ABSTRACT
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.
Subject(s)
Epilepsy, Temporal Lobe , Facial Recognition , Semantics , Temporal Lobe , Humans , Male , Female , Middle Aged , Temporal Lobe/surgery , Temporal Lobe/diagnostic imaging , Temporal Lobe/pathology , Adult , Facial Recognition/physiology , Epilepsy, Temporal Lobe/surgery , Epilepsy, Temporal Lobe/psychology , Epilepsy, Temporal Lobe/physiopathology , Recognition, Psychology/physiology , Functional Laterality/physiology , Neuropsychological Tests , Memory/physiology , Aged , FaceABSTRACT
Accurate and scalable quantification of amyloid-ß (Aß) 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 Aß 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 Aß deposit quantification in white matter (WM) and gray matter (GM); (2) define the distributions of different Aß deposit types in GM and WM, and (3) investigate correlates of Aß 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 Aß 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 Aß 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.
Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Machine Learning , Temporal Lobe , Humans , Temporal Lobe/pathology , Temporal Lobe/metabolism , Amyloid beta-Peptides/metabolism , Female , Male , Aged , Aged, 80 and over , Alzheimer Disease/pathology , Alzheimer Disease/metabolism , Tissue Banks , Gray Matter/pathology , Gray Matter/metabolism , White Matter/pathology , White Matter/metabolism , Plaque, Amyloid/pathology , Plaque, Amyloid/metabolism , Middle AgedSubject(s)
Cerebral Infarction , Intracranial Thrombosis , Magnetic Resonance Imaging , Venous Thrombosis , Humans , Male , Female , Middle Aged , Adult , Retrospective Studies , Venous Thrombosis/pathology , Intracranial Thrombosis/pathology , Intracranial Thrombosis/diagnostic imaging , Intracranial Thrombosis/metabolism , Young Adult , Cerebral Infarction/pathology , Cerebral Infarction/diagnostic imaging , Cerebral Infarction/metabolism , Fibrin Fibrinogen Degradation Products/metabolism , Headache/etiology , Cerebral Cortex/pathology , Cerebral Cortex/blood supply , Cerebral Cortex/diagnostic imaging , Diagnosis, Differential , Temporal Lobe/pathology , Temporal Lobe/diagnostic imaging , Cerebral Hemorrhage/diagnostic imaging , Cerebral Hemorrhage/pathology , Seizures/etiology , Brain Edema/pathology , Frontal Lobe/pathology , Frontal Lobe/diagnostic imaging , Frontal Lobe/blood supplyABSTRACT
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.
Subject(s)
Gene Regulatory Networks , Neurons , Parkinson Disease , Humans , Parkinson Disease/genetics , Parkinson Disease/metabolism , Parkinson Disease/pathology , Neurons/metabolism , Neurons/pathology , Male , Female , alpha-Synuclein/genetics , alpha-Synuclein/metabolism , Aged , YY1 Transcription Factor/genetics , YY1 Transcription Factor/metabolism , Genome-Wide Association Study , Transcriptome , Single-Cell Analysis , Temporal Lobe/metabolism , Temporal Lobe/pathology , Middle Aged , Gene Expression Regulation/genetics , MultiomicsABSTRACT
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.
Subject(s)
Alzheimer Disease , Magnetic Resonance Imaging , Neurofibrillary Tangles , Temporal Lobe , tau Proteins , Humans , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Temporal Lobe/diagnostic imaging , Temporal Lobe/metabolism , Temporal Lobe/pathology , tau Proteins/metabolism , Male , Female , Aged , Magnetic Resonance Imaging/methods , Neurofibrillary Tangles/metabolism , Neurofibrillary Tangles/pathology , Aged, 80 and over , Autopsy , Neuroimaging/methods , Middle Aged , Postmortem ImagingABSTRACT
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 GluN1356-385 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.
Subject(s)
Anti-N-Methyl-D-Aspartate Receptor Encephalitis , Cognitive Dysfunction , Disease Models, Animal , Hippocampus , Indenes , Inflammasomes , Microglia , NLR Family, Pyrin Domain-Containing 3 Protein , Sulfonamides , Animals , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , Cognitive Dysfunction/drug therapy , Cognitive Dysfunction/immunology , Cognitive Dysfunction/etiology , Inflammasomes/metabolism , Inflammasomes/antagonists & inhibitors , Inflammasomes/immunology , Mice , Hippocampus/drug effects , Hippocampus/pathology , Hippocampus/metabolism , Hippocampus/immunology , Anti-N-Methyl-D-Aspartate Receptor Encephalitis/immunology , Anti-N-Methyl-D-Aspartate Receptor Encephalitis/drug therapy , Indenes/therapeutic use , Sulfonamides/therapeutic use , Sulfonamides/pharmacology , Microglia/drug effects , Microglia/immunology , Furans/therapeutic use , Furans/pharmacology , Sulfones/therapeutic use , Sulfones/pharmacology , Mice, Inbred C57BL , Female , Heterocyclic Compounds, 4 or More Rings/therapeutic use , Heterocyclic Compounds, 4 or More Rings/pharmacology , Humans , Male , Temporal Lobe/pathologyABSTRACT
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.
Subject(s)
Frontal Lobe , Mental Disorders , Psychotropic Drugs , Temporal Lobe , Humans , Psychotropic Drugs/pharmacology , Frontal Lobe/metabolism , Frontal Lobe/pathology , Temporal Lobe/metabolism , Temporal Lobe/pathology , Mental Disorders/genetics , Mental Disorders/metabolism , Neurons/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Receptors, N-Methyl-D-Aspartate/genetics , Genetic Predisposition to Disease , Gene Expression Profiling , Transcriptome , Gene Expression Regulation , Schizophrenia/genetics , Schizophrenia/metabolism , Bipolar Disorder/genetics , Bipolar Disorder/metabolismABSTRACT
Background: Emerging diagnostic modalities suggest that miRNA profiles within extracellular vesicles (EVs) isolated from peripheral blood specimens may provide a non-invasive diagnostic alternative for dementia and neurodegenerative disorders. Given that EVs confer a protective environment against miRNA enzymatic degradation, the miRNAs enriched in the EV fraction of blood samples could serve as more stable and clinically relevant biomarkers compared to those obtained from serum. Objective: To compare miRNAs isolated from EVs versus serum in blood taken from Alzheimer's disease (AD) dementia patients and control cohorts. Methods: We compared 25 AD patients to 34 individuals who exhibited no cognitive impairments (NCI). Subjects were Singapore residents with Chinese heritage. miRNAs purified from serum versus blood-derived EVs were analyzed for associations with AD dementia and medial temporal atrophy detected by magnetic resonance imaging. Results: Compared to serum-miRNAs, we identified almost twice as many EV-miRNAs associated with AD dementia, and they also correlated more significantly with medial temporal atrophy, a neuroimaging marker of AD-brain pathology. We further developed combination panels of serum-miRNAs and EV-miRNAs with improved performance in identifying AD dementia. Dominant in both panels was miRNA-1290. Conclusions: This data indicates that miRNA profiling from EVs offers diagnostic superiority. This underscores the role of EVs as vectors harboring prognostic biomarkers for neurodegenerative disorders and suggests their potential in yielding novel biomarkers for AD diagnosis.
Subject(s)
Alzheimer Disease , Atrophy , Biomarkers , Extracellular Vesicles , MicroRNAs , Temporal Lobe , Humans , Alzheimer Disease/genetics , Alzheimer Disease/diagnosis , Alzheimer Disease/blood , Extracellular Vesicles/metabolism , Extracellular Vesicles/genetics , MicroRNAs/blood , MicroRNAs/genetics , Male , Female , Aged , Biomarkers/blood , Temporal Lobe/pathology , Temporal Lobe/diagnostic imaging , Magnetic Resonance Imaging , Middle Aged , Aged, 80 and overABSTRACT
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 (ß = -0.29, p = 0.001) and right fusiform (ß = -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.
Subject(s)
Gray Matter , Hallucinations , Magnetic Resonance Imaging , Schizophrenia , Temporal Lobe , Humans , Schizophrenia/diagnostic imaging , Schizophrenia/pathology , Hallucinations/diagnostic imaging , Hallucinations/etiology , Hallucinations/pathology , Hallucinations/physiopathology , Male , Female , Adult , Gray Matter/diagnostic imaging , Gray Matter/pathology , Temporal Lobe/diagnostic imaging , Temporal Lobe/pathology , Chronic Disease , Frontal Lobe/diagnostic imaging , Frontal Lobe/pathology , Middle Aged , Young Adult , China , East Asian PeopleABSTRACT
BACKGROUND: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-ß (Aß) 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., Aß 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 Aß-PET ([11C]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). [11C]PiB standardized uptake value ratio was calculated for regions typical for Aß 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 Aß 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.
Subject(s)
Amyloid beta-Peptides , Apolipoprotein E4 , Atrophy , Biomarkers , Positron-Emission Tomography , tau Proteins , Humans , Female , Male , Aged , Biomarkers/blood , Atrophy/pathology , Middle Aged , Apolipoprotein E4/genetics , tau Proteins/blood , Amyloid beta-Peptides/blood , Magnetic Resonance Imaging/methods , Neurofilament Proteins/blood , Temporal Lobe/diagnostic imaging , Temporal Lobe/pathology , Alzheimer Disease/blood , Alzheimer Disease/genetics , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/pathology , Heterozygote , Glial Fibrillary Acidic Protein/blood , Aniline Compounds , ThiazolesABSTRACT
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 18F-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.
Subject(s)
Alzheimer Disease , Biomarkers , Gray Matter , Positron-Emission Tomography , Temporal Lobe , Humans , Alzheimer Disease/pathology , Alzheimer Disease/diagnostic imaging , Temporal Lobe/pathology , Temporal Lobe/diagnostic imaging , Male , Female , Aged , Gray Matter/pathology , Gray Matter/diagnostic imaging , Biomarkers/blood , Amyloid beta-Peptides/metabolism , Neurofibrillary Tangles/pathology , Diffusion Magnetic Resonance ImagingABSTRACT
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.
Subject(s)
Anterior Temporal Lobectomy , Connectome , Epilepsy, Temporal Lobe , Temporal Lobe , Humans , Female , Male , Adult , Epilepsy, Temporal Lobe/surgery , Epilepsy, Temporal Lobe/physiopathology , Epilepsy, Temporal Lobe/diagnostic imaging , Epilepsy, Temporal Lobe/pathology , Temporal Lobe/pathology , Temporal Lobe/surgery , Temporal Lobe/diagnostic imaging , Anterior Temporal Lobectomy/methods , Middle Aged , Young Adult , Diffusion Tensor Imaging , Nerve Net/diagnostic imaging , Nerve Net/pathology , Drug Resistant Epilepsy/surgery , Drug Resistant Epilepsy/diagnostic imaging , Drug Resistant Epilepsy/physiopathology , Drug Resistant Epilepsy/pathologyABSTRACT
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.
Subject(s)
Attention Deficit Disorder with Hyperactivity , Child , Infant, Newborn , Humans , Selection Bias , Attention Deficit Disorder with Hyperactivity/pathology , Probability , Bias , Temporal Lobe/pathologyABSTRACT
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.
Subject(s)
Alzheimer Disease , Cognition , Locus Coeruleus , Positron-Emission Tomography , tau Proteins , Locus Coeruleus/metabolism , Locus Coeruleus/diagnostic imaging , Locus Coeruleus/pathology , Humans , tau Proteins/metabolism , tau Proteins/genetics , Alzheimer Disease/metabolism , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/pathology , Alzheimer Disease/genetics , Cognition/physiology , Male , Female , Aged , Magnetic Resonance Imaging , Aged, 80 and over , Temporal Lobe/metabolism , Temporal Lobe/diagnostic imaging , Temporal Lobe/pathologyABSTRACT
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 (FCLC-MTL) on cortical atrophy across Braak stage regions and its impact on cognition. METHODS: We analyzed functional magnetic resonance imaging and amyloid beta (Aß) positron emission tomography data from 128 cognitively normal participants, associating novelty-related FCLC-MTL with longitudinal atrophy and cognition with and without Aß moderation. RESULTS: Cross-sectionally, lower FCLC-MTL was associated with atrophy in Braak stage II regions. Longitudinally, atrophy in Braak stage 2 to 4 regions related to lower baseline FCLC-MTL at elevated levels of Aß, but not to other regions. Atrophy in Braak stage 2 regions mediated the relation between FCLC-MTL and subsequent cognitive decline. DISCUSSION: FCLC-MTL is implicated in Aß-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 Aß-dependent atrophy. This relationship extended to higher Braak stage regions with increasing Aß burden. Longitudinal MTL atrophy mediated the LC-MTL connectivity-cognition relationship. Our findings mirror the animal data on MTL atrophy following NE signal dysfunction.
Subject(s)
Alzheimer Disease , Atrophy , Cognitive Dysfunction , Locus Coeruleus , Magnetic Resonance Imaging , Positron-Emission Tomography , Humans , Locus Coeruleus/diagnostic imaging , Locus Coeruleus/pathology , Male , Female , Atrophy/pathology , Cognitive Dysfunction/diagnostic imaging , Cognitive Dysfunction/pathology , Aged , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/pathology , Cross-Sectional Studies , Temporal Lobe/pathology , Temporal Lobe/diagnostic imaging , Amyloid beta-Peptides/metabolism , Longitudinal Studies , Neural Pathways/diagnostic imaging , Neural Pathways/pathologyABSTRACT
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_STG) in FEP (left: râ =â -.709, Pâ <â .001; right: râ =â -.612, Pâ =â .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_STG on functioning were mainly mediated through MMN and neurocognitive pathways. CONCLUSIONS: Bilateral CT_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_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.
Subject(s)
Cognitive Dysfunction , Magnetic Resonance Imaging , Psychosocial Functioning , Psychotic Disorders , Humans , Male , Psychotic Disorders/physiopathology , Psychotic Disorders/diagnostic imaging , Psychotic Disorders/pathology , Female , Adult , Young Adult , Cognitive Dysfunction/physiopathology , Cognitive Dysfunction/diagnostic imaging , Cognitive Dysfunction/etiology , Temporal Lobe/physiopathology , Temporal Lobe/diagnostic imaging , Temporal Lobe/pathology , Evoked Potentials, Auditory/physiology , Electroencephalography , Cerebral Cortex/diagnostic imaging , Cerebral Cortex/physiopathology , Cerebral Cortex/pathology , Brain Cortical Thickness , Adolescent , Auditory Perception/physiology , Mediation AnalysisABSTRACT
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.
Subject(s)
Sclerosis , Humans , Sclerosis/diagnostic imaging , Temporal Lobe/diagnostic imaging , Temporal Lobe/pathology , Magnetic Resonance Imaging , Male , Cerebellar Diseases/diagnostic imaging , Cerebellar Diseases/complications , Female , Cerebellum/diagnostic imaging , Cerebellum/pathology , Middle Aged , Hippocampal SclerosisABSTRACT
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.
Subject(s)
Atrophy , Frontotemporal Dementia , Magnetic Resonance Imaging , Humans , Frontotemporal Dementia/pathology , Frontotemporal Dementia/diagnostic imaging , Frontotemporal Dementia/physiopathology , Female , Italy , Male , Middle Aged , Aged , Atrophy/pathology , Temporal Lobe/pathology , Temporal Lobe/diagnostic imaging , Cohort Studies , Neuropsychological Tests , Aphasia, Primary Progressive/pathology , Aphasia, Primary Progressive/diagnostic imaging , Retrospective Studies , Gray Matter/pathology , Gray Matter/diagnostic imagingABSTRACT
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.