DGI behavioral performance. CONCLUSIONS: Although the limited sample size may have led to lack of significant correlations with functional assessments, these results provide preliminary evidence that TLNS in conjunction with physical therapy can induce brain plasticity in TBI patients with balance and movement deficits.

Neuropathologic Features of Antemortem Atrophy-Based Subtypes of Alzheimer Disease.

OBJECTIVES: To investigate whether antemortem MRI-based atrophy subtypes of Alzheimer's disease (AD) differ in neuropathological features and comorbid non-AD pathologies at postmortem. METHODS: From the ADNI cohort, we included individuals with: antemortem MRI evaluating brain atrophy within 2y before death; antemortem diagnosis of AD dementia/mild cognitive impairment; postmortem-confirmed AD neuropathologic change. Antemortem atrophy subtypes were modeled as continuous phenomena based on a recent conceptual framework: typicality (spanning limbic-predominant AD to hippocampal-sparing AD) and severity (spanning typical AD to minimal atrophy AD). Postmortem neuropathological evaluation included AD hallmarks, amyloid-beta and tau as well as non-AD pathologies, alpha-synuclein and TAR DNA-binding protein-43 (TDP-43). We also investigated the overall concomitance across these pathologies. Partial correlations assessed the associations between antemortem atrophy subtypes and postmortem neuropathological outcomes. RESULTS: In 31 individuals (26 AD dementia/5 mild cognitive impaired, mean age=80y, 26% females), antemortem typicality was significantly negatively associated with neuropathological features, including amyloid-beta (rho=-0.39 overall), tau (rho=-0.38 regionally), alpha-synuclein (rho=-0.39 regionally), TDP-43 (rho=-0.49 overall), and concomitance of pathologies (rho=-0.59 regionally). Limbic-predominant AD was associated with higher Thal phase, neuritic plaque density, and presence of TDP-43 compared to hippocampal-sparing AD. Regionally, limbic-predominant AD showed higher presence of tau and alpha-synuclein pathologies in medial temporal structures, higher presence of TDP-43 and concomitance of pathologies subcortically/cortically compared to hippocampal-sparing AD. Antemortem severity was significantly negatively associated with concomitance of pathologies (rho=-0.43 regionally), such that typical AD showed higher concomitance of pathologies than minimal atrophy AD. DISCUSSION: We provide a direct antemortem-to-postmortem validation, highlighting the importance of understanding atrophy-based heterogeneity in AD relative to AD and non-AD pathologies. We suggest that: (a) typicality and severity in atrophy reflect differential aspects of susceptibility of the brain to AD and non-AD pathologies; (b) limbic-predominant AD and typical AD subtypes share similar biological pathways, making them more vulnerable to AD and non-AD pathologies compared to hippocampal-sparing AD, which may follow a different biological pathway. Our findings provide a deeper understanding of associations of atrophy subtypes in AD with different pathologies, enhancing prevailing knowledge of biological heterogeneity in AD and could contribute towards tracking disease progression and designing clinical trials in the future.

Assessment of Tau Pathology as Measured by 18F-THK5317 and 18F-Flortaucipir PET and Their Relation to Brain Atrophy and Cognition in Alzheimer's Disease.

BACKGROUND: In Alzheimer's disease (AD), the abnormal aggregation of hyperphosphorylated tau leads to synaptic dysfunction and neurodegeneration. Recently developed tau PET imaging tracers are candidate biomarkers for diagnosis and staging of AD. OBJECTIVE: We aimed to investigate the discriminative ability of 18F-THK5317 and 18F-flortaucipir tracers and brain atrophy at different stages of AD, and their respective associations with cognition. METHODS: Two cohorts, each including 29 participants (healthy controls [HC], prodromal AD, and AD dementia patients), underwent 18F-THK5317 or 18F-flortaucipir PET, T1-weighted MRI, and neuropsychological assessment. For each subject, we quantified regional 18F-THK5317 and 18F-flortaucipir uptake within six bilateral and two composite regions of interest. We assessed global brain atrophy for each individual by quantifying the brain volume index, a measure of brain volume-to-cerebrospinal fluid ratio. We then quantified the discriminative ability of regional 18F-THK5317, 18F-flortaucipir, and brain volume index between diagnostic groups, and their associations with cognition in patients. RESULTS: Both 18F-THK5317 and 18F-flortaucipir outperformed global brain atrophy in discriminating between HC and both prodromal AD and AD dementia groups. 18F-THK5317 provided the highest discriminative ability between HC and prodromal AD groups. 18F-flortaucipir performed best at discriminating between prodromal and dementia stages of AD. Across all patients, both tau tracers were predictive of RAVL learning, but only 18F-flortaucipir predicted MMSE. CONCLUSION: Our results warrant further in vivo head-to-head and antemortem-postmortem evaluations. These validation studies are needed to select tracers with high clinical validity as biomarkers for early diagnosis, prognosis, and disease staging, which will facilitate their incorporation in clinical practice and therapeutic trials.

Functional Connectivity and Compensation of Phonemic Fluency in Aging.

Neural compensatory mechanisms associated with broad cognitive abilities have been studied. However, those associated with specific cognitive subdomains (e.g., verbal fluency) remain to be investigated in healthy aging. Here, we delineate: (a) neural substrates of verbal (phonemic) fluency, and (b) compensatory mechanisms mediating the association between these neural substrates and phonemic fluency. We analyzed resting-state functional magnetic resonance imaging from 133 right-handed, cognitively normal individuals who underwent the Controlled Oral Word Association Test (COWAT) to record their phonemic fluency. We evaluated functional connectivity in an established and extended language network comprising Wernicke, Broca, thalamic and anti-correlated modules. (a) We conducted voxel-wise multiple linear regression to identify the brain areas associated with phonemic fluency. (b) We used mediation effects of cognitive reserve, measured by the Wechsler Adult Intelligence Scale-Information subtest, upon the association between functional connectivity and phonemic fluency tested to investigate compensation. We found that: (a) Greater functional connectivity between the Wernicke module and brain areas within the anti-correlated module was associated with better performance in phonemic fluency, (b) Cognitive reserve was an unlikely mediator in younger adults. In contrast, cognitive reserve was a partial mediator of the association between functional connectivity and phonemic fluency in older adults, likely representing compensation to counter the effect of aging. We conclude that in healthy aging, higher performance in phonemic fluency at older ages could be attributed to greater functional connectivity partially facilitated by higher cognitive reserve, presumably reflecting compensatory mechanisms to minimize the effect of aging.

Cortical Networks Underpinning Compensation of Verbal Fluency in Normal Aging.

Elucidating compensatory mechanisms underpinning phonemic fluency (PF) may help to minimize its decline due to normal aging or neurodegenerative diseases. We investigated cortical brain networks potentially underpinning compensation of age-related differences in PF. Using graph theory, we constructed networks from measures of thickness for PF, semantic, and executive-visuospatial cortical networks. A total of 267 cognitively healthy individuals were divided into younger age (YA, 38-58 years) and older age (OA, 59-79 years) groups with low performance (LP) and high performance (HP) in PF: YA-LP, YA-HP, OA-LP, OA-HP. We found that the same pattern of reduced efficiency and increased transitivity was associated with both HP (compensation) and OA (aberrant network organization) in the PF and semantic cortical networks. When compared with the OA-LP group, the higher PF performance in the OA-HP group was associated with more segregated PF and semantic cortical networks, greater participation of frontal nodes, and stronger correlations within the PF cortical network. We conclude that more segregated cortical networks with strong involvement of frontal nodes seemed to allow older adults to maintain their high PF performance. Nodal analyses and measures of strength were helpful to disentangle compensation from the aberrant network organization associated with OA.

Comparison of subtyping methods for neuroimaging studies in Alzheimer's disease: a call for harmonization.

Biological subtypes in Alzheimer's disease, originally identified on neuropathological data, have been translated to in vivo biomarkers such as structural magnetic resonance imaging and positron emission tomography, to disentangle the heterogeneity within Alzheimer's disease. Although there is methodological variability across studies, comparable characteristics of subtypes are reported at the group level. In this study, we investigated whether group-level similarities translate to individual-level agreement across subtyping methods, in a head-to-head context. We compared five previously published subtyping methods. Firstly, we validated the subtyping methods in 89 amyloid-beta positive Alzheimer's disease dementia patients (reference group: 70 amyloid-beta negative healthy individuals) using structural magnetic resonance imaging. Secondly, we extended and applied the subtyping methods to 53 amyloid-beta positive prodromal Alzheimer's disease and 30 amyloid-beta positive Alzheimer's disease dementia patients (reference group: 200 amyloid-beta negative healthy individuals) using structural magnetic resonance imaging and tau positron emission tomography. Subtyping methods were implemented as outlined in each original study. Group-level and individual-level comparisons across methods were performed. Each individual subtyping method was replicated, and the proof-of-concept was established. At the group level, all methods captured subtypes with similar patterns of demographic and clinical characteristics, and with similar cortical thinning and tau positron emission tomography uptake patterns. However, at the individual level, large disagreements were found in subtype assignments. Although characteristics of subtypes are comparable at the group level, there is a large disagreement at the individual level across subtyping methods. Therefore, there is an urgent need for consensus and harmonization across subtyping methods. We call for the establishment of an open benchmarking framework to overcome this problem.

Cohort study into the neural correlates of postoperative delirium: the role of connectivity and slow-wave activity.

BACKGROUND: Delirium frequently affects older patients, increasing morbidity and mortality; however, the pathogenesis is poorly understood. Herein, we tested the cognitive disintegration model, which proposes that a breakdown in frontoparietal connectivity, provoked by increased slow-wave activity (SWA), causes delirium. METHODS: We recruited 70 surgical patients to have preoperative and postoperative cognitive testing, EEG, blood biomarkers, and preoperative MRI. To provide evidence for causality, any putative mechanism had to differentiate on the diagnosis of delirium; change proportionally to delirium severity; and correlate with a known precipitant for delirium, inflammation. Analyses were adjusted for multiple corrections (MCs) where appropriate. RESULTS: In the preoperative period, subjects who subsequently incurred postoperative delirium had higher alpha power, increased alpha band connectivity (MC P<0.05), but impaired structural connectivity (increased radial diffusivity; MC P<0.05) on diffusion tensor imaging. These connectivity effects were correlated (r2=0.491; P=0.0012). Postoperatively, local SWA over frontal cortex was insufficient to cause delirium. Rather, delirium was associated with increased SWA involving occipitoparietal and frontal cortex, with an accompanying breakdown in functional connectivity. Changes in connectivity correlated with SWA (r2=0.257; P<0.0001), delirium severity rating (r2=0.195; P<0.001), interleukin 10 (r2=0.152; P=0.008), and monocyte chemoattractant protein 1 (r2=0.253; P<0.001). CONCLUSIONS: Whilst frontal SWA occurs in all postoperative patients, delirium results when SWA progresses to involve posterior brain regions, with an associated reduction in connectivity in most subjects. Modifying SWA and connectivity may offer a novel therapeutic approach for delirium. CLINICAL TRIAL REGISTRATION: NCT03124303, NCT02926417.

Brain aging in temporal lobe epilepsy: Chronological, structural, and functional.

The association of epilepsy with structural brain changes and cognitive abnormalities in midlife has raised concern regarding the possibility of future accelerated brain and cognitive aging and increased risk of later life neurocognitive disorders. To address this issue we examined age-related processes in both structural and functional neuroimaging among individuals with temporal lobe epilepsy (TLE, N = 104) who were participants in the Epilepsy Connectome Project (ECP). Support vector regression (SVR) models were trained from 151 healthy controls and used to predict TLE patients' brain ages. It was found that TLE patients on average have both older structural (+6.6 years) and functional (+8.3 years) brain ages compared to healthy controls. Accelerated functional brain age (functional - chronological age) was mildly correlated (corrected P = 0.07) with complex partial seizure frequency and the number of anti-epileptic drug intake. Functional brain age was a significant correlate of declining cognition (fluid abilities) and partially mediated chronological age-fluid cognition relationships. Chronological age was the only positive predictor of crystallized cognition. Accelerated aging is evident not only in the structural brains of patients with TLE, but also in their functional brains. Understanding the causes of accelerated brain aging in TLE will be clinically important in order to potentially prevent or mitigate their cognitive deficits.

Graph Theory Analysis of Functional Connectivity Combined with Machine Learning Approaches Demonstrates Widespread Network Differences and Predicts Clinical Variables in Temporal Lobe Epilepsy.

Understanding how global brain networks are affected in epilepsy may elucidate the pathogenesis of seizures and its accompanying neurobehavioral comorbidities. We investigated functional changes within neural networks in temporal lobe epilepsy (TLE) using graph theory analysis of resting-state connectivity. Twenty-seven TLE presurgical patients (age 41.0 ± 12.3 years) and 85 age, gender, and handedness equivalent healthy controls (HCs; age 39.7 ± 16.9 years) were enrolled. Eyes-closed resting-state functional magnetic resonance image scans were analyzed to compare network properties and functional connectivity (FC) changes. TLE subjects showed significantly higher global efficiency, lower clustering coefficient ratio, and lower shortest path lengths ratio than HCs, as an indication of a more synchronized, yet less segregated network. A trend of functional reorganization with a shift of network hubs to the contralateral hemisphere was noted in TLE subjects. Support vector machine (SVM) with linear kernel was trained to separate between neural networks in TLE and HC subjects based on graph measurements. SVM analysis allowed separation between TLE and HC networks with 80.66% accuracy using eight features of graph measurements. Support vector regression (SVR) was used to predict neurocognitive performance from graph metrics. An SVR linear predictor showed discriminative prediction accuracy for four key neurocognitive variables in TLE (absolute R value range: 0.61-0.75). Despite TLE, our results showed both local and global network topology differences that reflect widespread alterations in FC in TLE. Network differences are discriminative between TLE and HCs using data-driven analysis and predicted severity of neurocognitive sequelae in our cohort.

Rethinking Measures of Functional Connectivity via Feature Extraction.

Functional magnetic resonance imaging (fMRI)-based functional connectivity (FC) commonly characterizes the functional connections in the brain. Conventional quantification of FC by Pearson's correlation captures linear, time-domain dependencies among blood-oxygen-level-dependent (BOLD) signals. We examined measures to quantify FC by investigating: (i) Is Pearson's correlation sufficient to characterize FC? (ii) Can alternative measures better quantify FC? (iii) What are the implications of using alternative FC measures? FMRI analysis in healthy adult population suggested that: (i) Pearson's correlation cannot comprehensively capture BOLD inter-dependencies. (ii) Eight alternative FC measures were similarly consistent between task and resting-state fMRI, improved age-based classification and provided better association with behavioral outcomes. (iii) Formulated hypotheses were: first, in lieu of Pearson's correlation, an augmented, composite and multi-metric definition of FC is more appropriate; second, canonical large-scale brain networks may depend on the chosen FC measure. A thorough notion of FC promises better understanding of variations within a given population.