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Translocator protein (TSPO) is a mitochondrial protein expressed by microglia, ligands for which are used as a marker of neuroinflammation in PET studies of Alzheimer's disease (AD). We previously showed increasing TSPO load in the cerebral cortex with AD progression, consistent with TSPO PET scan findings. Here, we aim to characterise the microglial phenotype associated with TSPO expression to aid interpretation of the signal generated by TSPO ligands in patients. Human post-mortem sections of temporal lobe (TL) and cerebellum (Cb) from cases classified by Braak group (0-II, III-IV, V-VI; each n = 10) were fluorescently double labelled for TSPO and microglial markers: Iba1, HLA-DR, CD68, MSR-A and CD64. Quantification was performed on scanned images using QuPath software to assess the microglial phenotype of TSPO. Qualitative analysis was also performed for TSPO with GFAP (astrocytes), CD31 (endothelial cells) and CD163 (perivascular macrophages) to characterise the cellular profile of TSPO. The percentage of CD68 + TSPO + double-labelled cells was significantly higher than for other microglial markers in both brain regions and in all Braak stages, followed by MSR-A + TSPO + microglia. Iba1 + TSPO + cells were more numerous in the cerebellum than the temporal lobe, while CD64 + TSPO + cells were more numerous in the temporal lobe. No differences were observed for the other microglial markers. TSPO expression was also detected in endothelial cells, but not detected in astrocytes nor in perivascular macrophages. Our data suggest that TSPO is mainly related to a phagocytic profile of microglia (CD68 + ) in human AD, potentially highlighting the ongoing neurodegeneration., Competing Interests: Declarations Conflict of interests The authors report no competing interests. Ethical approval The study was carried out in accordance with relevant guidelines and regulations under the South–West Dementia Brain Bank ethical approval (NRES Committee South–West Central Bristol, REC reference: 08/H0106/28 + 5)., (© 2024. The Author(s).)

Declarative memory encompasses episodic and semantic divisions. Episodic memory captures singular events with specific spatiotemporal relationships, whereas semantic memory houses context-independent knowledge. Behavioural and functional neuroimaging studies have revealed common and distinct neural substrates of both memory systems, implicating mesiotemporal lobe (MTL) regions such as the hippocampus and distributed neocortices. Here, we explored declarative memory system reorganization in patients with unilateral temporal lobe epilepsy (TLE) as a human disease model to test the impact of variable degrees of MTL pathology on memory function. Our cohort included 31 patients with TLE and 60 age- and sex-matched healthy controls, and all participants underwent episodic and semantic retrieval tasks during a multimodal MRI session. The functional MRI tasks were closely matched in terms of stimuli and trial design. Capitalizing on non-linear connectome gradient-mapping techniques, we derived task-based functional topographies during episodic and semantic memory states, in both the MTL and neocortical networks. Comparing neocortical and hippocampal functional gradients between TLE patients and healthy controls, we observed a marked topographic reorganization of both neocortical and MTL systems during episodic memory states. Neocortical alterations were characterized by reduced functional differentiation in TLE across lateral temporal and midline parietal cortices in both hemispheres. In the MTL, in contrast, patients presented with a more marked functional differentiation of posterior and anterior hippocampal segments ipsilateral to the seizure focus and pathological core, indicating perturbed intrahippocampal connectivity. Semantic memory reorganization was also found in bilateral lateral temporal and ipsilateral angular regions, whereas hippocampal functional topographies were unaffected. Furthermore, leveraging MRI proxies of MTL pathology, we observed alterations in hippocampal microstructure and morphology that were associated with TLE-related functional reorganization during episodic memory. Moreover, correlation analysis and statistical mediation models revealed that these functional alterations contributed to behavioural deficits in episodic memory, but again not in semantic memory in patients. Altogether, our findings suggest that semantic processes rely on distributed neocortical networks, whereas episodic processes are supported by a network involving both the hippocampus and the neocortex. Alterations of such networks can provide a compact signature of state-dependent reorganization in conditions associated with MTL damage, such as TLE., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

This paper for the 20th anniversary of the Alzheimer's Disease Neuroimaging Initiative (ADNI) provides an overview of magnetic resonance imaging (MRI) of medial temporal lobe (MTL) subregions in ADNI using a dedicated high-resolution T2-weighted sequence. A review of the work that supported the inclusion of this imaging modality into ADNI Phase 3 is followed by a brief description of the ADNI MTL imaging and analysis protocols and a summary of studies that have used these data. This review is supplemented by a new study that uses novel surface-based tools to characterize MTL neurodegeneration across biomarker-defined AD stages. This analysis reveals a pattern of spreading cortical thinning associated with increasing levels of tau pathology in the presence of elevated amyloid beta, with apparent epicenters in the transentorhinal region and inferior hippocampal subfields. The paper concludes with an outlook for high-resolution imaging of the MTL in ADNI Phase 4. HIGHLIGHTS: As of Phase 3, the Alzheimer's Disease Neuroimaging Initiative (ADNI) magnetic resonance imaging (MRI) protocol includes a high-resolution T2-weighted MRI scan optimized for imaging hippocampal subfields and medial temporal lobe (MTL) subregions. These scans are processed by the ADNI core to obtain automatic segmentations of MTL subregions and to derive morphologic measurements. More detailed granular examination of MTL neurodegeneration in response to disease progression is achieved by applying surface-based modeling techniques. Surface-based analysis of gray matter loss in MTL subregions reveals increasing and spatially expanding patterns of neurodegeneration with advancing stages of Alzheimer's disease (AD), as defined based on amyloid and tau positron emission tomography biomarkers in accordance with recently proposed criteria. These patterns closely align with post mortem literature on spread of pathological tau in AD, supporting the role of tau pathology in the presence of elevated levels of amyloid beta as the driver of neurodegeneration., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Symmetrical lesions in the temporal poles and external capsules on brain MRI are known as radiological markers of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL); however, similar imaging findings have also been reported in neuromyelitis optica spectrum disorder (NMOSD), and this study investigated the frequency of such findings. The study included 55 NMOSD patients who met the 2015 international NMO diagnosis panel (IPND) criteria and were positive for aquaporin-4 antibodies (AQP4-Ab). Images were evaluated based on the consensus of two neuroradiologists, and brain lesions were detected in 33 patients, of whom 2 (6%) had symmetrical lesions in both the temporal poles and external capsules, and 1 (3%) had symmetrical lesions confined to the external capsules. Therefore, when symmetrical lesions in the temporal poles and external capsules are observed on MRI, NMOSD should be considered in the differential diagnosis., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Decreased microvascular levels of claudin-5 in the occipital and temporal lobe of patients with cerebral amyloid angiopathy are associated with intracerebral haemorrhage., (© 2024 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Advances in single-cell technologies have led to the discovery and characterization of new brain cell types, which in turn lead to a better understanding of the pathogenesis of Alzheimer's disease (AD). Here, we present a detailed analysis of single-nucleus (sn)RNA-seq data for three stages of AD from middle temporal gyrus and compare it with snRNA-seq data from the prefrontal cortices from individuals with alcohol use disorder (AUD). We observed a significant decrease in both inhibitory and excitatory neurons, in general agreement with previous reports. We observed several cell-type-specific gene expressions and pathway dysregulations that delineate AD stages. Endothelial and vascular leptomeningeal cells showed the greatest degree of gene expression changes. Cell-type-specific evidence of neurodegeneration was seen in multiple neuronal cell types particularly in somatostatin and Layer 5 extratelencephalic neurons, among others. Evidence of inflammatory responses was seen in non-neuronal cells, particularly in intermediate and advanced AD. We observed common perturbations in AD and AUD, particularly in pathways, like transcription, translation, apoptosis, autophagy, calcium signaling, neuroinflammation, and phosphorylation, that imply shared transcriptional pathogenic mechanisms and support the role of excessive alcohol intake in AD progression. Major AUD gene markers form and perturb a network of genes significantly associated with intermediate and advanced AD. Master regulator analysis from AUD gene markers revealed significant correlation with advanced AD of transcription factors that have implications in intellectual disability, neuroinflammation, and other neurodegenerative conditions, further suggesting a shared nexus of transcriptional changes between AD and AUD., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Joshi et al.)

Early stages of Alzheimer's disease (AD) are associated with volume reductions in specific subregions of the medial temporal lobe (MTL). Using a manual segmentation method-the Olsen-Amaral-Palombo (OAP) protocol-previous work in healthy older adults showed that reductions in grey matter volumes in MTL subregions were associated with lower scores on the Montreal Cognitive Assessment (MoCA), suggesting atrophy may occur prior to diagnosis of mild cognitive impairment, a condition that often progresses to AD. However, current "gold standard" manual segmentation methods are labour intensive and time consuming. Here, we examined the utility of Automatic Segmentation of Hippocampal Subfields (ASHS) to detect volumetric differences in MTL subregions of healthy older adults who varied in cognitive status as determined by the MoCA. We trained ASHS on the OAP protocol to create the ASHS-OAP atlas and then examined how well automated segmentation replicated manual segmentation. Volumetric measures obtained from the ASHS-OAP atlas were also contrasted against those from the ASHS-PMC atlas, a widely used atlas provided by the ASHS team. The pattern of volumetric results was similar between the ASHS-OAP atlas and manual segmentation for anterolateral entorhinal cortex and perirhinal cortex, suggesting that ASHS-OAP is a viable alternative to current manual segmentation methods for detecting group differences based on cognitive status. Although ASHS-OAP and ASHS-PMC produced varying volumes for most regions of interest, they both identified early signs of neurodegeneration in CA 2 /CA 3 /DG and identified marginal differences in entorhinal cortex. Our findings highlight the utility of automated segmentation methods but still underscore the need for a unified and harmonized MTL segmentation atlas., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Alzheimer's disease (AD) is associated with heterogeneous atrophy patterns. We employed a semi-supervised representation learning technique known as Surreal-GAN, through which we identified two latent dimensional representations of brain atrophy in symptomatic mild cognitive impairment (MCI) and AD patients: the "diffuse-AD" (R1) dimension shows widespread brain atrophy, and the "MTL-AD" (R2) dimension displays focal medial temporal lobe (MTL) atrophy. Critically, only R2 was associated with widely known sporadic AD genetic risk factors (e.g., APOE ε4) in MCI and AD patients at baseline. We then independently detected the presence of the two dimensions in the early stages by deploying the trained model in the general population and two cognitively unimpaired cohorts of asymptomatic participants. In the general population, genome-wide association studies found 77 genes unrelated to APOE differentially associated with R1 and R2. Functional analyses revealed that these genes were overrepresented in differentially expressed gene sets in organs beyond the brain (R1 and R2), including the heart (R1) and the pituitary gland, muscle, and kidney (R2). These genes were enriched in biological pathways implicated in dendritic cells (R2), macrophage functions (R1), and cancer (R1 and R2). Several of them were "druggable genes" for cancer (R1), inflammation (R1), cardiovascular diseases (R1), and diseases of the nervous system (R2). The longitudinal progression showed that APOE ε4, amyloid, and tau were associated with R2 at early asymptomatic stages, but this longitudinal association occurs only at late symptomatic stages in R1. Our findings deepen our understanding of the multifaceted pathogenesis of AD beyond the brain. In early asymptomatic stages, the two dimensions are associated with diverse pathological mechanisms, including cardiovascular diseases, inflammation, and hormonal dysfunction-driven by genes different from APOE-which may collectively contribute to the early pathogenesis of AD. All results are publicly available at https://labs-laboratory.com/medicine/ ., (© 2024. The Author(s).)

Introduction: Magnetic resonance imaging (MRI) segmentation algorithms make it possible to study detailed medial temporal lobe (MTL) substructures as hippocampal subfields and amygdala subnuclei, offering opportunities to develop biomarkers for preclinical Alzheimer's disease (AD)., Methods: We identified the MTL substructures significantly associated with tau-positron emission tomography (PET) signal in 581 non-demented individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI-3). We confirmed our results in our UCLouvain cohort including 110 non-demented individuals by comparing volumes between individuals with different visual Braak's stages and clinical diagnosis., Results: Four amygdala subnuclei (cortical, central, medial, and accessory basal) were associated with tau in amyloid beta-positive (Aβ+) clinically normal (CN) individuals, while the global amygdala and hippocampal volumes were not. Using UCLouvain data, we observed that both Braak I-II and Aβ+ CN individuals had smaller volumes in these subnuclei, while no significant difference was observed in the global structure volumes or other subfields., Conclusion: Measuring specific amygdala subnuclei, early atrophy may serve as a marker of temporal tauopathy in preclinical AD, identifying individuals at risk of progression., Highlights: Amygdala atrophy is not homogeneous in preclinical Alzheimer's disease (AD). Tau pathology is associated with atrophy of specific amygdala subnuclei, specifically, the central, medial, cortical, and accessory basal subnuclei. Hippocampal and amygdala volume is not associated with tau in preclinical AD. Hippocampus and CA1-3 volume is reduced in preclinical AD, regardless of tau., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objective: To determine the intracranial ictal onset and early spread patterns in pediatric patients with Temporal lobe epilepsy and its possible association with histopathology, temporal structure involved, mesial structural pathology, and possible implication in postsurgical outcome., Methods: A descriptive, retrospective, cross-sectional study was carried out in a group of children from Children's Wisconsin between 2016 and 2022., Results: This study showed a strong association between ictal onset patterns and underlying histology (p < 0.05). Low-Frequency High Amplitude periodic spikes were seen only in patients with HS (20.6 %). A strong statistically significant association was found between different ictal onset patterns and the temporal lobe structure involved in the ictal onset (p < 0.001). Seizures with ictal onset consisting of Slow Potential Shift with superimposed Low Voltage Fast Activity arise from the Inferior Temporal Lobe or Middle Temporal Gyrus in a more significant proportion of seizures than those that originated from mesial temporal structures (Difference of proportion; p < 0.05). Low Voltage Fast Activity periodic spikes as an ictal pattern were seen in a patient with seizures arising outside the mesial temporal structure. The most frequent early spread pattern observed was Low Voltage Fast Activity (89.4 %); this pattern did not depend on the type of mesial structure pathology. Ictal onset patterns were associated with postsurgical outcomes (p < 0.001). The ictal onset pattern depends on the histopathology in the ictal onset zone and the temporal lobe structure involved in the ictal onset (p = 0.001)., Conclusions: Intracranial ictal onset patterns in TEMPORAL LOBE EPILEPSY depend on underlying histology and the temporal lobe structure involved in its onset., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Understanding the neurobiology of semantic knowledge is a major goal of cognitive neuroscience. Taxonomic and thematic semantic knowledge are represented differently within the brain's conceptual networks, but the specific neural mechanisms remain unclear. Some neurobiological models propose that the anterior temporal lobe is an important hub for taxonomic knowledge, whereas the TPJ is especially involved in the representation of thematic knowledge. However, recent studies have provided divergent evidence. In this context, we investigated the neural correlates of taxonomic and thematic confrontation naming errors in 79 people with aphasia. We used three complementary lesion-symptom mapping (LSM) methods to investigate how structure and function in both spared and impaired brain regions relate to taxonomic and thematic naming errors. Voxel-based LSM mapped brain damage, activation-based LSM mapped BOLD signal in surviving tissue, and network-based LSM mapped white matter subnetwork integrity to error type. Voxel- and network-based lesion symptom mapping provided converging evidence that damage/disruption of the left mid-to-anterior temporal lobe was associated with a greater proportion of thematic naming errors. Activation-based lesion symptom mapping revealed that higher BOLD signal in the left anterior temporal lobe during an in-house naming task was associated with a greater proportion of taxonomic errors on the Philadelphia Naming Test administered outside of the scanner. A lower BOLD signal in the bilateral angular gyrus, precuneus, and right inferior frontal cortex was associated with a greater proportion of taxonomic errors. These findings provide novel evidence that damage to the anterior temporal lobe is especially related to thematic naming errors., (© 2024 Massachusetts Institute of Technology.)

Purpose: Low-grade glioma is the most common brain tumor among children and adolescents. When these tumors arise in the temporal lobe, patients frequently present with seizures that are poorly controlled with antiepileptic drugs. Here we summarize the clinical features, pathophysiology, preoperative evaluation, surgical treatment, and outcomes of pediatric patients with low-grade gliomas in the temporal lobe., Methods: We reviewed the literature on pediatric low-grade gliomas in the temporal lobe, focusing on cohort studies and systematic reviews that described surgical treatment strategies and reported both oncologic and epilepsy outcomes., Results: The differential diagnoses of pediatric low-grade gliomas in the temporal lobe include ganglioglioma, dysembryoplastic neuroepithelial tumor, desmoplastic infantile ganglioglioma, papillary glioneuronal tumor, pilocytic astrocytoma, pleomorphic xanthoastrocytoma, angiocentric glioma, and polymorphous low-grade neuroepithelial tumor of the young. There is no consensus on the optimal surgical approach for these tumors: lesionectomy alone, or extended lesionectomy with anterior temporal lobectomy, with or without removal of mesial temporal structures. Gross total resection and shorter preoperative duration of epilepsy are strongly associated with favorable seizure outcomes, defined as Engel Class I or Class II, approaching 90% in most series. The risk of surgical complications ranges from 4 to 17%, outweighing the lifetime risks of medically refractory epilepsy., Conclusion: Pediatric patients with temporal low-grade glioma and tumor-related epilepsy are best managed by a multidisciplinary epilepsy surgery team. Early and appropriate surgery leads to prolonged survival and a greater likelihood of seizure freedom, improving their overall quality of life., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: We investigated the effects of adding regions to current dissemination in space (DIS) criteria for multiple sclerosis (MS)., Methods: Participants underwent brain, optic nerve, and spinal cord MRI. Baseline DIS was assessed by 2017 McDonald criteria and versions including optic nerve, temporal lobe, or corpus callosum as a fifth region (requiring 2/5), a version with all regions (requiring 3/7) and optic nerve variations requiring 3/5 and 4/5 regions. Performance was evaluated against MS diagnosis (2017 McDonald criteria) during follow-up., Results: Eighty-four participants were recruited (53F, 32.8 ± 7.1 years). 2017 McDonald DIS criteria were 87% sensitive (95% CI: 76-94), 73% specific (50-89), and 83% accurate (74-91) in identifying MS. Modified criteria with optic nerve improved sensitivity to 98% (91-100), with specificity 33% (13-59) and accuracy 84% (74-91). Criteria including temporal lobe showed sensitivity 94% (84-98), specificity 50% (28-72), and accuracy 82% (72-90); criteria including corpus callosum showed sensitivity 90% (80-96), specificity 68% (45-86), and accuracy 85% (75-91). Criteria adding all three regions (3/7 required) had sensitivity 95% (87-99), specificity 55% (32-76), and accuracy 85% (75-91). When requiring 3/5 regions (optic nerve as the fifth), sensitivity was 82% (70-91), specificity 77% (55-92), and accuracy 81% (71-89); with 4/5 regions, sensitivity was 56% (43-69), specificity 95% (77-100), and accuracy 67% (56-77)., Interpretation: Optic nerve inclusion increased sensitivity while lowering specificity. Increasing required regions in optic nerve criteria increased specificity and decreased sensitivity. Results suggest considering the optic nerve for DIS. An option of 3/5 or 4/5 regions preserved specificity, and criteria adding all three regions had highest accuracy., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: The medial temporal lobe (MTL) is hypothesized to be relatively spared in early-onset Alzheimer's disease (EOAD). Yet, detailed examination of MTL subfields and drivers of atrophy in amnestic EOAD is lacking., Methods: BioFINDER-2 participants with memory impairment, abnormal amyloid-β and tau-PET were included. Forty-one amnestic EOAD individuals ≤65 years and, as comparison, late-onset AD (aLOAD, ≥70 years, n = 154) and amyloid-β-negative cognitively unimpaired controls were included. MTL subregions and biomarkers of (co-)pathologies were measured., Results: AD groups showed smaller MTL subregions compared to controls. Atrophy patterns were similar across AD groups: aLOAD showed thinner entorhinal cortices than aEOAD; aEOAD showed thinner parietal regions than aLOAD. aEOAD showed lower white matter hyperintensities than aLOAD. No differences in MTL tau-PET or transactive response DNA binding protein 43-proxy positivity were found., Conclusions: We found evidence for MTL atrophy in amnestic EOAD and overall similar levels to aLOAD of MTL tau pathology and co-pathologies., (© 2024. The Author(s).)

A 73-year-old woman with posterior cortical atrophy (PCA) presented with progressive apperceptive visual agnosia, alexia, agraphia, ventral simultanagnosia, prosopagnosia, and allocentric (stimulus-centered) left-sided hemispatial neglect. All of these symptoms were attributed to damage to the bilateral occipito-temporal cortices, consistent with ventral variant PCA. While the Pittsburgh compound B uptake was extensively distributed throughout the occipito-parietal (dorsal) and occipito-temporal (ventral) areas, the THK5351 (ligand binding to tau aggregates/astrocyte gliosis) accumulation was limited to the ventral area. These findings suggest that local accumulation of tau proteins and/or astrocyte gliosis over the occipito-temporal cortices can result in ventral variant PCA.

The medial temporal lobe (MTL) is a hotspot for neuropathology, and measurements of MTL atrophy are often used as a biomarker for cognitive decline associated with neurodegenerative disease. Due to the aggregation of multiple proteinopathies in this region, the specific relationship of MTL atrophy to distinct neuropathologies is not well understood. Here, we develop two quantitative algorithms using deep learning to measure phosphorylated tau (p-tau) and TDP-43 (pTDP-43) pathology, which are both known to accumulate in the MTL and are associated with MTL neurodegeneration. We focus on these pathologies in the context of Alzheimer's disease (AD) and limbic predominant age-related TDP-43 encephalopathy (LATE) and apply our deep learning algorithms to distinct histology sections, on which MTL subregions were digitally annotated. We demonstrate that both quantitative pathology measures show high agreement with expert visual ratings of pathology and discriminate well between pathology stages. In 140 cases with antemortem MR imaging, we compare the association of semi-quantitative and quantitative postmortem measures of these pathologies in the hippocampus with in vivo structural measures of the MTL and its subregions. We find widespread associations of p-tau pathology with MTL subregional structural measures, whereas pTDP-43 pathology had more limited associations with the hippocampus and entorhinal cortex. Quantitative measurements of p-tau pathology resulted in a significantly better model of antemortem structural measures than semi-quantitative ratings and showed strong associations with cortical thickness and volume. By providing a more granular measure of pathology, the quantitative p-tau measures also showed a significant negative association with structure in a severe AD subgroup where semi-quantitative ratings displayed a ceiling effect. Our findings demonstrate the advantages of using quantitative neuropathology to understand the relationship of pathology to structure, particularly for p-tau, and motivate the use of quantitative pathology measurements in future studies., (© 2024. The Author(s).)

Astrocytes and microglia can adopt two distinct phenotypes in various pathological processes: neurotoxic A1/M1 and neuroprotective A2/M2. Recent evidence suggests that these cells play a significant role in epileptogenesis. The objective of this study was to characterize the phenotype of astrocytes and microglial cells in the hippocampus and temporal cortex of young male Wistar rats at 3 h, 1, 3, and 7 days after pentylenetetrazole-induced seizures. RT-qPCR was employed to examine the expression of glial genes (Gfap, Aif1, Slc1a1, Slc1a2, Slc1a3, Itpr2, Gdnf, Bdnf, Fgf2, Tgfb, Il1b, Tnf, Il1rn, Lcn2, S100a10, Nlrp3, Arg1). The most notable alterations in the expression of glial genes were observed on the first day following seizures in the temporal cortex. An increase in the expression of the Gfap, Slc1a2, Slc1a1, Il1b, Tnfa, Bdnf, and Fgf2 genes, and the A2 astrocyte condition marker S100a10, was observed. An increase in the expression of the Gfap and Slc1a2 genes was observed in the hippocampus on the first day after seizures. However, in contrast to the changes observed in the cortex, the changes in the hippocampus were opposite for the Il1rn, Bdnf, Tgfb, and Arg1 genes. Nevertheless, the alterations in GFAP and EAAT2 protein levels were not corroborated by Western blot analysis. Conversely, a more comprehensive immunohistochemical analysis confirmed an augmentation in the number of GFAP-positive cells in the hippocampus 1 day after seizures. Based on the presented evidence, we can conclude that a single convulsive seizure episode in 3-week-old rats results in transient astroglial activation and polarization to a neuroprotective phenotype (A2)., (© 2024 Wiley Periodicals LLC.)

Focal atrophy of the left anterior temporal lobe has been associated with the semantic type of primary progressive aphasia evolving to semantic dementia. In contrast, focal atrophy of the right temporal lobe has more recently been described as a controverse entity reported as the right temporal variant of FTD. We describe two cases of FTD dementia syndromes: in Case 1, atrophy of the right temporal lobe led to significant behavioural impairment and difficulties in recognizing known people. In Case 2, atrophy of the left temporal lobe was associated with severe aggressive, ritualistic behaviour and aphasia., (© 2024 The British Psychological Society.)

Objective: Socioemotional changes, rather than cognitive impairments, are the feature that defines behavioral variant frontotemporal dementia (bvFTD). Investigators have attributed the socioemotional changes in bvFTD and other dementias to frontal lobe dysfunction; however, recent work implies a further contribution from right anterior temporal disease. The authors evaluated relationships between regional brain atrophy and socioemotional changes in both bvFTD and early-onset Alzheimer's disease (EOAD)., Methods: This study explored the neuroanatomical correlations of performance on the Socioemotional Dysfunction Scale (SDS), an instrument previously shown to document socioemotional changes in bvFTD, among 13 patients with bvFTD not preselected for anterior temporal involvement and 16 age-matched patients with early-onset Alzheimer's disease (EOAD). SDS scores were correlated with volumes of regions of interest assessed with tensor-based morphometric analysis of MRI images., Results: As expected, the bvFTD group had significantly higher SDS scores overall and smaller frontal regions compared with the EOAD group, which in turn had smaller volumes in temporoparietal regions. SDS scores significantly correlated with lateral anterior temporal lobe (ATL) atrophy, and a regression analysis that controlled for diagnosis indicated that SDS scores predicted lateral ATL volume. Within the bvFTD group, higher SDS scores were associated with smaller lateral and right ATL regions, as well as a smaller orbitofrontal cortex. Within the EOAD group, higher SDS scores were associated with a smaller right parietal cortex., Conclusions: This study confirms that, in addition to orbitofrontal disease, there is a prominent right and lateral ATL origin of socioemotional changes in bvFTD and further suggests that right parietal involvement contributes to socioemotional changes in EOAD., Competing Interests: The authors report no financial relationships with commercial interests.

Sarcomatoid renal cell carcinoma typically signifies an exceptionally poor prognosis, with patients rarely surviving beyond one year. An 83-year-old male presented to our hospital with complaints of headache and left-sided limb weakness. Computed tomography (CT) scans of the head and lungs disclosed a mass within the right temporal lobe, accompanied by peritumoral edema in the right cerebral hemisphere. Brain magnetic resonance imaging (MRI) with contrast enhancement and diffusion-weighted imaging (DWI) delineated a mass in the right temporal lobe, measuring 3 × 3 × 3 cm. He underwent cytoreductive surgery successively in the neurosurgery and urology departments. Despite experiencing postoperative tumour recurrence, the patient has lived close to four years to date. This case report illustrates that cytoreductive surgery combined with systemic pharmacotherapy can still confer significant survival benefits for elderly patients.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a neurological disorder, characterized by cognitive deficits as one of its vital features. The nucleotide-binding oligomerization domain-like receptor (NLRP3) inflammasome is a key contributor to neuroinflammation and cognitive deficits in neurological diseases. However, the underlying mechanism of anti-NMDAR encephalitis remains unclear, and the biological function of the NLRP3 inflammasome in this condition has not been elucidated. In this study, a mouse model of anti-NMDAR encephalitis was induced by active immunization with the GluN1 356-385 peptide (NEA model). The NLRP3 inflammasome in the hippocampus and temporal cortex was investigated using real-time quantitative PCR (RT-qPCR), western blotting, and immunofluorescence staining. The impact of MCC950 on cognitive function and NLRP3 inflammation was assessed. Confocal immunofluorescence staining and Sholl analysis were employed to examine the function and morphology of microglia. In the current study, we discovered overactivation of the NLRP3 inflammasome and an enhanced inflammatory response in the NEA model, particularly in the hippocampus and temporal cortex. Furthermore, significant cognitive dysfunction was observed in the NEA model. While, MCC950, a selective inhibitor of the NLRP3 inflammasome, sharply attenuated the inflammatory response in mice, leading to mitigated cognitive deficits of mice and more regular arrangements of neurons and reduced number of hyperchromatic cells were also observed in the hippocampus area. In addition, we found that the excess elevation of NLRP3 inflammasome was mainly expressed in microglia accompanied with the overactivation of microglia, while MCC950 treatment significantly inhibited the increased number and activated morphological changes of microglia in the NEA model. Altogether, our study reveals the vital role of overactivated NLRP3 signaling pathway in aggravating the inflammatory response and cognitive deficits and the potential protective effect of MCC950 in anti-NMDAR encephalitis. Thus, MCC950 represents a promising strategy for anti-inflammation in anti-NMDAR encephalitis and our study lays a theoretical foundation for it to become a clinically targeted drug., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Accurate and scalable quantification of amyloid-β (Aβ) pathology is crucial for deeper disease phenotyping and furthering research in Alzheimer Disease (AD). This multidisciplinary study addresses the current limitations on neuropathology by leveraging a machine learning (ML) pipeline to perform a granular quantification of Aβ deposits and assess their distribution in the temporal lobe. Utilizing 131 whole-slide-images from consecutive autopsied cases at the University of California Davis Alzheimer Disease Research Center, our objectives were threefold: (1) Validate an automatic workflow for Aβ deposit quantification in white matter (WM) and gray matter (GM); (2) define the distributions of different Aβ deposit types in GM and WM, and (3) investigate correlates of Aβ deposits with dementia status and the presence of mixed pathology. Our methodology highlights the robustness and efficacy of the ML pipeline, demonstrating proficiency akin to experts' evaluations. We provide comprehensive insights into the quantification and distribution of Aβ deposits in the temporal GM and WM revealing a progressive increase in tandem with the severity of established diagnostic criteria (NIA-AA). We also present correlations of Aβ load with clinical diagnosis as well as presence/absence of mixed pathology. This study introduces a reproducible workflow, showcasing the practical use of ML approaches in the field of neuropathology, and use of the output data for correlative analyses. Acknowledging limitations, such as potential biases in the ML model and current ML classifications, we propose avenues for future research to refine and expand the methodology. We hope to contribute to the broader landscape of neuropathology advancements, ML applications, and precision medicine, paving the way for deep phenotyping of AD brain cases and establishing a foundation for further advancements in neuropathological research., (© 2024. The Author(s).)

Introduction: Although frontotemporal dementia (FTD) with right anterior temporal lobe (RATL) predominance has been recognized, a uniform description of the syndrome is still missing. This multicenter study aims to establish a cohesive clinical phenotype., Methods: Retrospective clinical data from 18 centers across 12 countries yielded 360 FTD patients with predominant RATL atrophy through initial neuroimaging assessments., Results: Common symptoms included mental rigidity/preoccupations (78%), disinhibition/socially inappropriate behavior (74%), naming/word-finding difficulties (70%), memory deficits (67%), apathy (65%), loss of empathy (65%), and face-recognition deficits (60%). Real-life examples unveiled impairments regarding landmarks, smells, sounds, tastes, and bodily sensations (74%). Cognitive test scores indicated deficits in emotion, people, social interactions, and visual semantics however, lacked objective assessments for mental rigidity and preoccupations., Discussion: This study cumulates the largest RATL cohort unveiling unique RATL symptoms subdued in prior diagnostic guidelines. Our novel approach, combining real-life examples with cognitive tests, offers clinicians a comprehensive toolkit for managing these patients., Highlights: This project is the first international collaboration and largest reported cohort. Further efforts are warranted for precise nomenclature reflecting neural mechanisms. Our results will serve as a clinical guideline for early and accurate diagnoses., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The functional importance of the anterior temporal lobes (ATLs) has come to prominence in two active, albeit unconnected literatures-(i) face recognition and (ii) semantic memory. To generate a unified account of the ATLs, we tested the predictions from each literature and examined the effects of bilateral versus unilateral ATL damage on face recognition, person knowledge, and semantic memory. Sixteen people with bilateral ATL atrophy from semantic dementia (SD), 17 people with unilateral ATL resection for temporal lobe epilepsy (TLE; left = 10, right = 7), and 14 controls completed tasks assessing perceptual face matching, person knowledge and general semantic memory. People with SD were impaired across all semantic tasks, including person knowledge. Despite commensurate total ATL damage, unilateral resection generated mild impairments, with minimal differences between left- and right-ATL resection. Face matching performance was largely preserved but slightly reduced in SD and right TLE. All groups displayed the familiarity effect in face matching; however, it was reduced in SD and right TLE and was aligned with the level of item-specific semantic knowledge in all participants. We propose a neurocognitive framework whereby the ATLs underpin a resilient bilateral representation system that supports semantic memory, person knowledge and face recognition., (© The Author(s) 2024. Published by Oxford University Press.)

Crossed cerebellar diaschisis (CCD) is a phenomenon of functional diaschisis that occurs after damage to the cerebral hemisphere and results in decreased activity of the cerebellum outside the primary focus. In this case report, we present the case of a patient admitted for seizures who was diagnosed with CCD due to Mesial temporal sclerosis (MTS). This event is generally observed in ischemic stroke cases and can occur epileptic seizure disorders. However, association of CCD with MTS is very rare. This article provides a comprehensive overview of CCD and related MRI findings to better understand their pathophysiology, clinical implications, and potential therapeutic approaches. The article highlights the importance of MRI in CCD detection and monitoring and discusses its usefulness in different clinical scenarios., (© 2024. The Author(s) under exclusive licence to Belgian Neurological Society.)

Reduced cerebral blood flow (CBF) in the temporoparietal region and gray matter volumes (GMVs) in the temporal lobe were previously reported in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). However, the temporal relationship between reductions in CBF and GMVs requires further investigation. This study sought to determine if reduced CBF is associated with reduced GMVs, or vice versa. Data came from 148 volunteers of the Cardiovascular Health Study Cognition Study (CHS-CS), including 58 normal controls (NC), 50 MCI, and 40 AD who had perfusion and structural MRIs during 2002-2003 (Time 2). Sixty-three of the 148 volunteers had follow-up perfusion and structural MRIs (Time 3). Forty out of the 63 volunteers received prior structural MRIs during 1997-1999 (Time 1). The relationships between GMVs and subsequent CBF changes, and between CBF and subsequent GMV changes were investigated. At Time 2, we observed smaller GMVs (p<0.05) in the temporal pole region in AD compared to NC and MCI. We also found associations between: (1) temporal pole GMVs at Time 2 and subsequent declines in CBF in this region (p=0.0014) and in the temporoparietal region (p=0.0032); (2) hippocampal GMVs at Time 2 and subsequent declines in CBF in the temporoparietal region (p=0.012); and (3) temporal pole CBF at Time 2 and subsequent changes in GMV in this region (p = 0.011). Therefore, hypoperfusion in the temporal pole may be an early event driving its atrophy. Perfusion declines in the temporoparietal and temporal pole follow atrophy in this temporal pole region.

Ganglioglioma is a rare primary tumour of the central nervous system, which characteristically contain both neuronal and glial neoplastic components mainly in children and adolescents. The most common clinical presentation is refractory epilepsy. The imaging findings of ganglioglioma are obvious and varied. However, ganglioglioma with normal neuroimaging is rare. We report a 12-year-old boy presented with intractable focal epilepsy with normal CT and almost negative MRI. The epileptogenic focus was found to be located in the left posterior superior temporal gyrus by comprehensive evaluation including PET-CT imaging and stereo electroencephalography monitoring. The epileptogenic focus was resected, and the histological examination of the surgical specimen confirmed ganglioglioma. He was seizure-free at last follow-up 14 months after surgery.

Background: Cortical thickness (CT) alterations, mismatch negativity (MMN) reductions, and cognitive deficits are robust findings in first-episode psychosis (FEP). However, most studies focused on medicated patients, leaving gaps in our understanding of the interrelationships between CT, MMN, neurocognition, and psychosocial functioning in unmedicated FEP. This study aimed to employ multiple mediation analysis to investigate potential pathways among these variables in unmedicated drug-naïve FEP., Methods: We enrolled 28 drug-naïve FEP and 34 age and sex-matched healthy controls. Clinical symptoms, neurocognition, psychosocial functioning, auditory duration MMN, and T1 structural magnetic resonance imaging data were collected. We measured CT in the superior temporal gyrus (STG), a primary MMN-generating region., Results: We found a significant negative correlation between MMN amplitude and bilateral CT of STG (CT&#95;STG) in FEP (left: r = -.709, P < .001; right: r = -.612, P = .008). Multiple mediation models revealed that a thinner left STG cortex affected functioning through both direct (24.66%) and indirect effects (75.34%). In contrast, the effects of the right CT&#95;STG on functioning were mainly mediated through MMN and neurocognitive pathways., Conclusions: Bilateral CT&#95;STG showed significant association with MMN, and MMN plays a mediating role between CT and cognition. Both MMN alone and its interaction with cognition mediated the effects of structural alterations on psychosocial function. The decline in overall function in FEP may stem from decreased CT&#95;STG, leading to subsequent MMN deficits and neurocognitive dysfunction. These findings underline the crucial role of MMN in elucidating how subtle structural alterations can impact neurocognition and psychosocial function in FEP., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Network neuroscience offers a unique framework to understand the organizational principles of the human brain. Despite recent progress, our understanding of how the brain is modulated by focal lesions remains incomplete. Resection of the temporal lobe is the most effective treatment to control seizures in pharmaco-resistant temporal lobe epilepsy (TLE), making this syndrome a powerful model to study lesional effects on network organization in young and middle-aged adults. Here, we assessed the downstream consequences of a focal lesion and its surgical resection on the brain's structural connectome, and explored how this reorganization relates to clinical variables at the individual patient level. We included adults with pharmaco-resistant TLE (n = 37) who underwent anterior temporal lobectomy between two imaging time points, as well as age- and sex-matched healthy controls who underwent comparable imaging (n = 31). Core to our analysis was the projection of high-dimensional structural connectome data-derived from diffusion MRI tractography from each subject-into lower-dimensional gradients. We then compared connectome gradients in patients relative to controls before surgery, tracked surgically-induced connectome reconfiguration from pre- to postoperative time points, and examined associations to patient-specific clinical and imaging phenotypes. Before surgery, individuals with TLE presented with marked connectome changes in bilateral temporo-parietal regions, reflecting an increased segregation of the ipsilateral anterior temporal lobe from the rest of the brain. Surgery-induced connectome reorganization was localized to this temporo-parietal subnetwork, but primarily involved postoperative integration of contralateral regions with the rest of the brain. Using a partial least-squares analysis, we uncovered a latent clinical imaging signature underlying this pre- to postoperative connectome reorganization, showing that patients who displayed postoperative integration in bilateral fronto-occipital cortices also had greater preoperative ipsilateral hippocampal atrophy, lower seizure frequency and secondarily generalized seizures. Our results bridge the effects of focal brain lesions and their surgical resections with large-scale network reorganization and interindividual clinical variability, thus offering new avenues to examine the fundamental malleability of the human brain., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The genetic architecture of Parkinson's disease (PD) is complex and multiple brain cell subtypes are involved in the neuropathological progression of the disease. Here we aimed to advance our understanding of PD genetic complexity at a cell subtype precision level. Using parallel single-nucleus (sn)RNA-seq and snATAC-seq analyses we simultaneously profiled the transcriptomic and chromatin accessibility landscapes in temporal cortex tissues from 12 PD compared to 12 control subjects at a granular single cell resolution. An integrative bioinformatic pipeline was developed and applied for the analyses of these snMulti-omics datasets. The results identified a subpopulation of cortical glutamatergic excitatory neurons with remarkably altered gene expression in PD, including differentially-expressed genes within PD risk loci identified in genome-wide association studies (GWAS). This was the only neuronal subtype showing significant and robust overexpression of SNCA. Further characterization of this neuronal-subpopulation showed upregulation of specific pathways related to axon guidance, neurite outgrowth and post-synaptic structure, and downregulated pathways involved in presynaptic organization and calcium response. Additionally, we characterized the roles of three molecular mechanisms in governing PD-associated cell subtype-specific dysregulation of gene expression: (1) changes in cis-regulatory element accessibility to transcriptional machinery; (2) changes in the abundance of master transcriptional regulators, including YY1, SP3, and KLF16; (3) candidate regulatory variants in high linkage disequilibrium with PD-GWAS genomic variants impacting transcription factor binding affinities. To our knowledge, this study is the first and the most comprehensive interrogation of the multi-omics landscape of PD at a cell-subtype resolution. Our findings provide new insights into a precise glutamatergic neuronal cell subtype, causal genes, and non-coding regulatory variants underlying the neuropathological progression of PD, paving the way for the development of cell- and gene-targeted therapeutics to halt disease progression as well as genetic biomarkers for early preclinical diagnosis., (© 2024. The Author(s).)

Objective: We investigated how well a visual associative learning task discriminates Alzheimer's disease (AD) dementia from other types of dementia and how it relates to AD pathology., Methods: 3,599 patients (63.9 ± 8.9 years old, 41% female) from the Amsterdam Dementia Cohort completed two sets of the Visual Association Test (VAT) in a single test session and underwent magnetic resonance imaging. We performed receiver operating curve analysis to investigate the VAT's discriminatory ability between AD dementia and other diagnoses and compared it to that of other episodic memory tests. We tested associations between VAT performance and medial temporal lobe atrophy (MTA), and amyloid status ( n = 2,769, 77%)., Results: Patients with AD dementia performed worse on the VAT than all other patients. The VAT discriminated well between AD and other types of dementia (area under the curve range 0.70-0.86), better than other episodic memory tests. Six-hundred forty patients (17.8%) learned all associations on VAT-A, but not on VAT-B, and they were more likely to have higher MTA scores (odds ratios range 1.63 (MTA 0.5) through 5.13 for MTA ≥ 3, all p < .001) and to be amyloid positive (odds ratio = 3.38, 95%CI = [2.71, 4.22], p < .001) than patients who learned all associations on both sets., Conclusions: Performance on the VAT, especially on a second set administered immediately after the first, discriminates AD from other types of dementia and is associated with MTA and amyloid positivity. The VAT might be a useful, simple tool to assess early episodic memory deficits in the presence of AD pathology.

Background: Persistent auditory verbal hallucinations (pAVHs) are a fundamental manifestation of schizophrenia (SCZ), yet the exact connection between pAVHs and brain structure remains contentious. This study aims to explore the potential correlation between pAVHs and alterations in grey matter volume (GMV) within specific brain regions among individuals diagnosed with SCZ., Methods: 76 SCZ patients with pAVHs (pAVH group), 57 SCZ patients without AVHs (non-AVH group), and 83 healthy controls (HC group) were investigated using 3 T magnetic resonance imaging. The P3 hallucination item of the Positive and Negative Syndrome Scale was used to assess the severity of pAVHs. Voxel-based morphometry was used to analyze the GMV profile between the three groups., Results: Compared to the non-AVH and HC groups, the pAVH group exhibited extensive reduction in GMV within the frontotemporal cortex. Conversely, no significant difference in GMV was observed between the non-AVH and HC groups. The severity of pAVHs showed a negative correlation with GMV in several regions, including the right fusiform, right inferior temporal, right medial orbitofrontal, right superior frontal, and right temporal pole (p = 0.0036, Bonferroni correction). Stepwise linear regression analysis revealed that GMV in the right temporal pole (β = -0.29, p = 0.001) and right fusiform (β = -0.21, p = 0.01) were significantly associated with the severity of pAVHs., Conclusions: Widespread reduction in GMV is observed within the frontotemporal cortex, particularly involving the right temporal pole and right fusiform, which potentially contribute to the pathogenesis of pAVHs in individuals with chronic SCZ., Competing Interests: Declaration of competing interest None of the authors have competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Semantic behavioral variant frontotemporal dementia (sbvFTD) is a neurodegenerative condition presenting with specific behavioral and semantic derangements and predominant atrophy of the right anterior temporal lobe (ATL). The objective was to evaluate clinical, neuropsychological, neuroimaging, and genetic features of an Italian sbvFTD cohort, defined according to recently proposed guidelines, compared to semantic variant primary progressive aphasia (svPPA) and behavioral variant FTD (bvFTD) patients., Methods: Fifteen sbvFTD, sixty-three bvFTD, and twenty-five svPPA patients and forty controls were enrolled. Patients underwent clinical, cognitive evaluations, and brain MRI. Symptoms of bvFTD patients between onset and first visit were retrospectively recorded and classified as early and late. Grey matter atrophy was investigated using voxel-based morphometry., Results: sbvFTD experienced early criteria-specific symptoms: world, object and person-specific semantic loss (67%), complex compulsions and rigid thought (60%). Sequentially, more behavioral symptoms emerged (apathy/inertia, loss of empathy) along with non-criteria-specific symptoms (anxiety, suspiciousness). sbvFTD showed sparing of attentive/executive functions, especially compared to bvFTD and better language functions compared to svPPA. All sbvFTD patients failed at the famous face recognition test and more than 80% failed in understanding written metaphors and humor. At MRI, sbvFTD had predominant right ATL atrophy, almost specular to svPPA. Three sbvFTD patients presented pathogenic genetic variants., Conclusion: We replicated the application of sbvFTD diagnostic guidelines in an independent Italian cohort, demonstrating that the presence of person-specific semantic knowledge loss and mental rigidity, along with preserved executive functions and a predominant right ATL atrophy with sparing of frontal lobes, should prompt a diagnosis of sbvFTD., (© 2024. The Author(s).)

Our current understanding of the spread and neurodegenerative effects of tau neurofibrillary tangles (NFTs) within the medial temporal lobe (MTL) during the early stages of Alzheimer's Disease (AD) is limited by the presence of confounding non-AD pathologies and the two-dimensional (2-D) nature of conventional histology studies. Here, we combine ex vivo MRI and serial histological imaging from 25 human MTL specimens to present a detailed, 3-D characterization of quantitative NFT burden measures in the space of a high-resolution, ex vivo atlas with cytoarchitecturally-defined subregion labels, that can be used to inform future in vivo neuroimaging studies. Average maps show a clear anterior to poster gradient in NFT distribution and a precise, spatial pattern with highest levels of NFTs found not just within the transentorhinal region but also the cornu ammonis (CA1) subfield. Additionally, we identify granular MTL regions where measures of neurodegeneration are likely to be linked to NFTs specifically, and thus potentially more sensitive as early AD biomarkers., (© 2024. The Author(s).)

Introduction: Typical MRI measures of neurodegeneration have limited sensitivity in early disease stages. Diffusion MRI (dMRI) microstructural measures may allow for detection in preclinical stages., Methods: Participants had dMRI and either beta-amyloid PET or plasma biomarkers of Alzheimer's pathology within 18 months of MRI. Microstructure was measured in portions of the medial temporal lobe (MTL) with high neurofibrillary tangle (NFT) burden based on a previously developed post mortem 3D-map. Regressions examined relationships between microstructure and markers of Alzheimer's pathology in preclinical disease and then across disease stages., Results: There was higher isometric volume fraction in amyloid-positive compared to amyloid-negative cognitively unimpaired individuals in high tangle MTL regions. Similarly, plasma biomarkers and 18 F-flortaucipir were associated with microstructural changes in preclinical disease. Additional microstructural effects were seen across disease stages., Discussion: Combining a post mortem atlas of NFT pathology with microstructural measures allows for detection of neurodegeneration in preclinical Alzheimer's disease. Highlights Typical markers of neurodegeneration are not sensitive in preclinical Alzheimer's. dMRI measured microstructure in regions with high NFT. Microstructural changes occur in medial temporal regions in preclinical disease. Microstructural changes occur in other typical Alzheimer's regions in later stages. Combining post mortem pathology atlases with in vivo MRI is a powerful framework., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Frontotemporal lobe abnormalities are linked to neuropsychiatric disorders and cognition, but the role of cellular heterogeneity between temporal lobe (TL) and frontal lobe (FL) in the vulnerability to genetic risk factors remains to be elucidated. We integrated single-nucleus transcriptome analysis in 'fresh' human FL and TL with genetic susceptibility, gene dysregulation in neuropsychiatric disease and psychoactive drug response data. We show how intrinsic differences between TL and FL contribute to the vulnerability of specific cell types to both genetic risk factors and psychoactive drugs. Neuronal populations, specifically PVALB neurons, were most highly vulnerable to genetic risk factors for psychiatric disease. These psychiatric disease-associated genes were mostly upregulated in the TL, and dysregulated in the brain of patients with obsessive-compulsive disorder, bipolar disorder and schizophrenia. Among these genes, GRIN2A and SLC12A5, implicated in schizophrenia and bipolar disorder, were significantly upregulated in TL PVALB neurons and in psychiatric disease patients' brain. PVALB neurons from the TL were twofold more vulnerable to psychoactive drugs than to genetic risk factors, showing the influence and specificity of frontotemporal lobe differences on cell vulnerabilities. These studies provide a cell type resolved map of the impact of brain regional differences on cell type vulnerabilities in neuropsychiatric disorders.

Introduction: Animal research has shown that tau pathology in the locus coeruleus (LC) is associated with reduced norepinephrine signaling, lower projection density to the medial temporal lobe (MTL), atrophy, and cognitive impairment. We investigated the contribution of LC-MTL functional connectivity (FC LC-MTL ) on cortical atrophy across Braak stage regions and its impact on cognition., Methods: We analyzed functional magnetic resonance imaging and amyloid beta (Aβ) positron emission tomography data from 128 cognitively normal participants, associating novelty-related FC LC-MTL with longitudinal atrophy and cognition with and without Aβ moderation., Results: Cross-sectionally, lower FC LC-MTL was associated with atrophy in Braak stage II regions. Longitudinally, atrophy in Braak stage 2 to 4 regions related to lower baseline FC LC-MTL at elevated levels of Aβ, but not to other regions. Atrophy in Braak stage 2 regions mediated the relation between FC LC-MTL and subsequent cognitive decline., Discussion: FC LC-MTL is implicated in Aβ-related cortical atrophy, suggesting that LC-MTL connectivity could confer neuroprotective effects in preclinical AD., Highlights: Novelty-related functional magnetic resonance imaging (fMRI) LC-medial temporal lobe (MTL) connectivity links to longitudinal Aβ-dependent atrophy. This relationship extended to higher Braak stage regions with increasing Aβ burden. Longitudinal MTL atrophy mediated the LC-MTL connectivity-cognition relationship. Our findings mirror the animal data on MTL atrophy following NE signal dysfunction., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Mild mesial temporal lobe epilepsy (MTLE) patients may remain untreated for a considerable time after disease onset or achieve seizure control with a single anti-seizures medication (ASM). Thus, they represent an optimal population to investigate whether ASMs might have influence on brain structure. We consecutively enrolled 56 mild MTLE patients (22/56 untreated, 34/56 on-monotherapy) and 58 healthy controls, matched for age and gender. All subjects underwent 3T-brain MRI, using FreeSurfer for automated morphometry. Differences in gray matter were assessed using one-way Analysis of Covariance (ANCOVA), adjusting for age, disease duration and intracranial volume. No significant change was observed between treated and untreated patients. We observed a significant reduction in cortical thickness of left inferior parietal, inferior temporal, middle temporal gyri, and right inferior parietal gyrus, temporal pole in monotherapy patients compared to healthy controls, as well as an increase in left isthmus of cingulate gyrus in untreated MTLE subjects compared to controls. Surface and subcortical volumes analysis revealed no differences among groups. Our study demonstrated no substantial morphological abnormalities between untreated mild MTLE patients and those undergoing monotherapy. Although exploratory, these results may reassure about safety of commonly used drugs and their marginal role in influencing neuroimaging results. PLAIN LANGUAGE SUMMARY: This study investigated the following question: can medications against epileptic seizures have an effect on brain structure in mild mesial temporal lobe? Preliminary results from our analyses suggest not, as we did not find any difference in brain gray matter between untreated patients and those treated with a single anti-seizures medication. On the other hand, epilepsy patients presented cortical thinning compared to healthy controls in several regions of the temporal and parietal lobes, in line with previous studies investigating the disease., (© 2024 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

This systematic review examines the role of dosimetric parameters in predicting temporal lobe necrosis (TLN) risk in nasopharyngeal carcinoma (NPC) patients treated with three-dimensional conformal RT (3D-CRT), intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT). TLN is a serious late complication that can adversely affect the quality of life of NPC patients. Understanding the relationship between dosimetric parameters and TLN can guide treatment planning and minimize radiation-related complications. A comprehensive search identified relevant studies published up to July 2023. Studies reporting on dosimetric parameters and TLN in NPC patients undergoing 3D-CRT, IMRT, and VMAT were included. TLN incidence, follow-up duration, and correlation with dosimetric parameters of the temporal lobe were analyzed. The review included 30 studies with median follow-up durations ranging from 28 to 110 months. The crude incidence of TLN varied from 2.3 % to 47.3 % and the average crude incidence of TLN is approximately 14 %. Dmax and D1cc emerged as potential predictors of TLN in 3D-CRT and IMRT-treated NPC patients. Threshold values of >72 Gy for Dmax and >62 Gy for D1cc were associated with increased TLN risk. However, other factors should also be considered, including host characteristics, tumor-specific features and therapeutic factors. In conclusion, this systematic review highlights the significance of dosimetric parameters, particularly Dmax and D1cc, in predicting TLN risk in NPC patients undergoing 3D-CRT, IMRT, and VMAT. The findings provide valuable insights that can help in developing optimal treatment planning strategies and contribute to the development of clinical guidelines in this field., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) plaques, neurofibrillary tau tangles, and neurodegeneration in the brain parenchyma. Here, we aimed to (i) assess differences in blood and imaging biomarkers used to evaluate neurodegeneration among cognitively unimpaired APOE ε4 homozygotes, heterozygotes, and non-carriers with varying risk for sporadic AD, and (ii) to determine how different cerebral pathologies (i.e., Aβ deposition, medial temporal atrophy, and cerebrovascular pathology) contribute to blood biomarker concentrations in this sample., Methods: Sixty APOE ε4 homozygotes (n = 19), heterozygotes (n = 21), and non-carriers (n = 20) ranging from 60 to 75 years, were recruited in collaboration with Auria biobank (Turku, Finland). Participants underwent Aβ-PET ([ 11 C]PiB), structural brain MRI including T1-weighted and T2-FLAIR sequences, and blood sampling for measuring serum neurofilament light chain (NfL), plasma total tau (t-tau), plasma N-terminal tau fragments (NTA-tau) and plasma glial fibrillary acidic protein (GFAP). [ 11 C]PiB standardized uptake value ratio was calculated for regions typical for Aβ accumulation in AD. MRI images were analysed for regional volumes, atrophy scores, and volumes of white matter hyperintensities. Differences in biomarker levels and associations between blood and imaging biomarkers were tested using uni- and multivariable linear models (unadjusted and adjusted for age and sex)., Results: Serum NfL concentration was increased in APOE ε4 homozygotes compared with non-carriers (mean 21.4 pg/ml (SD 9.5) vs. 15.5 pg/ml (3.8), p = 0.013), whereas other blood biomarkers did not differ between the groups (p > 0.077 for all). From imaging biomarkers, hippocampal volume was significantly decreased in APOE ε4 homozygotes compared with non-carriers (6.71 ml (0.86) vs. 7.2 ml (0.7), p = 0.029). In the whole sample, blood biomarker levels were differently predicted by the three measured cerebral pathologies; serum NfL concentration was associated with cerebrovascular pathology and medial temporal atrophy, while plasma NTA-tau associated with medial temporal atrophy. Plasma GFAP showed significant association with both medial temporal atrophy and Aβ pathology. Plasma t-tau concentration did not associate with any of the measured pathologies., Conclusions: Only increased serum NfL concentrations and decreased hippocampal volume was observed in cognitively unimpaired APOEε4 homozygotes compared to non-carriers. In the whole population the concentrations of blood biomarkers were affected in distinct ways by different pathologies., (© 2024. The Author(s).)

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., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

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., (© 2024 The Authors. Hippocampus published by Wiley Periodicals LLC.)

Gender dysphoria and autism spectrum disorder (ASD) co-occur at high rates. Yet, it is unknown whether gender dysphoria and ASD are associated with common or distinct neurobiological correlates or how they relate to experiences of gender-related body incongruence. Using the Social Responsiveness Scale, we assessed autistic traits in 99 transgender and 99 cisgender individuals and investigated their associations with gender-related body incongruence, measured via a visually based "Body Morph" test, and with cortical thickness in the brain. Autistic traits were significantly higher among transgender individuals, and those with higher autistic traits had higher body incongruence scoring. Among transgender individuals, higher autistic traits were linked with a thinner cortex bilaterally in the temporal pole and the superior and inferior temporal gyri. Autistic traits were only partly associated with cortical morphology patterns previously reported in transgender individuals; instead, they were primarily linked to temporal lobe areas mediating social cognition. While replicating the previous literature on the increased prevalence of autistic traits among transgender individuals, this study reports specific regions in the brains of transgender individuals where cortical thickness is associated with autistic traits., (© 2024. The Author(s).)

Autopsy studies indicated that the locus coeruleus (LC) accumulates hyperphosphorylated tau before allocortical regions in Alzheimer's disease. By combining in vivo longitudinal magnetic resonance imaging measures of LC integrity, tau positron emission tomography imaging and cognition with autopsy data and transcriptomic information, we examined whether LC changes precede allocortical tau deposition and whether specific genetic features underlie LC's selective vulnerability to tau. We found that LC integrity changes preceded medial temporal lobe tau accumulation, and together these processes were associated with lower cognitive performance. Common gene expression profiles between LC-medial temporal lobe-limbic regions map to biological functions in protein transport regulation. These findings advance our understanding of the spatiotemporal patterns of initial tau spreading from the LC and LC's selective vulnerability to Alzheimer's disease pathology. LC integrity measures can be a promising indicator for identifying the time window when individuals are at risk of disease progression and underscore the importance of interventions mitigating initial tau spread., (© 2024. The Author(s).)

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., (© 2024 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

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., (© 2024 The Authors. Hippocampus published by Wiley Periodicals LLC.)