Highlights Cognitive impairment is a major comorbidity of temporal lobe epilepsy (TLE). Three discrete cognitive phenotypes of TLE are identified here. The phenotypes are linked to network, clinical, and socioeconomic characteristics. This taxonomy advances clinical and theoretical understanding of the cognitive complications of TLE.

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Neuroimaging biomarkers that distinguish between changes due to typical brain aging and Alzheimer’s disease are valuable for determining how much each contributes to cognitive decline. Supervised machine learning models can derive multi-variate patterns of brain change related to the two processes, including the SPARE-AD (Spatial Patterns of Atrophy for Recognition of Alzheimer’s Disease) and SPARE-BA (of Brain Aging) scores investigated herein. However, the substantial overlap between brain regions affected in the two processes confounds measuring them independently. We present a methodology, and associated results, toward disentangling the two. T1-weighted MRI scans of 4,054 participants (48–95 years) with Alzheimer’s disease, mild cognitive impairment, or cognitively normal diagnoses from the iSTAGING (Imaging-based coordinate SysTem for AGIng and NeurodeGenerative diseases) consortium were analyzed. Multiple sets of SPARE scores were investigated, in order to probe imaging signatures of certain clinically- or molecularly-defined sub-cohorts. First, a subset of clinical Alzheimer’s disease patients (n = 718) and age- and sex-matched cognitively normal adults (n = 718) were selected based purely on clinical diagnoses to train SPARE-BA1 (regression of age using cognitively normal individuals) and SPARE-AD1 (classification of cognitively normal versus Alzheimer’s disease) models. Second, analogous groups were selected based on clinical and molecular markers to train SPARE-BA2 and SPARE-AD2 models: amyloid-positive Alzheimer’s disease continuum group (n = 718; consisting of amyloid-positive Alzheimer’s disease, amyloid-positive mild cognitive impairment, and amyloid- and tau-positive cognitively normal individuals) and amyloid-negative cognitively normal group (n = 718). Finally, the combined group of the Alzheimer’s disease continuum and amyloid-negative cognitively normal individuals was used to train SPARE-BA3 model, with the intention to estimate brain age regardless of Alzheimer’s disease-related brain changes. The disentangled SPARE models, SPARE-AD2 and SPARE-BA3, derived brain patterns that were more specific to the two types of the brain changes. The correlation between the SPARE-BA Gap (SPARE-BA minus chronological age) and SPARE-AD was significantly reduced after the decoupling (r = 0.56 to 0.06). The correlation of disentangled SPARE-AD was non-inferior to amyloid- and tau-related measurements and to the number of APOE ε4 alleles but was lower to Alzheimer’s disease-related psychometric test scores, suggesting contribution of advanced brain aging to the latter. The disentangled SPARE-BA was consistently less correlated with Alzheimer’s disease-related clinical, molecular, and genetic variables. By employing conservative molecular diagnoses and introducing Alzheimer’s disease continuum cases to the SPARE-BA model training, we achieved more dissociable neuroanatomical biomarkers of typical brain aging and Alzheimer’s disease.

The Epilepsy Connectome Project examines the differences in connectomes between temporal lobe epilepsy (TLE) patients and healthy controls. Using these data, the effective connectivity of the default mode network (DMN) in patients with left TLE compared with healthy controls was investigated using spectral dynamic causal modeling (spDCM) of resting-state functional magnetic resonance imaging data. Group comparisons were made using two parametric empirical Bayes (PEB) models. The first level of each PEB model consisted of each participant's spDCM. Two different second-level models were constructed: the first comparing effective connectivity of the groups directly and the second using the Rey Auditory Verbal Learning Test (RAVLT) delayed free recall index as a covariate at the second level to assess effective connectivity controlling for the poor memory performance of left TLE patients. After an automated search over the nested parameter space and thresholding parameters at 95% posterior probability, both models revealed numerous connections in the DMN, which lead to inhibition of the left hippocampal formation. Left hippocampal formation inhibition may be an inherent result of the left temporal epileptogenic focus as memory differences were controlled for in one model and the same connections remained. An excitatory connection from the posterior cingulate cortex to the medial prefrontal cortex was found to be concomitant with left hippocampal formation inhibition in TLE patients when including RAVLT delayed free recall at the second level.

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The National Institutes of Health-sponsored Epilepsy Connectome Project aims to characterize connectivity changes in temporal lobe epilepsy (TLE) patients. The magnetic resonance imaging protocol follows that used in the Human Connectome Project, and includes 20 min of resting-state functional magnetic resonance imaging acquired at 3T using 8-band multiband imaging. Glasser parcellation atlas was combined with the Free-Surfer subcortical regions to generate resting-state functional connectivity (RSFC), amplitude of low-frequency fluctuations (ALFFs), and fractional ALFF measures. Seven different frequency ranges such as Slow-5 (0.01-0.027 Hz) and Slow-4 (0.027-0.073 Hz) were selected to compute these measures. The goal was to train machine learning classification models to discriminate TLE patients from healthy controls, and to determine which combination of the resting state measure and frequency range produced the best classification model. The samples included age-and gender-matched groups of 60 TLE patients and 59 healthy controls. Three traditional machine learning models were trained: support vector machine, linear discriminant analysis, and naive Bayes classifier. The highest classification accuracy was obtained using RSFC measures in the Slow-4 + 5 band (0.01-0.073 Hz) as features. Leave-one-out cross-validation accuracies were *83%, with receiver operating characteristic area-under-the-curve reaching close to 90%. Increased connectivity from right area posterior 9-46v in TLE patients contributed to the high accuracies. With increased sample sizes in the near future, better machine learning models will be trained not only to aid the diagnosis of TLE, but also as a tool to understand this brain disorder.