Attention-deficit hyperactivity disorder symptoms and brain morphology: Addressing potential selection bias with inverse probability weighting.

The goal of this study was to examine what happens to established associations between attention deficit hyperactivity disorder (ADHD) symptoms and cortical surface and thickness regions once we apply inverse probability of censoring weighting (IPCW) to address potential selection bias. Moreover, we illustrate how different factors that predict participation contribute to potential selection bias. Participants were 9- to 11-year-old children from the Generation R study (N = 2707). Cortical area and thickness were measured with magnetic resonance imaging (MRI) and ADHD symptoms with the Child Behavior Checklist. We examined how associations between ADHD symptoms and brain morphology change when we weight our sample back to either follow-up (ages 9-11), baseline (cohort at birth), or eligible (population of Rotterdam at time of recruitment). Weights were derived using IPCW or raking and missing predictors of participation used to estimate weights were imputed. Weighting analyses to baseline and eligible increased beta coefficients for the middle temporal gyrus surface area, as well as fusiform gyrus cortical thickness. Alternatively, the beta coefficient for the rostral anterior cingulate decreased. Removing one group of variables used for estimating weights resulted in the weighted regression coefficient moving closer to the unweighted regression coefficient. In addition, we found considerably different beta coefficients for most surface area regions and all thickness measures when we did not impute missing covariate data. Our findings highlight the importance of using inverse probability weighting (IPW) in the neuroimaging field, especially in the context of mental health-related research. We found that including all variables related to exposure-outcome in the IPW model and combining IPW with multiple imputations can help reduce bias. We encourage future psychiatric neuroimaging studies to define their target population, collect information on eligible but not included participants and use inverse probability of censoring weighting (IPCW) to reduce selection bias.

Remote Associations Between Tau and Cortical Amyloid-ß Are Stage-Dependent.

Background: Histopathologic studies of Alzheimer's disease (AD) suggest that extracellular amyloid-ß (Aß) plaques promote the spread of neurofibrillary tau tangles. However, these two proteinopathies initiate in spatially distinct brain regions, so how they interact during AD progression is unclear. Objective: In this study, we utilized Aß and tau positron emission tomography (PET) scans from 572 older subjects (476 healthy controls (HC), 14 with mild cognitive impairment (MCI), 82 with mild AD), at varying stages of the disease, to investigate to what degree tau is associated with cortical Aß deposition. Methods: Using multiple linear regression models and a pseudo-longitudinal ordering technique, we investigated remote tau-Aß associations in four pathologic phases of AD progression based on tau spread: 1) no-tau, 2) pre-acceleration, 3) acceleration, and 4) post-acceleration. Results: No significant tau-Aß association was detected in the no-tau phase. In the pre-acceleration phase, the earliest stage of tau deposition, associations emerged between regional tau in medial temporal lobe (MTL) (i.e., entorhinal cortex, parahippocampal gyrus) and cortical Aß in lateral temporal lobe regions. The strongest tau-Aß associations were found in the acceleration phase, in which tau in MTL regions was strongly associated with cortical Aß (i.e., temporal and frontal lobes regions). Strikingly, in the post-acceleration phase, including 96% of symptomatic subjects, tau-Aß associations were no longer significant. Conclusions: The results indicate that associations between tau and Aß are stage-dependent, which could have important implications for understanding the interplay between these two proteinopathies during the progressive stages of AD.

Communicative impairment and its neural correlates in Alzheimer's disease and frontotemporal dementia.

OBJECTIVE: Communication skills can deteriorate in neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD); however, their clinical assessment and treatment in patient care can be challenging. In the present study, we aimed to quantify the distinctive communication resources and barriers reported by patients and their relatives in AD and FTD and associated these communicative characteristics with clinical parameters, such as the degree of cognitive impairment and atrophy in language-associated brain areas. METHODS: We assessed self-reported communication barriers and resources in 33 individuals with AD and FTD through an interview on daily-life communication, using the Aachener KOMPASS questionnaire. We correlated reported communication barriers and resources with atrophy from high-resolution 3T brain magnetic resonance imaging, neuropsychological assessment, and neurodegenerative markers from cerebrospinal fluid. RESULTS: Communicative impairment was higher in FTD compared to AD. Increased reported communication barriers in our whole sample were associated with the atrophy rate in the left middle temporal lobe, a critical site within the neuronal language network, and with depressive symptoms as well as the semantic word fluency from neuropsychological assessment. The best model for prediction of communicative impairment included the diagnosis (AD or FTD), semantic word fluency, and depressive symptoms. CONCLUSIONS: Our study demonstrates that communication barriers and resources can be successfully assessed via a structured interview based on self-report and report of patients' relatives in practice and are reflected in neuroimaging specific for AD and FTD as well as in further clinical parameters specific for these neurodegenerative diseases. This can potentially open new treatment options for clinical practice and patient care.

Shared and differing functional connectivity abnormalities of the default mode network in mild cognitive impairment and Alzheimer's disease.

Alzheimer's disease (AD) and mild cognitive impairment (MCI) both show abnormal resting-state functional connectivity (rsFC) of default mode network (DMN), but it is unclear to what extent these abnormalities are shared. Therefore, we performed a comprehensive meta-analysis, including 31 MCI studies and 20 AD studies. MCI patients, compared to controls, showed decreased within-DMN rsFC in bilateral medial prefrontal cortex/anterior cingulate cortex (mPFC/ACC), precuneus/posterior cingulate cortex (PCC), right temporal lobes, and left angular gyrus and increased rsFC between DMN and left inferior temporal gyrus. AD patients, compared to controls, showed decreased rsFC within DMN in bilateral mPFC/ACC and precuneus/PCC and between DMN and left inferior occipital gyrus and increased rsFC between DMN and right dorsolateral prefrontal cortex. Conjunction analysis showed shared decreased rsFC in mPFC/ACC and precuneus/PCC. Compared to MCI, AD had decreased rsFC in left precuneus/PCC and between DMN and left inferior occipital gyrus and increased rsFC in right temporal lobes. MCI and AD share a decreased within-DMN rsFC likely underpinning episodic memory deficits and neuropsychiatric symptoms, but differ in DMN rsFC alterations likely related to impairments in other cognitive domains such as language, vision, and execution. This may throw light on neuropathological mechanisms in these two stages of dementia.

Alzheimer's Disease-associated Region-specific Decrease of Vesicular Glutamate Transporter Immunoreactivity inthe Medial Temporal Lobe and Superior Temporal Gyrus.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there are very limited treatment options. Dysfunction of the excitatory neurotransmitter system is thought to play a major role in the pathogenesis of this condition. Vesicular glutamate transporters (VGLUTs) are key to controlling the quantal release of glutamate. Thus, expressional changes in disease can have implications for aberrant neuronal activity, raising the possibility of a therapeutic target. There is no information regarding the expression of VGLUTs in the human medial temporal lobe in AD, one of the earliest and most severely affected brain regions. This study aimed to quantify and compare the layer-specific expression of VGLUT1 and VGLUT2 between control and AD cases in the hippocampus, subiculum, entorhinal cortex, and superior temporal gyrus. Free-floating fluorescent immunohistochemistry was used to label VGLUT1 and VGLUT2 in the hippocampus, subiculum, entorhinal cortex, and superior temporal gyrus. Sections were imaged using laser-scanning confocal microscopy and transporter densitometric analysis was performed. VGLUT1 density was not significantly different in AD tissue, except lower staining density observed in the dentate gyrus stratum moleculare (p = 0.0051). VGLUT2 expression was not altered in the hippocampus and entorhinal cortex of AD cases but was significantly lower in the subiculum (p = 0.015) and superior temporal gyrus (p = 0.0023). This study indicates a regionally specific vulnerability of VGLUT1 and VGLUT2 expression in the medial temporal lobe and superior temporal gyrus in AD. However, the causes and functional consequences of these disturbances need to be further explored to assess VGLUT1 and VGLUT2 as viable therapeutic targets.

Morphometric similarity differences in drug-naive Parkinson's disease correlate with transcriptomic signatures.

BACKGROUND: Differences in cortical morphology have been reported in individuals with Parkinson's disease (PD). However, the pathophysiological mechanism of transcriptomic vulnerability in local brain regions remains unclear. OBJECTIVE: This study aimed to characterize the morphometric changes of brain regions in early drug-naive PD patients and uncover the brain-wide gene expression correlates. METHODS: The morphometric similarity (MS) network analysis was used to quantify the interregional structural similarity from multiple magnetic resonance imaging anatomical indices measured in each brain region of 170 early drug-naive PD patients and 123 controls. Then, we applied partial least squares regression to determine the relationship between regional changes in MS and spatial transcriptional signatures from the Allen Human Brain Atlas dataset, and identified the specific genes related to MS differences in PD. We further investigated the biological processes by which the PD-related genes were enriched and the cellular characterization of these genes. RESULTS: Our results showed that MS was mainly decreased in cingulate, frontal, and temporal cortical areas and increased in parietal and occipital cortical areas in early drug-naive PD patients. In addition, genes whose expression patterns were associated with regional MS changes in PD were involved in astrocytes, excitatory, and inhibitory neurons and were functionally enriched in neuron-specific biological processes related to trans-synaptic signaling and nervous system development. CONCLUSIONS: These findings advance our understanding of the microscale genetic and cellular mechanisms driving macroscale morphological abnormalities in early drug-naive PD patients and provide potential targets for future therapeutic trials.

Comparison of histological delineations of medial temporal lobe cortices by four independent neuroanatomy laboratories.

The medial temporal lobe (MTL) cortex, located adjacent to the hippocampus, is crucial for memory and prone to the accumulation of certain neuropathologies such as Alzheimer's disease neurofibrillary tau tangles. The MTL cortex is composed of several subregions which differ in their functional and cytoarchitectonic features. As neuroanatomical schools rely on different cytoarchitectonic definitions of these subregions, it is unclear to what extent their delineations of MTL cortex subregions overlap. Here, we provide an overview of cytoarchitectonic definitions of the entorhinal and parahippocampal cortices as well as Brodmann areas (BA) 35 and 36, as provided by four neuroanatomists from different laboratories, aiming to identify the rationale for overlapping and diverging delineations. Nissl-stained series were acquired from the temporal lobes of three human specimens (two right and one left hemisphere). Slices (50 µm thick) were prepared perpendicular to the long axis of the hippocampus spanning the entire longitudinal extent of the MTL cortex. Four neuroanatomists annotated MTL cortex subregions on digitized slices spaced 5 mm apart (pixel size 0.4 µm at 20× magnification). Parcellations, terminology, and border placement were compared among neuroanatomists. Cytoarchitectonic features of each subregion are described in detail. Qualitative analysis of the annotations showed higher agreement in the definitions of the entorhinal cortex and BA35, while the definitions of BA36 and the parahippocampal cortex exhibited less overlap among neuroanatomists. The degree of overlap of cytoarchitectonic definitions was partially reflected in the neuroanatomists' agreement on the respective delineations. Lower agreement in annotations was observed in transitional zones between structures where seminal cytoarchitectonic features are expressed less saliently. The results highlight that definitions and parcellations of the MTL cortex differ among neuroanatomical schools and thereby increase understanding of why these differences may arise. This work sets a crucial foundation to further advance anatomically-informed neuroimaging research on the human MTL cortex.

Mapping hippocampal and thalamic atrophy in epilepsy: A 7-T magnetic resonance imaging study.

OBJECTIVE: Epilepsy patients are often grouped together by clinical variables. Quantitative neuroimaging metrics can provide a data-driven alternative for grouping of patients. In this work, we leverage ultra-high-field 7-T structural magnetic resonance imaging (MRI) to characterize volumetric atrophy patterns across hippocampal subfields and thalamic nuclei in drug-resistant focal epilepsy. METHODS: Forty-two drug-resistant epilepsy patients and 13 controls with 7-T structural neuroimaging were included in this study. We measured hippocampal subfield and thalamic nuclei volumetry, and applied an unsupervised machine learning algorithm, Latent Dirichlet Allocation (LDA), to estimate atrophy patterns across the hippocampal subfields and thalamic nuclei of patients. We studied the association between predefined clinical groups and the estimated atrophy patterns. Additionally, we used hierarchical clustering on the LDA factors to group patients in a data-driven approach. RESULTS: In patients with mesial temporal sclerosis (MTS), we found a significant decrease in volume across all ipsilateral hippocampal subfields (false discovery rate-corrected p [pFDR] < .01) as well as in some ipsilateral (pFDR < .05) and contralateral (pFDR < .01) thalamic nuclei. In left temporal lobe epilepsy (L-TLE) we saw ipsilateral hippocampal and some bilateral thalamic atrophy (pFDR < .05), whereas in right temporal lobe epilepsy (R-TLE) extensive bilateral hippocampal and thalamic atrophy was observed (pFDR < .05). Atrophy factors demonstrated that our MTS cohort had two atrophy phenotypes: one that affected the ipsilateral hippocampus and one that affected the ipsilateral hippocampus and bilateral anterior thalamus. Atrophy factors demonstrated posterior thalamic atrophy in R-TLE, whereas an anterior thalamic atrophy pattern was more common in L-TLE. Finally, hierarchical clustering of atrophy patterns recapitulated clusters with homogeneous clinical properties. SIGNIFICANCE: Leveraging 7-T MRI, we demonstrate widespread hippocampal and thalamic atrophy in epilepsy. Through unsupervised machine learning, we demonstrate patterns of volumetric atrophy that vary depending on disease subtype. Incorporating these atrophy patterns into clinical practice could help better stratify patients to surgical treatments and specific device implantation strategies.

Time-sensitive changes in the maternal brain and their influence on mother-child attachment.

Pregnancy and the postpartum period are characterized by an increased neuroplasticity in the maternal brain. To explore the dynamics of postpartum changes in gray matter volume (GMV), magnetic resonance imaging was performed on 20 healthy postpartum women immediately after childbirth and at 3-week intervals for 12 postpartum weeks. The control group comprised 20 age-matched nulliparous women. The first 6 postpartum weeks (constituting the subacute postpartum period) are associated with decreasing progesterone levels and a massive restructuring in GMV, affecting the amygdala/hippocampus, the prefrontal/subgenual cortex, and the insula, which approach their sizes in nulliparous women only around weeks 3-6 postpartum. Based on the amygdala volume shortly after delivery, the maternal brain can be reliably distinguished from the nulliparous brain. Even 12 weeks after childbirth, the GMV in the dorsomedial prefrontal cortex, and the cortical thickness of the subgenual and lateral prefrontal cortices do not reach the pre-pregnancy levels. During this period, a volume decrease is seen in the cerebellum, the thalamus, and the dorsal striatum. A less hostile behavior toward the child at 6-12 weeks postpartum is predicted by the GMV change in the amygdala, the temporal pole, the olfactory gyrus, the anterior cingulate, the thalamus and the cerebellum in the same period. In summary, the restructuring of the maternal brain follows time-dependent trajectories. The fact that the volume changes persist at 12 weeks postpartum indicates that the maternal brain does not fully revert to pre-pregnancy physiology. Postpartum neuroplasticity suggests that these changes may be particularly significant in the regions important for parenting.

Current advances in rodent drug-resistant temporal lobe epilepsy models: Hints from laboratory studies.

Anti-seizure drugs (ASDs) are the first choice for the treatment of epilepsy, but there is still one-third of patients with epilepsy (PWEs) who are resistant to two or more appropriately chosen ASDs, named drug-resistant epilepsy (DRE). Temporal lobe epilepsy (TLE), a common type of epilepsy usually associated with hippocampal sclerosis (HS), shares the highest proportion of drug resistance (approximately 70%). In view of the key role of the temporal lobe in memory, emotion, and other physiological functions, patients with drug-resistant temporal lobe epilepsy (DR-TLE) are often accompanied by serious complications, and surgical procedures also yield extra considerations. The exact mechanisms for the genesis of DR-TLE remain unillustrated, which makes it hard to manage patients with DR-TLE in clinical practice. Animal models of DR-TLE play an irreplaceable role in both understanding the mechanism and searching for new therapeutic strategies or drugs. In this review article, we systematically summarized different types of current DR-TLE models, and then recent advances in mechanism investigations obtained in these models were presented, especially with the development of advanced experimental techniques and tools. We are deeply encouraged that novel strategies show great therapeutic potential in those DR-TLE models. Based on the big steps reached from the bench, a new light has been shed on the precise management of DR-TLE.

Situating word deafness within aphasia recovery: A case report.

Word deafness is a rare neurological disorder often observed following bilateral damage to superior temporal cortex and canonically defined as an auditory modality-specific deficit in word comprehension. The extent to which word deafness is dissociable from aphasia remains unclear given its heterogeneous presentation, and some have consequently posited that word deafness instead represents a stage in recovery from aphasia, where auditory and linguistic processing are affected to varying degrees and improve at differing rates. Here, we report a case of an individual (Mr. C) with bilateral temporal lobe lesions whose presentation evolved from a severe aphasia to an atypical form of word deafness, where auditory linguistic processing was impaired at the sentence level and beyond. We first reconstructed in detail Mr. C's stroke recovery through medical record review and supplemental interviewing. Then, using behavioral testing and multimodal neuroimaging, we documented a predominant auditory linguistic deficit in sentence and narrative comprehension-with markedly reduced behavioral performance and absent brain activation in the language network in the spoken modality exclusively. In contrast, Mr. C displayed near-unimpaired behavioral performance and robust brain activations in the language network for the linguistic processing of words, irrespective of modality. We argue that these findings not only support the view of word deafness as a stage in aphasia recovery but also further instantiate the important role of left superior temporal cortex in auditory linguistic processing.

Evolution of radiation-induced temporal lobe injury after intensity-modulated radiation therapy in nasopharyngeal carcinoma: a large cohort retrospective study.

BACKGROUND: Previous studies have demonstrated conflicting findings regarding the initial MRI patterns of radiotherapy-induced temporal lobe injury (RTLI) and the evolution of different RTLI patterns. The aim of this study was to evaluate the initial MRI pattern and evolution of RTLI in patients with nasopharyngeal carcinoma (NPC) by means of a large cohort study. METHODS: Data of patients with RTLI were retrospectively collected from two hospitals between January 2011 and December 2021. The injured lobes were categorized into three patterns based on initial MRI patterns: isolated white matter lesions (WMLs), isolated contrast-enhanced lesions (CELs), and combined WMLs and CELs. The latency period, MRI appearances, and temporal changes in WMLs and CELs were evaluated. RESULTS: A total of 913 RTLI patients with 1092 injured lobes were included in this study. The numbers of isolated WMLs, isolated CELs, and combined WMLs and CELs identified at the first MRI detection were 7 (0.6%), 172 (15.8%), and 913 (83.6%), respectively. The evolution of bilateral RTLI was different in the same patient, and that of unilateral RTLI combined with WMLs and CELs also may occur asynchronously. The time intervals from the initial MRI detection of isolated WMLs, isolated CELs, combined WMLs and CELs to the last negative MRI scan were 8.6, 8.9 and 11.0 months, respectively. A significant difference was observed in the time intervals between the three patterns (H = 14.287, P = 0.001). And the time interval was identified as an independent factor influencing the initial MRI pattern of RTLI after Poisson regression (P = 0.002). CONCLUSION: Both WMLs and CELs could be the initial and only MRI abnormalities in patients with RTLI. This study is of great significance in accurately diagnosing RTLI early and providing timely treatment options. Additionally, it provides clinical evidence for guidelines on NPC, emphasizing the importance of regular follow-up of NPC patients.

Impaired perceptual discrimination of complex objects in older adults at risk for dementia.

Tau pathology accumulates in the perirhinal cortex (PRC) of the medial temporal lobe (MTL) during the earliest stages of the Alzheimer's disease (AD), appearing decades before clinical diagnosis. Here, we leveraged perceptual discrimination tasks that target PRC function to detect subtle cognitive impairment even in nominally healthy older adults. Older adults who did not have a clinical diagnosis or subjective memory complaints were categorized into "at-risk" (score <26; n = 15) and "healthy" (score ≥26; n = 23) groups based on their performance on the Montreal Cognitive Assessment. The task included two conditions known to recruit the PRC: faces and complex objects (greebles). A scene condition, known to recruit the hippocampus, and a size control condition that does not rely on the MTL were also included. Individuals in the at-risk group were less accurate than those in the healthy group for discriminating greebles. Performance on either the face or size control condition did not predict group status above and beyond that of the greeble condition. Visual discrimination tasks that are sensitive to PRC function may detect early cognitive decline associated with AD.

Towards validation in clinical routine: a comparative analysis of visual MTA ratings versus the automated ratio between inferior lateral ventricle and hippocampal volumes in Alzheimer's disease diagnosis.

PURPOSE: To assess the performance of the inferior lateral ventricle (ILV) to hippocampal (Hip) volume ratio on brain MRI, for Alzheimer's disease (AD) diagnostics, comparing it to individual automated ILV and hippocampal volumes, and visual medial temporal lobe atrophy (MTA) consensus ratings. METHODS: One-hundred-twelve subjects (mean age ± SD, 66.85 ± 13.64 years) with varying degrees of cognitive decline underwent MRI using a Philips Ingenia 3T. The MTA scale by Scheltens, rated on coronal 3D T1-weighted images, was determined by three experienced radiologists, blinded to diagnosis and sex. Automated volumetry was computed by icobrain dm (v. 5.10) for total, left, right hippocampal, and ILV volumes. The ILV/Hip ratio, defined as the percentage ratio between ILV and hippocampal volumes, was calculated and compared against a normative reference population (n = 1903). Inter-rater agreement, association, classification accuracy, and clinical interpretability on patient level were reported. RESULTS: Visual MTA scores showed excellent inter-rater agreement. Ordinal logistic regression and correlation analyses demonstrated robust associations between automated brain segmentations and visual MTA ratings, with the ILV/Hip ratio consistently outperforming individual hippocampal and ILV volumes. Pairwise classification accuracy showed good performance without statistically significant differences between the ILV/Hip ratio and visual MTA across disease stages, indicating potential interchangeability. Comparison to the normative population and clinical interpretability assessments showed commensurability in classifying MTA "severity" between visual MTA and ILV/Hip ratio measurements. CONCLUSION: The ILV/Hip ratio shows the highest correlation to visual MTA, in comparison to automated individual ILV and hippocampal volumes, offering standardized measures for diagnostic support in different stages of cognitive decline.

The neural correlates of topographical disorientation-a lesion analysis study.

Topographical disorientation refers to the selective inability to orient oneself in familiar surroundings. However, to date its neural correlates remain poorly understood. Here we use quantitative lesion analysis and a lesion network mapping approach in order to investigate seven patients with topographical disorientation. Our findings link not only the posterior parahippocampal gyrus (PHG) and retrosplenial cortex but also the lingual gyrus, the precuneus and the fusiform gyrus to topographical disorientation. We propose that topographical disorientation is due to the inability to integrate familiar landmarks within a framework of allocentric and egocentric orientation, supported by a neural network including the posterior PHG, the retrosplenial and the lingual cortex.

Disruption of TLE epileptiform activity retarded the seizure and reduced pathological HFOs.

In temporal lobe epilepsy (TLE), the epileptogenic zones, such as the temporal lobe structure, could generate pathological high-frequency oscillations (pHFOs, 250-500 Hz) before the ictal period. These pHFOs have also been observed during the process of seizures in both TLE patients and animals, exhibiting a critical role as promising biomarkers for TLE seizures. TLE seizures could be modulated via regulating the neural excitability in epileptogenic zones, for that TLE is primarily associated with the excitation-inhibition imbalance. However, whether these kinds of modulations could also impact the pHFOs characteristics during TLE seizures is still unclear. For this purpose, we pharmaco-genetically inhibited the principal cells (PCs) in the mouse CA3 region and tracked the difference in the behavioral and electrophysiological features during LiCl-pilocarpine-induced TLE seizure between the hM4Di+CNO (experimental) mice and mCherry+CNO (control) mice. Delayed latency, decreased averaged duration, and reduced counts of the generalized seizure were observed in the experimental mice. Besides, the electrophysiological characteristics, such as the firing rate of PCs and the count of pHFO, exhibited significant decline in the CA3 and CA1 regions. During TLE seizure, there existed strong phase-coupling between pHFO and PCs spike timing in the control mice, while it was abolished in the experimental mice. In addition, we also found that the counts of pHFO were significantly associated with the behavioral features, indicating the close relationships within them. Collectively, our findings suggested that alterations in pHFO and the retardation of seizures may be attributed to disruptions in neuronal excitability, and the variations of electrophysiological features were related to seizure severity during TLE seizures. These results provide valuable insights into the role of pHFOs in TLE and shed light on the underlying mechanisms involved.

Disease Progression Patterns of Brain Morphology in Schizophrenia: More Progressed Stages in Treatment Resistance.

BACKGROUND AND HYPOTHESIS: Given the heterogeneity and possible disease progression in schizophrenia, identifying the neurobiological subtypes and progression patterns in each patient may lead to novel biomarkers. Here, we adopted data-driven machine-learning techniques to identify the progression patterns of brain morphological changes in schizophrenia and investigate the association with treatment resistance. STUDY DESIGN: In this cross-sectional multicenter study, we included 177 patients with schizophrenia, characterized by treatment response or resistance, with 3D T1-weighted magnetic resonance imaging. Cortical thickness and subcortical volumes calculated by FreeSurfer were converted into z scores using 73 healthy controls data. The Subtype and Stage Inference (SuStaIn) algorithm was used for unsupervised machine-learning analysis. STUDY RESULTS: SuStaIn identified 3 different subtypes: (1) subcortical volume reduction (SC) type (73 patients), in which volume reduction of subcortical structures occurs first and moderate cortical thinning follows, (2) globus pallidus hypertrophy and cortical thinning (GP-CX) type (42 patients), in which globus pallidus hypertrophy initially occurs followed by progressive cortical thinning, and (3) cortical thinning (pure CX) type (39 patients), in which thinning of the insular and lateral temporal lobe cortices primarily happens. The remaining 23 patients were assigned to baseline stage of progression (no change). SuStaIn also found 84 stages of progression, and treatment-resistant schizophrenia showed significantly more progressed stages than treatment-responsive cases (P = .001). The GP-CX type presented earlier stages than the pure CX type (P = .009). CONCLUSIONS: The brain morphological progressions in schizophrenia can be classified into 3 subtypes, and treatment resistance was associated with more progressed stages, which may suggest a novel biomarker.

TAF15 amyloid filaments in frontotemporal lobar degeneration.

Frontotemporal lobar degeneration (FTLD) causes frontotemporal dementia (FTD), the most common form of dementia after Alzheimer's disease, and is often also associated with motor disorders1. The pathological hallmarks of FTLD are neuronal inclusions of specific, abnormally assembled proteins2. In the majority of cases the inclusions contain amyloid filament assemblies of TAR DNA-binding protein 43 (TDP-43) or tau, with distinct filament structures characterizing different FTLD subtypes3,4. The presence of amyloid filaments and their identities and structures in the remaining approximately 10% of FTLD cases are unknown but are widely believed to be composed of the protein fused in sarcoma (FUS, also known as translocated in liposarcoma). As such, these cases are commonly referred to as FTLD-FUS. Here we used cryogenic electron microscopy (cryo-EM) to determine the structures of amyloid filaments extracted from the prefrontal and temporal cortices of four individuals with FTLD-FUS. Surprisingly, we found abundant amyloid filaments of the FUS homologue TATA-binding protein-associated factor 15 (TAF15, also known as TATA-binding protein-associated factor 2N) rather than of FUS itself. The filament fold is formed from residues 7-99 in the low-complexity domain (LCD) of TAF15 and was identical between individuals. Furthermore, we found TAF15 filaments with the same fold in the motor cortex and brainstem of two of the individuals, both showing upper and lower motor neuron pathology. The formation of TAF15 amyloid filaments with a characteristic fold in FTLD establishes TAF15 proteinopathy in neurodegenerative disease. The structure of TAF15 amyloid filaments provides a basis for the development of model systems of neurodegenerative disease, as well as for the design of diagnostic and therapeutic tools targeting TAF15 proteinopathy.

Stability of face recognition abilities after left or right anterior temporal lobectomy.

Patients with anterior temporal lobe (ATL) resection due to mesial temporal lobe epilepsy (MTLE) have difficulties at identifying familiar faces and explicitly remembering newly learned faces but their ability to individuate unfamiliar faces remains largely unknown. Moreover, the extent to which their difficulties with familiar face identity recognition and learning is truly due to the ATL resection remains unknown. Here, we report a study of 24 MTLE patients and matched healthy controls tested with an extensive set of seven face and visual object recognition tasks (including three tasks evaluating unfamiliar face individuation) before and about 6 months after unilateral (nine left, 15 right) ATL resection. We found that ATL resection has little or no effect on the patients' preserved pre-surgical ability to perform unfamiliar face individuation, both at the group and individual levels. More surprisingly, ATL resection also has little effect on the patients' performance at recognizing and naming famous faces as well as at learning new faces. A substantial proportion of right MTLE patients (33%) even improved their response times on several tasks, which may indicate a functional release of visuo-spatial processing after resection in the right ATL. Altogether this study shows that face recognition abilities are mainly unaffected by ATL resection in MTLE, either because the critical regions for face recognition are spared or because performance at some tasks is already lower than normal preoperatively. Overall, these findings urge caution when interpreting the causal effect of brain lesions on face recognition ability in patients with ATL resection due to MTLE. They also illustrate the complexity of predicting cognitive outcomes after epilepsy surgery because of the influence of many different intertwined factors.

Correlation of magnetic resonance spectroscopy and magnetic resonance imaging with findings of electroencephalography in patients with temporal lobe epilepsy.

INTRODUCTION: This research aimed to see how well magnetic resonance spectroscopy (MRS) could identify the lateralization side in individuals with temporal lobe epilepsy (TLE) compared to electroencephalography (EEG) and magnetic resonance imaging (MRI) results. METHODS: Twenty-three individuals were included in this research and diagnosed with TLE (both clinically and by EEG). Clinical exams, interictal EEG, and MRI were performed on all patients. In addition, the individuals were also subjected to proton MRS. RESULTS: The age range of 23 participants was 20-55 years (mean = 34.6 ± 8.5); 10 were male (44%), and 13 were female (56%). The right temporal lobe MRI showed a sensitivity and specificity of 60% and 55% for detecting mesial temporal lobe sclerosis (MTS) foci, respectively (positive predictive value (PPV) of 27% and negative predictive value (NPV) of 83%). MRI showed 83% sensitivity and 35% specificity for MTS foci in the left temporal lobe (PPV of 31% and NPV of 86%). MRS showed 61% sensitivity and 100% specificity in the right temporal lobe (PPV 100%) and 80% sensitivity and specificity in the left temporal lobe (PPV 100%) for identifying MTS foci. Overall, MRS (both left and right) results matched EEG findings. CONCLUSION: MRS is a potential noninvasive neuroradiology technique for assessing epilepsy patients because it is more sensitive than structural MRI in identifying MTS. The results of the study overall appears to be of interest but still need further support from future studies with larger sample sizes.