Integrative genomic and spatial transcriptomic analysis elucidates the oligodendrocyte-mediated etiology of epileptic cortical thinning.

It is controversial whether epilepsy is a static or progressive disease. Evidence of progressive gray matter loss in epilepsy would support early diagnosis, rapid treatment, and early referral for surgical interventions. To demonstrate progressive cortical thinning in patients with focal epilepsy distinct from cortical thinning associated with normal aging. A case-control neuroimaging study was conducted from August 3, 2004, to January 26, 2016, among 190 patients with focal epilepsy at a tertiary epilepsy referral center (epilepsy data) and 3 independent comparison cohorts matched for age and sex (healthy volunteer data; n = 141). Two or more high-resolution T1-weighted magnetic resonance imaging scans at least 6 months apart (mean [SD] interval, 2.5 [1.6] years). Global and vertexwise rate of progressive cortical thinning. A total of 190 people with focal epilepsy (99 women and 91 men; mean [SD] age, 36 [11] years; 396 magnetic resonance imaging scans) were compared with 141 healthy volunteers (76 women and 65 men; mean [SD] age, 35 [17] years; 282 magnetic resonance imaging scans). Widespread highly significant progressive cortical thinning exceeding normal aging effects, mainly involving the bilateral temporal lobes, medial parietal and occipital cortices, pericentral gyri, and opercula, was seen in 146 individuals with epilepsy (76.8%; 95% CI, 58%-95%). The mean (SD) annualized rate of global cortical thinning in patients with epilepsy was twice the rate of age-associated thinning observed in healthy volunteers (0.024 [0.061] vs 0.011 [0.029] mm/y; P = .01). Progression was most pronounced in adults older than 55 years and during the first 5 years after the onset of seizures. Areas of accelerated cortical thinning were detected in patients with early onset of epilepsy and in patients with hippocampal sclerosis. Accelerated thinning was not associated with seizure frequency, history of generalized seizures, or antiepileptic drug load and did not differ between patients with or without ongoing seizures. Progressive atrophy in temporal (n = 101) and frontal (n = 28) lobe epilepsy was most pronounced ipsilaterally to the epileptic focus but also affected a widespread area extending beyond the focus and commonly affected the contralateral hemisphere. For patients with temporal lobe epilepsy, accelerated cortical thinning was observed within areas structurally connected with the ipsilateral hippocampus. Widespread progressive cortical thinning exceeding that seen with normal aging may occur in patients with focal epilepsy. These findings appear to highlight the need to develop epilepsy disease-modifying treatments to disrupt or slow ongoing atrophy. Longitudinal cortical thickness measurements may have the potential to serve as biomarkers for such studies.

Progressive Cortical Thinning in Patients With Focal EpilepsyGalovic M, van Dooren VQH, Postma T, et al. JAMA Neurol. 2019. doi: 0.1001/jamaneurol.2019.1708.Importance:It is controversial whether epilepsy is a static or progressive disease. Evidence of progressive gray matter loss in epilepsy would support early diagnosis, rapid treatment, and early referral for surgical interventions.Objective:To demonstrate progressive cortical thinning in patients with focal epilepsy distinct from cortical thinning associated with normal aging.Design, Setting, and Participants:A case–control neuroimaging study was conducted from August 3, 2004, to January 26, 2016, among 190 patients with focal epilepsy at a tertiary epilepsy referral center (epilepsy data) and 3 independent comparison cohorts matched for age and sex (healthy volunteer data; n = 141).Exposures:Two or more high-resolution T1-weighted magnetic resonance imaging scans at least 6 months apart (mean [SD] interval, 2.5 [1.6] years).Main Outcomes and Measures:Global and vertexwise rate of progressive cortical thinning.Results:A total of 190 people with focal epilepsy (99 women and 91 men; mean [SD] age, 36 [11] years; 396 magnetic resonance imaging scans) were compared with 141 healthy volunteers (76 women and 65 men; mean [SD] age, 35 [17] years; 282 magnetic resonance imaging scans). Widespread highly significant progressive cortical thinning exceeding normal aging effects, mainly involving the bilateral temporal lobes, medial parietal and occipital cortices, pericentral gyri, and opercula, was seen in 146 individuals with epilepsy (76.8%; 95% CI, 58%-95%). The mean (SD) annualized rate of global cortical thinning in patients with epilepsy was twice the rate of age-associated thinning observed in healthy volunteers (0.024 [0.061] vs 0.011 [0.029] mm/y; P = .01). Progression was most pronounced in adults older than 55 years and during the first 5 years after the onset of seizures. Areas of accelerated cortical thinning were detected in patients with early onset of epilepsy and in patients with hippocampal sclerosis. Accelerated thinning was not associated with seizure frequency, history of generalized seizures, or antiepileptic drug load and did not differ between patients with or without ongoing seizures. Progressive atrophy in temporal (n = 101) and frontal (n = 28) lobe epilepsy was most pronounced ipsilaterally to the epileptic focus but also affected a widespread area extending beyond the focus and commonly affected the contralateral hemisphere. For patients with temporal lobe epilepsy, accelerated cortical thinning was observed within areas structurally connected with the ipsilateral hippocampus.Conclusions and Relevance:Widespread progressive cortical thinning exceeding that seen with normal aging may occur in patients with focal epilepsy. These findings appear to highlight the need to develop epilepsy disease-modifying treatments to disrupt or slow ongoing atrophy. Longitudinal cortical thickness measurements may have the potential to serve as biomarkers for such studies.

BackgroundLoss of cortical volume in frontotemporal regions has been reported in patients with schizophrenia and their relatives. Cortical area and thickness are determined by different genetic processes, and measuring these parameters separately may clarify disturbances in corticogenesis relevant to schizophrenia. Our study also explored clinical and cognitive correlates of these parameters.MethodsThirty-seven patients with first-episode psychosis (34 schizophrenia, 3 schizoaffective disorder) and 38 healthy control subjects matched for age and sex took part in the study. Imaging was performed on an magnetic resonance imaging 1.5-T scanner. Area and thickness of the frontotemporal cortex were measured using a surface-based morphometry method (Freesurfer). All subjects underwent neuropsychologic testing that included measures of premorbid and current IQ, working and verbal memory, and executive function.ResultsReductions in cortical area, more marked in the temporal cortex, were present in patients. Overall frontotemporal cortical thickness did not differ between groups, although regional thinning of the right superior temporal region was observed in patients. There was a significant association of both premorbid IQ and IQ at disease onset with area, but not thickness, of the frontotemporal cortex, and working memory span was associated with area of the frontal cortex. These associations remained significant when only patients with schizophrenia were considered.ConclusionsOur results suggest an early disruption of corticogenesis in schizophrenia, although the effect of subsequent environmental factors cannot be excluded. In addition, cortical abnormalities are subject to regional variations and differ from those present in neurodegenerative diseases.

Febrile seizures reduce hippocampal subfield volumes but not cortical thickness in children with focal onset seizures

Integrating chromatin accessibility and gene expression data into context-specific regulatory networks can provide better regulatory categories for heritability enrichment and relevant tissue identification.

ObjectiveExamine whether cortical thinning is a disease-specific phenomenon across the spectrum of motor neuron diseases in relation to upper motor neuron (UMN) involvement.Methods153 patients (112 amyotrophic lateral sclerosis (ALS), 19...

BackgroundThe thresholds of plasma β‐amyloid(Aβ)42/Aβ40 and phosphorylated Tau181 (p‐Tau181) to detect Alzheimer’s disease (AD) pathophysiology in Chinese community older adults have not been well established. Besides, it is still unclear about the role of astrocyte reactivity in Aβ plaque deposition, tau tangle aggregation, and neurodegeneration in AD.MethodIn this study, we analyzed plasma Aβ42/Aβ40, p‐Tau181, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) using the Simoa platform in 470 Chinese older participants. Among them, 301, 195, and 70 individuals had MRI, Aβ PET, and tau PET images. The receiver operating characteristic curve analysis (Youden index) was conducted to define plasma Aβ42/Aβ40 (A) and p‐Tau181 (T) thresholds as £0.0609 and ³2.418 by comparing Aβ‐PET negative cognitively individuals and Aβ‐PET positive cognitively impaired patients. We compared plasma GFAP, Aβ plaque, tau tangle, plasma NfL, hippocampal volume, and temporal‐metaROI cortical thickness between different plasma A/T profiles and studied their association with each other using general linear models, controlling for age, sex, APOE‐ε4, and clinical diagnosis.ResultWe found that plasma A+/T+ individuals had the most astrocyte reactivity, Aβ plaque, tau tangle, axonal degeneration, hippocampal atrophy, and temporal‐metaROI cortical thinning (Figure 1). Lower plasma Aβ42/Aβ40 (p < 0.001) and higher plasma p‐Tau181 concentrations (p < 0.001) were associated with higher Aβ PET SUVR (Figure 2). Besides, higher plasma p‐Tau181 (p < 0.001) and plasma GFAP (p = 0.015) concentrations were associated with higher temporal‐metaROI tau PET SUVR, and they also showed significant interactive relation (p < 0.001) with higher tau PET SUVR (Figure 2). Higher plasma GFAP (p = 0.012) was related to more shrinking in temporal‐metaROI cortical thickness and showed significant interaction with plasma Aβ42/Aβ40 (p = 0.042) and plasma p‐Tau181 (p < 0.001) at predicting temporal‐metaROI cortical thinning (Figure 3). The voxel‐wise imaging analysis replicated these findings.ConclusionThese findings offer significant reference for using plasma biomarkers to detect AD in the Chinese community older population and provide novel insights into understanding how astrocyte reactivity affects cortical tau aggregation and thickness thinning in AD. This study emphasizes the importance of controlling reactive astrogliosis to prevent AD progression.

Cholinergic basal forebrain atrophy accelerates cognitive decline via cortical thinning: The moderating role of amyloid-β pathology in preclinical Alzheimer’s disease

Early dose-dependent cortical thinning of the femoral neck in anal cancer patients treated with pelvic radiation therapy

Advances in MRI acquisition and data processing have become important for revealing brain structural changes. Previous studies have reported widespread structural brain abnormalities and cortical thinning in patients with temporal lobe epilepsy (TLE), as the most common form of focal epilepsy. In this research, healthy control cases (n = 20) and patients with left TLE (n = 19) and right TLE (n = 14) were recruited, all underwent 3.0T MRI with magnetization-prepared rapid gradient echo sequence to acquire T1-weighted images. Morphometric alterations in gray matter were identified using voxel-based morphometry (VBM). Volumetric alterations in subcortical structures and cortical thinning were also determined. Patients with left TLE demonstrated more prevailing and widespread changes in subcortical volumes and cortical thickness than right TLE, mainly in the left hemisphere, compared to the healthy group. Both VBM analysis and subcortical volumetry detected significant hippocampal atrophy in ipsilateral compared to contralateral side in TLE group. In addition to hippocampus, subcortical volumetry found the thalamus and pallidum bilaterally vulnerable to the TLE. Furthermore, the TLE patients underwent cortical thinning beyond the temporal lobe, affecting gray matter cortices in frontal, parietal, and occipital lobes in the majority of patients, more prevalently for left TLE cases. Exploiting volume changes in individual patients in the hippocampus alone led to 63.6% sensitivity and 100% specificity for lateralization of TLE. Alteration of gray matter volumes in subcortical regions and neocortical temporal structures and also cortical gray matter thickness were evidenced as common effects of epileptogenicity, as manifested by the majority of cases in this study.

Despite evidence that clozapine may be neuroprotective, there are few longitudinal magnetic resonance imaging (MRI) studies that have specifically explored an association between commencement of clozapine treatment for schizophrenia and changes in regional brain volume or cortical thickness. A total of 33 patients with treatment-resistant schizophrenia and 31 healthy controls matched for age and gender underwent structural MRI brain scans at baseline and 6-9 months after commencing clozapine. MRI images were analyzed using SIENA (Structural Image Evaluation, using Normalization, of Atrophy) and FreeSurfer to investigate changes over time in brain volume and cortical thickness respectively. Significantly greater reductions in volume were detected in the right and left medial prefrontal cortex and in the periventricular area in the patient group regardless of treatment response. Widespread further cortical thinning was observed in patients compared with healthy controls. The majority of patients improved symptomatically and functionally over the study period, and patients who improved were more likely to have less cortical thinning of the left medial frontal cortex and the right middle temporal cortex. These findings demonstrate on-going reductions in brain volume and progressive cortical thinning in patients with schizophrenia who are switched to clozapine treatment. It is possible that this gray matter loss reflects a progressive disease process irrespective of medication use or that it is contributed to by switching to clozapine treatment. The clinical improvement of most patients indicates that antipsychotic-related gray matter volume loss may not necessarily be harmful or reflect neurotoxicity.

Longitudinal trajectory of clinical insight and covariation with cortical thickness in first-episode psychosis

To explore dynamic alterations of cortical thickness before and after successful anterior temporal lobectomy (ATL) in patients with unilateral mesial temporal lobe epilepsy (mTLE). High-resolution T1-weighted MRI was obtained in 28 mTLE patients who achieved seizure freedom for at least 24months after ATL and 29 healthy controls. Patients were scanned at five timepoints, including before surgery, 3, 6, 12 and 24months after surgery. Preoperative cortical thickness of mTLE patients were compared with healthy controls. Dynamic alterations of cortical thickness before and after surgery were compared among five scans using linear mixed models. Patients with mTLE showed cortical thinning pre-surgically in ipsilateral entorhinal cortex, parahippocampal gyrus, inferior parietal cortex, lateral occipital cortex; contralateral pericalcarine cortex (PCC); and bilateral caudal middle frontal gyrus (cMFG), paracentral lobule, precentral gyrus (PCG), superior parietal cortex. Cortical thickening was observed in contralateral rostral anterior cingulate cortex (rACC). Patients showed postsurgical cortical thinning in ipsilateral temporal lobe, fusiform gyrus, caudal anterior cingulate cortex, lingual gyrus, and insula. Ipsilateral cMFG, PCC, and contralateral PCG showed significant cortical thickening after surgery. In addition, contralateral rACC showed cortical thickening at 3 months follow-up, however, with obvious cortical thinning at 24months follow-up. Mesial temporal lobe epilepsy patients showed widespread cortical thinning before and after anterior temporal lobectomy. Progressive cortical thinning mainly existed in neighboring regions of resection. Postoperative cortical thickening may indicate cortical remodeling after successful surgery.

815 POSTER Androgen deprivation for cytoreduction prior to interstitial brachytherapy for early-stage prostate cancer is associated with an increased risk of urinary morbidity

Thinner cortex in the frontal lobes in mentally disordered offenders