Biology subjects

Irwin, D. J.

Publications and source records attributed to Irwin, D. J..

9 recordsLinked to original sources

bioRxiv2026

Microglial reactivity in the hippocampal CA2 is associated with advanced neuronal α-synulceinopathy

Lewy body diseases are thought to evolve by the spread of intraneuronal -synuclein pathology. However, staging models of -synuclein pathology in the human brain seldom evaluate regions with direct synaptic connectivity to model microglial processes in disease. Here, we address this gap by testing the hypothesis that, within the well-defined synaptic connectivity of the intrahippocampal circuit, neuronal -synuclein pathology is associated with microglial reactivity. We selected a cohort of autopsy-confirmed Lewy body disease patients with hippocampal neuronal -synuclein pathology and minimal age-related co-pathologies (n=62) and as a control for other intraneuronal hippocampal pathology, we used a cohort of cognitively healthy patients with focal hippocampal tau accumulation with minimal amyloid plaques, termed primary age-related tauopathy (n=12). We immunostained consecutive hippocampal sections for -synuclein pathology and established markers of microglial reactivity, Iba1, HLA-DR, and CD68. With validated digital histology methods, we measured percent area occupied in 6 hippocampal subfields to compare the percent area occupied within subfields between patient cohorts, correlate the percent area occupied within and between subfields, and use linear-mixed effects models to compare the percent area occupied across subfields while co-varying for demographics. We also constructed two groups of either low-level hippocampal -synuclein pathology restricted to the cornu ammonis 2-3 subfields (Focal Subtype) or widespread -synuclein pathology within additional subfields (Widespread Subtype) to model hypothesized -synuclein pathological spread within the intrahippocampal circuit. Lewy body disease patients exhibited increased HLA-DR and CD68 in most hippocampal subfields compared with primary age-related tauopathy. In Lewy body disease patients, staining for all microglial markers was highest in the cornu ammonis field 2. Neuronal -synuclein pathology in the cornu ammonis field 2 consistently correlated with only HLA-DR and CD68 but not Iba1. Patients classified as the Widespread Subtype had worse cognitive impairment and increased HLA-DR and CD68 within the cornu ammonis field 2. Furthermore, HLA-DR and CD68 in the cornu ammonis field 2 correlated with distal neuronal -synuclein pathology only in subfields with retrograde connectivity. We found increased hippocampal microglial abnormalities in Lewy body disease patients compared with cognitively normal controls with primary age-related tauopathy, suggesting a relatively specific microglial/inflammatory response to neuronal -synuclein pathology. Our data is consistent with predominantly retrograde transmission of neuronal -synuclein pathology across hippocampal subfields, where the focal microglial response in the cornu ammonis field 2 may influence clinical outcomes and -synuclein pathological spread. These data suggest that microglial processes can help refine Lewy body disease histopathological staging.

neuroscience↗

bioRxiv2025

Postmortem brain MRI reveals differential associations of subcortical and limbic volumes with cortical thinning and neuropathology patterns

Structured AbstractO_ST_ABSIntroductionC_ST_ABSThe impact of different neuropathologies on deep brain structures remains to be understood. We examine subcortical and limbic volumetry in neurodegenerative diseases involving p-tau, -synuclein and TDP-43. MethodsWe acquired neuropathological measures and brain segmentations from postmortem analysis of 132 donors with Alzheimers disease (AD), Lewy body disease (LBD), Frontotemporal Lobar Degeneration with TDP-43 (FTLD-TDP) and FTLD-Tau. ResultsLBD had the least subcortical, limbic and cortical atrophy compared to AD, FTLD-TDP and FTLD-Tau. In donors with both AD and LBD pathologies, primary LBD was associated with less atrophy than primary AD. While AD had cortico-subcortical and cortico-limbic morphometric associations, LBD had more limited parieto-occipital cortico-limbic associations. FTLD-TDP had cortico-subcortical while FTLD-Tau had cortico-subcortical and cortico-limbic associations. In AD and FTLD-Tau, hippocampal volumes correlated with p-tau burden, neuron loss and gliosis. In LBD, thalamic -synuclein severity was associated with subcortical/limbic volumes. DiscussionPostmortem neuroimaging reveals disease- and region-specific structure-pathology relationships.

neuroscience↗

bioRxiv2025

Characterization of hippocampal subfields using histology-based annotated postmortem MRI: Lessons for in vivo segmentation II

High-resolution in vivo magnetic resonance imaging (MRI) of hippocampal subfields is a rapidly advancing field due to their implication in cognition, disorder, and disease. Hippocampal subfield segmentation on in vivo MRI is generally guided by postmortem reference material, which has been limited by small sample sizes that preclude comprehensive characterization of subfield border locations and their variability. Addressing this, we characterized hippocampal subfield border variability in two ultra-high-resolution postmortem MRI datasets with combined annotated histological sections, including cases with and without dementia. We examined: 1) the order of appearance and disappearance of subfields along the long axis of the hippocampus; 2) the order of appearance and disappearance of subicular subregions; 3) the medial-lateral position of subicular subregional boundaries along the hippocampal body; 4) the location of the CA3 relative to hippocampal head digitations; 5) the subfield borders in the hippocampal body relative to a volume proportion of the dark band; and 6) the association of hippocampal length and subiculum-CA1 border location with diagnosis, demographic factors, and factors related to postmortem imaging. Our findings reaffirmed that there is a consistent order of appearance and disappearance of subfields in the hippocampal head and tail, respectively. The subicular subregions exhibited a first in, last out order of appearance and disappearance, and pre/parasubiculum consistently occupied half of the subicular complex in coronal slices throughout the hippocampal body. Hippocampal head digitations were not a reliable landmark for CA3 appearance, but SRLM proportionality did offer a potentially consistent approach for estimating CA2 and CA3 subfield borders in relation to the hippocampal border. No clear relationship was found between the anatomical features and diagnosis, demographic factors, and factors related to postmortem imaging. These findings have implications for the development and harmonization of hippocampal subfield segmentation protocols and interpretation of high-resolution functional MRI studies of the human hippocampus.

neuroscience↗

bioRxiv2025

Developing an anatomically valid segmentation protocol for anterior regions of the medial temporal lobe for neurodegenerative diseases

BackgroundThe anterior portion of the medial temporal lobe (MTL) is one of the first regions targeted by pathology in sporadic Alzheimers disease (AD) and Limbic-predominant Age-related TDP-43 Encephalopathy (LATE) indicating a potential for metrics from this region to serve as imaging biomarkers. Leveraging a unique post-mortem dataset of histology and magnetic resonance imaging (MRI) scans we aimed to 1) develop an anatomically valid segmentation protocol for anterior entorhinal cortex (ERC), Brodmann Area (BA) 35, and BA36 for in vivo 3 tesla (T) MRI and 2) incorporate this protocol in an automated approach. MethodsWe included 20 cases (61-97 years old, 50% females) with and without neurodegenerative diseases (11 vs. 9 cases) to ensure generalizability of the developed protocol. Digitized MTL Nissl-stained coronal histology sections from these cases were annotated and registered to same-subject post-mortem MRI. The protocol was developed by determining the location of histological borders of the MTL cortices in relation to anatomical landmarks. Subsequently the protocol was applied to 15 cases twice, with a 2-week interval, to assess intra-rater reliability with the Dice Similarity Index (DSI). Thereafter it was implemented in our in- house Automatic Segmentation of Hippocampal Subfields (ASHS)-T1 approach and evaluated with DSIs. ResultsThe anterior histological border distances of ERC, BA35 and BA36 were evaluated with respect to various anatomical landmarks and the distance relative to the beginning of the hippocampus was chosen. To formulate segmentation rules, we examined the histological sections for the location of borders in relationship to anatomical landmarks in the coronal sections. The DSI for the anterior MTL cortices for the intra-rater reliability was 0.85-0.88 and for the ASHS-T1 against the manual segmentation was 0.62-0.65. DiscussionWe developed a reliable segmentation protocol and incorporated it in an automated approach. Given the vulnerability of the anterior MTL cortices to tau deposition in AD and LATE, the updated approach is expected to improve imaging biomarkers for these diseases.

neuroscience↗

bioRxiv2023

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

The medial temporal lobe (MTL) cortex, located adjacent to the hippocampus, is crucial for memory and prone to the accumulation of certain neuropathologies such as Alzheimers 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 cortices that make up the parahippocampal gyrus (entorhinal and parahippocampal cortices) and the adjacent 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 {micro}m 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 (20X resolution) slices with 5 mm spacing. 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 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 more gradually. 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 human neuroimaging research on the MTL cortex.

neuroscience↗

bioRxiv2023

Seizures exacerbate excitatory: inhibitory imbalance in Alzheimer's disease with attenuation after rapamycin treatment in 5XFAD mice.

Approximately 22% of Alzheimers disease (AD) patients suffer from seizures, and the co-occurrence of seizures and epileptiform activity exacerbate AD pathology and related cognitive deficits. Hence seizures may be a targetable component of AD progression. As epileptogenesis is associated with changes in neuronal excitatory: inhibitory (E:I) balance, we hypothesized that decreased markers of inhibition relative to those of excitation would be present in AD patients and exacerbated further when seizures were a comorbidity. We similarly hypothesized that an E:I imbalance would be present in five times familial AD (5XFAD) mice and augmented following pentylenetetrazol (PTZ) seizure kindling. AD temporal cortical tissue from patients with or without seizure history and brain tissue from 5XFAD mice were examined for changes in several markers of E:I balance, including the inhibitory GABAA receptor, the chloride cotransporters, sodium potassium chloride cotransporter 1 (NKCC1) and potassium chloride cotransporter 2 (KCC2), and the excitatory NMDA and AMPA type glutamate receptors. We found that AD patients had decreased GABAA receptor subunits and those with comorbid seizures had worsened cognitive and functional scores, and increased in NKCC1/KCC2 ratios, indicative of depolarizing GABA responses. The E:I imbalance appears to occur early in the disease course, as patch clamp recordings from CA1 neurons in hippocampal slices from prodromal 5XFAD mice showed decreased GABAergic inhibitory transmission and increased intrinsic excitability. In addition, seizure induction in prodromal 5XFAD mice further dysregulated NKCC1/KCC2, and altered the excitatory AMPA glutamate receptor protein expression, with a reduction in GluA2 subunit, indicative of calcium permeable-receptors. Finally, we found that chronic treatment with the mTORC1 inhibitor, rapamycin, at doses we have previously shown to attenuate seizure-induced -amyloid pathology and cognitive deficits, could reverse aspects of E:I imbalance in these mice. Our data demonstrate novel mechanisms of interaction between AD and epilepsy and indicate that FDA-approved mTOR inhibitors hold therapeutic promise for AD patients with a seizure history.

neuroscience↗

bioRxiv2021

Joint ex vivo MRI and histology detect iron-rich cortical gliosis in Tau and TDP-43 proteinopathies

Frontotemporal lobar degeneration (FTLD) is a heterogeneous spectrum of age-associated neurodegenerative diseases that include two main pathologic categories of tau (FTLD-Tau) and TDP-43 (FTLD-TDP) proteinopathies. These distinct proteinopathies are often clinically indistinguishable during life, posing a major obstacle for diagnosis and emerging therapeutic trials tailored to disease-specific mechanisms. Moreover, MRI-derived measures have had limited success to date discriminating between FTLD-Tau or FTLD-TDP. T2*-weighted (T2*w) ex vivo MRI has previously been shown to be sensitive to non-heme iron in healthy intracortical lamination and myelin, and to pathological iron deposits in amyloid-beta plaques and activated microglia in Alzheimers disease (AD). However, an integrated, ex vivo MRI and histopathology approach is understudied in FTLD. We apply joint, whole-hemisphere ex vivo MRI at 7T and histopathology to the study autopsy-confirmed FTLD-Tau (n=3) and FTLD-TDP (n=2), relative to an AD disease-control brain with antemortem clinical symptoms of frontotemporal dementia and an age-matched healthy control. We detect distinct laminar patterns of novel iron-laden glial pathology in both FTLD-Tau and FTLD-TDP brains. We find iron-positive ameboid and hypertrophic microglia and astrocytes largely in deeper GM and adjacent WM in FTLD-Tau. In contrast, FTLD-TDP presents prominent superficial cortical layer iron reactivity in astrocytic processes enveloping small blood vessels with limited involvement of adjacent WM, as well as more diffuse distribution of punctate iron-rich dystrophic microglial processes across all GM lamina. This integrated MRI/histopathology approach reveals ex vivo MRI features that are consistent with these pathological observations distinguishing FTLD-Tau and FTLD-TDP, including prominent irregular hypointense signal in deeper cortex in FTLD-Tau whereas FTLD-TDP showed upper cortical layer hypointense bands and diffuse cortical speckling. Moreover, differences in adjacent WM degeneration and iron-rich gliosis on histology between FTLD-Tau and FTLD-TDP were also readily apparent on MRI as hyperintense signal and irregular areas of hypointensity, respectively that were more prominent in FTLD-Tau compared to FTLD-TDP. These unique histopathological and radiographic features were distinct from HC and AD brains, suggesting that iron-sensitive T2*w MRI, adapted to in vivo application at sufficient resolution, may offer an opportunity to improve antemortem diagnosis of FTLD proteinopathies using tissue-validated methods.

neuroscience↗

bioRxiv2020

Integrating gene expression, spatial location and histology to identify spatial domains and spatially variable genes by graph convolutional network

Recent advances in spatial transcriptomics technologies have enabled comprehensive characterization of gene expression patterns in the context of tissue microenvironment. To elucidate spatial gene expression variation, we present SpaGCN, a graph convolutional network approach that integrates gene expression, spatial location and histology in spatial transcriptomics data analysis. Through graph convolution, SpaGCN aggregates gene expression of each spot from its neighboring spots, which enables the identification of spatial domains with coherent expression and histology. The subsequent domain guided differential expression analysis then detects genes with enriched expression patterns in the identified domains. Analyzing five spatially resolved transcriptomics datasets using SpaGCN, we show it can detect genes with much more enriched spatial expression patterns than existing methods. Furthermore, genes detected by SpaGCN are transferrable and can be utilized to study spatial variation of gene expression in other datasets. SpaGCN is computationally fast, making it a desirable tool for spatial transcriptomics studies.

bioinformatics↗

bioRxiv2019

ATN status in amnestic and non-amnestic Alzheimer's disease and frontotemporal lobar degeneration

Under the ATN framework, cerebrospinal fluid analytes provide evidence of the presence or absence of Alzheimers disease pathological hallmarks: amyloid plaques (A), phosphorylated tau (T), and accompanying neurodegeneration (N). Still, differences in cerebrospinal fluid levels across amnestic and non-amnestic variants or due to co-occurring pathologies might lead to misdiagnoses. We assess the diagnostic accuracy of cerebrospinal fluid markers for amyloid, tau, and neurodegeneration in an autopsy cohort of 118 Alzheimers disease patients (98 amnestic; 20 non-amnestic) and 64 frontotemporal lobar degeneration patients (five amnestic; 59 non-amnestic). We calculated between-group differences in cerebrospinal fluid concentrations of amyloid-{beta}1-42 peptide, tau protein phosphorylated at threonine 181, total tau, and the ratio of phosphorylated tau to amyloid-{beta}1-42. Results show that non-amnestic Alzheimers disease patients were less likely to be correctly classified under the ATN framework using independent, published biomarker cutoffs for positivity. Amyloid-{beta}1-42 did not differ between amnestic and non-amnestic Alzheimers disease, and receiver operating characteristic curve analyses indicated that amyloid-{beta}1-42 was equally effective in discriminating both groups from frontotemporal lobar degeneration. However, cerebrospinal fluid concentrations of phosphorylated tau, total tau, and the ratio of phosphorylated tau to amyloid-{beta}1-42 were significantly lower in non-amnestic compared to amnestic Alzheimers disease patients. Receiver operating characteristic curve analyses for these markers showed reduced area under the curve when discriminating non-amnestic Alzheimers disease from frontotemporal lobar degeneration, compared to discrimination of amnestic Alzheimers disease from frontotemporal lobar degeneration. In addition, the ATN framework was relatively insensitive to frontotemporal lobar degeneration, and these patients were likely to be classified as having normal biomarkers or biomarkers suggestive of primary Alzheimers disease pathology. We conclude that amyloid-{beta}1-42 maintains high sensitivity to A status, although with lower specificity, and this single biomarker provides better sensitivity to non-amnestic Alzheimers disease than either the ATN framework or the phosphorylated-tau/amyloid-{beta}1-42 ratio. In contrast, T and N status biomarkers differed between amnestic and non-amnestic Alzheimers disease; standard cutoffs for phosphorylated tau and total tau may thus result in misclassifications for non-amnestic Alzheimers patients. Consideration of clinical syndrome may help improve the accuracy of ATN designations for identifying true non-amnestic Alzheimers disease. Abbreviated SummaryCousins et al. assess the 2018 ATN framework and find that non-amnestic patients with Alzheimers disease (AD) have lower cerebrospinal fluid (CSF) phosphorylated tau and total tau than amnestic AD, while CSF amyloid-{beta} accurately stratifies both non-amnestic and amnestic AD from frontotemporal lobar degeneration.

neuroscience↗